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Tracking No. 80f563f2
Docket: FDA-201 i -D-0597
Draft Guidance for Industry on Oversight of Clinical Investigations - A Risk-Based Approach to
Monitoring; Availability
Monitoring .
Comment On: FDA-201 I-D-0597-0002
Clinical Investigations; A Risk-Based Approach to
Draft Guidance for Industry; Oversight of
Document: FDA-201 I-D-0597-0012
Jil Matzat RN, BSN, CCRA - Comment
Submitter Information
Address:
FL,
Organization: Medical Research Management
General Comment
Risk based monitoring should not be about central versus onsite. The majority of issues I identify
via monitoring are due to lack of onsite visits, site selection, and monitor training. Risk based
monitoring should mainly be about a focused approach oppose to 100 % SDV. Currently,
Companies are using this guidance (one visit per year) to justify limited onsite monitoring. This is
the FDA. There is a direct correlation between adequate monitoring
a major mistake on the part of
risk based
via on
site and quality data as well as HSP. I have been performing different models of
monitors since i 999. I am a firm believer in a visit after first subject is enrolled. If an issues it
should occur until at least 2-3 subjects can be monitored without issues. I also only monitor
'critical elements while on site and use central monitoring for low risk items. All subjects have
critical elements monitored not one visit per year. We only use monitors that have been
extensively trained and competency tested, the training uses a systematic monitoring method, and
we employ a system that has checks and balances such as periodic performance assessments to
ensure monitoring adequacy.
this
The other issue is due to HIPAA most EMRs do not permit remote access making much of
suggestion null and void. Many EMRs do not even permit third party access and have to print all
documents for monitoring.
The proposed guidance does not address appropraite delegation, PI oversight or eligibiity of
determine this accurately.
subjects to enroll. Only onsite visits can
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CTSU, Oxford University comments on FDA-2011-D-0597
Draft Guidance for Industry:
Investigations - A risk-based approach to monitoring
Oversight of Clinical
Draft Guidance for Industry; Availabilty: Oversight of Clinical
Investigations; A Risk-Based
Approach to Monitoring (Document ID FDA-2011-D-0597-0001)
Comments provided by Martin Landray, Jane Armitage, Carol Knott, Jonathan Emberson,
Colin Baigent and Rory Collns on behalf of Oxford University Clinical Trial Service Unit (CTSU),
Oxford, UK
28th November 2011
General Comment:
The draft FDA guidance on a risk-based approach to monitoring is a big step forward.
Implementation of these guidelines should help to improve both the quality and cost-effectiveness
of trials. There are a few aspects which would benefit from further clarification in order to avoid
inappropriate interpretation by some in the future.
Lines 170-171 and 180-181
II.D. Steps FDA is Taking to Faciltate Wider Use of Alternative Monitoring Approaches
"The Agency also is initiating operational measures to ensure that its review, compliance, and other
functions reflect this view of monitoring. Specifically, FDA:
.. Wil ensure that all affected program areas within FDA are aware of the goals and purposes
180 of this guidance and its compatibilty with current CPGMs"
/1
Ç2i¡tD~Ot: It will be essential that FDA inspections are conducted in accordance with the principles
outlined in these guidelines. It would be helpful to state this explicitly, includingconsideration of any
modifications that might be necessary to the FDA's standard operating procedures/guidances for
inspection of Investigators and Sponsor sites.
Lines 240-251
IV.A.l On-Site Monitoring
"On-site monitoring is an in-person evaluation carried out by sponsor personnel or representative(s)
at the site(s) at which the clinical investigation is being conducted. On-site monitoring can identify
data entry errors (e.g., discrepancies between source records and CRFs) and missing data in source
records or CRFs; provide assurance that study documentation exists; assess the familarity of the
site's study staff with the protocol and required procedures; and assess compliance with the protocol
and investigational product accountabilty. On-site monitoring can also provide a sense of the quality
of the overall conduct of the trial at a site (e.g., attention to detail, thoroughness of study
documentation, appropriate delegation of study tasks, and appropriate investigator supervision of
site staff performing critical study functions). Therefore, on-site monitoring ordinarily should be
devoted to assessing the critical study data and processes and evaluating significant risks and
potential site non-compliance identified through other sponsor oversight activities."
Coi¡i¡liOt: One approach to on-site monitoring that can be particularly valuable is observation of
participant visits
(with the appropriate level of consent from participants). This can be very helpful in
assessing whether the researcher (investigator or delegated staff) is effective in explaining study-
related issues (important for consent, safety and encouraging compliance) and capturing important
information (by contrast retrospective comparison of data recorded on the case report form with
some routine medical record makes the assumptions that such documents exist, are accurate, and
are available). Visit observations have been used by monitors in many trials for over 20 years and
-1-
v
./
CTSU, Oxford University comments on FDA-2011-D-0597
Draft Guidance for Industry:
Oversight of Clinical
Investigations - A risk-based
approach to monitoring
have been found to be very effective in ensuring that participants are fully informed about the study
both at the initial visit (when consent is taken) and throughout (as the participant's health or other \ f
issues change, and new information becomes available about the study treatments). Furthermore, -\/
observation of participant visits allows a direct assessment of the way in which study staff perform
study procedures (e.g. clinical measurements) and prompt re-training where necessary.
Lines 251-254
IV.A.l On-Site Monitoring
"On-site monitoring is particularly critical early in a study, especially if the protocol is complex, and
includes novel procedures with which investigators may be unfamilar. Findings at the site may lead j
to training efforts both at the site visited and elsewhere (see section VI.A)." 'J
Cawment: Delete "is particularly critical" and replace with "can be particularly helpful"
Line 267
IV.A.2 Centralized Monitoring
ÇOWWlint: The explicit support for centralized statistical monitoring is very welcome. This approach
is key to improving efficiency, by limiting the amount of on-site monitoring necessary, and increasing
the effectiveness of visits that are done.
In addition to current reference 31 (RoryColiins presentation at CTTI work-stream 3 meeting), add:
Buyse M, George SL, Evans S, et al. The role of biostatistics in the prevention, detection and
treatment of fraud in clinical trials. Stat Med. 1999; 18:3435-51.
Line 299-308
IV.B Identify Critical Data and Processes to be Monitored
"Sponsors should perform a risk assessment that generally considers the types of data to be collected
in a clinical trial, the specific activities required to collect these data, and the range of potential
safety and other human subject protection concerns that are inherent to the clinical investigation.
Sponsors should consider the findings of the risk assessment when developing a monitoring plan.
There is increasing recognition that some types of errors in a clinical trial are mOre important than
others. For example, a low, but non-zero rate of errors in capturing certain baseline characteristics of
enrolled subjects (e.g., age, concomitant treatment, or concomitant illness) wil not, in general, have
a significant effect on study results. In contrast a small number of errors related to study endpoints
wing
protocol-specified definitions) can profoundly affect study results, as could failure
(e.g., not fol/o
to report rare but important adverse events."
çaWWept: It is important to emphasise that randomized controlled trials can be remarkably robust
to missing or incorrect data on clinical outcomes.
For errors that occur at random with respect to treatment allocation, data that are missing or
measured with greater error (including diagnostic misclassification or inaccuracies in clinical or
laboratory measurements) will add noise so that the chances of detecting a real effect are reduced
but will not bias the results in favour of any particular treatment. Where the results are to be used
to provide information on superiority of one intervention over another (including no treatment,
usual care or some other comparator), such random errors are conservative. By contrast, for results
-2-
J
CTSU, Oxford University comments on FDA-2011-D-0597
Draft Guidance for Industry:
Oversight of Clinical
Investigations - A risk-based approach to monitoring
that seek to provide information that one intervention is not inferior to another (i.e. non-inferiorityL
such random errors are counter-conservative, increasing the probability of falsely concluding that
two treatment strategies are similar.
Of much greater concern are errors that are not random with respect to treatment allocation since
these may bias the study conclusions. Important examples include errors in random sequence
or inallocation concealment (the abilty to predict which treatment a participant is likely
generation
to get if they are included in the trial), and differences in the ascertainment of endpoints between
the randomized treatment groups.
Furthermore, the extent to which missing data can be tolerated will depend on size of the study (or
more specifically the number of relevant outcomes). For example in a trial with 1:1 randomization
and 1800 primary events (800 vs. 1000 În the two randomized groups), the clinical and statistical
conclusions would not be materially altered even if information about 20% events was missing
(providing this was at random with respect to study treatment allocation).
Hence, the statement that "a small number of errors related to study endpoints can...profoundly V
affect study results" without the above
clarification could be widely misinterpreted.
Line 310-311, 320-321
IV.B Identify Critical Data and
Processes to be Monitored
that are critical to the reliabilty
"A study protocol should clearly identify those procedures and data
of the study findings. These generally should include:
. Processes that underpin the integrity of these data, such as blinding or referring specified events for
adjudication"
j
çOOJw~iit: The last bullet point (lines 320-321) should include randomization and allocation
concealment (i.e. the ability to predict which treatment a participant is likely to receive if they are
included in the trial) along with the other examples given (blinding or referring specified events for
adjudication).
Line 326-330
IV.B Identify Critical Data and Processes to be Monitored
"The following types of data and processes should ordinarily be subject to more intensive (e.g., higher J
frequency and more comprehensive) monitoring:
.. Conduct and documentation of procedures and assessments related to
- critical study endpoints,
Ç9tlr;~lJt: See comment in relation to Lines 299-308, above.
Line 326-327, 335-336
IV.B Identify Critical Data and Processes to be Monitored
"The following types of data and processes should ordinarily be subject to more intensive (e.g., higher
frequency and more comprehensive) monitoring:
. Adherence to protocol eligibilty criteria intended to include only subjects from the targeted study
population for whom the test article is most appropriate"
-3-
CTSU, Oxford University comments on FDA-2011-D-0597
Draft Guidance for Industry:
Oversight of Clinical
j
Investigations - A risk-based approach to monitoring
Comment: The focus should largely be on those
eligibility criteria that are designed to exclude
individuals for whom the treatment may be less safe than the protocol intended.
Line 326-327, 337-338
IV.B Identify Critical Data and Processes to be Monitored
"The following types of data and processes should ordinarily be subject to more intensive (e.g., higher
frequency and more comprehensive) monitoring:
. Conduct and documentation of procedures for ensuring that the study blind is maintained, both
at the site level and at the sponsor level, as appropriate"
J
CQmment: Not all trials are (or need to be) blinded. Similarly not all the parties involved
(participants, investigators, monitors) are (or necessarily need to be) blinded but it is Critical that the
randomization process is concealed (and therefore unpredictable) and that where event
adjudication is required it is conducted blind to treatment allocation.
Line 326-327, 339,340
IV.B Identify Critical Data and Processes to be Monitored
"The following types of data and processes should ordinarily be subject to more intensive (e.g., higher
frequency and more comprehensive) monitoring:
. Verification that initial informed consent was obtained appropriately, prior to any study-specific
procedures"
J
Comment: Verification is just one possible approach. Other approaches can be valuable:
. use of electronic systems, including electronic signature (as is done for some financial
transactions)
can ensure that consent is taken prior to study entry and can improve quality by
ensuring that participants are made aware of each of the issues covered by the consent process
and, where appropriate, specifically record their consent (or non-consent).
. observation of participant visits can help to ensure that participants are fully informed about the
study both at the initial visit (when consent is taken) and throughout (as the participant's health
or other issues change, and new information becomes available about the study treatments).
Line 326-327, 341-343
IV.B Identify Critical Data and Processes to be Monitored
"The following types of data and processes should ordinarily be subject to more intensive (e.g., higher
frequency and more comprehensive)monitoring:
· Procedures for documenting appropriate accountability and administration of the investigational
product (e.g., ensuring the integrity of randomization at the site level, where appropriate)"
Comment: See comment at beginning of this section. There are a number of errors that might
introduce bias. "Randomization at the site level" is just one component and it would be helpful to
introduce earlier the concept of errors that might introduce bias or which might introduce noise
(and the implication of such noise on the interpretation of the results).
- 4-
'..1
CTSU, Oxford University comments on FDA-2011-D-0597
Draft Guidance for Industry:
Oversight of Clinical
Investigations - A risk-based approach to monitoring
Lines 405-406
IV.D Monitoring Plan
"For each clinical trial, the sponsor should develop a monitoring plan that describes the monitoring
methods,responsibilties, and requirements for the trial."
Cornment: It would be helpful to explain that the Monitoring Plan should be part of a strategy for
ensuring oversight of the quality of the triaL. For example, by adding, "... and how these fit in with
the overarching plan to maintain the quality of the clinical trial" to the end of the opening sentence
¡
Vi
in this paragraph.
Lines 501-508
V Documenting Monitoring Activities
"Documentation of monitoring activities should include the following:
. The date of the activity and the individual(s) conducting it
. A summary of the data or activities reviewed
. A description of any noncompliance, potential noncompliance, data irregularities, or other
deficiencies identified
. A description of any actions taken, to be taken, and/or recommended, including the person
responsible for completing actions and the anticipated date of completion"
Cgwment: Some of this activity could be onerous or unnecessary, particularly if activities are being
undertaken very frequently or even continuously (e.g. central monitoring by automated IT checks). It
would be better to require that monitoring activities should be documented in sufficient detail to
allow retrospective audit that the Monitoring Plan was followed, perhaps listing the bullet points as
"for example".
-- 5-
i
J
l
eClinical Forum
Date 10-Nov-2011
Address: Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers
Lane, rm. 1061, Rockville, MD 20852
RE: Docket No. FDA-2011-D-0597
Dear Sir or Madam:
We are writing on behalf of the eClinical Forum Electronic Records Working Group, which represents
a cross-section of our member companies affected by this proposed guidance. The eClinical Forum
was started in 2000, the idea of a group of people who were keen to meet and discuss all aspects of
Electronic Data Capture and eClinical. In the ensuing time, the membership has grown, and there are
now over 40 member companies from the Pharmaceutical and associated industries. Today we are a
registered association in France.
Our mission is to provide a non-profit making environment to serve those members of the
pharmaceutical and allied industries who are or will be involved in 'eClinical (electronic data
acquisition, processing and use) initiatives by focusing on those systems, processes and roles
relevant to clinical data to support submission. We aim to establish open communication between
members and stakeholders to provide the practical information, approach and learning experiences
required to maximise the success of eClinical initiatives.
We have reviewed the subject document in detail and have developed a number of comments, both
general and specific. Specific comments are contained in the attached table. In general, we are very
pleased with the structure and content of this document and welcome it as a guidance.
We hope that our comments prove useful and contribute to the improvement of this draft guidance.
Please contact either of us with any questions regarding eClinical Forum's comments.
With kind regards,
Richard Perkins
President
richard.perkinsCWcon 7 .com
+33388748712
Suzanne Bishop
Facilitator
suzannekbishopCWgmail.com +1 9087524320
Page i of 2
eClinical Forum
eClinical Forum comments re: Guidance For Industry Oversight of Clinical
Investigations- A
Risk-Based Approach to Monitoring
FDA Docket No. FDA-2011-D-0597
eCF#
FDA Line
1
#
182 - 183
eClinical Forum Comment
eClinical Forum Recommendation
Will CBER also be contacted to voluntarily and prospectively
Add CBER to text
submit and receive feedback on proposed monitoring plans?
2
297
In general, it would be nice to see the same diagram around
risk assessment as in the EMA guideline (Line 248 Figure 1
and page 19-Risk Identification) to outline the risk based
assessment and include examples.
3
361
"
...Examples may include studies with adaptive designs,
stratified designs, complex dose titrations, or multiple device
placement or un
blinded studies."
4
61-62
"FDA is considering the need for additional guidance
describing overarching quality risk management approaches
to clinical trial oversight." Will this'guideline be similar to the
EMA guideline?
5
159- 162
Is this correct ..... "In addition, source data verification and
other activities traditionally performed by on-site monitoring
6
544
can now often be accomplished remotely, as both trial data
and source data typically become part of the central
submission."
Define oversight. (Not how to do it, but what they expect)
Layout high level with words Iike'such as', and 'for example'.
Can you approach this by using a risk-based approach to
vendor management?
Add complex or novel procedures to
this list.
Remove typiCally from this sentence
Add examples to the statement
Page 2 of 2
As4
Date: 2Znd Novembe 2011
Division ofDoket Mangement (H A.30S)
Fooc and Drg Admstrtion
S630 Fisher Lane
Roo 1061
Røckv.~ MI 20852
:Ie: Doeket NlJ FDA-2011-D-597
Itesns to FDA Call for Comments
Dr Oue for Indutr on Overght of CJ.eal Investigations: A Risk,.Based
Appaeh to Moiitorig
I.
i
Dear Sir Of Mac:
Ref$No is mad to tho 29ib Augu 2011 Fed Replf Dotieo wmunins tho reuest for
eommonts em Dr Guiôae for Irdustr on Ovmipt ofCliiea mvestiatons: A Risk..
Bas Aph to Momto.
Allr..lias revew. tbs~ee an OUT coimøt$ are athed.
'lea dit any queoii or reuets for adtioi iio1'cm to me, or in my absee, to
Mikal Wcm, Chan." Benfit Maiger/ LeaAdvsor, at+46 31. 706178.
~~
Sincerly, .... . ./A-:
Ma Tuey
St\y Stal'l$ _1.1$ Ttatin DiiGr
CIial Opot, Stuy Sta Pres _àTools
Telephone: +44 (0)162$ 51609
Enlos
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Ae.. LP
180 CoCQPie PO Bo 83 Wilming DE 198
AstraZeDeca Response to FDA Call for Comments on Draf Guidance for Industr on
Ovenigltt of Clinical Investigations: A Risk.Based Approach to Monitorig
Docket No. FDA-iOt 1-:097
General Comments
. Commentt
The concepts desribod in the gudace align closely with thng developed
with Astreneca. Consequently implementation of ths gudace wil faciltate
actusation of a risk..based monitorig approach with Astreneca.
2
. Comment
Overal, the gudance document is quite clear
. Comnient3
. Generally a ver comprehenive gudeline; however, there is quite a lot of
repettion
among sections and long explanations to why FDA is tag ths step now. We
the
reader to concentrte on the actu recommendations provided Although ths
øWdance is important and will provide important infonnation on FDA's view, it
th that it is possible to shorten the backgrund section for the beefit of
will arve at a point in tie when centrized (remote monitorng) is already
frequently used and as wrtten it sees like.it looks back more than forward.
4
. Comment
The increased use
of centrized monitorig, tageted monitorig and reduced
monitoring may lead to a tempora or longer..tei increase in the incidence of
compliance issues at those sites that rely heavily on on..site monitors to perorm
their QC. To ensur that sites take ful reponsibilty for the work perormed at thir
facilties, a suggestion is mad that guidace should be crated to recommend tht
all sites pacipatins in clinical studies have SOPs in place to gover the conduct of
studies at those sites and tht would t\er unercore the acountabilty of the
Prcipal Investigator and Sub-Investgator(s) reponsibilties.
. COlWDt5
Unforttely, the proposed ¡udace does not give cl. gudae HOW to
implement and apply risk bued quaty mangement.
- 1 -
~lul
5¿,1.e--
Doket No. FDA-2011-D-S97 Ast Respns to FDA eai forConunts Drft Guidae for Industr
on Oveript of Clical Investigations: A Rik-Bas Approach to Monitorig
.
Co...t6
.
Impact of non..compliance by ilivCStigators in c1ical trals should be cofted in
all countres by reSUlåtory authorities and IRIICs - and not only by the spnsor Æo
aftho tral
eJlitQllllåY Ai -- MODitoi
Q
se.,
'. or u. Co.... or propo np.......
Number
SecûQ1I" Line 19..20
lntrueti
Scope: Dos, tls pidae also aply to studies conducted usi
maeted pr eg no..inteerûonl stuies, RoWE, BEOR.?
n.
Sotioo I line 30 to 34,
au 176
loa-tty enoreable an should be
FDA indicats the ai_o. is BOt'
vicweG as areoneiticm; yet pl""s ar to upd the CPOM
moitori compliance pidae iiswith thse appoahes. ~ 0
Ths weuIG in tht FDA iito coul hold .
Spo to a
Sftti. ii liic 160, 194
stadad tl is noreu.~
'l.àos not apa to be spcifi pidace around ~c to
D
,nva ilgisklûcm.
Setinll Line 160, 194
Regangus.ofccmtrisomoiuto,the pidoe maes a
prorl as~tl cit1 Sp..livc lWestctedlccoss to'
D
subjeets' elmre medical ehls OM aotL soe) or tb ar
conini tb us of stu spific "souc.works-cis" tht wø'Ud
be.scd an set tothmontor. Tbuse of "soce
wwbhee" ha confthe inusti as th. worksheets often
eoata inortion tbtis trW'from th. oba an eanet
1'0"1)' be ~nsidød sourc..
s.ti D iht 1 82"¡ 86
:D
Fa,lli_ Widø Use of Al~tiv.
SMps :FAis'tåk¡ to
MRitoÂ~hes
Aceordtoth lat òuUet.. "VolUßtllY an ptsptively reG.i~
Íl.eølJk to mørinIPla.... If ths is. .,lerted it
to.know th
is impJtt
expetion ftmthe aØOY OI.matlal prvided
(should SOPs OW be pa of tb review if rof..,e4), time lines før
review,ø:ptions ftm the "OY on. su.stonson th pl..
Seti.:ø Lin 197..198
D
1's sttostl the col_abe- ofOlite m.tofl will
ow__ tobciuaus. WewO\ld questiJ1- whrwc wouWev
have a eomkiw' absce of ..sito in1Utornl to cn..th pi.
aua~ of tùclinical tral. sø. of which could not
reiwly.
..2..
be ped
Docket No. FDA-2011-D-597 Astrneca Response to FDA Ca for Commnts Draft Gudace for Indutr
on Oversight of Clincal Investigations: A Rik-Based Approach to Monitorig
Dli GlUdanel fqr Indllftrv QQ Ovenl2ht qf C'''dea Inviirtiiatio.. A Rlk-iJ AoorQach to. MQnitQrinli.
Secton
Page
or
SectionN
Comment or proposed replaeement text
Line
Number
.
Line 256-295
A
Many of the centrl monitorg strtegies prpoed involve sttistical
anlysis of data points, site chastcs; and peonnce metrcs.
Ths will place an incrasd ficial burde on companies of all
sizes to provide additional resourCls to peorm complex statistical
analyses to supplement trditiona monitorig.
hicreased central monitorig means tht a flexble workforce of
CRA would still be requird to visit the sites to follow..up on
identified issues.
SectionN
Centrized Monitoring
Line 265
A
Please add to bulleted list
/'
"Minimze impact of poor retetion rate and risk of patients lost to/
follow..up on data quality".
Also
"Identify at an ealy stage requirents for fuer tring needs on a
study, countr an site level".
SectionN
Line
A
288
277
and
Although ther is a disclaier tht implies tht reote SDV is
depdet on havig accessibilty to electronc reords, in most
countres, prvacy and health inortion protecton laws mae ths
vfl diffcult to achieve.
SectionN
A
Line 277
The strtegies and requients arund reote monitorg need
more development. For exaple, a descrtion should be provide of
tyical source documents tht can be reviewed remotely without
brhing subjec prvacy; and any necess seurty measurs tht
need to be in place.
For exale, ar they expectig the remote
inonitorini of soue docmnents and CRFs to be done at the company
loction or ca it be done at the CRA home location wher the
computer may
not have as may secuty contrls?
SectionN
ß
Line 339
While the nóed fot verfication of consent pror to stu~spific
predurs is idetified, ther is no mention of
vefication of patient
existcmce which is a key ast of soure data verfication.
- 3 ~
t' lÌ
Docket No. FDA-2011-~597 Astrneca Response to FDA Call for Comments Draft Gu for Indutr
on Oversight of Clincal Investigations: A Rik-Based Approach to Monitorig
Draft GilicJancl for lodiistr 00. Oversh!lit of êliiil IDvestltloo,; A IUk-8an ADnrocb to MonitQrltl.
Secon
Page
or
Line
Comment or proposed replacement text
Number
Section
IV
Line 348, 403
Recommend that FDA provide an examle of an acceptable
Monitoring Plan tht incorptes the varous monitorig strtegies
C
that ar proposed in the guidance.
Section IV
C
Section
IV
Line 348
Line 394-395
C
Section IV
D
Line
431
:Rethe option to submit the Monitorig plan for review by FDA. AZ .
has developed a tageted Source Data Verfication temlate and Local
Monitorig plan as
Monitorg plan tht togeter captue the idea of
while
the
SDY
template is
described in the guidance. However,
developed centrlly, the Local Montorig Pla ar develope on a
countr by countr basis and may pose a challenge to ths pror
cons\Ùtation aÐØach.
Ths talks of more monitorig at an ealy stage. It would be wort
mang it clea wheter ths is at the site-level or stdy-level
Suggest add the following "... .interet the prma endpoint or data
general
related to the
monitoring metod .....
SectionN
Line
473
Line
487
the tral, regadless of
integrty of
"
which
.
We see co-monitorig descrbe here as long existng best prctice.
D
Section
IV
D
The potential process for CDER Review of spoor monitoring plan
is seen as a positive way to obtain ealy feeback.
of
Would the evaluation be
the intial plan and not amended
versions?
Section V
Line 510
Ìt is stated Monitoring documentation should.i, provided to
approprate maagement in a timely maer for reew or, as
necessar, follow-up. It would be helpfu for gudace on wheth all
reprt should be reewed (M, Contats repor) or a sale of
that docuientati() is acceotable.
Section VI
Line 515
Suggest incoiprating languge as to what strtegies a QA or Qc
fuction could emloy to provide independent assessment and checks
A
im4 1)alMlçe$ Qf comolilIce to tb, MQllltorinii PllU.
Section VI
A
Line 533-536
It is imprtt to conider the use, appoprate to the stuy need of
other tring methods th jus trg at site. However not sur
are highlighted as "alterative trnig methods" since
why these
by now and can be
documented prpely. Also investigators meegs ar us.
these metods should also be quite established
.
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Pagelofl
PUBLIC SUBMISSION
As of: 11130/11 8:22 AM
Trackig No. 80flb059
Docket: FDA-201 1-D-0597
Draft Guidance for Industry on Oversight of Clinical Investigations - A Risk-Based Approach to
Monitoring; Availability
Comment On: FDA-20ll-D-0597-0002
Draft Guidance for Industry; Oversight of Clinical Investigations; A Risk-Based Approach to
Monitoring
Document: FDA-20ll-D-0597-0005
Anonymous - Cpmment
Submitter Information
Address:
IL,
Submitter's Representative: Self
Organization: Private
General Comment
It is with respect that I humbly must come forward and comment on the document: Draft
Guidance for Industry; Oversight of Clinical Investigations; A Risk-Based Approach to
Monitoring (Document ID FDA 201 1-D-0597-0002). I have to say, based on my 10 years of
experience conducting and overseeing clinical trials and other forms of clinical and outcomes
research, that I am in~iiearly.complete-disagreement with FDA regarding their position on
centralized monitoring for select types and portions of clinical trials. I have seen many studies in
need of on-site monitoring where it has either not occurred at all or not enough. I have monitored
sites myself, in person, where-:fraud is taking place, and the only way I would have discovered-it
was by being at~the site'and seeing it with my own eyes, going through documents that have not 0
been fitered, and seeing discrepancies between signatures, handwriting and errors/corrections.
What the FDA does not seem to recognize is just how much human behavior plays into the
conduct, and thus, data and results, of clinical trials. Centralized Monitoring, seems to be a way to
cut comers in efforts to save time and money in the name ofa more 'efficient' and 'appropriate'
approach to clinical trials, which, in my mind, is really neither. I guarantee that centralized
monitoring, if applied generally, would increase, not decrease, risks to both human subjects and
that integrity of the data that is reported, and therefore, the safety of drugs approved for
marketing. Further, the examples of ways it would be helpful, e.g. statistical analysis of current
data, patterns among subjects and sites, etc., are not necessarily those that on-site monitoring
seeks to achieve. Protecting human subjects cannot truly be done without in-person contact via
on-site monitoring, and thorough review of all study and relevant clinical records. Ultimately, I
would assert that the notion of centralized monitoring, with the exception of a few types of studie
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Page 1 of 1
As of: 11/30/1 1 8:25 AM
PUBLIC SUBMISSION
Tracking No. 80f144eO
Comments Due: November 28,2011
Docket: FDA-201 1-D-0597
Draft Guidance for Industry on Oversight of Clinical Investigations - A Risk-Based Approach to
Monitoring; Availability
Comment On: FDA-201l-D-0597-0001
Draft Guidance for Industr; Availability: Oversight of Clinical Investigations; A Risk-Based
Approach to Monitoring
Document: FDA-20l 1-D-0597-0004
Anonymous - Comment
Submitter Information
Address:
UT,
Organization: University of
Utah
General Comment
This is a well thought out document and is helpful in clarifying the regulation.
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Pag. I.
PUBLIC SUBMISSION
of i
As of: 11130/11 8:23 AM
Trackig No. 80f50d1e
Comments Due: November 28,2011
Docket: FDA-201l-D-0597
Draft Guidance for Industry on Oversight of Clinical Investigations - A Risk-Based Approach to
Monitoring; Availability
Comment On: FDA-201 l-D-0597-000l
Draft Guidance for Industry; Availability: Oversight of Clinical Investigations; A Risk-Based
Approach to Monitoring
Document: FDA-201 1-D-0597-0008
Janet Athene Lane - Comment
Submitter Information
Address: United Kingdom,
Organization: University of
Bristol
General Comment
We have conducted a systematic review of..the published literature on on-site monitoring systems.
for clinical trials that would help inform this guidance. Presented at the SCT conference, abstract
in Clinical Trials 2010 7:428, full paper under review at Clincial Trials. I can send this when
accepted if you wish? we have just had referees comments and are revising the paper.
Page 1 of1
PUBLIC SUBMISSION
As of: 11/30/11 8:24 AM
Tracking No. 80f5cc85
Docket: FDA-2011-D-0597
Draft Guidance for Industry on Oversight of Clinical Investigations - A Risk-Based Approach to
Monitoring; Availability
Comment On: FDA-2011-D-0597-0002
Clinical Investigations; A Risk-Based Approach to
Draft Guidance for Industry; Oversight of
Monitoring
Document: FDA-201 1-D-0597-0013
Colin Wilsher - Comment
Submitter Information
Address: United Kingdom,
Organization: BARQA
General Comment
The FDA Webinar stated that consent could-be monitored remotely as well as on site. How can
assurances that the subjects
this be done remotely without violating data privacy and stil giving
have given genuine informed consent? Mor~.guidance.on this.would be welcome.
Pag i oft
PUBLIC SUBMISSION
As of: 11/30/1 1 8:24 AM
Tracking No. 80f62936
Comments
Due: November 28,2011
Docket: FDA-201 1-D-0597
Draft Guidance for Industry on Oversight of Clinical Investigations - A Risk-Based Approach to
Monitoring; Availability
Comment On: FDA-201 1-D-0597-0001
Draft Guidance for Industry; Availability: Oversight of Clinical Investigations; A Risk-Based
Approach to Monitoring
Document: FDA-2011-D-0597-0014
Wayne Martin - Comment
Submitter Information
Address:
WA,
Organization: clinical research associate
General Comment
this draft guidance is really nothing new; risk-based approaches to data monitoring
have been implemented by many sponsors over the past 10 years. Unfortunately over the past 10
years the research landscape has also widely changed at the investigative site end with regard to
the training/experience of site staff performing data capture. (In today's tight economy more and
more sites are hiring people without medical training and/or research experience.) While
remote/central data reviews are an invaluable adjunct to monitoring when an EDC system is
utilized, it is unrealistic to expect that edit checks and reviews for data outliers, etc. wil ultimately
result in the same level of data accuracy resulting from on-site monitoring of data against the
actual source documentation.
The content of
P'
ag.loft
.
PUBLIC SUBMISSION
As of: 11/30/1 1 8:27 AM
Tracking No. 80f55070
Comments Due: November 28,2011
Docket: FDA-201 l-D-0597
Draft Guidance for Industr on Oversight of Clinical Investigations - A Risk-Based Approach to
Monitoring; Availability
Comment On: FDA-201 1-D-0597-0001
Draft Guidance for Industry; Availability: Oversight of Clinical Investigations; A Risk-Based
Approach to Monitoring
Document: FDA-201 1-D-0597-0011
Cheryl Elaine Kelly - Comment
Submitter Information
Address:
AZ,
Organization: St Joseph Hospital and Medical Center
General Comment
While lines 464 -469 seem to address monitor training it does not speak to qualifications or
training necessary for a particular type of triaL. Several references are made regarding investigator
experience and knowledge level as appropriate for a particular study, but the same is never
addressed for.monit.ors who actually perform both onsite and remote monitoring. The level of
expertise in relation to a particular trial of a monitor has direct bearing on the quality of data
reported, esp. in the area of adverse events, which bears directly on: human subject safety and
the study. I have had monitors come to verify data on intricate neurosugical clinical
effeciency of
studies whose back ground and most recent job was in Human Resources. If monitors are coming
to monitor clinical studies, they should at least have some sort of clinical background or training.
The data management people should work with the data, but when it comes to deciding what gets
reported to them for data inclusion and what does not and what emphaisis it has comes from the
monitor. How accurate can that be ifthe monitor does not even know the terminology ofthe area
to be monitored? How time consuming for the investigative site if for everyexplaination there
needs to be an anatomy and physiology lesson preceeding it. I am not suggesting that each
monitor be an expert in his/her field, but posess at least a general working knowledge of the
subject matter, ie nurses, respiratory therapists, etc., for clinical trials. Someone who understands
drug interactions, basic knowledge of
how the body functions, etc. Sponsors-should-tailor monitor
the study. Someone with a clinical background should
be sent to monitor a clinical study as a safe guard to subjects both in the trials and those that wil
later use the products as the general public.
expertiseand.background to the nature of
i
Paglofl'
PUBLIC SUBMISSION
As of: 11/30/11 8:24 AM
Tracking No. 80f273d1
Docket: FDA-2011-D-0597
Draft Guidance for Industry on Oversight of Clinical Investigations - A Risk-Based Approach to
Monitoring; Availability
Comment On: FDA-201 1-D-0597-0002
Clinical Investigations; A Risk-Based Approach to
Draft Guidance for Industry; Oversight of
Monitoring
Document: FDA-2011-D-0597-0006
Hans-Joachim Kremer - Comment
Submitter Information
Address: Germany,
Organization: Medical Writing Service
General Comment
I am overall appreciating the proposed guidance!
. However, lines 339 to 340 currently read:
obtained appropriately, prior to any study specific
"Verification that initial informed consent was
procedures"
I am proposing to discard the words "prior to any study specific procedures" from this bullet
point.
Rationale: The FDA Information Sheets "Screening Tests Prior to Study Enrollment" specifically
and very thoroughly address problems with informed consents and screening tests prior to study
enrollment. The words criticised above, however, appear to be too simple in this respect and
would many people wonder, whether the rules outlined in the information sheets are stil valid. In
fact, few have recognised that information sheet, but many believe in the strict "prior to any...".
The attribute "appropriately" appears to be clear enough, given that there are so many rules around
informed consents.
Pag
PUBLIC SUBMISSION
J
of
As of: 11/30/1 1 8:32 AM
Tracking No. 80fl0277
Comments Due: November 28, 2011
Docket: FDA-201 1-D-0597
Draft Guidance for Industry on Oversight of Clinical Investigations - A Risk-Based Approach to
Monitoring; Availability
Comment On: FDA-201 1-D-0597-0001
Draft Guidance for Industry; Availability: Oversight of Clinical Investigations; A Risk-Based
Approach to Monitoring
Document: FDA-201 1-D-0597-0003
Jules T Mitchel - Comment
Submitter Information
Address:
NY,
Organization: Target Health Inc.
General Comment
Congratulations on allowing the Industry to finally run clinical trials in a more sensible manner.
This is an excellent guidance which will permit the Industry to replace labor-intensive, minimally
productive procedures with currently available technologies and approaches to improve the
monitoring of the quality of clinical trials and the safety of patients participating in clinical trials.
Specifically, the following lines are critical:
Line 62: Quality is a systems property that must be built into an enterprise and cannot be achieved
by oversight or monitoring alone.
Line 176: Wil ensure that the bioresearch monitoring compliance program guidance manuals
(CPGMs) 176 for sponsors, CROs, and monitors (CPOM 78.810) 24 and for clinical investigators
and sponsor-investigators (CPGM 78.811)25 are compatible with the approaches described in this
guidance
Line 204: Many other factors contribute to the quality and integrity of a clinical investigation. The
most important tool for ensuring human subject protection and high-quality data is a welldesigned and articulated protocol. A poorly designed or ambiguous protocol or case report form
(CRF) may introduce systemic errors that can render a clinical investigation unreliable despite
rigorous monitoring. Study-specific training of investigators, other site staff, and monitors also
contrbutes significantly to study quality.
I
Page 1 of I
PUBLIC SUBMISSION
As of: 11/30/11 8:33 AM
Tracking No. 80f520e5
Docket: FDA-201 1-D-0597
Draft Guidance for Industry on Oversight of Clinical Investigations - A Risk-Based Approach to
Monitoring; Availability
Comment On: FDA-2011-D-0597-0002
Clinical Investigations; A Risk-Based Approach to
Draft Guidance for Industry; Oversight of
Monitoring
Document: FDA-201 1-D-0597-0010
Anonymous - Comment
Submitter Information
Address:
AZ,
Organization: Anon
General Comment
Much is made in the guidance about the advancement of EDC systems and factors that influence
study quality and integrity (lines 189-220). Given the increasing number of electronic systems
used by sites (eg, eCRF, IWRS), what is curiously missing is any mention of data security as a
component of on-site or centralized monitoring.
this
Data integrity is not possible without data security. And yet, in the monitoring plan parts of
guidance (lines 348-434), there is no reference to the monitoring of data security measures. This
includes the most basic security measure of checking accounts to make sure only authorized users
have access (ICH E6 5.5.3) CRO and sponsor monitoring plans are not completely different in this
regard. Given that monitoring (either on-site or centralized) is the only way to determine who
should have system access, it is unclear why data security is omitted.
Security problems typically begin with organizations (Baldwin. Heath Data Management Oct
1999). There is no published information to suggest that clinical trials function differently. So,
clinical trials should take a proactive approach to data security. Aside from that, the same
healthcare system that provides clinical research data is now afficted with medical identify theft,
identify theft in the US (MedPage Today Sept 23,2011). This is not to suggest
the fastest form of
that sponsors should monitor any and all possible security problems that take place at their sites
and within their organizations. Rather it is to suggest that data security/protection activities should
be created that are risk-based, well-documented, monitored, and adjusted as circumstances
emerge. To not explicitly recognize and formulate a plan to monitor data security is neither good
risk management nor good quality assurance.
Pagl
PUBLIC SUBMISSION
oft
. As of: 11/30/1 1 8:36 AM
Tracking No. 80f51351
Docket: FDA-201 1-D-0597
Draft Guidance for Industry on Oversight of Clinical Investigations - A Risk-Based Approach to
Monitoring; Availability
Comment On: FDA-201 1-D-0597-0002
Clinical Investigations; A Risk-Based Approach to
Draft Guidance for Industry; Oversight of
Monitoring
Document: FDA-2011-D-0597-0009
Anonymous - Comment
Submitter Information
Address:
NC,
Organization: Anon
General Comment
Definition of monitoring:
While it may be true that ICH E6 acknowledges the utility of central monitoring in assuring
appropriate conduct ofa trial (lines 189-196; ICH E6 5.18.3), it is important to note centralized
monitoring in this guidance is not synonymous with central monitoring in ICH E6 5.18. Central
monitoring in ICH E6 is performed by a monitor whereas centralized monitoring in this guidance
is performed by a monitor, data manager, and/or biostatistician (lines 259, 265-285).
and emerging data QC (conducted in the spirit ofICH E6 5.1.3) by
It is unclear why traditional
data managers and biostatisticians should be re-identified here as monitoring. This guidance's
idiosyncratic use of monitoring has the potential to cause ambiguity and confusion.
The Duke Ching, of Ch'i, asked Confucius about government. Confucius replied, "There is
governent, when the prince is prince, and the minister is minister; when the father is father, and
the son is son." ... "If names be not correct, language is not in accordance with the truth of things.
If language be not in accordance with the trth of things, affairs cannot be carred on to success."
111.,0.1.- MI,'"
Mek ".arch Latories
Director and U.S. Regulatory Policy leader
1700 Rockville Pike. Suite 525
Rockville, MD 20852
Global Regulatory, Strategy, Policy, and Safety
T 301 710 9524
F 301 710 7808
merck.com
Novembe 28, 201 i
o
MERK
Division ofÐockets Maaagement (HFA-305)
Foo and UN' Adminisitatioo
S630 Fishers Lat, Ib. 1061
R~kvile, fWD 20852
RE: Dock.t No. 'DA...20U..D-0597: Draft (jaW.iice for I'ndtn OI Ov.ni_. of
Clinicalla..tiatieDs: A .llk..Bad Approach to Menitoriiil;
Merck Sharp It Døbme Corp., a subsidiar of Merck 8rCo., Inc. (Merck) is a gloool
the best science an state-of;.tlie..ar medieine,
h.ealthçare le_r. Tho. a combination of
Merck has prøedmay importt medicines anvaecines. Tody thecoml'aRY is
continuing to aeiively develop a broad portf'Olìo of small molecules, v~ciMs and Ðiølogic
prots, including Ðisimilas to significantly imprve worldwide patient access to
importlife.savift¥ therapies.
In th course of bringing Merck drg an. biological produet canidates though
development, Merck scieJ'inc team bave acquired eJetensive expeience' that informs the
comme:nts bclow.
Ge.... CO."1I*5
We conmthe Foo
and Drg' Administiation (FD~ or the Agency) for issuini this
guidae to asist sponsors in dovelopini risk..base~l monitoring strategies and plan for
investiiatioo stdies of medieal prodts in or*r to cmhanee human subject protections
an(intepi ofdiitaltral da Specifically, we applaud,the guidance's foeus on cÅtical
stuà'y pamt4that ro'ties0l a combination of monitorin¡ aetivities as we'll as the strong
emphais OD, IMater use .of eentralize4apPl'ach to monitorin¡; an approach tha taes
adyaAap of avaìlablè ieebrlo¡ies suçhas electronic data capture (EDe) but also \
monitoring, when necessar. We ut'e the Ageney to J
for on..siw .
aduiøwledles th role
cleatly fttlme _ balancebeween on..site and centralized monitoring. As wient the
iui~e may M inte,.tedas to overly lean towar centralized monitoria._ A welt..
~finedand baketapproaeh is crucial since available teclmology is unlikely to repl.e
completely the beiwfltsof th human elemnt involved in on.site monitoril1. In addition,
the guidce ree'OpÌze that sposors may alreá4 be leveraging eentalizedmonitorng
capabilities across. fuirtions (such 41. medical mønitoring, SAE man~inell., and da
inangement).
Docket No. FDA-l011-J)597 Draft Giiidaiice for Iiidustry Oil Oversight of Cliiiicalliivestigatioii:r:
A Rlsk..Based Approach to Moiiitoring. page i
The title and Lines 163. i 66 suggest the guidance aims to "clarfy that risk.based
monitoring, including the appropriate use of centralized monitoring and technological
advances (...) can meet statutory and regulatory requirements under appropriate
the guidance is on "risk.
based monitoring" (i.e. only on higher risk areas) versus intense monitoring perfonned
remotely.
circumstaces." However, as wrtten, it is unclear if
the focus of
Furher, we note the additional emphasis on the creation of a dynamic monitoring plan
with the expectation to document all monitoring aspects, including management of
non.. /
compliance. The approach attempts to define responsibilties for site, sponsor, and health V
authority. However, it is unclear if "documenting monitoring activities" is the expectation
for centralized monitoring. The guidance should clarify if in..house personnel would be
recommended to document their activities routinely, how the expectations would be
accomplished for continual review across multiple sites, and how this documentation
would work seamlessly with reports from on..site visits.
For additional clarty and in order for the guidance to suffciently serve its purse, we
strongly recommend that CDER should:
· ensure internal consistency of the oversight processes across review divisions;
· describe the relationship of the guidance to the ongoing site selection model
pilot withn the CDER Offce of Scientific Investigations (OSI);
· specify if the monitoring plan wil be at the individual study level or is more
appropriate for the entire program;
· make a distinction in the guidance between monitoring plan from the medical
monitors' perspective vs. that
of clinical research associates (eRAs) and other
clinical trial staff; and
· recognize that if the monitoring plan is trial specific it may trup the sponsor's
"\
\j
standard operating procedures (SOPs) .
In addition, we believe this guidane should cross..reference the draft guidance on
electronic source documentation. i As we noted in our comments regarding the latter draft
guidance, it is critical that FDA and sponsors obtain a common understading of EDe with
respect to source data, data flow, and data release because the implications for
implementing the draf guidance on electronic source documentation and the current draft
guidance could be overly burdensome for clinical investigators and could impede sponsors'
abilties to monitor safety and data quaity in real time.
Moreover, while this draf guidance does not explicitly state how the monitoring plan may j/
what wil be in the
be submitted to the Agency for review, it seems to imply that much of
monitoring plan would be expected to be i~iuded in the protocol (Section IVB, pages 9..
10). We ar concerned
that any expetation to inelude the monitoring plan in the' protocol
and thereby having it reviewed by CDER OSI could have the unintended çonsequence of
delaying tral sta up. Furthermore, Merck is committed to making protocols available to
i Draft Guidace for Industr: Electonic Source Documentation for Clinical Investigations
htt://www. fda.gov/downloadslDnigs/GuidanceComplianceRegulatotyInfonntion/GuidancesJCM239052,
pdf
Indust 0" Oversight of Clinicallnyestigåtions:
DlJket No. FDA-2011-D-0597: Dråft Guidance for
A Risk-Based Approach to Monito,.ing- page 3
the covered study i~ submitted. To that end, we believe
protocols should be focused on the essentials of study design and more perpheral issues
would be bestaddressed in separate 40ciiments or appendices. Therefore, a prefered
peer reviewed jounuilsat the time
as par of other non- /
be to submit the monitoring plan separtely or
approach would
prot~l sUb.m. issi.on. to the, IND.. Ifthegu.idan.. ce... Sti......1
ex?e.ct
SUb.
mission. .ofthe.mO,niton. .'..ng.
plan in the prtocol, the Agency should ensure it estahshesclear turnaround times across. .
appropriate
revew divisions
and allow for it to be done
as an
appendix. Regardless of
the "
Agency'sprefer approach, the feeback should be timely and. theguidancesho1,d
if ar ongoing study should be put on
hQld until thespQnsor receives feeback on any monitorig planot amended plan that may
study. '
would he binding and
clarfy whether such feedback
have
Finally
bee submitted for that
ther is a reference to the practice that "goverent
agencies and oncology
coopeative groups visit sites only once ever two or thee yeal to qualify/cerify clinical
innovation if a cerification could be
stuy
sites". It wouid ind.eedbe a ver welcome
sites by an Qffcial body. This would ensure
granted to study
be
site and on-site monitoring can be less
expeced from the study
that adequate standards can
intense.
Speifc CC)IlDents
ñi additiÓ1 to the general cotnents above, the table that follows providesspecifc
the
conientson..sections of
Draft Guidance.
draft guidance tited
.Overiglt of Çlinical Investigations: A Risk-Based Approach to Monitorig. For fuer
information or questions, pleãse contact me by phone at301-77Q-88Øi, or email
We
appreciate
the opportnity
to shafeour coïnents on the
ekopimo ibia(àincrck.com.
Sincerely,
9d~
EkopimQ Ibia, MD, MPH
Director and US Rêsulatory Policy Lead
Global Regilatøry Strategy, Pø1icy& Safety
Agency's
Ol_\-¿'~
St;~
29'-300 & 323-343
292-295
L__
I
I
I
lii4-2íïS----
I
262-265
J
par oftbe inspection process.
assesmellt was doe. In aditio, the guidaRe is unlear ifrevicw ûfthe assessment wiU be
- ~ _. .._._......
the guidanc.. e is unclear regardmg the ex. pectaio on the documentati.on as evidence that tncJ'
Further, if the suggestion is to make risk assessmnt a crucial par ofthe inonitoring process,
tai:loed mon\tormg plass an centralized iuoi'Ioring inethoos.
prspectively deected an remediated shuld increase as more knowledge is gained abut
th invest,igatio drug and as more experience is gained using new risk-based assessments,
pilot
phse to understa anti develop the appiopiate risk assessmeliit
mehologies appopriate to different trial phaes. The extent to which errors witl be more
apoah or
The recommendtioo to perform risk assessment for each trial wi:U also need a phased
section fo clarity. _... .
Since guies, generally, tend to become the standard, we urge that the Agency revise the
\/
10
.-1
tht on-site monitoring is essential at the
beginning oftbe trial and that that reme moiiito-ring alon sliJd be sufficient thereall-er.
The guide may be interpeted to suggest
monitoring. .
in-tOrioo (with examles) 00 how such tass cow.d be completed by centralized
douments ).11 wouM be especia1y hepful if the Agency cooW provide addition
complete adinistrative an regl.llatory tasks (e.g., coUecting an arduving regulatory I ,.
The draft guidance recommnds that spsors tlse centraLized moortoring processes to
E!~velopnt of aditional technological capalities wil be necessarx.
I i:itoong are to be realized, exisiiag processes wil have to be re-engineered and
greaer reliace is to be placed on cenkalized moaitoring an the benefits of centraliZ~Cd
aproach or pilot phase to unerstan and develop the appropriate central-ized procsses, If i
The Agency's strong recommendaion to use centralized monitoring will need a phased 1 J
~ce cemraiiy or reinely.
doumæts, in addition toe-CRFs. Theefore, th Agency sÀOuld clarify thguidae's
frequent references to sponso's ability to remotely monitor/verify source daa. Generally,
sponsrs conting trials, including trials conducted utilizing EDC, do oot live access to
ePROs etc., the guidae seems to suggest tli sposors Àave cenralized acess to sorce
Wlik sllsors-may1lve-access to- ven~pcovided repos aOO - SoUfce-='ia assays,
/)det No, HM-Zlill-D-J97 11'11/1 Guithl1U fo Jiiduwy 01 Owmigbi of CliRicai JllvestigliJiOlS: A Risk-Based ApprlH/i to Monitring- page 4
515-545
40-4ß7
~lng .me wlll a CR.O ismvo.ved?
it.tl Agency'sdiii th tle maybe adioconsiratiOf wi. regard to seleng
espcialy m tight ofiireasiig.md move toward stategic outsomcing. For exame, is
furher, we suggest th Ageiiyprovidmoe detaiJ regarGigpootial delegatio to a CRO,
Agency sh claifyits ratioi for doing so.
is not qtUle iÐW!ive towia lip åcgati-oiito CR.. wider ths sectio. We suggest tli
huan simctprotectio. aø mgh dat quity" bu provides ony two poemial stps, one
regaiwn-g traig an th otr delegaioto a Ctilal Research Organiza (CRG). It
wwldbeDef-iial tfth Agency coolå fusi more examplsm the gwdan. Seoodly, it
1l guWe sts tl "(aJ numr of adtio stps caabe taen to eDSe apopriate
fr for .th oi eRA audnce.
~ pl woWt Demoe usfu at a stuy (Of progam) level~ bu pe less user-
difecteà to.w3ràaoy role ilivo.1ved wit mong. Th iiireasd deh ai comXtty of a
resch asociats (CRAs). Th propsed moatoplan Hi th dlalì guian seems to be
Th momlorg pllias trioy ooeii a 40umem gearætoward aaUseDY dinal
lMk,eJ NfL FIM2'JI-D-jl)7 Drfl ~e fo lllduSú 01 OvetJll øf Ciu mJlstigt Å llis-Biied ÂppllHli to MOIÎting- /Hge S
v
v
Page 1 of2
As of: December 07,2011
Received: September 19, 2011
Status: DoNotPost
PUBLIC SUBMISSION
Category: Individual Consumer
Trackig No. 80f22919
Comments Due: November 28,2011
Submission
Web
.--. . ..-......, Tvpe:
--" ',. .,Docket: FDA-201 1-D-OS97
Draft Guidance for Industr on Oversight of Clinical Investigations - A Risk-Based Approach to
Monitoring; Availability ,
Comment On: FDA-201 1-D-OS97-0001
Clinical Investigations; A Risk-Based
Draft Guidance for Industr; Availability: Oversight of
Approach to Monitoring
Document: FDA-201 1 -D-OS97-DRAFT -OOOS
Barbara Sanford - Comment
ll
Submitter Information
Name: Barbara Sanford
Address: GA
Submitter's Representative: N/A
Organization: N/ A
u., "
General Comment
Document:
Draft Guidance for Industr; Availability: Oversight of
Clinical Investigations; A Risk-Based
Approach to Monitoring (Document ID FDA 201 1-D-OS97-0001 )
I have been a nurse for over 30 years and also a patient in a Clinical triaL. I believe this draft
document is vague, does not provide definitive guidance and the implications are irresponsible.
The most important aspect of a Clinical Trial should stil be " patient safety". This document
suggests the most important aspect, moving forward, wil be cost saving measures for the
sponsors.
If a sponsor attempts to primarily monitor a tral electronically, how can they ensure investigators
are trly performing their duties as dictated by Good Clinical Practice, Operating Procedures etc.
( data errors, omissions, duplication, inaccurate data ).
As we know, all investigators are not created equaL. Most PI's want to do a good
job. They may be
a fantastic MD, but a very mediocre investigator.
ÚJ vLi-erv~ ( Vif~ h~;6. "'. "~~ c l¡'~1.
t~ ,.-Ì&~7 '
htts:/ /fdts.erlemaking.net/fdms..web..agency/component/contentstreamer?objectId=090... 12/7/2011
Page 2 of2
But other Investigators have been " black listed" for fraud and other serious errors of judgement
that risked patient safety. If sponsors only periodically conduct on-site visits, if their is an
unethical investigator identified, it may be too late. A patient would have possibly lost their life.
:. There~should be '~more" on-=site oversightby-sponsoi;s, notJess. Patient safety is not worth the risk,
of saving a few dollars by cutting comers monitoring.
If this decision is already made, there should be a general announcement made by the FDA, to the
public, that states they are relaxing sponsor oversight. This announcement should not be buried in
another disclaimer in the Informed Consent.
This wil give the public & potential trial participants knowledge of additional potential risks &
lack of oversight, that wil help them and their families decide if participating in a clinical trial is
worth the risk of a trial that mayor may not possess proper sponsor oversight.
This is a slippery slope !
https://fdms.erulemaking.net!fdms-web-agency/ component! contentstreamer?objectId=090... 12/7/2011
Page 1 of2
As of: December 07, 201 1
Received: September 22,.201 1
PUBLIC SUBMISSION
Status: DoNotPost
Category: Individual Consumer
Trackig No. 80f27dbe
Comments Due: November 28,2011
Submis~ion Type: Web
Docket: FDA-201 1 -D-0597
Draft Guidance for Industr on Oversight of Clinical Investigations - A Risk-Based Approach to
Monitoring; Availability .
Comment On: FDA-2011-D-0597-0001
Clinical Investigations; A Risk-Based
Draft Guidance for Industr; Availability: Oversight of
Approach to Monitoring
Document: FDA-201 1 -D-0597 -DRAFT -0007
Linda M Vineski - Comment
Submitter Information
Name: Linda M Vineski
Address:
NY,
Organization: rersona1 comment - QA perspective
r
General Comment
Please consider:
Line 249-251 "on-site monitoring ordinarily should be devoted to assessing the critical study data
and processes and evaluating significant risks and potential site non-compliance identified through
.other sponsor oversight activities." This implies on-site review is not one of
the agency's ~0~"\f
suggested primary assessment tools. There is no mention of onsite and central monitoring C~- L .
combined early on to establish a sponsor/CRO/ site comfort level with protocol understanding and -§.
compliance then yielding to an optional sampling method for on-site review for ongoing oversite.
Line 277-278 - Verifying source data remotely... EMR central access by CROs/sponsors off-site e~'
in my opinion does not protect subjects and spelled out in a consent wil significantly impact ':ll\ Ct''J V
recruitment.
Line 286-289: "Sponsors WHO PLAN TO RELY on central monitoring" once in a final document
implies a sponsor can rely only on central monitoring. Is this what the agency wants in writing? ,1\0
"F'DAenourases peater 1"eli_e on 'ientraIiie monitoringpntices &. less emphasis on site
fÌ
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Page 2 of2
monitoring" contradicts the risk..based emphasis intended by the guidand ceo I agree with this ¡
emphasis - but feel there is much to be gained from quality on-site an central monitoring. The
problem in the work I see is the quality not the approach. Assessing quality requires varous
modalities. This draft focuses more on approach not quality.
Line 467- 469 does not include the expectation of ethical human subject training. ..
Section V (in accordance with the regulations) does not (but in my opinion) should include written /
notification/communication with the site PI which on ocassion does not occur and should to V
ensure clear identification of the problem and corrective/preventative action plan for all
improvement areas and all peronnel respnsible.
htts:/ /fdms.erulemaking.net/fdms-web-agency/component/contentstreamer?objectId=090... 12/7/2011
Page 1 ofl
As of: December 07, 201 1
Received: September 27,2011
PUBLIC SUBMISSION
Status: DoNotPost
Category: Individual Consumer
Trackig No. 80f30tìf
Comments Due: November 28,2011
Submission TVDe: Web
Docket: FDA-201 1 -D-0597
Draft Guidance for Industr on Oversight of Clinical Investigations - A Risk -Based Approach to
Monitoring; Availability
Comment On: FDA-201 1-D-0597-0001
Clinical Investigations; A Risk-Based
Draft Guidance for Industr; Availabilty: Oversight of
Approach to Monitoring
Document: FDA-201 1-D-0597-DRAFT-0008
Luba N Maxwell - Comment
I t J
Submitter Information
Name: Luba N Maxwell
Address:
GA,
Organization: American Miltary University
or i
General Comment
To whom it may concern:
I completely agree with your efforts in order to make clinical trals safer for everone. Modem
science has come a long way since the inhumane and cruel trials that took place during Wodd
War II and we stil have quite a bit to go before clinical trials are safe for humans & animals that
undergo them.
I also believe that this regulations should be enforced in conjunction with the public database that
tfk's physiQiats reçønl ofmatice ,"ord.
f\o
htts:/ /fdms.eremaking.netfdms-web..agency/componet/contentstreamerobjectId=090... 12/7/201 i
Page 1 of2
As of: December 07, 201 1
Received: November 04,2011
Status: DoNotPost
PUBLIC
SUBMISSION
Category: International Public Citizen - LO007
Trackig No. 80f66234
Comments Due: November 28,2011
Submission Type: Web
Docket: FDA-201 1-D-0597
Draft Guidance for Industr on Oversight of Clinical Investigations - A Risk-BasedApproach to
Monitoring; Availability
Comment On: FDA-201 1-D-0597-0001
Draft Guidance for Industry; Availability: Oversight of Clinical Investigations; A Risk-Based
Approach to Monitoring
Document: FDA-201 1-D-0597-DRAFT-0017
David Montgomery - Comment
Submitter Information
Name: David Montgomery
Address: United Kingdom,
Organization: Individual comment
General Comment
On balance an excellent document encouraging new thinking (Lines: 188 - 189) as well as
highlighting recurrent areas of weakness (Lines 207 - 209) - to remedy a bad protocol with
copious doses of guidance and/or monitoring is an exercise in futilty However, I do have
concerns with: Lines 209 - 210 "Study-specific training of investigators, other site staff, and
monitors also contributes significantly to study quality. "
464 - 469 "Training should include principles of clinical investigations, ...... the study
monitoring plan, ...... techniques."
Lines 531 -532 "On-site visits should include suffcient time for mentoring, feedback, and
additional training, if needed, ....."
often intended
The.term&training-is~already misused in clinical research, particularly.when what is
is..instruction or guidance. Furthermore, the use ofthè:"word'mentoring~is~a&bridge~too-far: In what
'iay_are sponsors' monitors qualified to~fulfii.the-se~roles;-or are we going to waive the
requirements of ICH GCP 2.8 for those undertaking a role which "contributes significantly to
study quality."?
telling
Providing instructions is rather different to providing training as Dr Robert Mager, said, "If
was the same as training we'd all be so smart that we can hardly stand ourselves." Likewise an
article in 2003 in the BMJ "There has always been an assumption that if a person simply knows a
lot about their subject, they wil be able to teach it."
To avoid misperceptions abouNhe ters training and.mentoring, what:does.the FDA.expe"ct L
\"t Ii' \ -\ 6,e.\-,V\_ L-IA..-lrv-e
"'"" 'b -t"\hA~ j
htts://fdms.erulemaking.net/fdms-web-agency/component/contentstreamer?objectId=090... 12/7/201 1 . ,
Page 2 of2
. sponsors~to-provide: a review of-study specific pr.Qcedures and-documents coupled with feedback
complete rwith intended
. during-monitoring~visits,.as. stated=-in IGH.GGP.or structured-training.
leaming-outcomes.andTevaluations?
training appears oniy twÍcë in ICH GCP yet over the years it pops up increasingly in
guidance documents and regulations e.g. 2009 FDA Guidance on Investigator Responsibilities
defines adequate training - but what is meant by training?
The term
https://fdms.eru1emaking.net!fdms-web-agency/ component! contentstreamer?objectId=090... 12/7/201 1
BAUSCH+LOMB
Division of Dockets Management (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Room 1061
Rockvile, MD 20852
November 21, 20 i i
Re: Docket No. FDA-2011-D-597, Guidance for Industry Oversight of Clinical
Investigations - A Risk-Based Approach to Monitoring
7 Giralda Farms, Suite 1001
Madison, NJ 07940
T 877442.6925
Dear Sir or Madam:
Reference is made to the August 29, 2011 Federal Register (VoL. 76, 53683-53685)
whereby the Agency requested comments on Guidance for Industry entitled "Oversight
of Clinical Investigations: A Risk-Based Approach to Monitoring." The guidance is
intended to assist sponsors in developing risk-based monitoring strategies and plans for
clinical investigations of human drugs, biologics, medical devices, and combinations
thereof. The overarching goal of the guidance is to enhance human subject protection
and the quality of clinical trial data.
Bausch + Lomb is one of the best-known and most respected healthcare companies in
the world. Our core businesses include contact lenses and lens care products,
ophthalmic surgical devices and instruments, and ophthalmic pharmaceuticals.
Founded in 1853, our company is headquartered in Rochester, N.Y., and employs more
than 10,000 people worldwide. Our products are available in more than 100 countries.
We appreciate the opportunity to comment on this draft guidance and support the
Agency in its efforts to provide industry with recommendations on a modem, riskbased approach to monitoring. We offer the following comments and
-..-
recommendations to enhance the issuance of the final guidance.
A. Request for Clarifcation of "Source Data"
Section iV. A.2. Centralized Monitoring of the draft guidance (lines 277-278) states
that centralized monitoring processes should be used to the extent appropriate and
feasible to achieve various objectives including, "Verify source data remotely,
provided that both source data and CRFs can be accessed remotely."
With regard to "source data", we believe the Agency is referring to masked electronic ~
data from a third party such as lab test results, imaging data, etc. As presented in the
draft guidance, "source data" may be misconstrued as original data containing
confidential personal information.
Page 2 of 4
BAUSCH + LOMB
To
assure the safeguard of patient privacy we recommend the revision of lines
277-278 as follows:
Verif source data (e.g.. lab test results. imaging) remotely, provided that both
source data and CRFs can be accessed remotely.
B. Experience of the Clinical Investigator and Sponsor With the Investigator
Section iv. C. Factors to Consider when Developing a Monitoring Plan of the draft
guidance (lines 379-381) appropriately notes that investigators who lack significant
experience in conducting and overseeing investigations, using a novel or innovative
medical device, etc. may' benefit from more intensive monitoring and early
mentoring.
We agree with the above statement and believe these recommendations can be
enhanced by including "site personnel" as well; particularly in cases where the site
personnel may be largely responsible for daily key activities. An assessment of
experience may be based on both the clinical investigator's expenence and those
\l'0)'
participating at the site in day to day study conduct. .
¡
To ensure the investigator and site are considered in totality when developing a
monitoring plan, we recommend tlze following revision to lines 381-383.. "In
addition, the relative experience of a sponsor with the clinical investigator or other
site personnel involved in co.n~~ict of trial may be a factor in determining an
appropriate monitoring plan. "
C. Reporting Suspected and/or Confirmed Data Falsification
Section iv. 0.3. Management of Noncompliance of the draft guidance (lines 454-455)
states "FDA recommends that sponsors develop and include specific processes for
addressing, investigating, and reporting suspected and/or confirmed data falsification."
Reference is also made in the draft
guidance to FDA's February 2010 proposed rule on
data falsification!.
We remind the Agency that while this draft guidance references "suspected and/or
confirmed data falsification" and references the proposed rule; finalization of the V
proposed rule, based on public comments submitted, may impact the definition of these
terms interpretation and as such, the development of related
processes.
We recommend that the Agency reference the final rule, once available in this
guidance and consider any revisions and/or clarifcations for the guidance.
Specifcally with respect to use of "suspected" and "data" and how these
terms are defined.
i http://edocket.access.gpo.govI20iO/pdf/2010-3123.pdf
Page 3 of4
BAUSCH+LOMB
D. Clarification of "Important" Deviations
Section iv. 0.3. Management of Noncompliance of the draft guidance (lines 456-458)
states "Processes to ensure that root cause analyses are conducted where important
deviations are discovered and that appropnate corrective and preventative actions.. .."
To ensure consistency in the interpretation and application of implementing corrective
actions, we recommend that the term "important" be clarified2. Doing so can support a
consistent management of noncompliance when addressing these deviations.
We recommend that "importall" be clarifed as a deviation that affects:
~û)
patiell safety, data illegrity, and/or integrity of
v
the trial asfollows:
Processes to ensure that root cause analyses are conducted where impeFkll
deviations which may impact the patients' safety. trial data. and/or trial
integrity are discovered and that appropriate corrective and preventive
actions.... "
E. Monitoring Plan Amendments
Section IV. D. 5 Monitoring Plan Amendments (lines 493-496) states, "Sponsors
should consider what events may require review and revision of the monitonng plan
and establish processes to permit timely updates where necessar. For example, a
protocol amendment, change in the definition of significant protocol deviations, or
identification of new nsks to study integnty, could result in a change to the monitoring
plan.
We agree with the above but believe the examples provided can be further enhanced by
adding "frequent outliers by a study site" since variances in reporting adverse events,
experience of study site personnel, or outliers in ensunng quality in the course of a ~J \
clinical investigation, wil not become apparent until study is in process. xii ~\v\
'Ðe(,~
To enhance the examples provided, we recommend revision of lines 493-496 as ~
follows, "Sponsors should consider what events iliay require review and
revision of the monitoring plan and establish processes to permit timely
updates where necessary. For example, a protocol amendment, change in the
definition of signifcant protocol deviations, frequent outliers by a study site. or
identifcation of new risks to study integrity, could result in a change to the
monitoring plan. "
2 Reference is made to the EMA Reflection Paper on risk based quality management in clinical
trials (published 5 August 20 i i) which provides specific context regarding 'important deviations'
http://www.ema.europa.euldocs/en GB/document Iibrary/Scienti fic guideline/20 Ii/08IWC500 i
I0059.pdf
Page4of4
BAUSCH + LOMB
We appreciate the opportunity to provide feedback on the draft guidance and trust
these comments wil enhance the final guidance, when issued.
Sincerely,
qf6Jl
Kimberly Belsky
Director, Policy and Communication
Global Regulatory Affairs -
Pharmaceuticals
o QUINTILESGl
4820 Empero lBulaar
OurhaM, NC 27703
1'.1: +1 9199920
Fø: +1 91999& 9113
wwqu"'ØI
Nøember22,2011
Diisn ofDoe. Maagement (HFA.305)
FOH' aFl;On. Aclfaöon
Ma Pishet' ""i'M. 1011
Aøckville\ Me 2011
Stjeet
Doet No. FDA.2011-D.5tl.. Oval Cuidnce for Instiy on Ovesi.ght of Clinical
lnv."itons: A Ris.Based Appoac to Moitrin
Dear PÂ. Kux:
QuintiJe a fv.' ifaM biharmeut Mfiee coll8ny olfl cliniC. comme. consultng and
ca,itai søtiø. woldwic, ."ec the o,lIartunit to cømenton the FDA Or.
Guide for Industry..
ave.. øfCliic Investigati: A Risk-aued Approa to Mcitnt (heeir Dra GUifAe),
pulished In the AuM 29, 2011 Fedra Reg_ (Vot 76, No: 187'). The Drd Gurdne ha ben reieed
an dlscu.. by r.prseta. of Quintle Quaty ..ra. CliniØt Opeions, QaMament,
Aag Al an Leg depa.
Quin" _ tc 'UPfMt~ copt th. risk-ba at$O know as ''tred'' monltAli if approprialy
suppamK byrøÐust ope'allf'' proedures and bee' pras, meets the re_ry an\ ieN €lP
requllemtof"ac.- ~t". and, 8erEfl'llly. Cuntie has beA devetgjUl such ll,ocees
_but,._s.
Quinll ~.tM A"nc in
the il of_ Qra G~.. .. itdeal..... to pr'. the
clin.l, ~.ci.~ wlt .... to, monitoring activities.. F4 ...~ti., lA ef
app.tltlroU$s _ cFiki studY 1D.- an r"leon at cobl_ J'~ni aGivtlto
that
Òv'" ... efieAt. P'U_'\ Quil_ ¡s .ncOUfI-. by th. Îlu.. Of'''' Or..~. Md.
the FtOA h.......to.hecl*fand\lIN.i* plce areund "~mørlf mol$, _in
~. lfeent~,,~.'may bl levlØ'Cas.. In_ .rniet'ål eirive rØQ as part of
the ..te:~fil1l .i..
Bet. Qu~.. ...cont aA' r~ft_CDsto help reaie tlgo. st. by FÐA in
dev.. _ Ð_~ which are to ast .pønsotSincktl,inl'l';ob. mønAg: Sti",
an plns foelifiUl irtis of l:niinan dNl biOlogics, medical df. d. eoml~iMti)f.',*of.nd
to .nccnrras~ tou... vari of 8f8C to meethlÎmon¡tores~ea when
1
Docket No. FDAo2011-1)0579
clinical I commercial I consulting I capital
o QUINTILES.
conducting investigational new drug (INC) or investigational device exemption (IDE) studies. Quintiles
recognizes that the overarching gø81 of this guidanc is to ensure human subject protection, enhance the
quality of clinical trial data, and increase effciency in the conduct of clinical trals.
...
Firstly, Quintiles recognizes that the I!uropean Medicines Agency (IMA) published a draft Reflection Paper,
August, 2011, on risk~based quality management in clinical trials. In the UK, a revision to the previously
publised paper, 'Risk-adapted Approahes to the Management of Clinical Trials of Investigational Medicnal
Products', was release in OCtober, 2011, with the inclusion of Appendix 2, 'Quidanclt on risk..propoftionate
approaches to the management and monitoring of clinica trials'. This paper was the result of a joint project
by the Medicines and Healthcare products Reguiatør Agency (MHRA), Medicines Research Council and the
Department of Health in the UK. Both of these dOQumentsinclude elements of concpts around risk.. based
monitoring that are included in the FDA Draft Guidance.
Quintlles strngly encourages FDA to consider how It may work with thes agencies to standardize the J'
concepts of rjsk..base monitoring approaGhes put fort by each in order to ensure harmoniztion of
approaches use In running
global clinical trials.
section II IlkgroUfd
Lines 62-63 state thlit quality is a systems propert that must be built into an enterprise and canot be
achieved by oversight or monitoring alone. Quintiles agrees that quality must be par of the inherent design of
I
all processes applied to the conduct øf clinical trls; howeer, we recommnd that FDA clarify what is meant
by a "systems" propert to ensure that readers do not interpret this to be applible only to teChnoloy.
site pratices
that COUld result in Inadequate human subject prot4etn-andlor poor dat quality. Quintiles recommend that
Lines 79--0 inclicate that findings frøm monitorng should be used to correct Investigtor and
the wording be expaded to include all non..mpliance. for example. The findngs should be use to correct
~
investiga and site practis that could result in inadequate investigator oversight and instas of non..
compliance, that
jeopardize human subject protection and data interit.
L.ines 93..106 ilustrate the succssful use of r1sk~baed monitoring strie USing less extensive on~site
monitoring by academic cordinating. centers, cøperatïve groups, an goernment organizations. The
example are provided to demonstrate that use of aiternative monitong approahes should be considered by
, . , --
aU sponsors when developing rlsk..ed monitring strateies and plans. Howeer, the section is vague
rearding how r1sk..based monitoring should be approached, the types of stu referred to in
the examples
as well as ttK elemei:ts of the strategies and the circumstanc under which they were used successfully. For
e)fample. baSedo~QUirr¡;~;~exp;riëñ¿e:"r'i$i(ba$8d monitoring strategies. Including on..site and various
methods of remote monitoring can be applied succcssfully on all studies of vaous clinical trial phases and
indications. A successfl risk-based model will employ monitoring
,-. .. - - - - - - - - - '., - just
-from a varety of perspectives, not
2
o
o QU.INTILES.
C:~ . oC_ ._ __
direct investigr monitoring on sit and
from in-house bi. asned monitoring staff. Ratr; the model must
include the moito,insof dat coming in frornsit" as wel as on-oing and retrospetive informatiõñ about
site plOce.. and permance, such that the'. it a$onnuing evaluation of, and rean to,
risk as the
stuy prores. Monitoring on this sc requir.. commitmnt of resource of expertis and teehnology. In
order to bring a leel of maturity to the mol, the remains a need to inrpra. tenoy into the /.. 7
prOC such that the Qn~oing review and analsi of incoming dáta by m~l st, data maemt an L
bitatitics, for exam, c; autatily triger afl ¡ncr...., dec.... or oth chang in sc near liJT
to ensure subje s. and daa integrily. Matuty in tnl& Ifea reu¡'es the suppooflnfomi í (J\ 5euhvV\
TlChAgy (IT), to build systems, capable of collg,anô organlzing date inte the inffatrucr. of a VIAt/\h ~S
sponws I CAO's prøcsses For example, Quintll hulntrced InfoTM, Îleoehensiv. ,yst,.-erlf)
that I.verag data, processes. systems and eXØCfte. Thi. syste prc:id current, qual informaton tlt el.ic-~
gives a" immedat pieure of study staus and subtle underlyin lrnd, allin on-gøng moniting of th
data ki tr fTnit"'lactivty auteticly and to Ides issues proactively, quickly and effiently.
Similar. LiM13&-139 make referenc to FDA!. 11Uguidrieon ProvidClinicllvic Of
errlien.s for (:ni and llioglc PI'CC, whieh cites suee.... in studie. which hid ver.il. oHite
manlorm,. but adressed quait cønt in other way.. The ref...nce, guiance al strH.es co_deion
of tri desin an size, spilally menting fators suen ii simplicit of prwres an non..crïü entry
crte. Thø. ci,...tle se to .mph_i. studiØ$ with reUvely sm sampk sii_ and simple . /
des; howr, the stments are unc_ regardi appllily to iarer moe complex trals. As stad V
above. Quintile !Mlie, risk..bue moitoring strategie, incluin Ofslte an variømehoo$ of remte
monitiF can be 8lPIi succesfu on all studis of varios cllnic trial phass anel iJ'llone when risks
are idntifi appøp)fiatly upfrOAt and during on-oing data revis. suppor.d by apprø~ FØQUft.
that "iiier'mønltori, aei¥il. The critri fo .pliabiily ofrlsk..blSeOj altrnatve monitoring
methcdlos tø v8ÂU$ diicali trel phases. i.e., Ph.. 1.1'1 should be eleaÄY sttedè in th., Draft Guidane.
Lines 152.153 iAtroóuce tAe conc offocngOA crl cd.. To ensre this cønept, is. ctearly uncrsood
within tM conte'" of the DrGune, Qumts reemends that ii' deflAilêlft of tt. term is incluH.
AddialY'. eulßtile$ ~nd strnifthit "$lIon in the follin ways.
· Ae..poitien this sedeal!_ in
the 1)F8IGuie in ÐRrto underlne the impørt$lC8 of I 1"0
identilngcrti.. as II key compcnlof l"ik"baed monitoring; :.
.. Make ..nc. to the mere in..ptll cdiH.tJi.ionofcfilc et it _lkln lll8 ottheOraft~.
Sueh.:
o sa. Asmen 'f' L/ V
o 1~'Prim Anall$ 0.) ~"'. /
o R..~_nlB"nd9
o Il'foed Conset
o PrelOllllbilíy
· Provide key el of an appropriate 8fro to identifl of erin data.
o The ot 1r..prol is the fIlng døemen.1b. sho be .CQulte wNtn deng ~v
criMtdat.
3
o QUINTILES.
o Critical data should be tied to aspects of the protocol that include, but are not limited to,
primary effcacy andlor safety endpoints, serious adverse events. subject eligibility,
Investigational PFQuct accountaøility, and protectin of subject rights.
Lines 159-161 Indicates source data typically become part of the central submision, However, the Draft
Guidance is not clea in its intent regarding inclusion of soure. data in submiSions. While we recogniZe that ".. I
some data, such as from a clinical or analytical
i., may be import directly into the tral database and V
become part of a submission, it is unusualfor cOmmon site source data, i.e., subject medical records, to
be
included in submisSions. Rather, subjec data should be house at the investigatonal site and avaHable upon
request
statement that data verification ca "now be accomplished remotely". We
do not believe that 'verification' is the correct description Itl this instance, becuse an actual venfication of ¡
In adition. Qulntlles questions the
the site cannot be done remøtely. Many research iAStitlition. have been
reluctant to provide remote acess to medical recrds and even when subjters chart are accessed
documentatioFl that
resides at
electroniclly, ac_s is given loclly, often using the site's computers.
We note that the EMA's Guidance addresses privacy prottions with respect to remote monltoring, Wih ¡
respect to global clinicl trals, patient privacy issues should be harmonized among the regulatory agncies
and data protection authorit.$ with a balancing of the import of protecng data integit and patient
safety with patient privaey.
Lines 164-166 indicate that PDA is encouraging the.... of technologicl advanees (e.g., e.mail, webcsts"
and online training mocules) within risk-based monitorig, and that suèh use can met statuory an
~ /~\æ)
regulatory requlrements under appropriate circumstances. Quit"" recmmends that this setion of the
Draft Guidance should include an expanded dlSCsio of different tecnologies that could be used for oentral
monitring, for example, clinical tral management systems (elMS), eletronic data ca,ture (eOC), eletronic / ).~~\
medicl record (eMA), projeot planning tool., soial media. vidtaping, etc. In adtion, we recmmeFld 'lù
inclusion
of a discussion regarding hmw such varid systems would be valida.
Quintiles applauds FOA for its commitment state in Line 116..119 to ensure that the bioreséarch monitoring
compliance program guidance manualsara compatible with th approaches descrid in this guidance. We \\ \ IX
would look forwrd to issuanc of update compliance program guidance docments and any joint FOA- ~ 'I
industry sessions the Agency may consider implmenting to ensure consistent Intrpretation.
Line 198 indictes the expectation that the oomplete ablSnce of on-site monitong wiN likely continue to be
unusual, per ICH &8. Quintiles strongly agr... that there will continue to be value in so level of "triggered"
on.site monitoring. However, the degee to which trgered monitOring is employed will depend on the clinical
4
o QUINTILES.
I nOI)Atervtinal studies, may require little on-site
f'oriAg¡ othr clinical tral ma. more typlcHy require on site review of data coletion and ent,
tral design. While some tl'aii, suc as observatnal
investito survisioo, site complance, crtical da revie, invtig.tlcal product maagment and
suit_ility, of the research facliy .
Quintil believe. that the "" of appropnately planned' trggers fer on..slte visit are a key element in the j.
rectien, 0' riek. Elements such as predictive algol'thms lAd histori... can be used to pre-detrmine a
øhe~J!tlltf
'l .ftctØNdïct .~~~lleg~~'!9Ilm.
r~rciri0ee.
~..~ ----"-=-~o'o-......__~,~._._~~--.-- ,..and
-- .....-.
-.-.~ As da obtaln;'~~
centraly moitoed fOF sites on if on-glnb8$is, the sche of evnts is adjuste and a
visit may be
~ to ocoor soner or later than the pre-tefmifed scheue.
Lim 184' note the aovarntin eDC systes .n... ced' ac to both trial an source daa.
Quiltil ag,... that Steh advanceents leera rik.. bia nmnitng, wilt cetll mOl"itoril'; however, I'
we ..i tha FDA expand this secton beyond th wee 0' øÐ to lMIt' aU da soúrces and systems
use
I... IlL. '...1'* lnnc Stud Qual all h\'
The Dl' Gunc., in liM 221', Iloote (28), encoura.. sponsrs to seek consult with the ~'
a_QID- Feiedlisn rega quali as efelinic tr8ldesig. More guidce is nel to
c~ the. prces fo c:wlt with the FDA's mec: prødti cent.., tor example, the tilin8$ fo r.ceit
aM' revie WitiA the Agenc, aiy stencforat thwøul be required, and. guidanc on the type aM
conte of any dGumel$ submit for reie shuld be inlw;
_..w. C..l....fl..~n..
Quinti.. ag.. with the ~ provi in Lines 246254, reding tl' propriety of on..site assessment
of si~ Slwcda and pro... evati"l sigMiAt ri$ks and; pontl site non..plianeat
an ear '-'0' th sluy, TypicaiY, tt site seectil' aAt init8ttltviedress the.lssui.. W. al
beilve tha, a ciple Fitk..be, mame pl will enompas soe'level of .... mii.. Quilila (
..FilA to pild~ii ~..-..~ _.- ac'~lI- '
.~ an. initiaon vis. lff acdioA¡ we request th.ome gui arOU FOA's I)Qtas of
I'~ leerain of prevlo. daaA iratin r... tc! sty d..IIA-. si exllerlAC',eic. wokllO. uUll.fOrinu" a ri.k~ ffiF pi8:-~-~-~~-~~~---"-~'~'''--'-- ' '=-~~--~
Llne.21"1 sh. be cla to ittet how the FÐA r.la__u~ ver' to ...nio mediCal
ree.. an what constutes sour da in this contxt. If PÐA 1$ adYO dl trs.f' of et._nl /
med'reCØ di Into clinic trial datbases. we stron'Y' ura~arM' whatconsti an ~
aøØl... iiess. If diect trr of the eleetrie med ~i. avail8ble. does the Agncy ble
this.. th need tøcordUd aditiona on-ste sourc data v.~n. whi could be nec to
cl,.e-tnre is no contl noHlronic da aveílelll.? Al; wh...lr. ar coted Uf, US
5
o QUINTILESaI
Line 417 requires that the decl'ption of mônitoring appro"h.- include criteria for determining the timing,
frequency, and.
intensity of planned monitoring activities. It would be helpful if the Draft Guidance would also
include examples of information required in the descptioS of these activties, and that example, are (\o
consistent with clinicl trials of commonly conducted phse 11..11 trials, e.g., cardiovascular, diabetes,
oncology, clinicl nervous system (eNS).
At Line .455. FDA recomme...lh.i_rs. ¡ncIU.dO in 1I mo. nitoring plan specific. proces$Øs related to. ~
detection of misconduct. Sponsors typically hive stadard procedwes in place that are employed across
projeets, specificlly to inve,ligate and reportsuspeted miscnduc Also, Quintiles questions the necessity
to include this information in each monitoring plan as wel, but rater make reference to standard procdures
already in place.
Lines 487-489 state FDA's intention to evaluate a proeess through which spon$OFS may voluntarily submit
monitoring plans for review. However, in a recent FDA webct relate to the Draft Guida~e, there seemed
to be a conflicting message indicting the submission of monitoring ptans may becme a
requiment. In
addition, this section of the Draft Guidance includes a footnote (35) referencing the requirement. under
v
21CFft 812.25(e), to submit monitoring plans for eignifit risk devi studies. The Draft Guidance should
clearly state the Agency's intent regrding volunta or required submission.
I
Section V. Documenting Monitring ActlvW..
Quintiles recommends that the information in Lines 501-51Q provide more guidane reporting of both on-site
and centralized monitoring. The requirements for documentatin of activites of either on-site or remote
monitoring should be included in the clinical monitorin plan.
seetlon Vi.
Additional Strategies to Insure Stu Quali
6
o QUINTILES.
Lines 531-532 advise that on-sit visits should include suffcient time for mentoring, feedback,and additional J
training, if needèd, during the conduct of the study. Quintiles agrees that these elements are crucial to ensure
study quiility and data protecion, but should be extended to centrized activities as weD.
.. . *
Quintfles appreciates the opportunity to provide comments to this Draft Guidance. In summary, Quintiles
support the Agency's efforts. through this Draft Guidance, to provide the clinicl research community with
strtegies for monitoring activities that reflec a modem, risk-based approach that focuses on criticl study j
parameters and relies on a combination of monitoring actiities to oversee a study effctively. We believe
that this guidance wil help define and provide encouragement around alternative monitoring models that
leverage centrlized monitoring as a more efcient and effective resource as part of the overal monitoring
plan. Our recmmendations would further enhance the goals of the Agency to assist sponsors in developing
risk-base monitoring strategies and plans for clinical investigations an to make clear that sponsors can use
a varety of approaches to meet their monitoring responsibKities when conducting investigatinal new drug
(I NO) or investigational device exemption (IDE) studies.
Further, Quintiles endorses the comments submited by the Association of Clinical Research Organizations
(ACRO).
Sincerely, , /1 ,
,YiiltL¿Cj!J.d, tu,~
Florence Reavis, RAe
Director, Quality Assurance
QuintUe.
7
..
Line
number
NA
NA
182.186
Chapter
No.
NA
NA
Ii.D
NA
NA
S-6
Page
Bioresearch Monitoring."
IDE application may either submit a pre.
IDE, or contact CDRH's Division of
to the submission ofthe
wishing to solicit feedback on their monitoring procedures prior
feedback on proposed monitorig plan. Sponsors oflDE studies
sponsrs to VOliultarly and prospectively submit and receive
How wil compliance by indusll be ensured?
How binding will tbe feedback be?
Wil similar processes be established for all of FDA's divisions?
identify their main risks and risk mitigation strtegies.
effcient monitoring should be accomplished, sponsors should be encouraged to
Instead of submittng monitoring plan for review or providing guidance on how
.
.
.
constnictive learing exercise forindusll.
findings discovered durng inspections and their consequences. This would be a more
on the outcoine of FDA's and EMA's inspections; i.e. to get infonntion on the key
applicable to different organiztiona structures. It would be more useful to get feedback
number of parties involved, etc. It is therefore diffcult to create one guidance which is
and how to comply with them. Ensuring GCP is dependent on different factors, e.g. the
There are many detailed guidance documents existing which address GCP requirements
guidelines.
principle cover the same aspects, This would facilitate companies to be compliant with all
isolation but instead harmnize their draft guidance and reflection paper, which in
indusll, Kuros believes that FDA and EMA should not release guidace documents in
clinical trials for consultation. Since ICH intends to harmnize quaity stanards across
EMA recently has released a draf reflection paper on risk-basd quaity management in
Comment and rationale
"
November 23.2011
CH-8005 Zürich
Switzerland
Tel: + 41 (0)44 200 56 00
Fax: +41 (0)442005700
Technoparkstrasse 1
Kuras Biosurgery AG
"FDA (... J wil consider establishing processes within CDER for
General comment
Genera comment
Item/Question
Date:
Commenter:
Docket No. FDA-2011-D-0597
Submission of comments on "Oversight of Clinical Investigations - A RiskBased Approach to Monitoring"
f\0
(\O
1 of 1
(B
~.
Docket No. FDA-20l i -D.0597
Draft Guidace for Industry on Oversight of Clinicallnvestigations: A Risk-Based Approach to Monitonng
novo nordisk~
General Correspondence
Draft Guidance for Industry on. Oversight of Clinical Investigations:
A Risk-Based Approach to Monitoring
November 17,2011
Dockets Management (HF A-305)
Division of
Food and Drug Administration
5630 Fishers Lane
Room 1061
Rockvile, MD 20852
RE: Docket No. FDA-2011-D-OS97
Draft Guidance for Industry on Oversight of Clinical Investigations: A Risk-Based
Approach to Monitoring
Dear Sir or Madam:
Novo Nordisk Inc. appreciates the opportity to provide comments to the above-referenced ~
docket on the Drft Guidance for Indùstr on Oversight of Clinical Investigations: A Risk-Based
Approach to Monitoring.
Novo Nordisk is a pioneer in biotechnology and a world leader in diabetes care and has a leading
position within areas such as hemostasis management, growt hormone therapy, and hormone
therapy for women. Novo Nordisk manufactures and markets pharaceutical products and
servces that make a significant difference to our patients, the medical profession, and society.
After reviewig the draft guidance, we identified one area that warts comment as detailed
below.
Development of monitoring plans
In Par IV, Section C. "Factors to Consider when Developing a Monitoring Plan," the draft ~
guidance states that a monitoring plan should normally focus on "critical data and processes ,
identified by the risk assessment." The gudance also overvews a number of factors for
consideration durng the risk assessment Oines 350 to 401). We recommend that FDA.elaborate
Novo Nordlsk Inc.
100 College Road West
Pnnceton, NJ 08540
609.987-5800
ww.novonordisk.us.com
Docket No. FDA-201 1-0-0597
Draft Guidace for Industry on Oversight of
Page
2 of2
Clinical Investigations: A Risk-Based Approach to Monitoring
Qn hpw lhe-q!!k assessment çould b_e performed when developing the.monitoring plan (e.g., how V
should sponsors evaluate the factors described in this section of the draft gudance?).
Secondly, this section also discusses how more intensive monitorig approaches may be needed
for more complex study designs, and gives unblinded studies as one example of a complex stUdY.. / '
design (lines 361-362). As the complexity of study designs is an importt aspect to consider V
when developing a monitoring plan, we recommend that the Agency provide additional ,
information on the complex study design examples in.this section. For example, it would be
helpfu to know what aspect of unblinding FDA sees as introducing more complexity into the
. study design.
Novo Nordisk fully supports FDA's effort to assist clinical investigation sponsors in developing
risk-based monitoring strategies. We appreciate your consideration of our comments on this draft
guidance.
Sincerely, . "
~'s .~~sJ:::UU_&~ é: u,-v C;
Eddie Li, Ph.D.
Vice President, Regulatory Affairs
Novo Nordisk Inc.
Novo Nordlik Inc.
100 College Road West
Princeton, NJ 08540
609-987-5800 phone
www.novonordisk-us.com
1\.
sanoFi aventis
--.
-Because health matters
23 November 2011
Division of
Dockets Management (HFA-305)
Food and Drug Administration
. w __ _ -5630 Fishers Lane, Room 1061
Rockvile, MD 20852
Re: Docket No. FDA-2011-D-0597
Clinical Investigations:
Draft Guidancefor Industry on Oversight of
A Risk-Based Approach to Monitoring
Dear SirlMadam:
Reference is made to the Federal Register notice of29 August 2011 (76 FR 53683), announcing
, a request for comments on the Draft Guidance for Industry on Oversight of Clinical
Investigations: A Risk-Based Approach to Monitoring.
the Sanofi Group, appreciates the opportunity to provide
feedback on this draft guidance, and offers the following comments:
Sanofi-aventis U.S. Inc, a member of
GENERAL COMMENTS
The Agency has stated several times within the guidance that centralized and on-site monitoring
are not competitive but rather complementary, but there is no further guidance on how to . /
determine an adequate balance between the two. Does FDA have examples or proposals for V
typical and appropriate ways to achieve a balance between the two approaches, for example, for
pivotal phase III trials as opposed to phase IV/post-marketing trials?
Another concern is related to clinical trials conducted outside the United States. Consider the
paradigm ofthe foreign investigator that did not have the same "obligations" and\ÍÚ' ')(,-¿/
"consequences" as investigators conducting their studies within the U.S.
saiiofi-aventis u.s.. Corporate Regulatory Affairs Office, 4520 East West Highway, Suite 210, Bethesda. MD 20814
T('I: (01) 771.4261 . www.o;,tiofi.avcriti~.u'$
Sanofi-aventis comments
Docket No. FDA-2011-D-0597
§ilS;III£.ÇQMMENI§:
1. Page 5
line 1S9-160
Refe,rnc; Text
In addition, source data verifcation and other activities traditionally performed by on-site
monitoring can now often be accomplished remotely, as both trial data and source data
typically become part of the central submission.
Comment:
The reference to "as both trial data and
source data typically become par of
the central
submission." is unclear.
Due to data privacy concerns, routine access to electronic medical records is not routine. It /
would be beneficial if
the agency could faciltate remote sponsor access toEMR. A more V
explicit agency position in this guidance on the benefi of remote EMR access and
acknowledgement that sponsor access is feasible with appropriate subject consent would be
beneficial to overcome constraints imposed by institutions based on their interpretation of data
privacy rules.
2. Lines 159 -163, 277..:/.78-, and 287.289
Reference T ext
In addition, source data verifìcation and other activities traditonally peiformed by on-site
, monitoring can now often be accomplished remotely, as both trial data and source data typically
become part of the central submission. These electronic data capture (EDC) systems are making it
possible to implement centralized monitoring methods that can enable decreased reliance on on-site
monitoring ,
and CRFs can be accessed remotely
Verif source data remotely, provided that both source data
The extent to which centralized monitoring practices can be employed wil depend to some extent on
accessibility of electronic records and EDC systems.
Ç,mment:
the use of electronic
The line items referenced above support the Agency's endorsement of
source data and direct remote access to these.
Sanofi would like to inquire about the Agency's position regarding the use of electronic health D
required by the HITECH Act and
records (EHR), which are certified according to the criteria
defined by HHS in 45 CFR 170. Although the HHS criteria include the requirement for an audit
compliant with the requirements in 21 CFR 11. In
log, it
appears that this audit tril is not
2
SaDofi~aventis comments
Doket No. FDA~20ii~D-oS97
paricular, 45 CFR 170.210(b) requires that the audit log records the date and time, the patient
identification, the user id, and the general activity performed by the user including the creation,
modification, access, and deletion of EHR. However, the HHS audit log does not preserve the
original data in case of a record modification or deletion, as would be required for a part 11
audit trail (21 CFRi-i.l0 (e)).
this
Upon inquiry with the certification authority (CeHIT) we leared further that the lack of
feature in the audit log is intentional, because the audit log is primarily for the use by IT
security staff, which has no need to receive.informatioll about apatients medical condition. Per
the CCHIT website, there are currently a total of 394 iHR systems in use, which have an audit
trail that is certified according to HUS criteria. Therefore, and because ofthe incentives
encountering such
available for the purchase ofHHS certified ERR. systems, the likelihood of
EUR systems in hospitals and physician offices that participate in e1inical trials is high.
Win FDA exercise enforcement discretion when HaS certified EH:l systems that are not
compliant with par 11 are utilzed as source data for clinical trials, or wil hospitals and
physicians who paricipate in clinical trials be required to implement additional measures to
enance the audit logs of their EHR systems to become compliant with part 11?
3. Liles 1-!9..168 and lines 277;.218
RlteøuS' Text:
In addition, source data verifcation anti other activities traditionallyperformed by on..site
monitoring can now often be accomplished remotely, as both trial data and source data
typically become part of the central submission. These electronic data capture (EDC) systems
are making it possible to implement centralized monitoring methods that can enable decreased
to clarif that ri-sk~based
reliance on on~site monitoring. This guidance is therefore intended
monitoring. including the appropriate use of centralized monitoring and technological
advances (e.g., e..mail, webcasts, and online training modules); can meet statutory and
regulatory requirements under appropriate circumstances.
CO!1ill¡
Within the EU framework, which hM strict data protection and privacy rules, it appears difficult
to give the sptuso remote electronic aecesi to source data or have sponsors keep a copy of
them on oø of their
servers. In the SMA. ret1lction paper, uExpeçtations Eol' Electronicc s-ourcev J.
Data and'DataTranscribedto EI~etrnic Data Collection tools in CJin:ical Trials," there
is' a t-
requirement that source data at site level needs to remain under the exclusive contrl of the
investigat.
We also foree. $imUar prøblenis ¡nthe US under HIPAA. WhUe su,ffciemt de~identif1Cation of
datasets would likely be manageable in at oli(Hime transfer of data.froni EHR, many clinical
trials continue over longer periods of time, so that real time Jlonitoriiig of electronic $OutcO data
woulóreuire ongoing or repeted access to ai transfer from the EH~. Ensuring that such
transfer always capture data from the COlTect patiens and avoiding any mix..u))s may require .
3
Sanofi.aventis comments
Docket No. FDA-20ii.D.0597
retaining more patient identifiers in the sponsor's database than pennissible under HIPAA or
acceptable to IRBs and patients.
precaution where it discusses
We suggest that FDA add to this draft guidance a statement of
remote comparison of electronic source and CRF data.
4. Pages 5..6, Lines i 70-186:
Reference Text
The Agency is also initating operational measures to ensure that its review, compliance, ami
other functions reflect this view of
monitoring. Specifcally, FDA:
. Has withdrawn the 1988 guidance on monitoring of clinical investigations.
. Is issuing this draft guidance encouraging risk-based monitoring approaches, including
adoption of alternative monitoring methods.
. Will ensure that the bioresearch monitoring compliance program guidance manuals
(CPOMs)forsponsors, CROs, and monitors (CPOM 7348.810) andforclinical
investigators and sponsor-investigators (CPOM 7348.811) are compatible with the
approaches described in this guidance.
. Wil ensure that all affected program areas within FDA are aware of the goals and
purposes of this guidance and its compatibilty with current CPOMs.
. Wil consider establishing processes within CDERfor sponsors to voluntarily and
prospectively submit and receive feedback on proposed monitoring plans (see section
IV.DA). Sponsors of IDE studies wishing to solicit feedback on their monitoring procedures
the IDE application may either submit a pre-IDE, or contact
prior to the submission of
CDRH's Division of Bioresearch Monitoring.
Comment:
front review and
compliance of chosen approaches. However, if most sponsors submit study-specific monitoring
plans for review prior to application this would require dedicated Agency resources allowing for
bottlenecks during the inidation of a clinical triaL. If sponsors
rapid feedback and avoidance of
choose to avoid prior review (which appears to be voluntar) in order to gain time (e.g., if
review times are too long due to lack of resources)t they carry the risk of a negative future
Sanofi welcomes the proposals for operational measures on how to ensure up
ii:spectors. ~ .
?ut-come, perhaps too late to remediate any shortcomings perceived by the agency or by \I\,V
Although the FDA plans to update the compliance manuals for inspectors and raise inspectors'
awareness of
the risk.based approach, thee is a concern on how to ensure this in practice.
Issues that could arise include bow to prevent inspectors from citing sponsors for taking too
erors (which is a potential
much risk, for insuffcient site coverage, or for allowing isolated
consequence of a risk~based approach).
4
Saoft.aventis comments
Docket No. FDA-201 t.D-597
5. Page Sline 182..184
ß¡fçlÇDeIs¡Z't
processes within eVERfor sponsors to voluntarily and prospectively
submit and receive feedback on proposed monitoring plans (see section IV-VA).
Wil consider establishing
v
çsimm.
Tho process to submit monitoring plans for review would be useful if it resulted in consensus
agreement on critical data elements that would be applkable throu¡h any later BIMO evaluation.
6:. Pal.S 9-10, Lines 310-343
ßçf'i:ØÇI Tçxt
A study protocol should clearly identif those procedures and data that are critical to the
reliabilty of the study findings. These generally should include:
. Data that are critical to the reliabilty of the study findings, specifcally those data that
support primary and secondary endpoints
. Other data that are critical to subject safety, such as seriou adverse events and events
leading to discontinuation of treatment
. Processes that underpin subject safety and ethical treatment, such as seeking
appropriate medical consultation or scheduling extra visits in the event of specifed
clinical or laboratory findings
. Processes that underpin the integrity of these data, such as blinding or referring
specified events for adjudication .....
GBwøt:
critical parameters and proceures (i.e., patient existence and eligibilty, endpoints,
safety related data. blindinilrandomization, inforiedconsent andeIPmgt) covers quite a bit of
infGnnation (even routine lab determinations ifconsidered to fall into safety data). If all of these
area noid attention, then it is difficult to distinguish whe,e the savings of risk..based
The list of
prioritization lie. This ~as a fruent feedback from monitors when they awlieda
raoom/focused SDV procemie, which was previously tesed by Sanofi in seveni large
trials; several monitors felt it was even easier and faster to do 100% than to apply the seleetion
rules.
5
v
Sanofi-aventis eomments
Docket No. FDA-ZOll-D-0597
7. Page 13, lines 481-489
Referençs¡ I¥2t
CDER intends to evaluate potential processes through which sponsors could voluntarily submit
their monitoring plans to the appropriate review division and request feedback from the clinical
trial oversight component for the Center.
Commsmt¡
. The draft guidance indicates it is not a requirement to submit the Monitoring Plan to the
Agency for review - what could be the implication, if any, if the Monitoring Plan were ../.'
not submitted? .
plan, is it a
requirement to submit subsequent amendments each time the risk assessment changes?
. Wil FDA describe the review process (paricularly timelines) ofthe monitoring plan?
. To what
extent does the FDA requires risk minimization for sponsor's monitor training
records?
. Uthe Monitoring plan is submitted with an initial risk minimization
8. Page 14, line 509-511
Reference 1911
Monitoring documentation should be provided to appropriate management in a timely manner
for review or, as necessary, follow-up,
COmw&m:
The statement to provide monitoring documentation to "appropriate management" in a timely
also
manner seems to address internal communication within the sponsor. The guidance should
more specifically address requirements/expectations for communication of monitoring
outcomes/findings to the investigator/study site.
comments provided are
Sanofi appreciates the opportunity to provide feedback and hopes the
useful in the finalization of this draft pidane.
Sincerely,
~.c.()~
,,'
Brian E. Harvey, M.D., Ph.D.
Vice President
U.S. Regulatory Policy
6
J
Society of Quality Assurance
Promoting Quality in the Regulated Research Community
154 Hansen Rd., Suite 201
23 November 2011
Charlottesvile, VA 22911
USA
Tel: +1 434.297.4772
Fax: +1434.9771856
Dockets Management Branch (HFA-305)
Food and Drug Administration
5630 Fishers Lane, RM 1061
Rockvile, MD 20852'USA
sqa~sqa.org
ww.sqa.org
Re: Guidance for Industry Oversight of
Clinical Investigations - A Risk-Based
Approach to Monitorig (Docket 2011-D-0597-0001)
SQA is a professional
membership organization
dedicated to promoting
On behalf of the Society of Quality Assurance (SQA) Clinical Specialty Group, we
appreciate the opportunity to submit comments to the Food and Drug Administration
(FDA) on their recently released Draft Guidance for Industry Oversight of Clinical
Investigations - A Risk-Based Approach to Monitoring.
and advancing the
pnnciples and knowledge
of qualiy assurance
essential to human, animal
and environmental health,
SQA is a professional membership organization dedicated to promoting and
advancing the principles and knowledge of quality assurance essential to human,
animal, and environmental health. Current membership of the Society approaches
working in
2,500 Active and Affiliate members in more than 30 countries
industry, governent, academia, and consulting. The Society includes general
membership, special interest and administrative Committees, Regional Chapters,
Sections. More information about SQA can be found at
and Specialty
www.sqa.org.
SQA supports FDA's position that the time has come to re-addresshow
monitoring should be conducted during investigational studies in support for FDA
applications. Much time, money, and effort has been devoted to monitoring with
little changes in overall negative Inspection findings over the years. We support
FDA's stance that developing risk-based monitoring strategies and plans for
conducting clinical investigations to be a viable approach to obtain adequate
human subjects,
the rights, welfare, and safety of
Sponsor oversight, protection of
and the quality and integrity of
the resulting data submitted to FDA.
As FDA reviews the comments they receive on this draft guidance, we
respectfully request that you consider our following comments in regards to this
guidance.
this guidance,
monitoring generally refers to the methods used by sponsors of
investigational studies, or CROs delegated responsibilities for the conduct
of such studies, to oversee the conduct of and reporting of data from
clinical investigations, including appropriate investigator supervision of
. Page 2,1. Introduction, lines 73-80: "For purposes of
SQA Comments on Docket 2011-D-0597-0001
23 November 2011
Page 2 of5
study site staff and third party contractors. The primary focus should be on the processes
that are critical to protecting human subjects, maintaining the integrty of study data, and
compliance with applicable regulations. The findings should be used to correct
investigator and site practices that could result in inadequate human subject protection
and/or poor data quality."
Comment: The first sentence in the paragraph appears too broad and may ultimately be
misinterpreted with respect to what the guidance is intended to cover. Although the
sentence that follows states the primary focus, it does not mean it is the only focus. The
first sentence essentially states that for this guidance, monitoring refers to:
1. The methods used to oversee the conduct of clinical investigations AND
2. The methods used to oversee the reporting of data from clinical investigations.
Those two elements can extend to every aspect of study oversight, e.g., clinical
investigator management, clinical vendor management, data management, investigational
product management, from the sponsor's own internal systems to the clinical vendors and
clinical investigators. There does not appear to be any distinction from the paragraph that
precedes the one in question, which intends to be more general.
A possible solution is to revise the first sentence ofthe paragraph to read, "~'For purposes
ofthis guidance, monitoring generally refers to the methods used by sponsors of,. I
investigational studies, or CROs delegated responsibilties for the conduct of such studies, Y
to oversee the conduct of and reporting of data from clinical investigators..." as this
seems to be more consistent with the focus of this particular guidance.
. Page 5, II. Background, Section C. Rationale for Facilitating Risk-Based Monitoring,
lines 159-162: "In addition, source data verification and other activities traditionally
performed by on-site monitoring can now often be accomplished remotely, as both ,!aL
data and source data typically become part of the central submission. These electronic
da capture (EDC) systems are making it possible to implement centralized monitoring
methods that can enable decreased reliance on on-site monitoring."
Comment: We would recommend that further clarfication be provided in regards to the
difference between trial data and source data. One interpretation could be that tral data is, /
data recorded on the CRF while source data is found within the subject's medical records, 'V
or it could be interpreted that they are one and the same. For example if one was to
interpret trial and source data to be the same then the traditional process of source
verification which requires a check of source or raw data against the Case Report Form
these two terms upfront would head off
would not be necessary. Further clarfication of
"trial" versus "source" data would be helpful in
considerable confusion. Definitions of
ensuring misinterpretation by Industry and Clinical Investigators of what FDA means by
these two terms does not occur.
SQA Comments on Docket 2011-D-0597-0001
23 November 2011
Page 3 ofS
Monitoring 2.
Centralized Monitoring, the last bullet point (lines 284-28S): "Complete administrative
and regulatory tasks (e.g., collecting and archiving regulatory documents)."
. Page 7, iv. General Monitoring Recommendations, Section A. Types of
Comment: Further clarification would be beneficiaL Is this referrng to the collection of
documents electronically from the sties, in lieu of a monitor visiting the site to collect the
forms? Are there other tasks this relates to?
J
. Page 9, iV. General Monitoring Recommendations, Section B. Identify Critical Data and
Processes to be Monitored, lines 339-340: "Verification that initial informed consent was
obtained appropriately, prior to any study-specific procedures."
Comment: We suggest expanding this point beyond the initial informed consent. As in ~ /
certain cases there are significant changes/modifications to the consent form after the V
study has initiated. We believe it is just as relevant to check that informèd consent was
obtained in a timely fashion anytime significant changes to the informed consent form
have occurred.
. Page 10, iv. General Monitoring Recommendations, Section C. Factors to Consider
when Developing a Monitoring Plan, lines 360-362: "Examples may include studies with
adaptive designs, .stratifiied designs, complex dose titrations,. o. r multiple device piacement;
or unblinded stnies."
blinded studies in this list would be helpful as it
this type of study is
important within the context of this section.
Comment: Clarification of
inclusion of
un
is unclear as written why the FDA feels that the inclusion of
. Page 10, iv. General Monitoring Recommendations, Section C. Factors to Consider
when Developing a Monitoring Plan, lines 366-367: "More objective endpoints (e.g.,
death, hospitalization, or clinical
laboratory values and standard measurements) may be
more amenable to remote verification."
from Sponsor vendors such as.in
the case of electronic centralized lab data) does the FDA anticipate would be available to
Comment: What source data (other than data obtained
the monitor for remote verification on a routine basis? Even though we understand that .V
FDA does not oversee the HIPAA regulations, because ofHIPAA restraints Sponsor
monitors are currently finding it more difficult and at times impossible to obtain direct
FDA foresees monitors accessing
raw data from medical records, further direction on how this can be achieved, e.g., which
access to source data while at the Investigative site. If
processes/procedures need to be in place to achieve this goal while meeting HIP AA and
maintaining subject confidentiality would be beneficiaL
. Page 10, iv. General Monitoring Recommendations, Section C. Factors to Consider
when Developing a Monitoring Plan, lines 379-381: "Investigators who lack significant
experience in conducting and overseeing investigations, using a novel or innovative
SQA Comments on Docket 2011-D-0597-0001
23 November 2011
Page 4 of5
medical device, or with the surgical procedure associated with medical device use may
benefit from more intensive monitoring and early mentoring."
Comment: It would be helpful for the FDA to clarify if their use of "intensive
monitoring" is on-site monitoring. Line 387 specifically indicates this, but it is not
consistently addressed throughout the guidance and could potentially lead to confusion.
v
. Page 13, iv. General Monitoring Recommendations, Section D. Monitoring Plan, 4.
Training and Study-specific Information, lines 464-480:
o "Description of any specific training required for personnel carring out
monitoring activities, including personnel conducting internal data monitoring,
statistical monitoring, or other centralized review activities
Training should include principles of clinical investigations, critical protoco1specifc requirements, the study monitoring plan, applicable standard operating
procedures, and appropriate monitoring techniques.
o Planned quality monitoring to ensure that sponsor and CRO staff conduct
with the monitoring plan, applicable
regulations, guidance, and sponsor policies, procedures, templates, and other
study plans.
monitoring activities in accordance
For example, many companies have successfully implemented on-site comonitoring visits (i.e., monitoring visits performed by both a study monitor and
the monitor's supervisor or another evaluator designated by the sponsor or CRO) (/
to evaluate whether monitors are effectively carring out visit activities, in ..\, .
compliance with the study monitoring plan. These visits may be conducted either
for randomly selected monitors or may be targeted to specific monitors, based
upon questions arising from review of monitoring visit documentation.
the study, its objectives, and the critical data and study
procedures, 479 with paricular attention to data and procedures that are unusual
and require on-site training"
o A brief description of
Comment: The three bullets presently in this section should be separated by different
For example,
4. Training
Monitoring
5. Quality Assessments of
6. Study Essentials
headers to avoid confusion.
The first bullet is appropriately identified as training; however, the second bullet is a
quality control/quality assurance activity that is neither training nor informationaL. The
third bullet ifkept under the present header could erroneously give the impression that
training is necessary. Monitors need comprehensive training rather than a brief
only brief
SQA Comments on Docket 201 1-D-0597-0001
23 November 2011
Page 5 of5
description. Monitors who are not provided detailed training on the study often do not
have a complete understanding of the study and its requirements and, therefore, do not
often recognize deficiencies, seriousness of missed or out-of-window visits/tests, and
other iss4es. The brief study description should be included in a monitoring plari under a
Study Essentials section alQng ~åtb the objectives and ideDtifiçation of critical
data fields
'and critical study procedures The last part of
the third bullet, "particular attention to data
. and procedures that ar; unusual and require on-site training" should be moved up under
Training.
. Page 13, iv. General Monitoring Recommendations, Section D. Monitoring Plan, 4.
Training and Study-specific Information, lines 482-485: "A monitoring plan may
reference existing policies and procedures (e.g., a standard operating procedure
describing issue investigation and resolution). In this case, the sponsor should take
appropriate steps to ensure that monitors, whether sponsor or CRO employees, are aware
of and are trained on these policies and procedures as well as on the monitoring plan."
Comment: Based on experience in reviewing monitoring plans that lack suffcient
reference information and training on revisions, it is recommended to revise this
paragraph to read, "A monitoring plan may reference existing policies and procedures J'
(e.g., a standard operating procedure describing issue investigation and resolution).~
monitoring..~!!ßhould identify for each referenced document, its number, version, title,
'and ôWñ (i.e., sponsor or CRO). The sponsor should take appropriate steps to ensure
tlm monitors, whether sponsor or CRO employees, are aware of and are trained on all
-
relevant documents, including any revisions that occur during the study." --
· Page 15. Vi. Additional Strategies to Ensure Data Quality, Section B. Delegation of
Monitoring Responsibilities to a CRO, lines 543-545: "Although sponsors can transfer
responsibilties for monitoring to a CRO(s), they retain responsibility for oversight of
the
work completed by the CRO(s) who assume this responsibility."
Comment: It would be beneficial if the FDA would provide further guidance as to what is
meant by oversight ofthe work completed by the CRO. That is, what is expected in terms
of documentation to support that appropriate oversight was administered by the sponsor?
For example beyond the contract between the Sponsor and CRO and associated
documents including SOPs, could this include meeting minutes that reflect the
participation ofCRO and sponsor personnel in managing the conduct ofthe study, and
the use of joint monitoring of sites by the CRO and Sponsor? A discussion of Sponsor
oversight of CRO activities would be beneficial in ensuring proper vendor management is
occurrng. One can derive some hints based on the Good Manufacturing Practice/Quality
System guidances put forth by the FDA but we feel it would be beneficial to hear from
the FDA how this applies to the clinical vendor oversight perspective.
.
The following terms are used interchangeably throughout the guidance including the VI'
guidance document title: investigation, study, and triaL. In an effort to prevent any
confusion, we recommend choosing and consistently using one term.
Thank you for consideration of these comments.
Helping CarUivIlCu/ llioll1s
Lettn. AdVdnct. lúal
November 28, 2011
Heart House
2400 N Steet. NW
Washington, DC 20037.1153
USA
202.375.6000
800.253.4636
Fax: 202.375.7000
ww.CardioSo(/rce.org
President
The Honorable Margaret A. Hamburg, MD
Commissioner
Food and Drug Administration
5630 Fishers Lane, room 1061
Rockville, MD 20852
RE:
Draft Guidance for Industry; Oversight of Clinical
Investigations: A Risk-
Based Approach to Monitoring; Availabilty (FDA-iOll-D-OS97)
David R. Holmes Jr, M.D, FAC.C.
President-Elect
William A Zoghbi, MD, FACC
Dear Commissioner Hamburg:
bmne¿j,itt Past Pmident
Ralph G. Brindis, M.D., MP.H., MACC.
Wet Pmident
John Gordon Harold, M.D.. MAC.C.
Secrtar
Thad F Waite, M.D, FAC.C.
Tridsurer
Richard A. Chazal, M.D., FAC.C.
Chair, Board o/Governors
Thad F Waite, M.D., FAC.C.
ñ,tlstees
Eric R. Bates, M.D, FACC.
Alfred A Bove, M.D. Ph.D., MAC.C.
Ralph G. Brindis, M.D, M.P.H.. MAC.C.
John E. Brush Jr, M.D., FAC.C.
A.John Gamm, MD, FAC.C
Josph G. Gacchione, M.D., FAC.C.
Richard A. Chazal, M.D., FAC.C.
Gregory J Dehmer, M.D., FAC.C.
Josph P. Drozda Jr. M.D.. FA.C.C.
RobertA. Guyton, M.D. FAC.C.
Eileen M. Handberg. Ph.D. ARNp.BC. FAC.C.
John Gordon Harold. M.D., MAC.C.
RobertA. Harrington, M.D. FAC.C.
David R. Holmes Jr. M.D.. FAC.C.
The American College of Cardiology (ACC) is pleased to submit comments to the
Food and Drug Administration (FDA) on Draft Guidance for Industry on Oversight of
Investigations: A Risk-Based Approach to Monitoring." The College, a
39,OOO-member nonprofit medical society, is dedicated to enhancing the lives of
Clinical
cardiovascular patients through continuous quality improvement, patient-centered
care, payment innovation and professionalism. Comprised of physicians, nurses,
nurse practitioners, physician assistants, pharmacists and practice managers, the
College bestows credentials upon cardiovascular specialists who meet its stringent
qualifications. Above all, the ACe's commitment to its members and their patients
has driven the College to be a leader in the formulation of health policy, standards
cardiovascular research. The College
provides professional education and operates national registries for the
measurement and improvement of quality care:
and guidelines a staunch supporter of
Overall, the ACC is supportive of efforts to streamline the process of monitoring
clinical investigations. Streamlined processes wil reduce administrative costs for
the
federal government, monitoring entities, and organizations
conducting clinical
trials. This wil hopefully translate towards a. reduction in costs for the end user and
the healthcare system.
Dipti Itchhaporia. M.D. FACC."
Richard J. Vovacs. M.D. FAC.C."
However, the ACC does have concerns regarding the sections of the draft guidance
Harlan M. Krumholz, M.D., S.M., FAC.C.
Gerard R. Martin. M.D., FA.C.C.
Charles R. McKay. M.D.. FAC.C.
William J. Detgen. M.D. FAC.C.
pertaining to remote monitoring; Through the National Cardiovascular Data
Athena Pappas. M.D. FACC.
George P. Rcgers, M.D.. FACC.
variety of sources. The information technology systems used by hospitals and
John S. Rumsfeld, M.D.. Ph.D.. FAC.C.
E. Murat Tuzcu. M.D.. FAC.C.
C. Michael Valentine, M.D.. FAC.C.
Thad F Waite. M.D., FAC.C"
Mary Norine Walsh. M.D.. FAC.C.
GaroleA. warnes. M.D.. FAC.C.
W. Douglas Weaver. M.D, MAC.C:
Stuart
A Winston. D.O. FAC.C.
William A Zoghbi. M.D.. FAC.C.
Registry(l (NCDR(l), the College has extensive experience collecting data from a
these systems are still not interoperable.
Additionally, there are a myriad of regulations governing the use of those data and
physician practices vary greatly, and
the systems. Most institutions do not allow external entities, such as NCDR, direct
access to their systems. They are concerned that they may violate the Health
Insurance Portability and Accountabilty Act (HIPAA) or other laws.
.lx~dl)
Chit/Executive Offcer
John C. Lewin, M.D.
Tbe missùm ()f tbe American C()llege ()f Cardi()l()gy is t() adv()e.te fir quality cardi()/lsCllar car.. - tbr()ugb edlicatÎ()¡I,
researcb pr()m()tÎ()n, devel()pmmt and applicati()1 ()fJtaudaids and guul.lines - aud t() ùrfiimu beakb care P()licy
The ACC strongly recommends that the FDA work with the HHS Office of Civil Rights to guide
institutions in understanding how remote monitoring can occur in compliance with the HIPAA
Security Rule.
Recognizing this guidance would de-emphasize lengthy source document verification, the ACC
does still believe that the verification of essential data points, such as safety and efficacy
endpoints, is paramount to the ethical conduct of clinical trials. Current HIPAA interpretations
and institutional regulations make it difficult to conduct any source document verification
remotely. Furthermore, many catheterization laboratories are still operating on a paper-based J
hemodynamic record system, Often their records are not available electronically. As an interim
step, the ACC would recommend that the FDA work with the Office of the National Coordinator
for Health Information Technology to encourage the widespread adoption of standardized
electronic health record systems that can be used to transmit data using Hl7 specifications and
structure data for seamless interchange with CDISC-compliant clinical trials. Once this has been
implemented, the discussion of remote monitoring of clinical trial data can be revisited as the
standard method of monitoring for clinical trial data.
The ACC appreciates the opportunity to review this draft guidance. The College would welcome
the opportunity to work with the FDA on this issue and many others. Please direct any questions
or concerns to lisa P. Goldstein at (202) 375-6527 or Igoldstein(ëacc.org.
~(L~
Sincerely,
David R. Holmes, Jr., M.D., FAe.e.
President
AMERICA
. COLLEGEø!
. CARIOLOGY
Heart House 2400 N St., NW Washington, DC 20037.1153 USA
202.375.6000 800.253.4636 Fax 202.375.7000 www.C8rdioSource.org
TO: U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH (CDER)
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH (CBER)
CENTER FOR DEVICES AND RADIOLOGIC HEALTH (CDRH)
FROM: NOVELLA CLINICAL
(DURHAM, NORTH CAROLINA)
SUBJECT: COMMENTS TO DRAFT GUIDANCE IN REGARDS TO A RI
MONITORING (AUG 2011)
DATE: NOVEMBER 28, 2011
CC:
Thank you for the opportunity to revie
ards to a risk based approach
to have a profound impact
I. ial data for the development
, questions and suggestions on
to monitoring. This is an important guida
on enhancing human subject protection an
of medical products. Below, pi find a su
the document:
.'
ere may be the possibility of establishing
voluntarily and prospectively submit and
e mö plans. Wil this also apply to CBER and CDRH?
a time limit established for review by the Agency as with
.:
J
ards t he access of remote data, many institutions do not allow j
ronic Medical
Becords (EMR). In addition, data security does not
in the document and seems to be relevant to the topic of remote
ider expanding on this area or providing additional guidance.
.
6- In regards to the utilization of centralized monitoring in lieu of on site ¡
monitoring (where possible), does the Agency have an expectation on how to track
feedback/performance regarding the site? For example, when utilizing on-site
monitoring visits, feedback regarding the visit would typically be captured in the form of
a monitoring report and/or follow-up letter.
..
~¥lIi~gQilQtiQ& er~n- As not all institutions utilze electronic medical records and J
even fewer allow remote access, would it be acceptable to have a monitoring plan that
tailors to the systems availability of participating sites? E.g., 3 of 10 sites in a study can
1
I
have data reviewed remotely but remaining 7 must all have 100% on site review of data
due to lack of EMR?
.
PI. resgonsibility - Although this. document discusses an alternate approach to the j;
common practice of 100% âource Qata yerification (SDV), suggest the inclusion of, 0
information regarding the PI's having the primary responsibility to ensure the safety of ~
the patient and conduct of the triaL. This of course is not withstanding the initial and
ongoing training provided the Sponsor or CRO who have been delegated this
responsibilty.
. Training and Exgerience - If a remote or centralized proces
wil it be necessary for Sponsors and or CROs to demon
have completed any specialized training program and
risk-based monitoring as required in 21 CFR 312.5.?
2
¡zed on a clinical trial, VW ~. \ III
'r CRAs or clinical staff \~VJ ,"&
cific to this type of ~. ~ "" ~
,'V
Page i ofl
As of: December 07, 201 1
Received: November 28,2011
Status: Posted
Posted: December 05,2011
Category: Academia - E0007
PUBLIC SUBMISSION
Tracking No. 80tï56d8
Comments Due: November 28,2011
Submission Type: Web
Docket: FDA-201 1-D-0597
Draft Guidance for Industry on Oversight of Clinical Investigations - A Risk-Based Approach to
Monitoring; Availability
Comment On: FDA-201 1-D-0597-0001
Clinical Investigations; A Risk-Based
Draft Guidance for Industry; Availability: Oversight of
Approach to Monitoring
Document: FDA-201 1-D-0597-0032
Johana Stamates, University of
Miami - Comment
Submitter Information
Name: Johanna Stamates
Address:
FL,
Submitter's Representative: Johanna Stamates
Organization: The University of
Miami
111.1
General Comment
In an effort to gain further knowledge and guidance on the monitoring requirements from an
academic standpoint, we would like to request further clarfication to some parts of the guidance:
Oversight of Clinical Investigations - A Risk-Based Approach to Monitoring, as would apply to
Sponsor-Investigators holding INDs at academic institutions.
In reference to Part IV, page 7, lines 224 - 229 (General Monitoring Recommendations), a risk
based plan for monitoring is defined as a "mix of centralized and on-site monitoring practices". . I
Furter clarficatÍon would be ideal for Sponsor-Investigator IND trials that are multi-center, V
involving separate institutions in regards to monitoring requirements and whether or not a hybrid
monitoring (on site for some, 100% centralized for others)
model, including different methods of
would be acceptable for sites participating in the same triaL.
In reference to Part VI, page 14, lines 523 - 536 (Clinical Investigator Training and
Communication), further clarification would be ideal for Sponsor-Investigator responsibilities for ~~
the same academic
protocol training, not only for the monitor(s) (who happen to be part of
institution) but also the training of the site staff.
htts://fdms.eremaldng.netfdms-web-agency/comporient/contentstreamer?objectld=090... 12/7/201 1
Page 1 oil
As of: December 07, 201 1
Received: November 28,2011
Status: Posted
PUBLIC SUBMISSION
Posted: December 05,201 1
. Category:
Private Industry - C0003
Trackig No. 80f7 48ee
Comments Due: November 28,2011
SUlJmission Type: Web
Docket: FDA-2011-D-0597
Draft Guidance for Industr on Oversight of Clinical Investigations - A Risk-Based Approach to
Monitoring; Availability
Comment On: FDA-2011-D-0597-0001
Clinical Investigations; A Risk-Based
Draft Guidance for Industr; Availability: Oversight of
Approach to Monitoring
Document: FDA-201 1-D-0597-0031
Regeneron Pharmaceuticals, Inc. - Comment
III
Submitter Information
Address:
. i II
NY,
Organization: Regeneron Pharmaceuticals, Inc.
General Comment
Regeneron Pharmaceuticals appreciates the opportnity to comment on the Agency's draft
guidance and respectfully submits the following comments:
\\-~
DO"
Line 75 - There is a challenging boundary between what the investigator's responsibilty is and
vc 5vA'ì
by a sponsor may be considered to occur. Canthe agency elaborate on the
role of the sponsor in investigator supervision?
where undue influence
Line 271 - To adequately conduct centralized monitoring, sponsors wil need to adopt a sampling rv-J \
approach to review data. We propose that industry be provided an opportnity to establish
jointly v_~~(ýW'
a minimal sampling standard for acceptance by the Agency.
Line 277 - As the acceptance of electronic source documentation continues, we would propose
that, where possible, the electronic verification of source documentation be accepted within the \\0
bounds of this guidance.
Line 487 - When a sponsor voluntarily submits.
a monitoring plan for review, what is the timeline J
for the Ageey's review?
htts:/ /fdms,erlemakng.netfdms..web.ageney/ component/contentstreaer?objectId=090... 12/7/201 1
Page I ot2
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Document ID: FDA-2011-D-0597-0029 Docket ID: FDA-2011-D-0597
c e
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Title:
Comment on Document
ID:
Received Date :
SAIC Frederick - Comment 0
FDA-2011-D-0597-0001 0
11/28/2011 G
Submitter Info
Tracking Number: 80f74809
Submitter
First Name: Amy
Middle Name: S
Last Name: Adams
Address
Mailng Address:
City:
Country: United States"
State or Province:
Postal Code:
o
Contact
Email Address:
Phone Number:
Fax Number:
Organization
Organization Name: SAIC Frederick 0
Submitter Representative
Submitter's i6
Representative: Amy Adams v
Category
Category: Federal Government - G0007 "
Submission
1. In section IV. General Monitoring Recommendations, A, #2,
bullet 5 discusses remote source documentation verification.
Would HIPAA laws interfere with this type of monitoring? This
does not appear to be an industry standard as it is very difficult
to gain electronic access to source documentation (i.e.
electronic Medical Records), hence is this the direction the FDA
would like for industry to move in and can you offer any advice
Comment: for this type or monitoring? 2. In section II. Background, D
bullet 5, has a timeline for this review been considered for this
review process? If it becomes a lengthy process, the study may
have already begun enrolling subjects and monitoring should
begin shortly afterward, hence the monitoring plan may hold up
monitoring. Also, how strictly will you hold industry to your
recommendations for the monitoring plan? 3. General comment
- What is the FDA's expectation in regards to the completion of
htts://fdms.erulemaking.net/fdms-web-agency/ custom/jsp/ agency/ documentmgt/Docume... 12/7/2011
~
rage L 01 L
protocol procedures that have not been monitored? For
example, if the monitoring focus is reduced to a limited number
of subjects or visits, how would it be received if the FDA were
to audit subjects that were not monitored and note
errors/omissions? "
Original Comment:
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æ KKS Netzwerk
Koordinierungszentren für Klinische Studien
Comments of the KKS-network on the FDA Guidance for Industry - Oversight of Clinical Investigations - A RiskBased Approach to Monitoring
Comments of the Network of Coordinating Centres for Clinical
Trials (KKS-Netzwerk)
Guidance for Industry
Oversight of Clinical
Investigations - A Risk-Based Approach to Monitoring
Draf Guidance distributed for, comment purposes.
8/24/2011
Docket No. FDA-2011-D-0597
General comments:
We highly appreciate the draft EMA reflection paper on quality management in clinical
trials
as well as the draft FDA guidance on risk-based-monitoring. Both papers could be used
complementary.
\
\
We agree with the statement in the FDA guidance that quality is a systems property that
must be built into an enterprise and cannot be achieved by oversight or monitoring alone. We
also share the view that risk-based approaches to monitoring, such as focusing on the most
critical data elements, are more likely to ensure subject protection and overall study quality,
and wil permit sponsors to monitor the conduct of clinical investigations more effectively than
routine visits to all clinical sites and 100 % data verification.
We therefore very much welcome the clarification within the guidance document that
sponsors can use a variety of approaches to fulfi their responsibilties related to monitoring
investigator conduct and the progress of investigational new drug studies and that a
combination of monitoring activities including on site and
centralized monitoring methods can
be usedt which can be identified by focussing on
critical study parameters; l
One very important point to achieve quality nevertheless is that the findings. should
\
\
\
i
¡~~
i '\\rY
i (j-' ':J"
I 0
be used
to correct investigator and site practices that could result in inadequate subject protection
and./ or poor data quality. We therefore appreciate the recommendation that the
documentation of monitoring activities should include the responsibilties for
I ¡/\
completing
actions and the anticipated date of completion.
The idea-to establish processes within CDER for sponsors to voluntarily and prospectively
submit and receive feedback on proposed monitoring plans is also very much appreciated.
We would recommend that this stays a-voluntary measurement.
I
I
We think that the recommendations provided are as valid for investigator initiated clinical
trials
as for clinical trials conducted
by industry.
§Bg~lfic..çomment$:
II: Background
D Steps FDA is Taking to Faciltate Wider Use of Alternative Monitoring Approaches
190 -193: FDA sees the guidance with the greater emphasis on centralized monitoring to be
consistent with ICH ESt as the flexibilty in ICH ES was intended to permit innovative new
approaches to improve the effectiveness of monitoring. in general.we agree with this
statement, but we find it necessary that at least one on-site visit per site should be conducted
to review patient safety and reliabilty of the data.
25. November 2011
I
EU.F
Guidance for Industry
Oversight of Clinical Investigations - A
Risk-Based Approach to Monitoring
DRAFT GUIDANCE
Docket No. FDA-2011-D-0597
'\" ....
"
'Name~of:Orgariization
v
.,
EUCROF
European eRO Federation
Secretariat
Marian Ritchie
Viale dei Parioli 12
00197 - Roma - Italia
+39-06807.60.72
Tel:
infotâeucrof.eu
Email :
Country
CRO Associations
located in EEA:
Belgium
Czech Republic
France
Germany
Italy
Norway
Spain
The Netherlands
Representative on this matter:
Dr. Dagmar Chase
+49 - 89-92 92 87-0
Tel:
Email:
dagmar. chasetâclin rex. com
UK
plus
Associated Members
from
Greece
Portugal
Poland
Ireland
EUCROF Comments on Guidance for Industry:
Oversight of Clinical Investigations - A Risk-Based Approach to Monitoring
Page 1/5
3
84 -110
II, 8
However, this document allows replacement of one nonevidence-based method of monitoring by other nonevidence-based methods, which is fair enough.
reasoning for recommendations for the future.
past out of necessity and lack of resources form suffcient
The information presented in this section does not provide
sound scientific evidence for any type of monitoring
approach. It is simply a listing of what was reported in the
CTTI survey by sponsors of different nature. To draw the
conclusion from that survey that sponsors should consider
different monitoring approaches is lacking scientific
evidence. While, for very good reasons, sound scientific
evidence is required to get an authorization for a medical
treatment, it appears that monitoring methods used in the
on-site oerformance.
November 27,2011
Page 2/5
Add:
"Only very limited scientific evidence for any
monitoring approach is available at the moment.
Corporate and public institutions are encouraged to
conduct more research on different types of quality
control measures in order to better substantiate
proposed monitoring strategies.
Add: In addition, the findings might surface that the
clinical trial protocol is defective and cannot be
translated into medical practice.
Proposed change
EUCROF Comments on Guidance for Industry Oversight of Clinical Investigations - A Risk-Based Approach
3
78-80
EUCROF misses acknowledgement to the fact that through
on-site monitoring deficiencies of the clinical trial protocol
might be detected, e.g., it might be impossible to translate a
protocol into medical practice. Focus here is only on
deficiencies of investigators and site practices. We think,
however, that on-site monitoring can support more than just
"The findings should be used to correct investigator and site
n
practices ....
Page Comment
no.
II
Chapter Line
· Sectionl
Paragraphl
1. EUCROF Comments on Proposed Text
EU~F
\'0
(to
5
5
6
156 - 158
159 - 161
196 - 198
H,C
n, C
ll, D
that more and more source data are availble
monitoring (and forms a tool whic is taken on-site by the
on-site monitors), whereas centralized monitoring methods
are usually described in a plan, which is called "Data
Manaçiment Plan" or "Data Validation Plan" reflectinçi the
thinks th.at it should
be mentioned that usually the term
"Mo,oitClring Plan" c1scrib.es the methods for on-site
Alough this comment is on terminology only, EUCROF
"The moni~oring plsn ~hoLild ipentify various methods
intended tòbe íisesi ..."
accountabUity, infprmed çpns,ent)
it is hard to see hQw they
should be controlled without ön-site monitorina.
For the issues listed in lines 329 - 343 (adherence to
.inclusion criteria, main,tenanCc of the study blind, drug
. .
electronically, and SDV might no,t be necessary for these
. data, however, we cannot see that SDV ~n be done
., remotelv.
fact
EUCROF doubts that source data and trial data become
"typically" p~rt of a s.ubmiss.ion in such a way that source
data verification can be done remotely. We acknowledge the
coDts, not evidence.
The papers cited to prove this statement present mostly
formúlated more carefully.
As tong as evidenc is missing the statement should be
Jnciude a statement
November 27,2011
avoid confusion.
Page 3/5
on terminology in order to
is stil the éxception).
It should be emphasized that some critical issues
cannot be cqntrolled by central monitoring unless a
sponsor has full access to medical records (which
Please clarify
concept."
Add:
"Evidence has to be obtained to support this
"For example, incorporation of centralized
monitoring practices, where appropriate, MIGHT
improve a sponsor's abilty to ensure the quality
and inteçiritv of clinical trial data."
Proposed change
7
227
JV
EUCROF Comments on Guidance for Industry Oversight of Clinical Investigations - A Risk-Based Approach
5
154 -156
no.
Page Comment
ll, C
Chapter . Life
Paragiaphl
. ~,ctionl
EU~F
.
¡
/
v/
j
J
8
8
9
281 - 283
292 -295
305 - 306
A,
IV,A,2
iV, B
November 27,2011
.
Page 4/5
Find another example for "not so important data"
Investigations - A Risk-Based Approach
Baseline characteristics like "age, concomitant treatment, or
impact on the decision
whether a patient is eligible for the triaL. Furthermore, not
checkinQ this information miQht put the subiect at severe
concomitant ilness" often have an
-
- . Combine lines 268 - 270 with lines 268 - 270.
It is hard to see how a sponsor could check whether consent
was obtained correctly and whether drug accountability is
done properly if study sites are visited only once, early in the
conduct of the study. EUCROF thinks, that at least two
monitoring visits would represent the minimum, the early one
to check on availability of source data, train procedures etc.
and a late one to check ICFs, drug accountabilty, etc. See
also lines 339 and 340. This is a contradiction.
268-270.
Part of these lines refer to very similar issues as the lines
.
267.
Combine lines 265 - 267 with lines 279 - 280.
Add:
"If source data are accessed remotely, data
protection measures should be established which
prevent sponsors to access un-coded patient data.
If source data are accssed by sponsors, appropriate
measures have to be implemented to protect patient
confidentialitv.
These lines refer to very similar issues as the lines 265 -
Widen the goals of on-site monitoring .
for
Proposed change
implementation. This aspect is missinQ.
given that a clinical trial protocol is always perfect
As mentioned for lines 78 - 79, on-site monitoring might also
detect weaknesses of the clinical trial protocol. It is not a
carried out.
fact by which discipline (department) the activities are
EUCROF Comments on Guidance for Industry Oversight of Clinical
2
8
279 -280
IV,A,2
LV,
8
277 -278
IV,A,2
7
241 - 248
no.
Page Comment
LV, A, 1
Chapter Line
Paragraphl
SectionJ
EU~F
v
v
i
J
-I
/lLl
Paragraph/
Please clarify. Maybe the use of the term
"investigational product/device" would be better.
"test article" is a term which is used nowhere else in the text.
We understand that "test article" does not include any
comparator product in controlled trials.
9-10
9
13
329-343
336
480
LV,S
LV, S
N, D, 4
November 27, 2011
EUCROF Comments on Guidance for Industry Oversight of Clinical Investigations - A Risk-Based Approach
Page 5/5
Add "in relation to clinical routine "after "unusual".
Please clarify
We understand that the items listed in the bullet points
ordinarily require on-site monitoring. Is this a correct
interpretation? Or can "higher frequency and more
comprehensive monitoring" also be understood as
centralized monitorina?
"unusual"
Please clarify
.
9
LV,S
327
9
317 - 319
iV, S
Comprehensive monitoring is explained in line 352 as 100%
SDV. In this line 327 "intensive monitoring" is defined as high
frequency and comprehensive. Does this mean that for the
types of data and processes defined in line 329-343 100%
SDV of 100% pts would be the norm?
risk. In this case a 100% control of the correctness of this
information is crucial.
Proposed change
Please explain or delete.
no.
Page Comment
It is not clear why "seeking appropriate medical consultation
or scheduling extra visits in the event of specified clinical or
laboratory findings" is "critical to the reliabilty of the study
findinas". These actions are critical for subjects' safetv.
Chapter Line
. SectionJ
EU~F
v
v
,vi
\-
./
vi
November 15, 2011
Dockets Management Branch (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Room1061
Rockvile, Maryland 20852
Re: Request for Comments on
the Draft Guidance for Industry on Oversight of
Clinical Investigations: A Risk-Based Approach to Monitoring (Docket No. FDA2011-0-0597)
Dear Sir/Madam:
The attached comments on the above mentioned draft guidance are submitted on behalf
of the Pharmaceutical Research and Manufacturers of America (PhRMA). The
Pharmaceutical Research and Manufacturers of America (PhRMA) represents the
countrys leading pharmaceutical research and biotechnology companies, which are
devoted to inventing medicines that allow patients to live longer, healthier, and more
productive lives. PhRMA companies are leading the way in the search for new cures.
PhRMA members alone invested an estimated $49.4 billon in 2010 in discovering and
developing new medicines. Industry-wide research and investment reached a record
$67.4 bilion in 2010.
A PhRMA team of experts from our member companies has carefully reviewed the draft
guidance and would like to take this opportunity to provide comments. The General
Comments are provided in the body of this letter while the Section and Line-Specific
Comments are attached below. We applaud the Agency for producing the guidance and
welcome continued dialogue on this important topic.
Overall PhRMA welcomes this draft guidance as a positive step forward that we hope wil
promote more effective and effcient oversight of clinical trials. With the ever increasing
size and complexity of clinical trials, a risk-based approach faciltates use of an
appropriate mix of on-site and centralized monitoring activities which we expect wil
enhance human subject protection and the quality of clinical trial data.
We encourage the Agency to continue to collaborate with other major regulatory
agencies, such as EMA (Reflection paper on Risk-Based Quality Management in Clinical .,j
Trials) and MHRA (Risk-Adapted Approaches to Clinical Trials) on providing a v
harmonized framework for risk management of clinical trials.
Pharmaceutical Research and Manufacturers of America
950 F Street, NW, Suite 300, Washington, DC 20004. Tel: 202-835-3544 FAX: 202-715-7089. E-Mail: mgarvn~phrma.org
PhRMA supports the concept of a nsk-based approach to clinical trial monitoring;
however, the document seems to lack specific guidance on the development and
utilzation of a risk assessment plan, appropriate mitigation plans and the execution of I
those mitigation plans through the monitoring plan. The inclusion of guidance on the use
of risk management tools, along with potential
applications for using risk-based
monitonng strategies would help faciltate the implementation of such nsk-based
approaches,
PhRMA requests that FDA_c1anfy the references to remote monitonng of source data.
Sponsors do not routinely have access to source data remotely, Remote access to
electronic medical records presents additional legal and data privacy challenges in
addition
to technological challenges (e.g., HIPAA compliance). PhRMA proposes
alignment with this draft guidance to the FDA Guidance for Industry-- Electronic Source
Document for
Investigations, which further c1anfies acceptable methods for
Clinical
sponsors to access source data remotely.
PhRMA welcomes the opportunity to voluntanly obtain feedback from the Agency on
proposed monitoring plans. We propose that the Agency's feedback be an element of
voluntary engagement between the sponsor and Agency. We look forward to further
information following Agency evaluation around how this process might work including
considerations for timing, reviewers and expectations of the process.
PhRMA believes that the monitoring plan, not the protocol, is the appropnate place to
differentiate important data-points from non-important data points. The protocol should
be value-neutral so that clinical investigators pay equal attention to obtaining all data as
well as data inclusive of the primary/secondary endpoints. The draft guidance also
implies that the monitoring plan may consist of one document, when in many cases it
may consist of a compilation of
/
¡/
v
sponsor SOPs and other existing documents. We
recommend that the guidance reflect the fact that one document is not necessary to
descnbethe monitoring plans, so that sponsors have flexibilty with using existing
documents that outline monitoring procedures across functions.
It would be helpful to understand the Agency's definition and expectations for "real time" ,/,
review and acceptable means to document such reviews. The draft guidance ¡/
emphasizes real-time (lines 274 and 386) concerning the centralized data review.
It would be helpful, especially to sponsors who decide to implement an alternative
approach to monitonng, to have more detailed plans regarding specific anticipated V
changes to the alMO Compliance Program Guidance Manuals (7348.810 and
7348.811), including plans to update and implement these manuals.
Your consideration of these comments and line specific proposals is appreciated.
Please contact me if you have
~~
Michael Garvin, Pharm.D.
any questions.
1. Specific comments on text
20-21
Comment: The second sentence ~The overarching gOal of this
guidance is to. enhance human subject protection and the
quality of clinical trial data", does not seem to encompass the
overall intent of the guidance.
Proposed change: The overarching goal of this guidance is to
maintain human subject protection and the quality Of clinical
trial data in an effcient and effective manner through the
appropriate use of the varied monitoring tools and methods
89
currently available.
Comment: Clarification of wording - sponsor vs. company
Proposed change:";...To aU clinical investigator sites by
sponsør peirson..e....."
159-161
COrnment:!n line 159, the guidance states "...source data
remotely..." In line 161
verifi.cation...ca'n now be
accomplished
it further
states "Theseelectronicdata capture
systems
(EDCl
are making it possible to implement centralized. monitoring
methods..."
Is thereferençe to EDt referringto electronic case reportform
information or electronic source
data, which could include
medic:alrecords? If EDCin this
case
medical.
relates
to
electronic
to access
records, it can be diffcult for sponsors
this
information. remoteiy.
appreciate . that
the
Agency's. intention for these statements
maybeto incorporateJlJtlJre eleetroriiccapabiHties and we
We
welcomeworkiQgWith the
remote
data
AgencytcffUrther
understand hoW
verification wil be ac:complished.
Comment:
Currently the so.urcè data is not part .of the central submission,
but PhRMA agrees that at some paint in the future this may be
Proposed ch~l1ge: Werec;ommend removing thewording
"source data
part offhe central
typicaIIY....becorne
submission". (lines 160-161)
182-184
draft
Commenb.. The
states that FDA. wil. consider
guidance
and obtain the
Elstablishingproc:esSesf'orsponsors to submit
review.of..proposedalter!1ative..rnonii:orin~plansbasedon a.risk
is
based approach. . It
recom
a planlprocessbe defin~d
")endedi
by FDA tQ~stablisha mechanismand/or guidance that allows
for the sponsQrto sul)mit, discuss
and ol)tainfe~dback on
detailed'iprQtocol-specifiC risk based monitorihttPlans .to
promote
clear understanding in the
approach..
This planshouid also be .
an
revisions. to
204
application of the risk based
applicable .for. significant
existing . risk,.basedmonitQring · plan.
Comment: The draftguidal"ce mentions the FDAexpeetation
that
quality .and
a . rnulti-faetorapproach is needed to ensure
integrity
of thEldinical trials. Per footnote
27 , the
is
Agency
an
additional guid~nceto describe
the need for
quality riskmc1nagemenfapproaches.
considering
change: We support the creation Qf an additional
approaches in clinical
management
guidancefor qu~litY risk
Proposed
trials.
207..209
Comment: We suggest the FDA enc:ouragethe use of
protocol
ass~ssm~nt/evaluation tools forguidånceon qualitydesigri
encourage the FoAto
parametersfol'protocQlsand eCRls. We
between the FDA R.eview DiVisior1.andthe
Inspection. DjysionCln protocol design responses.
build
310-320
co
Í1 munic:ati
Comment: Draft
on
guidance states "A stud"orótocol shoold
X /~
ÔL; ':lvrv
clearly identify .thosepröcedtires ancÎdatathëÌt arE!criticaitö
the reliabilty of the study findings." The Protocol should be
value-neutral
so that sites pay equal attention to;
obtaining all. .
data as well as. data inclusive of the primary/secondary
endpoints.
Proposed change (if any): .
A
study monitoring plan should clearly identify those
procedures and data... .
339..340
Comment: The Agency only mentions verification of
initial .
imply
informed consent was obtained appropriately; this could
that there would
be an expectation that reconsent would not
need to be checked. . . .
Proposed change:
that i..itiel informed consent was obtained
appropriately,.... .
Verification
345 - 346 Comment: Investigator staff qualificationsldelegationOfdûties
Principal Investigat()r oversight are not mentioned âSiterns
that need more Intensive level of monitoring, yet non
verificati()noftheseiiteniscouldhave a significant impact
on
and
the
data
collected
and
the
protection Of patient
safety.
Additionallyi these re.asonshave been/included in recent
Warning
Letters
to Clinical Investigâtors. If
Would be
advantageousto add items to the guidance as considerati()ns
for morefrequent monitoring activities.
Proposed change: Includeadditiorial bullettosection that
begins
on line 322
. yerification9finvestigator staff qualifications,
(lel.eqationOf(llitlesand Principallnvestigatqr oVersight.
360.362
Comment: Question inclusion of "unblinded" studies in section
"Complexity of the study design".
PropOsecLcltai'ge:Deléte uoblinded and replace With
"blinôecW.
405
develop a
Cornment:"For ea.ch.clini.cal triai, the sponsor should
monitoringplal1..." ThisirhPliesthat the monitoring plahisone
a compilation
of
document/when In manycases Jtwil be
sponsor SOPs, formsalÌdottierexistil1gdocurnentsrelated to
monitoring activities.
change: "...thesponsorshoulddevelop a monitoring
Proposed
may
plan/.""hich
436
be
il
c:ompilation
of multiple
documents
and rèfèr'êrtcestf) !;Pf)l'isr$OPsthëtdescrit)es the
monitoring methods.
Cornmerit: Thé,guidance document notestl'etOmmúniCation of
the results.Qfthe monitQring to thesponsorandCRO¡ howe'/er,
there is
no
indication how/whentheinvestigatorwil be
inforrnedoftheseresults/outcornes.
482-485
Comrnent:Thistextunder 0.4 should be for the whole section
o and not just
under
section 4.
change: Move to line 410 before the last sentence
and change sentence in lines 482-485 to "Sponsors stiould take
appropriate steps to ensure that monitors whether spohsor or
Proposed
CRO employees, .are aWare of and trained on policiesahd
procedures that comprise or are referenced by the monitoring
531
plan.
Comment: . Clarification of wording - coaching vs. mentoring
Proposed change (if any): "...suffcient time for coaching, rtv
feedback"
701 Pennsylvania Avenue, NW
Suite 800
Washington. DC 200°4-2654
Tel: 202 783 8700
Fax: 2027838750
www.AdvaMed.org
November 28, 201 1
Division of
~
AdvaMed
Advanced Medical Technology Association
Dockets Management (HF A-305)
Food and Drug Administration
5630 Fishers Lane, Room 1061
Rockvile, MD 20852
Re: Docket No. FDA-2011-D-0597: Draft Guidmice for Industry on Oversig/it of Clinical
Investigations: A Risk-Based Approac/i to MoiiitorÏ1ig; Availability
Dear Sir/Madam:
On behalf of AdvaMed, the Advanced Medical Technology Association, we are pleased to
submit these comments in response to the notice of availability of Draft Guidance for
Industry on Oversight of Clinical Investigations: A Risk-Based Approach to Monitoring;
Availabilty.
AdvaMed represents manufactuers of medical devices, diagnostic products, and health
information systems that are transforming health care through earlier disease detection, less
invasive procedures, and more effective treatments. Our members produce nearly 90 percent
of the health care technology purchased anually in the United States and more than 50
percent of such technology purchased anually around the world. These members range
from the smallest to the largest medical technology inovators and companies. Nearly 70
percent of our members have less than $30 milion in sales annually.
AdvaMed has both general comments and specific comments below.
General Comments
AdvaMed commends FDA for proposing risk-based monitoring. . Current informatics and
statistical techniques allow for new ways to assure high clinical data quality durng clinical
trals and we believe the appropriate, synergistic use of on-site and centralized monitoring
methods could lead to both more effective and more effcient monitoring of
human subject
and of study data. We also commend FDA for clearly communicating that FDA understands
that 100% on-site data verification is unecessar for all trials and that risk-based monitoring
approaches, including centralized monitoring, can and should be incorporated where
appropriate.
Bringing innovation to patient care worldwide
Division of
Dockets Management (HFA-305)
November 28, 2011
Page 2 of7
their efforts to facilitate the wider
use of alterative monitorig methods is also noteworty and demonstrates FDA's
understanding of the network of change that wil be needed to successfully move industr
the Agency) to adopt and accept newer monitoring methods.
the gudance of
The FDA's description in section II. D. of
(and all parts of
FDA has indicated a wilingness to allow sponsors to voluntarly submit their monitoring
plans for review (Section II. D. last bullet and Section IV. D. 4.). If
submission of
monitoring plans is to add value and improve quality, the review will need to occur at the
earliest stages of the clinical tral plang before the investigational device exemption
(IDE) submission. Review of
the plan must be timely; any delay in clinical tral starp is
expensive and it can be challenging to sponsors to reinvigorate site interest afer delays in the
triaL. FDA should commit to review
the
the entire plan and clearly specify which elements of
plan may not be acceptable along with reasons and suggestions. The. spnsor should also
the
plan in order to reach a common
"acceptance" of the entire )llan. Finally, in order to minimize the potential for CMS
Medicare contractors to deny coverage for device clinical trals, it wil be important for FDA
to avoid issuing conditional approvals for monitoring plans whenever possible.
have an opportnity to discuss and revise portions of
AdvaMed would also like to strongly encourage FDA to explicitly articulate in the
monitoring guidance that device sponsors may tranfer responsibilty for monitorig to
contract research organzations (CRO), as is curently allowed under 21 CFR 312.52 and as
is detailed in Section VI. B. of the dr gudance for IN trals. Weare not aware of any
requirement in 21 CFR 812 that prohibits the transfer of any or all responsibilty for device
tral conduct to a CRO and we believe explicit support by FDA for such transfer of
responsibilty for device trals can only enhance human subject protection and the qualty of
clinical tral data by giving CROs a shared responsibilty for the conduct of device trals and
thus a strong rationale to comply with all relevant FDA regulations and gudance.
Specifc Comments
Please fid our specific comments in the enclosed table. The line numbers reference the
enclosed line-numbered version of
the draft guidance.
In closing, than you for the opportty to provide our comments and recommendations on
the draft gudance on a risk-based approach to the monitoring of clinical trals. Please don't
hesitate to contact me if you have any questions.
~~~
Sincerely,
Tara Federici
Vice President
Technology and Regulatory Mfairs
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Oversight of Clinical
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Guidance for Industry
Oversight of Clinical Investigations - A
Risk-Based Approach to Monitoring
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 90 days of
publication in the Federal Register of
the notice announcing the availabilty of
the draft
guidance. Submit comments to Dockets Management Branch (HF A-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockvile, MD 20852. Submit electronic
comments to http://www.regulations.gov. All comments should be identified with the docket
number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft document contact (CDER) Ann Meeker O'Connell at 301-796Communication, Outreach and Development at 800-835-4709 or 3013150, (CBER) Office of
827-1800, or (CDRH) Chrssy Cochran at 301-796-5490.
Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Biologics Evaluation and Research (CBER)
Center for Devices and Radiological Health (CDRH)
u.s. Department of
Center for
August
2011
Procedural
Monitoring-Guidance.doc
8/24/2011
Novembe 28,2011
.
Dockets Management (HFA-305)
Division of
Food and Drug Administtion
5630 Fishers Lan
Room 1061
Rockvile, MD 20852
Re: FDA Draft Guidance for Industry on "Oversight of Clinieal Investigations: A
Rik-based Approach to Monitoring" (Doeket No. FDA-2011-D-597)
Dear SirlMadam:
Pfizer Ine is providing comments on the FDA (Agency) draf guidance for industr on
Clinical Investigations: A Risk-based ApprøQch to Monitoring that was
Oversight of
published
in the Federal Register of August 29, 201 i (76 Fed. Reg. 53683-53685).
We appreciate the opportity to comment on this draft guidance and trt that.
the
Agency will tae these comments into consideration. Accordingly, please refer to the
attched table of comments/reommendtions.
Please do not hesitate to contat the undersigned if
clarification is needed.
Sincerely,
.0 '"\.
-~.L-.-,2:
~--..
Louaine Warng
Senior Diretor, Site Monitoring Process OWÐer
Pfizer
Inc
8604413072
Attahment
there are any questions or if
risk assessment pl
20f7
htt://www .fda.gov/downloads/Drugs/GuidanceComplianceRegulatorvInformation/Guidances/UCM0735 i l.pdf.
2 FDA, Güe fo hi: Q9 Qu ltisk Maeme .J 200, availe at
htt://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM2699 i 9.pdf.
i FDA, Dra, Gte folD: Oversi of ClWal Investgatio - A Risk.Base Apoah.lQ Momg, Aug. 2Bi t, at m. l &&-19, avaü at
mvesigator, aa l. apab of aly loal laws (iag privacy laws) im iegury reee-mes.
level of
ri. Tk fHl gnide sh alrecøg tB Gler fatos sh al be cOlidred widregards to usg OR._ moit or cemrd
mon or a com theo for apaid clial trl, iBlu th avaiit an accessillí of apopia telmolgies to bo spsor aB
dm. Coois wi ià ~s Gf qu ris maem,2 spso sà he CfOUaged to øs Blrig apoa ComBSwa wid th perceived
CO toem d& ~ pls he taed to dl .Re of th lr taiag ia ac di sm ph .aB. e~iiee Qf ui spsø wid th st
.Pf al agee wit FDA's po "eiiDg) SJS to la in pta W th Re ofdi tria" i aa helives th.t: fu göide slkl
expectatio fo moiB beytm wh is ,~ ~ CUeBt regus.
lì elle tl ex,s are ~ amst al steholdrs. In ad, allougi we s~ th ttse of ceM J:iiiag meoos, PfIZr beieves
thtl fi gle sh give equa e~sis to th fact tl od moin methiiy al be app-oia, an sh al not creaw aDY new
exas, along wdb pontia apats for usitg risk-bd moiag stategies woo help facit th imlemeio of sucftFis..bad apoas an
wlicis th comers of ut1izi a risk.basd appoah, aø inlud apopia exales of risk miigatio. The iiWsof risk managemnt tos aDd
me whee apop. However, we believeth f.m guie sh inlude SpeCiflC gu on th develo an miliz of a
Pfzer apiadie isSle of uH draf glid. We agree wit th coept of a risk-base apoah to lBtoiD am have uûd ceRtal IIg
l. GENERA COMMNTS
COMMNTS FROM: PFIZER INC
SUBMISN OF COMMNTS ON FDA DRA GUIDANCE ON "OVElGIlT OF CLINICAL INVESTIGATIONS: A RlSK..BASED
APPROACH TO MONITOING"lDOCKE NO. FDA-ZOU-BS'71
Noem 28, 2.H1
~
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2&5-200
192-l%
NulÙF(s)
LiD
pre-ID, or conta C.D's Divisio of Bioesearch
th
IIcordae wit IDm ÚlS tN rellemems. "
4 of7
For coneny wit th seond sente, we s~~es th th flfst semelle be
are l""uuJ' SIe- or IóWtgUOS.
'........1., de . _.,,,l __L' "
al wid th protol as doumnts th "may imode systemi eims" if thy
llwever, .th llxt seeie iaodes a seow too the case repo form (CRF),
pc,oti aD.lu ll lslle a well..de aD
protii an.lu da is a welsid aw aiicWaproc."
may iB.oe systeic errors. "
t1ise doumms lIe poy àesi QI am ibey
arüld protol iiiid cas report form (eRF). Wbn
"'IBeæest Twi im tok fo etSUÍA.lw subct
Th dr gu sts: "Th IBst im to for ellÍl .lw SDct
loal pracylaws aD rceaøem.
a ceifie cop thre is iØy cap deoaaly aa in acordae wit
ca an BW of SOce da is onpoib wh. th oriD recd (or
mel' .ve. Speiñal, ll fm gWe slW ieog th -d remo
Pl claify th eiqctio regarai th capin of soce da liy EDC as
ree adl irai ..or Dl."
apeciM Gfdi ah of stal assesms to.~ clial sies tb
syst eøa ce~ aces to ho ki aM SO dM as tà giowmg
to ike Brin re£ortl or uniied copies
of li tr as SOce da wbere IIjJropUlie and in
ceial access
" .ooy, th adaa ia EDC systems eii
Pre eliag(if apaW)
to inøve th e1feceaess of~: lly, th advaiemeBt it EDC
ftKi descri wICKE.6 was if. topeniiit iavalve aew aps
Th dm lD sts: "FDA belives it is reasOl to COlH th
ii.~_~~.,_' . "
lYiIlI.
ei su a
møiigprQCedues pr to th suissiO of th ID applicall m.ay
Bliag pl. . .Spor of ID st wis to soit fek OI thir
· '1DAl (w)i cOllsi est prQCesse witm CDER.t0 spSOS tø
vohily aspisptively sub ai receive fedbk ORpr-od
7341.8l0) as fo etiaal .investigats aD sposo-mvestgairs (CPGM
734&.IU) are ~ wid th a,oalis descibd in il gue."
. '1DA)(wlü eBSUce tl th hiesearch l1in coe pr
gue maauals (Cf-GMs) fo spsors,CROs, aal1s (CPGM
CamlIt aJHRaioal
297
277~271
2SS~260
2si~253
u.
N..rfs)
tåprol iscøx, nd in.lu llvel pE~es wit whih jnvesûgas
59f7
~ r~gag th AgellY's ~~~ aø recios fo
D1iag. We rec6a th FDA issue ~al.dr gue fo
11 se ~s dl te risk asessmetl wid rega. to clial
lawsaù~s.
sis,.~ acof SO da ma aøbepeni du to loal pEivacy
it ispreseat uawi for sooce tl svk as siga Ìl. cois aaor
~al ~dstobe acssib remoiY før çliid tiii. Als, fe gl
We Slsl elBasizth là scio w~ ~ be al excep, sie
acsse~y"
. "Verif so _remoiY, provKitf bø so~ da _ CUs CaB De
Am oi po th dr gWdoo st: "Ceaaä ~Íl procses
sh be usd to th ext WI~ an feasible to achive åe îo&iø:"
dß. ~l1 personl, slaician siaetà may iqat a Rl logial
may var depead Ol.~.~ pl aa ~ia cl-ialmø ~mre
prøgiessio. .
For clait, we sugest làlle ofih~in ie asignd si di perSOl
eI., &f eli ~!i) at a loal al ll th sls)
clWal ÍBveSÛatio is ~. cOBle."
adve apli, aD recOl di di draf
ap, provid gu Of risk fato aa risk
We pr .. .di fma gWde sl Îfhi a 4e
IIdø l! -II prwIIY las ii ref_ewe_."
da aBCRFs CaB be accesse remly, ti in
. "Ven søce da re, WlWuI ib ¥t soce
at whi th cimical mvest is bein coated."
1I, da lDemeft pesomil, lltM ststia,
lligll spso peso orrep.esates (e.g., cliøJ
çen llia is a reø eval ca ou by
~ia, QfC_al~s) at a loat odr.tÅ th sits) at wlu th
ou By sp pesol or iqesealves (e.g., da magemell peso,
Th dr. gu sts: ''Cøtli lBin is a rem evalu carie
mayhe_~"
~exiJ). "
"'~~(if"".le)
cla th left early or pmviØ exas, wii reg to th " .~ (46 t#I'BJ by UJe risk ~II ai sùu
seiince, "OD~simonioria is pllicul criticalea1YHi a sQy, espiay if
ltmay .be he~ to
~diø iefeen th çK. to.
e...... nd lliø
..
w)ì)",
,),f
miigat th id.if risks.
the spiEit of ~. .ham wit respct to
For adlo clait, caa dl AgeACY provid so
lVliÏ3s.
develpmnt. For exa, th us of a ceDlal lDorÍRg aph fo ph
clinicaJ experience with the invesJigalion prodt and the phae of clinical
An aêio fato cor wlR develog a lUil ..pl is prior
tys of eiif a clal tr. ar lIe lman th edrs''?
e~s aoor cit refs coa.fBg th "iBreasmg recognit th so
iBea sP .
.. ~ ex"'s ¡n.be.~ ~ iaCØxt of a la ph ll
geiihave a si.i effct OR streSDlts."
~ (e.g., age, C.QitJa tiDt, -O ~ ilss) wilno, in
'hø BO",zero,ra øi eiLVS ia capg ce ha clreiss øi eivol
dl so type øi elTøi ÎI a clìal tria are moe i. tl otrs..., a low,
assesmnt wldevela a Rlg pl Thre is iareasiarecgi
The dr ~ ~s: "Spos sh coosl dt fmtgs of tlieri
ap.o wit tà gui pl0viddhy th Ml, whereposmle.
clial tr moria pEocess, we would al enouage cooèmiag
ris-bad apoac.3 In
its tocoir iß th Øevel of a risk asssm; siar to d& Octo
2011 Meins ai Heakaie prodts lleg A~l\cy (MHR) papr on
We wou also Sl~st adg al apx pievid iu deta glle OI
be us to
wOl thn fr ti diSClisl of apop lBriag apoas th coul
We sugest tR iaodÏO of risk assessm muh ea in this guid wlill
(jv~ _ ~~ suh fis assessmms.
c.... aa Ra._aI
expriee wit die investgatiol prod as a fator.
Propse exp of tk setio to ad pr clial
sl.lJreleased fo pu coRt _ st
ia.
P..nøe4... (if lp,plgJ)
óof7
htt://www .mha. gov. uk/home/ groups/l-ctuJ documents/websîteresources/ con 111784.pdf.
3 Ml, ldC/D.m Projet: It-add Appøas lø th Maeme ofCllal Tria 9flivestat MeiB Prodts, Od. 10, 2lH t, at '-18, avai at
34.
302-38
Nwaherts:)
Li
417-419
407-41:8
357
Nllmber(s)
Li
regads
to
th complxit of the stu design. as a
fator to cosidr wli
less ÏDenive
7of7
wI sps coo volil su thic ßlg pls to th apopia
review divisio anfest feedk Romdi clial tria oversight comnt
fo th CeBr."
Th dr gnidnçe sis: "CUER iBBd to eval pontil processes l1ougl
roles?
.pl by all itvoled Spso aaCR.O pesol, reg.dss oftliir assignd
respihs ll a lBiB .pi versus a review of th eBtiremoiting
Blpl." Is th Ageay referriag to fam wit OR'S assig
iivoet". In adio clait is requ regarøia th p1as "sl review tbe
Rar th All Sp aa CR.O pesol, we believe th scop sl be
.li io pm Sfif~l ooy i.e., "are iAvoled" fadr tÀ "may he
mog pla."
r-ega_g po_ isss idifi though lDiD, shoiiM review th
wid moiag, inwmg il wh review anor determin apopriate actio
Tli draf pidce sts: "AU spo aM CRO persoel who may be iavolveØ
iarvelio stus.
taÎDg iDt acco th ot fators to be coidred) an phase IV aon~
exas inlu ROomx sties utilizing aCORveatio study design (while
lling apoahes may be apopia wou als be usefu. PossiW
risk..,d apoah towaIds moiting, exas .of stlls whee
mutiple l11!itoringopoaches). For fllr clait wit regal. to utzmg a
moe imDslVe lliag ~oohe (e.g., increasedfrequenc of review an/or
develog a moing pl exales ale provid of sls th may reqe
Wid
ComBlelt aw Ratiaal
pl, whea ap0pia.
Øeeløm ad imnt of ris-lased moitog
As meÐt eadie, ween0tage th Ageiiy to wor
piootively wid spS aR otr stels OR tÀe
PrCled ehaage .(if applahle)
i''')
~~
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK, N.J. 08933
November
28, 201 1
Division of Dockets Management (HF A-305)
U.S. Food and Drug Administration
5630 Fishers Lane,
Room 1061
Rockvile, MD 20852
Re: Docket No. FDA-2011-D-0597: Comments on Updated Draft Giiidalieefor Industry, Oversight of
Investigations - A Risk-Based Approac/i to Monitoring
Clinical
Dear SirlMadam:
Johnson & Johnson's Medical Devices & Diagnostics' family of companies (Johnson & Johnson MD&D)
is the world's largest
and most diverse medical devices and diagnostics company, with its entities having
supplied doctors and patients with hundreds of life-changing medical devices, including HIV drug
resistance kits, orthopedic implants, endoscopic surgical tools, vascular stents and blood glucose
monitors, to name a few.
We commend and support the FDA on updating the proposed draft guidance entitled Oversight of
Clinical Investigations - A Risk-Based Approach to Monitoring. We believe that this updated guidance
wil be helpful in aligning the device industry with the current informatics and statistical techniques that
are available. These alternative monitoring approaches allow for new ways to assure high quality data
during clinical trials beyond on-site source data verification. The guidance is comprehensive, lists critical
to quality items, allows a high degree of flexibilty and is stil precise in defining requirements (e.g.,
monitoring plan). The language is easy to follow, transparent, and designed to change behavior which will
refocus industry to be more comfortable in reducing on-site monitoring techniques and increasing its use
of centralized monitoring. The FDA's description, in section D of this guidance, of their efforts to
facilitate the wider use of alternative monitoring methods is commendable and shows that the agency
understands the network of change that wil be needed to successfully move industr (and all parts ofthe
agency) to adopt and accept newer monitoring methods. The appropriate and synergistic use of on-site
more efficient monitoring that
and centralized monitoring methods could result in more effective and
should lead to higher quality clinical studies while enhancing subject protection.
In this submission, we focus our comments on two main areas of concern: I) awareness that future
technological advances may further increase use of centralized monitoring in lieu of on-site monitoring,
and 2) establishing a process for obtaining pre-approval on proposed monitoring.
Future technological advances
Using current methodologies, some amount of on-site monitoring is expected, but future advancement in
technoiogy may increase the use of centralized monitoring such that the complete absence of on-site
monitoring could become possible. The draft guidance document does mention that new and innovative
1
approaches may enable the increased utilization of centralized monitoring for both tral and source data.
We support
guidance to include the acceptace of
the agency's forward thinking approach in updating the
centralized monitoring and its recognition that alternative risk-based monitoring methods are more likely
to ensure subject protection and lead to more effective and effcient clinical investigations when
compared to traditional on-site monitoring. The guidance would be furher strengthened by
acknowledging in which cases clinical investigations may be conducted in the absence of on-site
monitoring (e.g., with incorporation of proper escalation protocol, accessibility of electronic records and
EDC systems, etc).
Pre;.Approval Processes
potential processes through which sponsors can voluntarily
submit monitoring plans for feedback. The establishment of such a process wil provide a measure of
certainty that the sponsor's plans are in alignent with the agency's expectations in the event that the
sponsor, CRO or study site should be audited. It is important that any process pertaining to the review of
the clinical study. Furthermore, we support FDA's
monitoring plans not delay the commencement of
initiative in facilitating the wider use of alternative monitoring approaches through the education of all
parties involved with clinical oversight (e.g., reviewers, inspectors, other agency deparments).
We commend the agency's
Additional specific
consideration of
comments are included in
the attachment to this letter.
Johnson & Johnson MD&D appreciates this opportnity to comment on the proposed draf guidance
entitled Guidance for Industr Oversight of Clinical Investigations - A Risk-Based Approach to
Monitoring.
Sincerely,
t1~~
~ 't'tI., - YL
Janet Vargo, PhD
Executive Director, Clinical Trial Design
Minnie Baylor-Henry, JD
WW Vice President, Regulatory Affairs
Johnson & Johnson
2
Attachment: Additional Specific Comments
Below, please find a list of specific comments organized by Line Number.
Item
No.
Line
No.
Recommended Change
1
20-21
2
27
Reword sentence to make it more inclusive:
"The overarching goal of this guidance is to maintain human subject protection and the
quality of clinical trial data in an effcient and effective manner through the appropriate
methods currently available."
use of
the vared monitoring tools and
Suggestion to define "centralized monitoring" the first time it is mentioned and
distinguish risk-based monitoring activities in this guidace from those activities
usually peronned by data safety monitoring committees
3
41
4
48
5
78-80
6
163-166
Addition to the sentence:
Suggest adding the increase in use of electronic medical records, and advances in data
transfer, informatics and statistical techniques that can be applied to more effciently
and effectivelv monitor clinical quality "off site".
Revise sentence for clarity
"The regulation requires sponsors of clinical investigations in humans involving drugs,
biological oroducts.,."
Reword sentence to include the ability to escalate/surface and increase
transparency/visibilty to the sponsor and FDA.
"The findings should be used to correct investigator and site practices that could result
in inadequate human subject protection and/or poor data quality as well as provide
visibilty to the spOnsor as a means for approÐriate escalation and action."
Reword sentence to allow hybrid approach to monitoring
"This guidace is therefore intended to claritY that risk-based monitoring, including the
9
196-198
appropriate use of centralized monitoring with or without on-site monitoring and
various technological advances ..."
Suggest addition
" . .. contiue to be unusual, at least in the near future."
10
200
Section
11
226-227
HI
,0
.
Recommend revision of section to add elements of GCP that aFe the responsibilty of
the site personnel as well (e.g., proper documentation, timely submittl of data, proper
consenting procedures, etc.)
Add the following sentence:
"Alternatively, a monitoring procedure may be developed for those studies whose
monitorinlZ tasks are repetitive in nature".
12
251-252
13
254
14
265
15
268
Revise sentence to make it more
16
274
Add sites that are new to clinical research or recent change in critical staff
Add the following sentence:
Suggest changing to "on-site monitoring may be paricularly critical especially if
the
protocol is como1ex. .."
Recommend adding "although it is recognized tht advancing technologies may
mitigate the need for mandatory on-site monitoring" after "elsewhere".
Clarify sentence:
"Replace, augment or reduce on-site monitoring for monitoring activities that can be
done as well or beer"
inclusive:
"When collecting data through ROC, where ÐOssible, prolUam checks into the entr
3
\\J
1"~.l,S
..1-'j"~-'
\\0
\ l\-y
ù.')'¿)';
l ' L ,-,,'c"
system such that data entered that is inconsistent with study entr criteria or logic be
rejected immediately so that the site data entr personnel can correct the entr
immediately. "
17
277-288
18
284-285
19
348
20
369
Suggest addition:
"... when data protection can be assured and country regulations can be followed."
Expand the bullet to include examples of what types of administative and regulatory
tasks mi~ht be completed through centralized monitoring.
.
Suggest addition
"Number and location of study sites" as a factor to be considered
Suggest addition:
"...more intensive monitoring (on-site and/or centralized, as appropriate)..."
21
375
22
379
23
417
24
423-424
25
426
Clarification needed for this section:
It is not clear why more intensive monitoring would be beneficial when there are
differences in standards of medical practice or in subject demographics. For example,
translations of consents or assents, infrastructure differences such as a lack of internet
access, removing abilty to review data in real time..
Clarification:
"InvestigatorS and site staffwho lack significant experience in conducting and
overseeing investigations. .."
Suggest inclusion of some examples of monitoring activities such as remote, onsite
monitoring, telephone and web conferences, email exchange could all be considered
monitoring activities.
Suggest addition
" ... the site should be considered for increased targeted on-site visits and training."
Add as section to assure that the sponsor, and when appropriate. sponsor upper
management is informed to cover upward notification:
On the importance of
26
427-428
27
441
29
462
30
481
31
487-489
determining in advance of
the study escalation procedures to
inform sponsor management when critical non-compliance or other study quality or
human protection issues are identified by the sponsor or the CRO.
Suggest addition
"Identification of possible deviations or failures that would be critical to study integrty
and how these are to be recorded, reported and resolved with corrective and
preventative actions"
Suggest addition
"of routine monitoring results to management investigators, monitors and other
stakeholders... "
training of all parties on test product accountabilty and
1. Add discussion of
blinding procedures, when appropriate.
2. Add discussion of the criticality of documenting training and of plans for
trainin~ new personnel who come on board durin~ the study.
Suggest adding - Description of plans for refresher or re-training for compliance issues,
longer or slow enrollng studies.
We commend the agency for this suggestion asit wil provide a measure of certnty
that the sponsor's plans are in line with the agency's expectations should the sponsor,
4
G~~:\~ ~..
~\...\)¡)
C'"
\,\0
\10
eRO, or study site be audited by the agency. IT would be helpful ifthe process were
defined with associated timelines.
Suggest addition
"The date of
the activity and the individual(s) conducting and participating in activity"
32
503
33
518
Suggest addition:
"A fundamental component of ensuring quality monitoring is a sponsor's compliance
with the protocol, written monitoring plans and any accompanying procedures."
34
524
It is suggested that this section should be more flexible, as we believe training of
experienced investigators and their staff can effectively be handled by WebExlvideo
conferencing technologies .
5
Page 1 of 1
As of: December 07, 201 1
Received: December 05,2011
PUBLIC SUBMISSION
Status: Draft
Category: Drug Industry - C0022
Tracking No. 80fìb981
Submission Type: Web
Docket: FDA-2011-D-0597
Clinical Investigations - A Risk-Based Approach to
Draft Guidance for Industr on Oversight of
Monitoring; Availability
Comment On: FDA-201 1-D-0597-0002
Draft Guidance for Industry; Oversight of
Clinical Investigations; A Risk-Based Approach to
Monitoring
Document: FDA-201 1-D-0597-DRAFT-0050
- EComment
I
Submitter Information
Name: Francoise Rossi
Address:
Paris, France,
Submitter's Representative: Regulatory Intellgence
Organization: LFB
General Comment
"General comment"
We understand that the monitorig practices must change to adapt to a more globalization of clinical
trals in order to speed up the collection of data from the investigators sites and reduce the costs. For
these reasons, systems like EDC are very good tools.
However, we do not think that these systems should be used without a good percentage of on-sitemonitoring. The proposal made in this guide to make one on-site-monitoring in few sites at the
beginning of the trial is in our opinion not suffcient to guaranty the absence of fraud along the
conduct of the whole tral.
The risk of validating this guide is to create two kinds of sponsors:
- those who wil continue to use a good percentage of on-site-monitorig to assure the quality and the
integrity of their data
and
- those who wil act on this guide to do faster and cheaper
The result of this is, in our opinion, that some new drgs may be marketed too quickly with the
possible risk of
post-marketing adverse events/serious adverse events, not appropriately.identified
durig the "monitoring phase" of
the tral(s).
This approach does not seem to tae much care of th safety of future patients.
htts:/ /fdms.erlemakig.net/fdms..web..agency/component/contentstramer?objectld:i090... 12/7/201 1
Page 10ft
As of: December 07, 2011
Received: December 06,2011
PUBLIC SUBMISSION
Status: Draft
Category: Drug Industry - C0022
Trackig No. 80f7c95a
Submission Type: Web
Docket: FDA-201 1-D-0597
Clinical Investigations - A Risk-Based Approach to
Draft Guidance for Industr on Oversight of
Monitoring; Availability
Comment On: FDA-2011-D-0597-0002
Draft Guidance for Industr; Oversight of
Clinical Investigations; A Risk-Based Approach to
Monitoring
Document: FDA-201 1 -D-0597 -DRAFT -0052
- EComment
Submitter Information
Name: Gina M. Newton
Address:
MA,
Organization: Milennium: The Takeda Oncology Company
General Comment
While I feel the guidance includes some valuable information, I feel as though it's stil unclear the
parameters in which a sponsor must conduct on site versus central monitoring. I think you wil
have sponsors that wil always continue to monitor in a more conversative manner (myself
included) in an effort to ensure data quality, an for the agency to view my sponsor conduct as
being too flexible and having this result in quality issues. The guidance seems
adequate for fear of
to encourage a more lax approach in monitoring but then concludes with giving many instances
where this approach would not work. I feel in the end, we may fiter down to very limited trals
using this more lax approach. I for one am not confident that central monitoring can take the place
of on site monitoring. I've have many experiences where things are not as they seem until you are
actually on site - I cannot imagine going to a site as little as yearly. I hope yòu find this feedback
helpful! Again, there was definitely value in this guidance, Ijust stil feel that sponsors (at least
myself) wil stil be more conservative to ensure data quality and appropriate oversight as viewed
by the ageney.
htts:/ /fdms.ereraking.netfdms-web-agency/component/contcmtstreamerobjectId=090... 1217/201 1
Comments and Suggestions on Draft Guidance entitled:
Guidance for Industry: Oversight of Clinical Investigations A Risk-based Approach to Monitoring
Issued: 24 August 2011
Timothy King
td n k68(ãfrontier.com
+1 919.597.9060
23 November 2011
Thank you for allowing me to comment. My comments are general but mostly pertain to
section IV.B - Identify Critical Data and Processes to be Monitored and also IV.D.1 Description of Monitoring Approaches.
When "targeted" data monitoring has been used in clinical trials, as opposed to 100%
Source Document Verification (SDV), the process has tended to be transparent. A
common approach is to announce to the study team and investigator site staff that the
first three patients will be monitored and then every third patient thereafter. Therefore,
investigators know, a priori, which subjects are likely to be reviewed.
I suggest that any targeted monitoring approach employ randomization. While 100% of
certain key variables may be reviewed (primary endpoints, key safety data, inclusion
and exclusion criteria, for example), the remaining data to be source verified should be
chosen randomly.
To make this operationally feasible, the randomization schema should be programmed
into the electronic data capture (EDC) system, whenever EDC is used. A randomized
approach may not be feasible for traditional paper-based case report form (CRF)
studies.
On a related note, the current paper-based data systems and "major" EDC systems (Le.
Oracle InForm, Medidata RAVE, etc.) were designed assuming a 100% SDV monitoring
strategy. They are not able to distinguish between a) data that is not to be monitored,
as opposed to b) data that has not been monitored yet but will be. Therefore, these
systems wil run programmed edit checks and generate queries on un-monitored data
and send to sites for resolution. This essentially creates a de facto 100% SDV process,
but in a less effcient way (rather than queries being issued to discover errors missed by
monitoring). For example, on a Phase III osteoporosis trial, the use of a "targeted SDV"
approach lead to three times more queries being issued to investigator sites which
created a tremendous additional workload for both the Pharma and site staff. The
targeted approach actually increased timelines, efforts, and the overall study budget,
with no resulting benefit in terms of patient safety or data quality.
The more rational approach would be for data queries to be generated and reviewed by
statisticians and medical staff to uncover trends (fraud, systematic error, etc.), but not
sent to sites if not deemed a priori as "critical".
Again, thank you for inviting feedback.
COOK GROUP INCORPORATED
750 DANIELS WAY.
COOK~
P.O. BOX 1608
BLOOMINGTON, IN 47402.1608 U.S.A.
'HONE,812.331.1025 'Al,812.331.8990
GROUP
WWW.COOKGROUP.COM
November 28,2011
Dockets Management (HFA-305)
Food and Drug Administration
Division of
5630 Fishers Lane, Room 1061
Rockvile, MD 20852
Re: Docket No. FDA-2011-D-0597
Draft Guidance for Industry on Oversight of Clinical Investigations: A Risk-Based
Approach to Monitoring
Dear Sir or Madam:
Cook Group Inc. (Cook). Cook is a holding company
of international corporations engaged in the manufacture of diagnostic and interventional
products for radiology, cardiology, urology, gynecology, gastroenterology, wound care,
products used in the
emergency medicine, and surgery. Cook pioneered the development of
Seldinger technique for angiography, and in techniques for interventional radiology and
cardiology. Our products benefit patients by providing doctors with a means of diagnosis and
intervention using minimally invasive techniques, as well as by providing innovative products
for surgical applications. Cook sells more than 15,000 different products, which can be
purchased in more than 60,000 combinations. Our company employs more than 10,000 people
those are based in the United States. While 50 percent of
around the world. Eight thousand of
our products are sold outside the United States, 85 percent are manufactured in this country.
We submit these comments on behalf of
We appreciate the opportnity to comment on the Draft Guidance for Industry on Oversight of
Clinical Investigations: A Risk-Based Approach to Monitoring. Many of our products have
required clinical data to support a regulatory approval in the United States from which these data
were collected during a clinical study with regulatory and Institutional Review Board (IRB)
oversight. Cook currently sponsors more than 75 clinical studies in 30 countries. It is primarily
for this reason that we are keenly interested in providing our comments for consideration.
Cook would like to commend the FDA on revising the agency's guidance document on
monitoring. As a sponsor of global clinical studies, Cook has for many years used a risk-based
approach to monitoring that has provided alternative mechanisms to evaluate the overall
scientific integrity of the studies while protecting the rights, welfare and safety of patients
treated. This approach has lead to an improved use of resources (both human and financial) for
Dockets Management
Docket No. FDA-2011-D-0597
November 28,2011
FDA Division of
all parties involved including the sponsor, the Contract Research Organization (CRO), the
monitor, and the investigative sites.
Any organization that implements a risk-based approach to monitoring must recognize the
potential consequences of
unforeseen outcomes and build in mechanisms to identify the risk(s)
early and to frequently monitor to determne when the sources of the risks have reached a
meaningful threshold requiring further mitigation. Recognizing this, Cook would like to offer
additional considerations for developing a comprehensive and balanced risk-based plan for
monitoring clinical studies that complement the utilization of on-site and centralized monitoring,
training of research staff and physicians and the use of qualified and trained monitors.
Vendor Assessment
It is common practice for a sponsor or CRO to outsource specific areas of clinical research to a
vendor that has the expertise and personnel to perform the clinical research services. It is
strongly recommended that vendor assessments be encouraged as a part of the overall monitoring
plan. The assessment should not be limited to outsourced responsibilities of the sponsor or CRO
but should include assessments of the proposed investigative sites, the proposed principal
investigators, the IRBs and core laboratories utilized by the hospital, sponsor or CRO.
Safety Monitoring
In addition to on-site and centralized monitoring as defined in the guidance, consideration should
be given to the use of a Data Safety Monitoring Board and/or Clinical Events Committee to
assist with the overall monitoring of the study with a focus on patient safety and outcomes.
These committees, comprised of independent physicians and researchers, can be useful in some
studies to provide perspective that may not be provided by those closely involved in the conduct
of
the study.
Data Protection/Patient Privacy
Although access to source data for use during central monitoring could lead to more frequent
review of the clinical data, challenges exist at the investigative site, hospital or laboratory to
ensure that adequate procedures and infrastructures (i.e., electronic medical records) are in place
to allow non-employees access to patient level data while adhering to data protection laws and
regulations. The data protection and patient privacy policies vary from site to site and the
reliance on accessing these systems to augment or even replace theon-site monitoring must be
realistically balanced with the increasing emphasis on data protection, patient privacy, and the
local interpretation of the regulations.
Page 12
FDA Division of
Dockets Management
Docket No. FDA-2011-D-0597
November 28, 2011
Escalation
Emphasis should be placed on mechanisms by which potential concerns related to compliance
with the regulations, protocol, and agreements, especially those related to the rights, welfare and
patient safety, are quickly identified and subsequently escalated to the investigators, research
staff, IRB(s), sponsor and/or FDA as appropriate. The mechanism for the escalation should also
identify potential corrective action(s) to secure future compliance.
Auditing
As part of a sponsor's quality system, consideration should be given to performing periodic
the study), CRO, monitor and site(s)
audits ofthe sponsor (functions involved in the oversight of
throughout the clinical study to evaluate adherence to the regulations, protocol, agreements,
procedures and stipulations imposed by FDA and the IRB. The results ofthe audit should
provide opportnities for preventative or potential corrective action(s) to be implemented by the
audited function.
Harmonization
We would encourage the FDA toreference the recently published IS014155:201 1, Clinical
investigation of medical devices for human subjects - Good clinical practice and further clarify
its relationship to the proposed guidance. A large percentage of clinical studies conducted today
to support regulatory submissions to FDA include data from outside the United States.
Recognition of international consensus standards leads to efficiencies for all stakeholders,
collaboration, and increases the confidence in the data and the processes used to gather the data.
We welcome the opportnity to work further with the FDA on revising this guidance. In our
high-quality research are of great
clarify and expedite the conduct of
view, any steps that
helping patients.
importance to our common goal of
Thank you for considering our views and
comments.
'/ 2- ~
tep n L. Ferguson r~
Chainnan of the Board
Page 13
Bio
BIOTECHNOLOGY
INDUSTRY ORGANIZATION
1201 Maryland Avenue SW, Suite 900, Washington, DC 20024
202-962-9200, ww.bio.org
November 28,2011
Dockets Management Branch (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockvile, MD 20852
Re: Docket No. FDA-2011-D-0597: Draft Guidance for Industry on Oversight of
Clinical Investigations: A Risk-Based Approach to Monitoring; Availabilty
Dear Sir/Madam:
The Biotechnology Industry Organization (BIO) thanks the Food and Drug
Administration (FDA) for the opportunity to submit comments on the "Draft Guidance
for Industry' on Oversight of
Clinical Investigations: A Risk-Based Approach to
Monitoring."
BIO represents more than 1,100 biotechnology companies, academic institutions, state
biotechnology centers and related organizations across the United States and in more than
nations. BIO members are involved in the research and development of
30 other
innovative healthcare, agricultural, industrial and environmental biotechIology products,
thereby expanding the boundaries of science to benefit humanity by providing better
healthcare, enhanced agrculture, and a cleaner and safer environment.
clinical investigations in
the guidance to assist sponsors of
developing risk-based monitoring strategies and to enhance human subject protection and
the quality of clinical trial data. Biotechnology companies are at the forefront of
biomedical innovation and welcome proposed strategies for monitoring activities that wil
assist them in conducting clinical investigations in a more modem, risk-based manner.
BIO supports the goals of
the Clinical Trials Transformation Initiative (CTTI), BIO
commends the work that the Agency and CTTI have done to survey current monitoring
As an active member of
practices while compiling recommendations. BIO looks forward to continuing to
BIO Comments on "Oversight of Clinical Investigations: A Risk-Based Approach to Monitoring"
FDA Docket FDA-2011-D-0597 November 28,2011, Page 1 of7
articulate and build support for these concepts through CTTI and among clinical tral
stakeholders, including industry, contract research organizations, academia, and
regulators.
Approaches such as centralized clinical trial monitoring and a focus on the most critical
data elements can help Sponsors and FDA to deploy resources to the areas that wil best
promote the integrty and quality of clinical trial data. Conceptually, the approaches
detailed in the guidance should enhance the efficiency and effectiveness of clinical trial
monitoring, but great care should be taken in implementation of these approaches to
reduce the potential for duplicative or burdensome monitoring requirements.
BIO appreciates this opportnity to comment on the "Draft Guidance for Industry on
Clinical Investigations: A Risk-Based Approach to Monitoring." Specific,
detailed comments are included in the following chart. We would be pleased to provide
Oversight of
fuher input or clarification of our comments, as needed.
Sincerely,
lSI
Kelly Lai
Director, Science & Regulatory Affairs
Biotechnology Industry Organization (BIO)
BIO Comments on "Oversight of
Clinical Investigations: A Risk-Based Approach to Monitoring"
FDA Docket FDA-20l1-D-0597 November 28, 2011, Page 2 of7
COMMENTS
Lines: 182-183
Lines: 156-158
'I
position that ha previous experience at sites with monitoring.
While BIO agrees that a protess for sponsors to prospectively submit
within CDER, we
a detailed monitoring plan should be established
request that the Agency include a clearer definition and explanation
of
what wil be the focus and intent ofCDER's review. In addition,
for this review to be a value added exercise for both CDER and
sponsors, it would be beneficial to have CDER staff in the reviewing
and industry would agree on data that would be inspected at a site
visit, as this would potentially affect the monitoring plan, to assure
that expectations bttween industry and regulatory agencies are clear.
begins enrolling patients. It is also the expeçtation that the Agency /I 0
These criteria and examples should clarify the expectation that
Industry would provide to the regulatory agencies a detailed
monitoring plan, including type of monitoring; intervals in which it
be monitored, and would reach
would occur; and exact data to
agr~ement w~th the ~gencie~ on the outlined pl~n before the stud~ ~
We request that the Agency provide examples of centralized
monitoring techniques to identify data anomalies. We also
stating that sponsors
recommend that the Agency include language
should establish criteria for on-site monitoring.
BIO Comments on "Oversight ofC1inica1lnvestigations: A Risk-Based Approach to Monitoring"
FDA Docket FDA-2011-D-0597 November 28,2011, Page 3 of7
"Wil consider establishing processes withi
CDER for sponsors to voluntarily and
prospectively submit and receive feedback on
proposed monitoring plans..."
on-site monitoring."
by centralized monitoring technques than by
"Several publications suggest that data
anomalies (e.g., fraud, including fabrication
of data, and other non-random data
distributions) may be more readily detected
evidence can be assured."
II. BACKGROUND
Line: 134 "as long as the adequacy of the scientific
We recommend clarifying and elaborating on this statement.
-~~ ~ - -~ ~- - - ~ ~~ --
~ ~ ~
SPECIFIC
,.
Lines: 271-276 "Augment
on-site monitoring by performing
monitoring activities that can only be
accomplished using centralized processes
(e.g., statistical anlyses to identify data
clinical investigation is being conducted."
"
.,
1\ 0
Clinical Investigations: A Risk-Based Approach to Monitoring"
FDA Docket FDA-2011-D-0597 November 28,2011, Page 4 of?
We suggest including the following:
Data management, clinical science, and other functions may be well
placed to facilitate the analysis of data trends.
Additionally, we suggest additional wording: "Centralized
monitoring could be considered to ensure more timely feedback and
identification of protocol deviators and completeness and accuracy of
data. It also allows identification of issues at sites."
We believe that the Agency needs to be clear about the intent of the
centralized monitoring.
appropriate consent procedures).
data that cannot be assessed remotely (such as valid consent and 1\0
In addition, on site monitoring should be used to assess critical study
.
We believe that informed consent should be explicitly included in this 0-ù
. list. Equally, in the list of
tasks that can be performed remotely,
remote training could be included.
BIO Comments on "Oversight of
at a location other than the site( s) at which the
"Centralized monitoring is a remote
evaluation carried out by sponsor personnel or
representatives (e.g., data management
personnel, statisticians, or clinical monitors)
Lines: 258-260 Centralized monitoring is defined beginnng
on line 258:
should be devoted to assessing the critical
study data and processes and evaluating
significant risks and potential site noncompliance identified through other sponsor
oversight activities."
Lines: 249-25 i "Therefore, on-site monitoring ordinarily
appropriate investigator supervision of site
staff performing critical study functions)."
Informed consent by the subject may be
implicit in the sentence that begins on line
242 that states: "... provide assurance that
study documentation exists..."
appropriate delegation of study taks, and
Lines: 245-248 "On-site monitoring can also provide a sense
of the quality of the overall conduct of the
trial at a site (e.g., attention to detail,
thoroughness of study documentation,
III. FACTORS THAT INFLUENCE STUDY QUALITY AND INTEGRITY
~
"Conduct aggregate statistical analyses of
study data to identify sites that are outliers
relative to others and to evaluate individual
subject data for plausibility and
completeness"
"A sponsor's monitoring activities should
focus on these critical measurements and on
preventing important and likely sources of
error in their collection and reporting."
" . . . versus targeted or random review of
Lines: 279-280
Lines: 322-323
Lines: 353-355
Clinical Investigations: A Risk-Based Approach to Monitoring"
FDA Docket FDA-201 I-D-0597 November 28,2011, Page 5 of?
" . . . versus targeted or random review of certain data (less than 100%
We suggest deleting "considered during the risk assessment" so the
statement reads:
The phrase "considered during the risk assessment" is redundant per
lines 350 al1d 351: "A monitoring plan ordinarily should focus on the
critical data and processes identified by the risk assessment."
"A sponsor's Monitoring Plan should focus on these critical
measurements and on preventing important and likely sources of
error in their collection and reporting of study data."
We suggest editing the statement to read:
completeness. "
"Conduct aggregate statistical analyses of study data to Identify sites
that are outliers by evaluating the site data statistically relative to
others and to evaluate individual subject data for plausibility and
We suggest changing the statement to read:
"Verify CRF data from source data remotely, provided that both
source data and CRFs can be accessed remotely."
We suggest rewording the statement to read:
BIO Comments on "Oversight of
certain data (less than 100% data verification)
of monitorng activities wil depend to some
extent on a range of factors, considered
during the risk assessment, including the
following"
. .
"Verify source data remotely, provided that
both sourct data. . . "
Lines: 277
"Data management, clinical science, and other functions may be able
monitoring)" and "Monitor data quality
to facilitate this type of process working with a centralized
though routine review of submitted data in
real-time to identify missing data, inconsistent monitoring group."
data, data outliers, and potential protocol
deviations that may be indicative of systemic
and/or significant errors in data collection and
reporting at a site"
trends not easily detected by on-site
"Sites in geographic areas where there are
differences in standards of medical practice or
subject demographics or there is a less
established clinical trial infastructure may
require more intensive monitoring, including
some level of on-site monitoring."
"For example, if it is determined that an
investigator deviates significantly from other
sites in making safety-related findings or
other key safety metrics, the site should be
considered for targeted on-site visits. ..."
"Identification of possible deviations or
failures that would be critical to study
integrity and how these are to be recorded and
reported"
"The study monitoring plan should also
describe how various monitoring activities
wil be documented, regardless of whether
Lines: 375-377
Lines: 422-423
Lines: 427-428
Lines: 433-434
Clinical Investigations: A Risk-Based Approach to Monitoring"
FDA Docket FDA-201 I-D-0597 November 28,201 I, Page 6 of?
We suggest changing "centralized" to "centrally" so the statement
reads:
"Any site that has been identified to be collecting information that in
any way adversely affects the study integrity would need a full
evaluation. The results of this evaluation would need to be collated
and reported."
Ths is unclear. Would this include failures and/or errors? Please
provide clarification. We suggest adding the following text:
"For example. ifthe safety findings at a paricular site deviate
significantly from safety findings at other sites. a targeted on-site
monitoring visiIto the outlier site should be considered."
Investigators do not deviate from sites, but rather from other
to read:
investigators. We request the statement be edited
"Sites in geographic areas where there are differences in standards of
medical practice or subject demographics or there is a less established
clinical trial infrastructure may require more intensive monitoring,
including a greater level of on-site monitoring."
We request the statement be edited to read:
established... "
"Sites in geographic areas where there are differences in standards of
medical practice or subject demographics, or where there is a less
Please add "where" so the statement reads:
BIO Comments on "Oversight of
"Sites in geographic areas where there are
practice or
differences in standards of medical
subject demographics or there is a less
established... "
Lines: 375-377
monitoring activities wil depend to some extent
on a range of factors considered during the risk assessment, including
the following."
data verification) of
"Th. sty moorpla sh also descrihe how varios
We suggest th COER als neds a process to review an aprove
plaf aft a st is mi.rway.
We agree &a th sponsor neds spcific ways to ak a mooring
c~ed on-site or centrally."
mooriig activitie will he doimmed, regass of whethr
FDA Døket FDA-201 1-0-0597 November 28, 20,11, Page 7 of 7
RIO CaDts 00 "Oversight ofCliallnvestigatio: A Risk-Bad Approach to Monitorig"
up."
"Motag doumntio sh be providd to appropria
magement in a timly mar for review or. as necessaw follow-
follow.up. "
Pleas remove "as necessar" so the stam- read as follows:
.li marfo review or, as necessar,
Pfovid to apopat magement in a
Lil: Sl~Sll I "Moia domnma slid be
pla."
coul result in a change to th monitorg
identification of new risks to stuy integrity,
of signifian protocol deviaton, or
pcolol amndnt, chae in th deñiiti suh chges in an expedid ma.
uptes wftre necessa. For example, a
plan an estaish processes to perit timely
feqereview an revison of tl mog
Lines: 493-496 I "Spoors shoul conidr wha evens may
condæte OI-site or centalized."
Nancy Hutchinson, PhD
Head Drug Regulatory Affairs North America
l') NOVARTIS
Novarlis Pharmaceuticals Corporation
One Health Plaza
East Hanover. NJ 07936-1080
Tel 862-778- 5057
Fax 973-781- 3649
Email: nancy.hutchinson(inovartis.com
November 28, 2011
FDA Dockets Management Branch (HF A305)
Food & Drug Administration
5630Fishers Lane
Rockvile, MD 20852
Docket No. FDA-2011-D-0597: Draft Guidance for Industry on Oversight of Clinical Investigations:
A Risk-Based Approach to Monitoring
Dear Sir or Madam
Please find attached comments from Novartis Pharmaceuticals Corporation ("Novartis") on the
Food and Drug Administration (FDA) Draft Guidance for Industry on Oversight of Clinical
Investigations: A Risk-Based Approach to Monitoring.
Overall, Novartis fully supports and commends FDA on recognizing the value of alternative
monitoring approaches and proposing a risk-adapted Monitoring Plan to determine the intensity,
frequency and focus/scope of the monitoring activities, while ensuring patient protection, protocol
and regulatory adherence, as well as data accuracy ànd integrity. Novartis has implemented riskbased monitoring approaches, as appropriate, for its trials and finds this Draft Guidance important
and timely.
Novartis appreciates the opportunity to provide comments and respectfully requests that
consideration be given to our comments and recommendations.
Kind regards,
Nancy Hutchinson, PhD
Head Drug Regulatory Affairs
- North America
Attachment
Submission of
Comments For:
FDA Draft Guidance: Oversight of Clinical Trials - A Risk Based Approach to Monitoring
NovaHis Comments
Comments Submitted by: Novartis Pharmaceuticals Corporation
Proposed content (reg:ulation/g:uidance)
Specific
Section / Line #
Comments
I. Introduction
(Lines 21-24)
"This guidance is intended to make
clear that sponsors can use a variety of
approaches to fulfll tlieir
responsibilities related to monitoring
.
CPGMs"
and its compatibility with current
goals and purposes oftltis guidance
areas within FDA are aware of tIie
· "Will ensure that all affected program
described in this guidance
"Will ensure that tIie bioresearch
Sponsors that have already begun to employ alternative monitoring
monitoring compliance program
approaches often have questions raised during FDA inspections
guidance manuals (CPGMs) for
because these processes deviate from the "traditional" approach to
sponsors, CROs, and monitors (CPGM monitoring. Therefore, it would be helpful for the Guidance to outline
7348.810) andfor clinical
the additional changes and communications that wil be made by FDA
investigators and sponsorto ensure the FDA inspection program is in alignment with this the
investigators (CPGM 7348.811) are
final Guidance. Defining/committing to timeframes for implementing
compatible with tIie approaches
these additional changes and communications with respect to the
finalization of
the guidance would'help to faciltate more robust and
seamless implementation by sponsors and FDA.
of investigational new drug (IND) or
investigational device exemption (IDE)
studies. "
investigator conduct and the progress
It is suggested that the guidance be made applicable to any trial
submitted to FDA. The Guidance specifically makes reference to IND
and IDE clinical trials; however, there are many trals that are
performed at the request of FDA as post approval trials. These studies
are typically performed with a dose and patient population that is
consistent with the approved labeling and as per the IND regulations
would not meet the definition of investigational use of a drug, however
maybe submitted to the IND.
II. D. Steps FDA is
Taking to faciltate Wider
Use of Alternative
Monitoring Approaches
(Lines 176-181)
Page 1 of4
For:
prices" to coduct
dat verification (SDY) may dOt always be feaibl.
review of patient
sorce dat. Th sa
applicble for any signifcan revision to an existing rik baed
ìlorng procedre prior to the
Page
2 of4
"CDER intends to evaliiate potentil
øroesses throwh which SDOIISOlS could
Information
Monitrig. "
CDIt's Divion of BUJresearch
rih~r sibmi a pr-IDE, or contact
Study-Spefic
IV. D. 4. Training and
and
siilmswn oflhe mE applicaion ma
(see
and prospectively submit and
monitorg plan.
that a mechansm anor gUance include prvisions that allow tl
monitorig pmns base on a nsk bas approach, an reommeds
propsed alrnative
spnsor tò sltìt discuss an obtin feeck on detaled, procolspific risk ba moirorg plans. This prssshould also be
(Lines 182-184)
Monitoring Approaches
Use of Alternative
sposors to submit and obin the review of
wiin CDERfor spnsors to volunarily
receiv
feedbtck on propoed monitring plans
secon W-D.4). Sponsors "fIDE
sttu wihing i" solicit feedbak on tlldr
Taking to facilitate Wider
Novaris suppor the FDA prposa to esblish processes for
wO\ldalsobeir for the verfication of infored consent fOfs since
they ãlo contàipealt idntifable medical infonation.
primaly be foudduri th
Thus on-site monitorng may stil be reire in most instncs to
and idification, of any deviatis that. would
cofinn th accury,
re soue
to dee that th us of "ceizd monitorig
"Will consider esablishing,prtJesses
EDC systems "
tlces;1Jit of electoiiic records and
eltØY wil depen 10 some exent "n
clitrd monh"ring prties can be
niitorlng. The exent I" which
corresondingly less emhtlis on on-sil
However, reogrizig th prvacy issues related to acsing
electnic medical m:ord's tbat would be ne to be addressed to verify
may be ltlpful
patie S0 da agins th submitted infonation, it
IBftoring acivities al with reed on-sit moitong.
Novaris ags with th conce of grter relian on centrl
ß. D. Step FDA is
(Le 186-289)
Monitorig
been the cie hisoricaUy, with
"FDA encolUages greater reliance on
ce moning praces than htl
IV. A. 2. Celltrli
Comments Submitted by: Novarts Pharmaceuticals Corporation
FDA Draft Guidance: Oversight of Clinical Trials - A Risk Based Aproach to Monitoring
Submission of Comments
Page 3 of4
III. D. 4. Trainin2 and
(Lines 436-460)
"A monitorinf! Dian may reference
"3. Management of Noncompliance"
and
"2. Communication of Monitoring
Results"
IV. D. Monitoring Plan
(Line 420-421)
"Definitions of events orresults tliat
trigger clianges in planned monitoring
activities for a particular clinical
investigator. "
IV. D. 1. Description of
request feedback from the clinical trial
oversig/it component for the Center. "
Monitoring Approaches
(Lines 487-489)
voluntarily submit their monitoring plans
to the appropriate review division and
It is suggested that a statement be added denoting that if
the sponsor
Since many of
the components of
the monitoring plan
recommendations in these two sections are often addressed in
applicable Sponsor SOPs and written processes related to monitoring
activities, it may be helpful to denote that these recommended
components of
the monitoring plan can be addressed within individual
study monitoring plans or, more generally, in related sponsor SOPs or
other written general monitoring processes.
tolerance ranges or establishing acceptable variations has
not been addressed in this Guidance document. It is recommended that
tolerance ranges be established "per protocol" for trial procedures and
data (based on statistical components). These in tum would act as a
"trigger" to initiate increased monitoring activities. These Tolerance
ranges have been proposed by the EMA (Draft EMA Reflection Paper
on Risk Based Quality Management in Clinical Trials, dated 14 June
2011.
The use of
/
Comments Submitted by: Novartis Pharmaceuticals Corporation
FDA Draft Guidance: Oversight of Clinical Trials - A Risk Based Approach to Monitoring
Submission of Comments For:
Page
4 of4
(Line
.
.
.
.
completon"
actions and the anticipate daie of
including responsible for completing
betaken, and/or recommended
A description of any actions taken, to
i"egularitie, defICencies identified
The dlleof the activty and the
individual(s) conducting it
A summar of the daa or activities
reviewed
A d~scription of any noncompliance,
potential noncompliance, daia
V. Documenting
Monitoring Activities
501)
"Documentaton of monitoring actvities
should include the foUowing:
(Lines 482-485)
resolution). In.this
case, the sponsor shoul take appropriate
steps to ensure thllnwnitors, whether
spnsor or eRO employees, are aware of
and are trained on these policies and
procedures as well as on the m()nitorig
Dian."
issue invesatn and
exting policies and procedures (e.g., a
standard operatng procedure describing
Study Spefi
Information
monitonng activities are docU1ented in some form of monitoring
Also since FDA iispeOl" are required to review monitoring logs
during pre-approval inspections, the guidance should include a
recommedation that both on-sit monitonng and centrlized
infonatIón using validated syems.
which wiU ensure the data integrity and abilty to reteve the
log.
meet appropriate controls regarding access, back up and audit trails,
activities and follow up actions should be acceptble provided the
the "centrl" or "remote" monitoring metod, we recommend the
acknowledgement that th use of alternative electronic or automated
documentation metods; to demonstrate and document data review
focuse on the tyic "on-site" methods of monitonng. When using
The section. for documenting monitoring activities appears to be
agree to the adequacy of those procedures pnor to use
propes to use the eRO's procedures, the sponsor should reiew an
Comments Submitted by: Novartis Pharmaceuticals Corporation
FDA Draft Guidance: Oversight of Clinical Trials - A Risk Based Approach to Monitoring
Submission of Comments For:
in two sessions to discuss the Draft
Personnel from the Duke Clinical Research Institute (DCRI) met
Guidance for Industry: Oversight of Clinical
Investigations - A Risk-Based Appraach to Monitoring.
Comments of the 14 participants have been summarized below.
We support the FDA's efforts to encourage the clinical research industry to re-assess monitoring
practices so that resources are better allocated to meet the requirements of each specific triaL.
DCRI is proud of it broad experience with cost effective, targeted monitoring and respectfully submits
the following comments on the draft Guidance.
1) Assessing risk
There has been much buzz in the research community that the Guidance will be used only to reduce, not
to increase, the amount of monitoring for a study. We do not agree with this assessment: we believe the
Agency has clearly laid out an expectation for a comprehensive monitoring strategy that-while it may
reduce the time a monitor spends on-site-will increase the frequency at which issues are identified and
markedly improve both the time to resolution and the quality of the data from the site.
Some have remarked that FDA has lowered its expectations for monitoring to effect "cost savings" for
industry. We do not believe this to be true. While adopting a risk based approach to monitoring may
lead to cost savings, cost should not be a primary factor in the risk assessment procedure. Initially it may
be difficult for sponsors to have confidence that any monitoring plan based on a "new" approach will
comply with the expectations of FDA inspectors, and sponsors may resist stepping down from whats
perceived to be the "gold standard": on-site 100% source document verification. Alternatively, the
pendulum could swing too far, and a bare bones approach to monitoring-one based solely on a desire
to cut study costs-could become the vogue.
We believe contract research organizations can, and should, guide their sponsors through the process by
a documented risk assessment.
including risk based monitoring plans in project bids, supported by
Documentation of the risk assessment may never have been part of the overall project plan in the past,
but the draft guidance seems to encourage its development. The protocol remains the most important
project document, and it is from the protocol that the monitoring's plan initial risk assessment will be
drawn. However; the relationship between the two - the protocol and the monitoring plan - has
historically not been a documented piece of the overall project planning. Incorporating this logical
connection between the protocol and the monitoring plan as part of the initial project planning will be
an important step in ensuring that the adequacy of the monitoring plan and its compliance to the
Guidance.
2) Submitting monitoring plans to FDA for review
With all due respect, we do not believe that submitting monitoring plans for FDA review is a good way
to achieve compliance. We believe its rare that an FDA reviewer has experience as an inspector and,
therefore, able to recognize potential compliance pitfalls. Furthermore, the persons designing the
investigation and those responsible for its proper conduct should not rely on regulatory oversight as a
safety net for the propriety of their monitoring. If the sponsor or CRO is in doubt that the plan is
sufficient, they should re-think the plan, not just send it along to FDA and hope for the best. We are
loath to think that an inspector's finding that study monitoring was inadequate would be laid at a
reviewer's doorstep with the assertion, "But FDA approved our plan."
In any event, it see;ms unlikely that the FDA has the resources to spare for this additional workload. To
layer this additional responsibilty on the Agency is contrary to one of the objectives of the new
Guidance: the most beneficial allòcation of resources.
3) Monitoring for omissions or misconduct
Questions have arisen as to how centralized monitoring can uncover the non-reporting of safety data. In
a webinar presented by FDA on 24 October 2011, a presenter described using electronic data capture
(EDC) in real time to spot anomalies across sites as one of the best ways to uncover reporting omissions.
We agree and would go further: it is our experience that the training of monitors-whether those
monitors visit a site or contact the site remotely by phone or web conference tools-is key to detecting
errors of negligence or those that raise suspicions of malfeasance. For those who do not have an EDC
system, one is not required: centralized monitoring can be accomplished with adequately trained
personneL. It should be emphasized that training includes development of what are termed "soft skills";
those interaction skills that as face time with sites decreases, wil help monitors establish and maintain
the most productive working relationship with sites.
In addition, the notion of "breaking down silos" raised by the FDA in its October 2011 webinar is
important here. Biostaticians or data managers may be the first to detect trends, aberrations, and
outliers. Good and open communication among all the members of a project team is fundamental. The
adoption of the concept of risk based monitoring will provide the opportunity for sponsors and eROs to
review their internal operating procedures and look for ways to modify other areasto make them risk
appropriate.
4) IRBs
Neither the
Guidance document itself nor the FDA's October 2011 webinar addressed the role of the
Institutional Review Board (IRB) in a risk-based monitoring approach. A study site's IRB is on the front
line of human subject protection. The experience of the site's IRB, its resources and how they are
allocated to the study are all factors that should be included in a risk assessment procedure for a site
and for the study overalL.
In addition, if source documents are to be scanned or photocopied to be sent off-site for monitoring,
this activity must be approved by the site's IRB and the site's privacy officer and disclosed in the
informed consent document.
5) Relevance to small studies
Establishing and carrying out a monitoring plan that utilizes different modalities -i.e., centralized
monitoring and on-site visits, live training and remote training resources - is common practice for
"mega" trials, which enroll thousands of subjects at hundreds of sites. Adapting these procedures to
smaller trials can present more of a challenge, particularly when there may be technological challenges
on either (or both) the site and sponsor side. We believe that the final Guidance should address this
issue by emphasizing that monitoring plans are fluid documents, expected to be amended as needed.
Smaller sites will certainly require closer, "customer service" oriented monitoring at the outset. It is our
policy to establish good relations with our sites initially, having found that this ultimately saves time and
money over the course of the triaL. The intensity or tenor of the initial monitoring need may change as
the trial progresses: it may become more focused, it may become less frequent, it may result in more
on-site training sessions. Regardless of how the monitoring changes over the course of a study, we urge
the Agency's assurance that it will not to ascribe the change to initial error or fault.
6) Paper records
A question was raised in the October 2011 webinar concerning sites or sponsors that do not have the
advanced technological resources that larger entities enjoy. The concern was that limited technology
would impair or preclude the ability to adapt monitoring beyond the customary on-site reviews. We
have conducted studies, even large trials, relying on paper records rather than EDC. It is our experience
you can successfully conduct remote monitoring of a site that has solely paper records; however,
sites often propose that they receive added payments to compensate for additional time and resources
spent making copies or scans of study documents, such as IRS approvals, for the purposes of remote
monitoring. Perhaps this is the only point at which cost considerations should playa role in determining
the parameters of the monitoring plan: the project team should take a hard look at what must be
photocopied or scanned. As an FDA commentator noted in the October 2011 webinar, it is common to
that
collect
more information
than is actually needed for a study. Copying every document and record at a
site is counterproductive to focusing monitoring on critical items based on a documented risk
assessment. Establishing the remote monitoring piece for sites that utilize paper files may be a good
way for the sponsor to evaluate not only its monitoring plan but its recordkeeping policies overalL. In any
event, just because a site is using paper files does not mean that every piece of paper they collect or
generate should be copied and sent to a remote monitor. If a site balks at the requirements to enable
remote monitoring, the site's reasons should be explored objectively and with an eye to mutual
education and collaboration in problem-solving.
7) The monitor as trainer/educator/mentor
Frequent communication with a site-Le., at time intervals less than the
6-8 week span between
customary visits to sites-gives in-house monitors the opportunity to assess how well site personnel
understand the protocol and study procedures, and to offer guidance and training, as needed. The
combination of centralized monitoring and study visits that are focused on review of critical variables
will increase confidence in the accuracy and completeness of the data.
Some have expressed concern that sponsors will reject research naïve sites in favor of experienced sites
that are more easily monitored remotely. On the contrary, an experienced in-house monitor build a
reiàtionship with and mentor site personnel to ensure that increasingly more sites are capable of
conducting clinical research.
November 28, 2011
U.s. Deparment of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Center for Devices and Radiological Health (CDRH)
Docket No. F1A-20ii-~597
Draft Guidance for Industry on Oversight of Clinical Investigations: A Risk-Based
Approach. to Monitoring
Dear Ms. Meeker-O'Connell:
The Association of Clinical Research Organizations (ACRO) represents the world's leading
clinical research organizations (CROs). Our member companies provide a wide range of
specialized services across the entire spectrm of development for new drugs, biologics and
medical devices, from pre-clinical, proof of concept and first-in-man studies through postapproval and pharacovigilance research. With more than 70,000 employees engaged in
research activities around the world, ACRO advances clinical outsourcing to improve the quality,
efficiency and safety of biomedical research.
AeRO applauds the issuance of the above-titled Draft Guidance, which is meant to allow study
sponsors and their representatives to develop risk-based monitoring strategies and plans for
investigational studies of medical products, using a "modem, risk-based approach that focuses on
critical study parameters and relies on a combination of monitoring activities to oversee a study
effectively." ACRO member companies have long supported the idea that risk-based monitoring,
if appropriately supported by robust operating procedures and best practices, meets the FDA and
ICH GCP requirement of "adequate monitoring" and we agree that effective implementation of
appropriate risk-based monitoring strategies and plans has the potential to result in more effective
oversight of complex, modem trials.
ACRO appreciates the opportunity to offer the following comments.
Section II. Background
At lines 62-64 the Draft Guidance states that, "Quality is a systems property that must be built
into an enterprise and cannot be achieved by oversight or monitoring alone." While ACRO
agrees with this principle, and with the corollary statement that in the realm of clinical research
quality begins with a well-designed and executed protocol, we believe that in regard to
monitoring per se the appropriate focus of quality management activities should be on human
subject protection and the quality and
integrity of research data. A wide range of activities may
lead in the direction of research that is less costly or more efficient or faster, but the goal of
915 15h Street, NW, 2nd Floor, Washington, DC 20005
T 202 4649340 E infoc¡acrohealth.org www.acrohealth.org
AeRO
ASSOCIATION OF CLINICAL RESEARCH ORGANIZATIONS
At lines 197-198, the Draft Guidance indicates that the complete absence of on-site monitoring
wil
likely continue to be unusual, consistent with ICH E6. ACRO agrees that there wil continue
to be value in some level of "trggered" on-site monitoring. However, the degree to which
triggered monitoring is employed wil depend on the clinical tral design. While some trals,
such as interventional studies, may require little on-site monitoring, other clinical trals may more
typically require on site review of data collection and entry, investigator supervision, site
compliance, critical data review, investigational product management and suitability of the
research facilty. Thus, appropriate planning for site visit triggers wil be a
key element of risk
reduction. Design elements such as predictive algorithms and historical data can be used to predetermine a schedule of monitoring site visits and predict an expected work volume and
resourcing needs. As data is obtained and centrally monitored for sites on an on-going basis, the
schedule of visits and other monitoring activities can be adjusted and anin-person monitoring
visit may be triggered to occur sooner or later than the pre-determned schedule.
Section III. Factors that Influence Study Quality and Integrity
In line 221 at footnote 28, the Draft Guidance encourages sponsors to seek consultation with the
appropriate review division regarding quality aspects of clinical tral design. While we are
mindful that the FDA's resources are limited, AeRO suggests that
prospective review of
the
proposed monitoring plan by the appropriate Agency division would
significantly advance the
transition from current outmoded, retrospective practices to alternative monitoring approaches
that more efficiently focus on patient safety and data integrity.
accelerate a transition to risk-based
monitoring approaches, would be to issue an Addendum to the Draft Guidance that includes Use
Cases to ilustrate a "modern, risk-based approach that focuses on critical
study parameters and
relies
on a combination of
monitoring,
activities to oversee a study effectively" across studies of.
varying size, therapeutic areas, design complexities, etc.
A second way that,the Agency could faciltate and
Section
iv. General Monitòring Recommendations
on-site
risks and potential
site non-compliance at an early stage of the study. We encourage the FDA to provide further
guidance regarding the critical activities of site selection and site initiation.
AeRO agrees with
the guidance provided in lines 248-254, regarding
assessment of site-critical study data
and
processes and
the utilty of
evaluating significant
be accomplished when
At lines 277-278, the Draft Guidance suggests that remote monitoring can
source data can.be verified remotely, provided that both source data andCRFs can be accessed
remotely. While we appreciate this encouragement for remote monitoring of electronic data, we
do have some concerns that such a straightforward. model of the relationships between and
aiong sponsor, CRO, study site, and data seldom exist in today's world. It is not at all
uncommon for one CRO to be charged with site monitoring while another does data storage and
a third performs data
analyses; simply, to say that one participant has remote access to electronic
data does not mean that all paricipants do.
3
AeRO
ASSOCIATION OF CLINICAL RESEARCH ORGANIZATIONS
At lines 299-308, the Draft Guidance mentions, but does not provide detail on, the issues of
prospective quality planning and upfront site risk assessment. In its similar draft reflection paper
(Reflection Paper on Risk-Based Quality Management in Clinical Trials), the European
Medicines Agency (EMA) notes that risks might be anticipated especially at the intedaces of
quality systems or the points of movement of information/data across systems. ACRO believes it
would be useful for the FDA to elaborate further on differing methods that might be used to
assess risk at both the site and system intedace levels.
At lines 322-327, the Draft Guidance mentions that the sponsor's risk assessment "should
consider the impact and likelihood of error, and the extent to which error would be detectable, for
identified data and processes." Perhaps the biggest issue with centralized monitoring is in the
identification of what it is important to know (what are the greatest risks?) as well as the level of
risk in being uncertain about what you don't know. Referrng again to the EMA's Draft
Reflection Paper, it would be helpful if the FDA would further discuss methodologies for
establishing the acceptable varation or tolerance limits for particular clinical trial procedures.
At line 417, the Draft Guidance suggests that the description of monitoring approaches would
include criteria for determining the timing, frequency, and intensity of planned monitoring
activities. Again, ACRO thinks it would be helpful if the Draft Guidance would provide
examples of such criteria across commonly conducted phase II-III trals (e.g. cardiovascular,
diabetes, oncology, central nervous system).
Conclusion
ACRO thanks the FDA for issuing this Draft Guidance, and we appreciate the opportunity to
provide these comments. We believe that this Draft Guidance wil help define and provide
encouragement for alternative monitoring models that leverage centralized monitoring as a more
efficient and effecthre resource as par of the overall monitoring plan. Having several times
referenced the EMA Draft Reflection Paper, ACRO encourages the Agency to consider how it
may work with European regulators to standardize the concepts of risk-based monitoring
approaches put forth in order to ensure haronization of approaches used in running global
clinical trials.
Please feel free to contact ACRO at any time for additional input.
Respectfully submitted,
ll1~
Douglas Peddicord, Ph.D.
Executive Director
4
AeRO
ASSOCIATION OF CLINICAL RESEARCH ORGANIZATIONS
invivodata Response
Investigations - A Risk-Based Approach to Monitoring
Lines 156-158
General
General
that some ePRO data collection systems track patient and site
behavior in such a way that they can help to detect fraud or
anomalies such as fraud or fabrication of data. invivodata suggests
FDA refers to centralized monitoring helping to detect data
triaL.
track patient and investigative site activities, that FDA more clearly
specifies the types of non-compliance that may occur in a clinical
In a number Of places in the draft Guidance FDA refers to 'noncompliance.' It is presumed that this refers to non-compliance of
the investigative site with the investigation plan. However, non- .
compliance can also occur by patients, possibly based upon
inappropriate training by the investigative site. It is recommended
that in this context, where centralized monitoring may be used to
term EDC, or preferably that FDA consider the use of the term
eClinical systems.
specifies the range of technology enabled systems covered by the
While such systems are central to clinical trials, they represent only
one potential venue for collecting electronic data. Other examples
include electronic patient report outcomes (ePRO); clinical data
managernent systems (CDMS); clinical trial management systems
(CTMS); etc. invivodata recommends that FDA either more clearly
the context of clinical trials. However, it is the observation of
invivodata that EDC is synonymous with electronic CRF systems.
by technology, It is clear from FDA's current thinking that such
rocesses may enhance
patient safety and data integrity.
FDA uses the acronym 'EDC' for electronic data capture throughout
the draft Guidance. It appears that FDA is referring generically to
any technology enabled system that captures ahy type of data in
centralized monitoring procedures, especially those that are enabled
invivodata commends FDA for encouraging industry to consider
Please find below a table of the responses to sections of the draft Monitoring Guidance.
invivodata is pleased to have the opportunity to respond to the FDA Draft "Guidance for Industry: Oversight of Clinical
Investigations - A Risk-Based Approach to Monitoring" (referred to here as the 'draft Monitoring Guidance').
FDA Draft Guidance: Oversight of Clinical
that can
execute screening calculations, which in turn ensures that only
subjects that meet the screening criteria are enrolled in the study.
technology enabled screening systems already exist
FDA states that "adherence to protocol eligibility criteria intended to
include only subjects from the targeted study population..." is
subject to more intensive monitoring. invivodata notes that
fraud through central monitoring and/or analytic processes.
Lines 279-280
Lines 274-276
Lines 271-273
Lines 268-270
..
statistical analyses to identify data trends not easily detected by onsite monitoring)"
"Monitor data quality through routine review of submitted data in
real-time to identify missing data, inconsistent data, data outliers,
and potential protocol deviations that may be indicative of systemic
and/or significant errors in data collection and reporting at a site"
"Conduct aggregate statistical analyses of study data to identify
sites that are outliers relative to others and to evaluate individual
subject data for plausibility and completeness"
that can only be accomplished using centralized processes (e.g.,
consistency, and completeness of data and checks for unusual
distribution of data within and between study sites, such as too
little variance)31"
"Target on-site monitoring by identifying higher risk clinical sites
(e.g., sites with data anomalies or a higher frequency of errors,
rotocol violations, or dropouts relative to other sites)"
"Augment on-site monitoring by performing monitoring activities
done as well or better remotely (e.g., standard checks of range,
"Replace on-site monitoring for monitoring activities that can be
specific sections of the draft Monitoring Guidance are noted:
monitoring tasks, and therefore support invivodata's recommendation to broaden the terminology, the following
In order to provide specific examples where "EDC systems" would include ePRO systems that perform appropriate
Line 335-336
fabrication of data. It is suggested that FDA consider indicating
that data collections systems may already assist for detecting such
Lines 363-366
on-site visits to assess the totality of subject records and to review
application of protocol definitions with the clinical investigator."
trial sites with characteristics correlated with poor performance or
noncompliance"
"Endpoints that are more interpretative or subjective may require
"Conduct analyses of site characteristics, performance metrics
(e.g., high screen failure rates, high frequency of eligibility
violations, and delays in reporting data), and clinical data to identify
ATII BIOLOGICS'.
ADVANCING SCIENCE, SAFETY & INNOVATION
November 17,2011
Division of Dockets Management (HFA-305)
Food & Drug Administration
5630 Fishers Lane
Room 1061
Rockvile, MD 20852.
Submitted electronically to http://ww.regulations.gov
Re: Docket FDA-2011-D-0597
Draft Guidance for Industry on Oversight of Clinical Investigations: A Risk-Based
Approach to Monitoring
Dear FDA,
This letter represents the views of RTI Biologics, Inc. (RTI) concerning FOA's request for
comment on the draft Guidance for Industry, Oversight of Clinical Investigations: A Risk-Based
Approach to Monitoring. RTI is the leading provider of sterile biological implants for surgeries
around the world with a commitment to advancing science, safety and innovation. RTI prepares
human donated tissue and xenograft tissue for use in orthopedic, dental, hernia and other
specialty surgeries. We appreciate the opportunity to respond to FDA's request for input. Please
see the following pages for our comments.
Respectfully Submitted,
Robin Waite
Director Clinical Projects
RTI Biologics, Inc.
11621 Research Circle. Alachua, FL 32615
Tel 386.418.8888 . 877.343.6832.. Fax 386.418.0342' Customer Service 800.624.7238. www.rtix.cofT
RTII BIOLOGICS'"
ADVANCING SCIENCE, SAFETY & INNOVATION
Balancing On-Site and Centralized Monitoring in the Monitoring Plan
We appreciate FDA acknowledging that industry has the perception that the frequent on-site
monitoring visit model, with 100% verification of all data, is FDA's preferred way for sponsors to
meet their monitoring obligations (lines 96-99). We also appreciate FDA recognizing that it is
important for the Agency to clearly articulate your recognition of the value of alternative
approaches to faciltate change in industry's monitoring practices (lines 148-149). This
guidance has much practical insight which appears to be based, at least in part, on FDA's
experience (lines 216-220). It would be very helpful if FDA could provide some case study
examples of monitoring plans, to step the reader through an example risk assessment process,
taking into consideration the relevant factors when developing a monitoring plan, and
articulating these decision points in the monitoring plan itself.
11621 Research Circle. Alachua, FL 32615
Tel 386.418.8888 . 877.343.6832 . Fax 386.418.0342. Customer Service 800.624.7238. www.rtix.colT
Triangle PEERS
Research Triangle Park
North Carolina
22 November 2011
Dockets Management Branch (HFA-305)
Food and Drug Administration
5630 Fishers Lane, rm. 1061
Rockvile, MD 20852
Re: Docket No. FDA- 2011-D-0597
To Whom It May Concern:
Triangle PEERS is pleased to submit comments on the FDA Draft Guidance for
Industry: Oversight of Clinical
Investigations - A Risk-Based Approach to Monitoring.
Triangle PEERS ( Part Eleven & Electronic Records Stakeholders) is an association
based in Research Triangle Park, North Carolina, whose membership represents over
forty organizations, including pharmaceutical companies, clinical research
organizations, academic research organizations, validation and IT systems consultants,
and technology vendors. PEERS members possess expertise in a variety of
perspectives such as technology, process engineering, qualiy assurance, regulatory
affairs, data collection and management, legal, and data security. PEERS members
focus primarily on the practical implementation of regulations, guidance and standards
pertaining to electronic records, including 21 CFR Part 11, particularly as this applies to
Good Clinical Practices (GCPs) in the conduct of clinical trials.
PEERS applauds the Agency for its wilingness to recognize a variety of approaches to
monitoring clinical sites and to consider risk assessment as a key component of
determining monitoring methodology. PEERS appreciates the Agency's flexibilty in
allowing technology to enhance the effectiveness of clinical monitoring. PEERS
recommends, however, that the Agency emphasize that risk-based monitoring
Page 1 of7
methodologies should be implemented with care and, in particular, that remote
monitoring should enhance or complement but not necessarily replace on-site
monitoring,. The Guidance, when finalized, should clarify that risk-based monitoring
does not suggest any less vigilance in clinical monitoring. To that end, PEERs
recommends that the risk-based approach to clinical monitoring be clearly documented
and justify how alternative monitoring methodologies wil adequately protect patient
safety, data integrity, and product quality.
PEERS also agrees with the Agency in line 203 that clinical monitoring should be one
part of an overall quality management system and recommends that the Agency
emphasize this aspect more or add cross-references to other available resources and
industry Guidance on the topic of quality management systems.
global trials, with clinical investigational sites
located in several different countries. The appendix to the European Medicines Agency
draft "Reflection paper on risk based qualiy management in clinical trials" (04 August
2011) addresses privacy concerns related to remote access to site/study records and
controls to consider. For harmonization of a global clinical trial, PEERS requests that
FDA address privacy with respect to considerations of other global regulatory agencies
and data protection authorities in terms of balancing of the interests, namely safety and
data integrity with privacy standards.
Increasingly, this industry is conducting
The specific comments of PEERS follow, organized sequentially by the sections and
lines of the draft Guidance.
Lines
Comment
Section II.A.
PEERS recommends that the Agency delete Section II.A.
altogether. Instead,the surveys and white papers cited could
Lines 93-11 0
be referenced in a new Section VII as additional resources. If
the Agency elects to retain Section II.A., lines 93 -110 in
particular should be clarified; lines 93-110 may be misconstrued
as standards for monitoring frequency. Instead, lines 93-110
should be used as illustrative examples with the caution that
monitoring frequency should be based on such factors as type
of study, patient safety considerations, subject enrollment time
frame, and critical assessments.
Section 11.8.
PEERS recommends that the Agency give examples of when
reliance entirely on centralized monitoring would be appropriate.
Further, what kind of technical processes would be expected to
Lines 125-127
Page 2 of?
be in place?
Section fI.C.
Lines 144-166
PEERS recommends that the Agency clarify what types of
centralized monitoring are alluded to in this draft Guidance. For
example, is this a reference principally to electronic centralized
monitoring based on electronic data capture, or does this also
include more traditional monitoring means, such as reviewing
paper document, spread sheets, and queries?
Additionally, an elaboration on acceptable processes and
technical measures of centralized monitoring would also be
helpfuL.
Section II.C.
Lines 156-158
PEERS agrees that data anomalies can more effectively be
assessed, and outliers become more obvious, as long at timely
data from the sites is available. Remote access to data also
makes it easier to more quickly determine whether a site is
data collection,
following the protocol in terms of both timing and
or whether the clinical site may need additional education.
However,it should be noted that this abilty to review the data
implies a dependency on implementation of an electroriic data
capture (EDC) system. Traditional data entry of paper case
timely enough to catch issues early.
report forms will not be
Section II.C.
Lines 163-166
.
PEERS recommends moving this important sentence into the
Introduction (Section I) of the Guidance since it is a key
concept: 'IThis guidance is therefore intended to clarify that riskbased monitoring, including the appropriate use of centralized
monitoring and technological advances (e.g., e-mail, webcasts,
and online training modules) can meet statutory and regulatory
requirements under appropriate circumstances." PEERS also
recommends that the examples be broadened to include
videoconferencing, Skype for real-time interviews and meetings
with study site staff.
Section IV.A
Lines 231-295
Although this Section distinguishes the differences in types of
monitoring, the content should be expanded to emphasize that
centralized monitoring really is sJ.. monitoring, and possibly
checking on accuracy of subject inclusion/exclusion at sites.
The Section should also clarify that there are some activities
(e.g., verification of accurate drug storage, potential sharing of
passwords) that, without further technological advancements,
may be diffcult to determine remotely and that relying on one,
Page 3 of?
or very few, on-site monitoring visit(s) could raise concerns.. For
example:
.
In the case that there is no access to electronic source
documentation and subject charts, verification of
exclusion/inclusion criteria and detection of adverse events
and other safety issues may be difficult without on-site
monitoring visits.
. Assessing study drug accountability may also be difficult in
many cases remotely.
. Verification that products are properly stored and secured as
per Good Manufacturing Practice or protocol requirements
would be difficult, as would verify some instrument
calibrations.
. Assuring that subject and study records are properly secured
would be a challenge remotely.
.
Evaluating the informed consent process may also pose
some problems, especially when there is no access to
electronic clinical management systems.
.. There is also the aspect of human nature which causes many
individuals, including Principal Investigators and site study
staff, to conduct themselves in a more appropriate manner if
they perceive that they are being directly observed. The
clinical site monitor can also get a better understanding of the
dynamics and relationships among site study staff.
.
There is an element of human relationships and trust
between the clinical site monitor and site study staff that
cannot be fostered and developed as successfully without
some face- to- face interactions. On-site monitoring visits may
foster an awareness of compliance issues, and a willingness
report evidence of potential
to discuss concerns or
misconduct that may not be as readily achieved with
centralized monitoring.
Section IV.A.1
Lines 240-241
PEERS recommends revising the definition of on-site
monitoring: "On-site monitoring is an in-person evaluation
gldriQQlbef#Qyr~!¡tQt tbe§iYQ¥ carried out by sponsor personnel
or representative(s) during the course of the study at the site(s)
at which the clinical investigation is being conducted. .(Additions
Page 4 of?
underlined for ease of identification.)
SectionIV.A.1.
Lines 249-251
PEERS recommends revising the language to read as follows:
"Therefore, on-site monitoring ordinarily should be devoted to
assessing the critical study data and processes and evaluating
significant risks and potential site non-compliance, iOQ!ygiOQ
diltslilOQOJslliesQ( riatieO! §Sl!W'iQt Qlber 9Yâli!¥QQIJ,,~ros,
identified through other sponsor oversight activities." (Additions
underlined for ease of identification.)
Section IV.A.2.
Lines 268-270
SectionIV.A.2.
Lines 277 -278
PEERS recommends adding unusually high rates of enrollment
at a site as another factor for identifying higher risk clinical sites.
The draft Guidance notes that source data verification can also
occur remotely, provided the electronic source data and the
collected trial data (case report forms) can be accessed
remotely. It should be noted that accessing electronic source at
a clinical site or institution may not be that feasible, as some
institutions wil have data privacy concerns, potentially
incompatible network protections in place, and administration of
use accounts may be problematic. Also, electronic source
systems, such as electronic health records (EHR) systems need
to be set up to segregate subject- specific files with remote
access in order to facilitate remote source data verification.
PEERS recommends that the Agency reiterate that to trust the
electronic source there must be an appropriate level of
verification or validation of the electronic source system.
Section IV.A.2.
Lines 286-287
Section IV.C.
PEERS understands that industry has been looking
to the
Agency for encouragement in the use of risk-based monitoring
approaches. It is also recognized that focusing limited
resources on high risk sites can actually increase patient safety.
PEERS recommends that the Agency reinforce the concept of
documenting the study and site risks and linking those directly
to criteria for when on-site monitoring visits will or will not occur.
Lines 348 - 401
PEERS agrees with the factors noted playing into whether to
conduct on-site monitoring. PEERS suggests that an additional
factor of past experience of a less than positive nature with an
investigator may also be a reason to conduct on-site monitoring.
Section IV.C.
PEERS agrees that additional monitoring should be undertaken
Page 50f7
in vulnerable populations, but recommends that it should be
clarified that the criteria for classification of vulnerable
populations can encompass aspects other than health risks,
and include issues such as coercion or social, privacy and/or
Lines 371-373
legal risks.
Section IV.D.
Lines 403-496
.
Section IV.D.2
Lines 436-447
Section IV.D.3
Lines 449 - 460
Section IV.D.4.
Lines 462-489
PEERS agrees that it is advisable to create a monitoring plan,
to proactively define the approach to be taken and the rationale,
to avoid the appearance of monitoring visits being solely based
on cost and timing factors once a trial begins. PEERS
recommends also that metrics be defined to access the
effectiveness of the monitoring plan and that a backup plan be
documented in the event the monitoring plan is determined not
to be effective. The monitoring plan should also include criteria
for triggering on-site monitoring visits when centralized
monitoring is utilized more heavily. There should also be
predefined triggers that would lead to revision of the
documented monitoring plan.
PEERS agrees with the Agency with the emphasis on timely
reporting from monitoring visits, in order to identify and respond
to issues in a timely manner, and mitigate further risks.
PEERS strongly agrees with the Agency that clear procedures
are necessary to address site non-compliance in a consistent
and prompt manner. Identifying the root cause for issues is a
critical activity to ensure that corrective action truly addresses
the problem, and that adequate preventive action can be
implemented to prevent recurrence.
PEERS recommends that training also include any computer
systems that wil be used to analyze data, including for outliers;
potential noncompliance. This training would extend not only to
the EDC system, but also to potential analysis softare, and
EHR systems at the clinical sites, if electronic source will be
accessed.
In situations of centralized, remote monitoring, PEERS
recommends that training also include enhanced subject
protection and ethics training.
Section VI.B
Lines 539-545
PEERS recommends that there be procedures in place for
timely reporting between the Contract Research Organization
(CRO) and sponsor regarding site issues that are identified via
Page 6 of?
monitoring conducted by the CRO. The procedures should also
identify responsibility for site issue resolution and escalation,
including how communications will be handled.
New Section ViI.
PEERS recommends that the Agency include a new Section VII
to list additional resources and references. PEERS
recommends deleting Section II.A. Current Monitoring Practices
altogether from the Guidance and retain this information and
foot notes as references within the new Section VII.
.
In closing, Triangle PEERS appreciates the opportunity to comment on the draft FDA
Guidance for Industry, Oversight of Clinical
Investigations - A Risk-Based Approach to
Monitoring.
Sincerely,
Triangle PEERS
Research Triangle Park
North Carolina
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