Comment Biotechnology Ind Appendix A 8-26-13

APPENDIX A

FDASIA Modernization and Expansion of Accelerated Approval
Key Statutory Changes, Legal Interpretation, and Implementation

June 2013

I.

BACKGROUND AND INTRODUCTION:

On July 9th, 2012, President Barack Obama signed the Food and Drug Administration Safety and
Innovation Act of 2012 (FDASIA, P.L 112-144) into law. In addition to reauthorizing FDA’s
user fee programs, the legislation made significant reforms to help speed the development and
availability of innovative new therapies. This includes a modernization and expansion of FDA’s
existing Accelerated Approval pathway.
First implemented via regulation in 1992 and partially codified in 1997, the Accelerated
Approval pathway can facilitate earlier approval of drugs to treat serious and life-threatening
diseases or conditions on the basis of the determination that the product has an effect on a
surrogate that is reasonably likely to predict a clinical benefit or clinical endpoints other than
mortality or irreversible morbidity that can be measured earlier in drug development and
reasonably likely to predict a clinical benefit. This is followed by post-marketing clinical trials
to verify the anticipated clinical benefit. Accelerated Approval can considerably shorten the time
from discovery to FDA approval and provide patients with important medical needs with earlier
access to new medicines.
While the legal scope of the Accelerated Approval pathway may include any serious or lifethreatening disease with an appropriate regulatory surrogate or clinical endpoint, in practice the
pathway has been largely used for approval of HIV/AIDS and oncology therapies. However,
modern drug development has changed substantially since 1992 and Congress sought to expand
the program to additional diseases and to better leverage recent scientific advancements. For
example, the Congressional findings included in FDASIA provide a detailed description of what
Congress intends to achieve by expanding Accelerated Approval, and what it expects FDA to
accomplish when applying these expanded authorities:
“FDA should be encouraged to implement more broadly, effective
processes for the expedited development and review of innovative new
medicines intended to address unmet medical needs for serious or lifethreatening diseases or conditions, including those for rare diseases or
conditions, using a broad range of surrogate or clinical endpoints and
modern scientific tools earlier in the drug development cycle when
appropriate. This may result in shorter clinical trials for the intended
patient population or targeted subpopulation without compromising or
altering the high standards of the FDA for approval of drugs.”
Given the general similarities between the FDASIA statutory amendments and the existing
regulations governing FDA’s Accelerated Approval [21 CFR 314.50 (Subpart H) and 21 CFR
601.41 (Subpart E)], some observers have suggested that FDASIA only codifies FDA’s existing
authorities and makes little practical change to how FDA interprets and applies the pathway.
However, the intent under these reforms was to apply these authorities more broadly in
additional areas beyond just HIV/AIDS and oncology by providing FDA and Sponsors with
greater clarity and flexibility to rely upon additional types of data and trial endpoints. Seemingly
minor or editorial changes to the underlying statute were in fact deliberate and intentional, and
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carry meaning in how Congress expects FDA to implement the pathway. Each change carries
significance and should be evaluated as part of the Agency’s implementation of FDASIA.
Taken in total and in full context, these changes represent a significant paradigm shift in how the
Agency should more broadly and innovatively apply the Accelerated Approval pathway to
encourage the expedited development and approval of the next generation of modern therapies
for serious and life-threatening diseases intended to address important medical needs. This
paper reviews the legal considerations regarding the Congressional intent of specific edits to the
underlying statute and issues for FDA implementation.

II.

STATUTORY CONSIDERATIONS

The following sections 1) address each specific amendment made to Section 506 of the Food
Drug and Cosmetic Act related to Fast Track Products, 2) highlight specific red-line amendments
to the statute, and 3) discuss the interpretation and implementation considerations related to each.
A. Designation of a Combination of One or More Drugs:

“(b) Designation of Drug as a Fast Track Product. —
(1) In General. — The Secretary shall, at the request of the sponsor of a new drug, facilitate the
development and expedite the review of such drug if it is intended, whether alone or in
combination with one or more other drugs, for the treatment of a serious or life-threatening
condition, and it demonstrates the potential to address unmet medical needs for such a disease or
condition, or if the Secretary designates the drug as a qualified infectious disease product under
section 505E(d). (In this section, such a drug is referred to as a “fast track product”.)”

Interpretation:
This provision clarifies that a drug used in conjunction with another new or existing drug or
biologic is eligible for fast track designation and consideration under the Accelerated Approval
pathway.
Implementation:
Within 12 months of enactment, FDA is required to publish draft guidance addressing
implementation of the Fast Track and Accelerated Approval provisions. FDA’s current
Guidance for Industry: Fast Track Development Programs (2006) identifies criteria for a serious
or life-threatening condition, as well as the demonstration of unmet medical need. FDA should
include in the guidance how a combination of two or more drugs will be evaluated under the
expanded Accelerated Approval statutory language. This should include the various scenarios
regarding such combinations of drugs (e.g., if one of the products is already approved or if both
products are novel), as well as designation of infectious disease products.
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B. Clarification and Distinction Between Fast Track Designation and the Accelerated
Approval Pathway

“(c) Accelerated Approval of a Drug for a Serious or Life-Threatening Disease or
Condition, Including Application for a Fast Track Product. — “

Interpretation:
Prior to enactment of FDASIA, FDA regulations addressed “Accelerated Approval of New
Drugs for a Serious or Life-Threatening Condition,” but statutory language did not exist
authorizing an Accelerated Approval pathway per se, separate and apart from the Fast Track
designation. FDASIA now codifies that the Accelerated Approval pathway for products for
serious or life-threatening diseases or conditions is separate, regardless of whether there is
designation as Fast Track. FDASIA provides both Sponsors and FDA with greater flexibility
and statutory support in the application of the Accelerated Approval pathway.
Implementation:
Within 12 months of enactment of FDASIA, the FDA is required to publish draft guidance
addressing implementation; accordingly, the 2006 Guidance should be updated for consistency
with the new law, and FDA’s Accelerated Approval regulations, 21 C.F.R. 314.500 (drugs) and
21 C.F.R. 601.40 (biologics) should also be updated to conform with these FDASIA
requirements, as detailed below.

C. Serious or Life-Threatening Disease or Condition

“(1) In General. —
(A) Accelerated Approval. — The Secretary may approve an application for approval of a
product for a serious or life-threatening disease or condition, including a fast track product, under
section 505(c) or section 351(a) of the Public Health Service Act…

Interpretation:
The language reinforces FDA’s authority to grant Accelerated Approval of a drug for a serious
or life-threatening disease or condition, regardless of whether the drug meets the eligibility
criteria for, or the Sponsor seeks designation of it as, a “fast track” product. Notably, there is no
longer any explicit “unmet medical need” criterion to be eligible for Accelerated Approval.
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Rather, the availability of alternative therapies is a factor - but not a requirement - balanced
along with other factors such as the severity, rarity, or prevalence of the condition that the
Agency shall consider when determining whether to grant Accelerated Approval in a particular
case (see discussion below). Accordingly, the Accelerated Approval statutory language under
FDASIA is now broader and provides the Agency and Sponsors with greater flexibility in
utilizing this amended pathway. For example, this provision provides additional clinical options
in certain circumstances (consistent with accepted medical practices and ethics) to study a
therapy earlier in the disease progression rather than waiting until patients have already
progressed through all other alternative therapies in order to demonstrate head-to-head clinical
superiority as part of an “unmet medical need” test.
Importantly, FDA’s 2004 Guidance on Available Therapy 1 construing FDA policy on the terms
and definitions for “available therapy” and related terms, such as “existing treatments” and
“existing therapy”, appear in a number of regulations and policy statements and should be
revised and clarified following the expansion of Accelerated Approval language in FDASIA and
modifications to the “unmet medical need” standard. For example, in this Guidance, the Agency
states that “available therapy (and the terms existing treatments and existing therapy) should be
interpreted as therapy that is specified in the approved labeling of regulated products, with only
rare exceptions.” The FDA further indicates that “only in exceptional cases will a treatment that
is not FDA-regulated (e.g., surgery) or that is not labeled for use but is supported by compelling
literature evidence (e.g., certain established oncologic treatments) be considered available
therapy”. To enhance predictability and flexibility in the application of the Accelerated
Approval pathway per FDASIA and reflect that the unmet medical need standard is a factor, but
not a requirement, the FDA should clarify when a treatment that “is not FDA-regulated” or “that
is not labeled for use but is supported by “compelling literature evidence” is applicable and when
such “rare exceptions” will apply.
Implementation:
FDA’s regulations and existing guidance, including FDA’s 2004 Guidance on Available
Therapy, need to be amended to reflect these statutory changes, as well as the broader
Congressional “findings” that make clear Congress’ intent for the Agency to expand the use of
Accelerated Approval where appropriate. These revisions should include the fact that there is
no longer an explicit “unmet medical need” criterion to be eligible for Accelerated Approval.
Specifically, FDA’s Accelerated Approval regulations at 21 C.F.R. 314.500 and 21 C.F.R.
601.40 should be revised to reflect that the statute no longer requires as a condition of eligibility
for Accelerated Approval that an unmet medical need or “meaningful therapeutic benefit . . .
over existing treatments” be demonstrated. FDA’s 2006 Guidance should be revised to reflect
that as well. Further, FDA’s 2006 Guidance, which currently expands upon whether a condition
is considered “serious or life- threatening,” should be revised to clarify that this factor applies to
Accelerated Approval, in addition to Fast Track.

1

FDA “Guidance for Industry: Available Therapy”, July 2004, Section IV. POLICY: DEFINITION OF AVAILABLE
THERAPY, http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm126637.pdf

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D. “Intermediate” Clinical Endpoints that can be Measured Earlier in Development

…upon a determination that the product has an effect on a clinical endpoint or on a surrogate
endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be
measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an
effect on irreversible morbidity or mortality or other clinical benefit,”…

Interpretation:
Accelerated Approval is based on a determination that the product’s effect on a surrogate
endpoint is “reasonably likely to predict clinical benefit,” and provides for more expansive use of
non-surrogate clinical endpoints as the basis for granting Accelerated Approval. Specifically, the
new language expressly authorizes FDA to grant Accelerated Approval based on the use of
clinical endpoints that can be measured earlier in the development process than irreversible
morbidity or mortality, and that are reasonably likely to predict an effect on irreversible
morbidity or mortality or other clinical benefit.
For instance, the President’s Council on Science and Technology has cited the following
examples of “intermediate” clinical endpoints that could be utilized under an expanded
Accelerated Approval pathway.
•
•
•
•

“Using improvement in minimal cognitive impairment in likely early-stage Alzheimer’s
patients as a predictor of delayed progression rather than waiting to assess progression.
Using improvement in isolated muscle strength in patients with muscular dystrophy as a
predictor of benefit, rather than waiting to assess overall deterioration of the patient.
Using clearance of drug-resistant organisms as a predictor of likely clinical benefit, rather
than waiting to measure overall survival rate.
Using measures of the amount of air that a patient can exhale by force (a measure of lung
capacity known as forced vital capacity) or functional motor tests as an endpoint for
predicting a drugs’ likely impact on 2 serious diseases lacking good treatments: spinal
muscular atrophy, a genetic neuromuscular disease, and amyotrophic lateral sclerosis
(ALS), a progressive neurodegenerative disease.”

Other examples of intermediate clinical endpoints may include:
• Reduced kidney function in various kidney diseases, which typically only leads to frank
kidney failure over a decade or more; and
• Total kidney volume in polycystic kidney disease - this is a very slowly progressive
disease is which the kidney expands and causes a series of progressively worsening
symptoms based on expanded volume.
These examples represent “intermediate” clinical endpoints in terms of the speed and efficiency
with which therapeutic intervention can be measured and evaluated. However, they are also
viewed as neither a surrogate endpoint nor a “hard” clinical endpoint, such as kidney failure or
survival. These types of intermediate clinical endpoints are important in that they can be
6

measurable and evaluable earlier which makes drug development more feasible, faster and more
efficient than a traditional endpoint which may develop much later in the course of a given
disease in a clinical trial.
Under the previously existing law and regulations, there have been few submissions or
Accelerated Approvals based on the use of clinical endpoints largely because the statutory
framework was unclear and FDA regulations and practice took a narrow approach to the use of
such endpoints.
In this respect, the Congressional “findings” that were enacted along with the FDASIA statutory
changes are instructive. They direct the FDA to “implement more broadly effective processes
for the expedited development and review of innovative new medicines…using a broad range of
surrogate or clinical endpoints and modern scientific tools earlier in the drug development cycle
when appropriate.” In particular, Congress recognized that this expanded approach “may result
in fewer, smaller, or shorter clinical trials for the intended patient population or targeted
subpopulation without compromising or altering the high standards of the FDA for the approval
of drugs.” Through these amendments, Congress intended to “enhance the authority of the FDA
to consider appropriate scientific data, methods, and tools, and to expedite development and
access to novel treatments for patients with a broad range of serious or life-threatening diseases
or conditions.”
Implementation:
FDA’s regulations and existing guidance should also be revised in regard to the expansion of the
“clinical endpoint” provisions. Specifically, 21 C.F.R. 314.510 and 21 C.F.R 601.41, which
currently refer to approval based on “an effect on a clinical endpoint other than survival or
irreversible morbidity” must be revised to reflect the new statutory language, “effect on a . . .
clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is
reasonably likely to predict an effect on irreversible morbidity or morality or other clinical
benefit. . .” i.e., the connection between an observed clinical endpoint (demonstrated through
adequate and well-controlled clinical trials) and the ultimate clinical benefit of a drug may be
based on the same “reasonably likely to predict” standard applied to surrogates, and that the
types of evidence that can support such linkage now expressly include non-clinical data (see
below).

E. Severity, Rarity, or Prevalence of the Condition and the Availability or Lack of
Alternative Treatments

…“taking into account the severity, rarity, or prevalence of the condition and the availability or
lack of alternative treatments.”

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Interpretation:
The language affirmatively directs FDA, in determining whether to grant Accelerated Approval
under the statutory standard set forth in this section, to consider the “severity, rarity or
prevalence of the condition and the availability or lack of alternative treatments.” This supports
greater risk/benefit balancing that includes the needs and views of patients suffering from serious
or rare conditions, without explicit requirements for direct clinical trial comparisons to other
treatments.
The term “rarity” also reinforces Congressional intent that FDA should more broadly apply the
Accelerated Approval pathway to rare diseases, including low prevalence populations, low
prevalence or enriched subpopulations, and genomic subpopulations.
Implementation:
FDA’s regulations and existing guidance need to be amended to include this explicit statutory
balancing of factors in FDA decision-making in this area. Specifically, changes are necessary in
FDA’s regulations at 21 C.F.R. 314.500 and 21 C.F.R 601.40, the “Scope” sections of the drug
and biologic Accelerated Approval regulations, which refer to a required demonstration of
“meaningful therapeutic benefit over existing treatments.” (see section II.C. above)
We also encourage FDA to continue to engage with rare disease stakeholders through a public
process to further define and interpret the meaning of the phrase “taking into account the
severity, rarity, or prevalence of the condition and the availability or lack of alternative
treatments,” and to fully explore the opportunities to utilize Accelerated Approval for rare
disease therapies.

F. Evidence to Support an Endpoint

“(B) Evidence. — The evidence to support that an endpoint is reasonably likely to predict
clinical benefit under subparagraph (A) may include epidemiological, pathophysiological,
therapeutic, pharmacologic, or other evidence developed using biomarkers, for example, or other
scientific methods or tools.”

Interpretation:
The language provides clear statutory direction to FDA that the evidence to support that either
type of endpoint is reasonably likely to predict clinical benefit may include non-clinical or
clinical evidence such as epidemiological, pathophysiological, therapeutic, pharmacologic, or
other evidence developed using biomarkers or other scientific methods or tools.

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Implementation:
FDA’s current regulations in 21 C.F.R 314.50 and 21 C.F.R. 601.41 state that FDA may grant
marketing approval on the basis of adequate and well-controlled clinical trials establishing an
effect on a “surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic,
pathophysiologic, or other evidence, to predict clinical benefit…” (emphases added). These
regulations must be updated to reflect the use of clinical or non-clinical evidence to support the
use of a surrogate or clinical endpoint under this new statutory provision.
In addition, surrogate endpoints in Accelerated Approval need not have been previously
qualified, nor would their use require a comprehensive qualification as part of a confirmatory
study. The confirmatory study will confirm the efficacy and safety of the drug and the
qualification of the surrogate limited to the specific accelerated study in which it is used. Data
from these studies may also be combined with other data within the FDA to provide cumulative
evidence for the qualification of this surrogate in a broader context of use.
A focus on surrogates for the earlier detection of therapeutic benefit is exemplified in both the
use of novel surrogates for clinical endpoints as cited in the President’s Council on Science and
Technology, as well as in the use of novel surrogate platforms to replace current platforms.
Noteworthy examples of the application of novel surrogate platforms include:
•
•

Circulating tumor cells (CTCs) use instead of biopsies to assess the efficacy of
anti-cancer drugs.
MRI imaging measurements instead of X-ray radiography.

Use of surrogates such as these should require only an analytical validation with reference to the
pre-existing surrogate platform, showing equivalent or superior performance for the same
biological measurement of therapeutic efficacy.

G. Post-Approval Verification Studies

“(2) Limitation. — Approval of a fast track product under this subsection may be subject to 1 or
both of the following requirements: —
(A) Tthat the sponsor conduct appropriate post-approval studies to validate the surrogate
endpoint or otherwise confirm the effect on the clinical endpoint verify and describe the
predicted effect on irreversible morbidity or mortality or other clinical benefit.; and”

Interpretation:
The FDASIA language regarding post-approval requirements for Accelerated Approval is
amended to provide FDA and Sponsors with greater flexibility as to the type of studies that may
be used to verify clinical benefit in the post-approval setting. Specifically, such post-approval
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studies may now focus on verifying the predicted clinical benefit, rather than having to validate
the surrogate or clinical endpoint. This change was not intended to prevent such post-approval
studies, but to provide greater flexibility with respect to the type of studies that could be
required. Importantly, as the Senate legislative history on this change makes clear (see
Congressional Record – Senate, May 24, 2012, at S3564), the striking of post-approval studies to
validate a surrogate endpoint does not signal any intent that surrogate or clinical endpoints be
validated prior to Accelerated Approval, or for the Agency to change its historical practice of
granting Accelerated Approval based on unvalidated endpoints.
Implementation:
As this provision codified existing FDA practices, no specific regulatory changes are necessary,
but it would be useful for FDA to expand upon this provision in Guidance. In particular, in the
case of oncology, the FDA should clarify what type of Accelerated Approval verification studies
may be appropriate.

H. Awareness Efforts & Development of Surrogate and Clinical Endpoints

“(e) Awareness Efforts. —
The Secretary shall —
(1) develop and disseminate to physicians, patient organizations, pharmaceutical and
biotechnology companies, and other appropriate persons a description of the provisions of this
section applicable to breakthrough therapies, accelerated approval, and fast track products; and
(2) establish a program to encourage the development of surrogate and clinical endpoints,
including biomarkers, and other scientific methods and tools that can assist the Secretary in
determining whether the evidence submitted in an application is that are reasonably likely to
predict clinical benefit for serious or life-threatening conditions for which there exist significant
unmet medical needs exist.”

Interpretation:
The Secretary’s awareness efforts must now extend beyond Fast Track to include the new
Breakthrough Therapy designation and enhanced Accelerated Approval pathways. FDA also is
required to establish a program to encourage the development of both surrogate and clinical
endpoints, including biomarkers and other scientific methods and tools that can assist the Agency
in determining whether evidence is reasonably likely to predict clinical benefit.

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Implementation:
FDA should implement these new provisions in a transparent manner through a public process
that involves relevant stakeholders. FDA should also elaborate upon how the process to engage
stakeholders to develop new endpoints is complementary to the PDUFA V and FDASIA
programs to advance regulatory science, qualify biomarkers, qualify patient reported outcome
tools, and develop new endpoints for rare diseases (PDUFA V commitment letter, sections IX C,
D, E; FDASIA §1124, §1102). To the extent practical, the Agency should leverage resources
and synergies from these programs to achieve the common goal of developing new endpoints
and utilization of modern scientific tools and approaches for a broad range of serious and lifethreatening conditions. For example, open stakeholder meetings or hearings to develop a public
research agenda of priority disease areas and a list of potential new endpoints would be a
welcome element of such a public process.
In particular, the implementation of these provisions should include a viable, efficient regulatory
process for the consideration and acceptance of novel surrogates and of novel surrogate
platforms. This process must be incremental, matching a qualifiable context of use to the preexisting data and providing guidance on evidentiary standards needed for increments in the value
of the context of use for the surrogate. While pre-qualification is not required to use a surrogate
for Accelerated Approval, a viable qualification process will encourage the use of surrogates in
drug development and provide uniform guidelines for the interpretation of these results in
regulatory review.

I. Rule of Construction

“(f) Construction.--(1) Purpose. — The amendments made by the Food and Drug Administration Safety and
Innovation Act to this section are intended to encourage the Secretary to utilize innovative and
flexible approaches to the assessment of products under accelerated approval for treatments for
patients with serious or life-threatening diseases or conditions and unmet medical needs.”
(2) Construction. — Nothing in this section shall be construed to alter the standards of evidence
under subsection (c) or (d) of section 505 (including the substantial evidence standard in section
505(d)) of this Act or under section 351(a) of the Public Health Service Act. Such sections and
standards of evidence apply to the review and approval of products under this section, including
whether a product is safe and effective. Nothing in this section alters the ability of the Secretary
to rely on evidence that does not come from adequate and well-controlled investigations for the
purpose of determining whether an endpoint is reasonably likely to predict clinical benefit as
described in subsection (b)(1)(B).

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Interpretation:
Paragraph one explicitly states that the purpose of these amendments is to encourage the FDA to
“utilize innovative and flexible approaches to the assessment of products under accelerated
approval,” while maintaining safety and efficacy standards.
Paragraph two establishes that the current FFDCA statutory standard – requiring adequate and
well-controlled studies showing that the drug is safe for its intended use and that provide
substantial evidence that the drug will have its intended effect – applies to Fast Track,
Accelerated Approval and Breakthrough Therapies. (However, the new FDASIA provisions do
not require that this level of evidence support the relationship between a surrogate or clinical
endpoint and the intended clinical benefit of a drug.) This language simply codifies FDA’s
current practice in evaluating drugs under Accelerated Approval, an approach that requires
substantial evidence of the drug’s effect on the surrogate or clinical endpoint, but permits other
clinical and non-clinical evidence (as described above) to be used to meet the “reasonably likely
to predict clinical benefit” part of the approval standard.
Implementation:
Consistent with current law, no implementation is necessary.

J. Publication of Guidance

“(1) DRAFT GUIDANCE.—Not later than 1 year after the date of enactment of this Act, the
Secretary of Health and Human Services (referred to in this section as the ‘‘Secretary’’) shall
issue draft guidance to implement the amendments made by this section. In developing such
guidance, the Secretary shall specifically consider issues arising under the accelerated approval
and fast track processes under section 506 of the Federal Food, Drug, and Cosmetic Act, as
amended by subsection (b), for drugs designated for a rare disease or condition under section 526
of such Act (21 U.S.C. 360bb) and shall also consider any unique issues associated with very
rare diseases.”
(2) Final Guidance. – Not later than 1 year after the issuance of draft guidance…the Secretary
shall –
(A) issue final guidance; and
(B) amend the regulations governing accelerated approval…
(5) NO EFFECT OF INACTION ON REQUESTS. – The issuance (or non-issuance) of guidance
or conforming regulations…shall not preclude the review of, or action on, a request for
designation or an application for approval” under Section 506 of the FFDCA.
[Note: Included within FDASIA, but not part of the FFDCA]

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Interpretation:
FDASIA directs FDA to issue revised guidance and regulations within two years to implement
these amendments, including special considerations for the greater use of this pathway for rare,
and very rare, diseases. Specifically, the Agency must consider how to “incorporate novel
approaches to the review of surrogate endpoints based on pathophysiologic and pharmacologic
evidence” in instances where “the low prevalence of a disease renders the existence or collection
of other types of data unlikely or impractical.” [FDASIA Sec. 901(c)(3).]
Significantly, the statutory changes made to the Accelerated Approval pathway, Fast Track
designation, and Breakthrough Therapy designation are available immediately upon enactment
of FDASIA—Sponsors need not wait for FDA guidance to be issued.
Implementation:
FDA is directed to draft guidance(s) on Fast Track, Breakthrough Therapy, Accelerated
Approval, and rare disease issues. Specific regulatory and guidance changes are detailed above.
Additionally, it is expected that, among other things, FDA will describe how it intends to
incorporate more modern scientific approaches and tools into the Accelerated Approval process,
so as to ensure the fulfillment of Congressional intent that these new authorities will help
expedite the development and availability to patients of treatments for serious or life-threatening
diseases or conditions.
Specifically, we expect that FDA will clarify and broaden the circumstances in which an
intermediate clinical endpoint can be used to support Accelerated Approval (that is, to support a
determination that the endpoint is reasonably likely to predict an effect on irreversible morbidity
or mortality or other clinical benefit), across a wider range of diseases or conditions (beyond
cancer and HIV/AIDS). Further we expect clarification that the availability of alternative
therapies (or lack thereof) is a factor - but not a requirement - balanced along with other factors
such as the severity, rarity, or prevalence of the condition that the agency shall consider when
determining whether to grant Accelerated Approval in a particular case.
We also expect FDA will describe how it will more explicitly incorporate considerations of
disease severity or rarity and the lack of alternative treatments into the risk/benefit analysis for
Accelerated Approval. Further, in developing guidance, FDA must consider issues associated
with very rare diseases and how to incorporate novel approaches to the review of surrogate
endpoints based on pathophysiologic and pharmacologic evidence, especially in instances where
there is a low prevalence of the disease and traditional data collection is impractical.

A. Relation of Accelerated Approval to Breakthrough Therapy Designation

(a) Designation of a Drug as a Breakthrough Therapy

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(1) In General.-- The Secretary shall, at the request of the sponsor of a drug, expedite the
development and review of such drug if the drug is intended, alone or in combination with 1 or
more other drugs, to treat a serious or life-threatening disease or condition and preliminary
clinical evidence indicates that the drug may demonstrate substantial improvement over existing
therapies on 1 or more clinically significant endpoints, such as substantial treatment effects
observed early in clinical development. (In this section, such a drug is referred to as a
“breakthrough therapy”.)

Interpretation:
In addition to expanding the Accelerated Approval pathway, this provision establishes a new
designation for the approval of “Breakthrough Therapies” intended to treat serious or lifethreatening diseases where “preliminary clinical evidence indicates that the drug may
demonstrate substantial improvement over existing therapies on 1 or more clinically significant
endpoints, such as substantial treatment effects observed early in clinical development.” The
pathway was established partly in response to the development of new therapies that target the
underlying molecular pathways of disease and can demonstrate remarkable efficacy or decreased
toxicity in early stage clinical testing, such as in Phase 1 or early Phase 2 of clinical trials. The
new provision enables robust FDA-sponsor communications (above and beyond those required
for all PDUFA and Fast Track products) to identify an expeditious path for clinical development
and minimize patient exposure to ineffective control regimens.
Implementation:
The FDA response to a Breakthrough Therapy designation has informally been described as an
“all hands on deck” process. Within 18 months of enactment (January 9, 2014), FDA is required
to publish draft guidance addressing implementation of the Breakthrough Therapies provisions;
to finalize such guidance within one year of the comment period; and, if necessary, to revise any
relevant regulations by July 9, 2014. FDA is also directed to develop and disseminate a
description of the Breakthrough Therapies provisions.
FDA should provide additional details regarding the Breakthrough Therapy designation,
including: distinguishing Breakthrough designation from Fast Track designation and both of
these designations from the Accelerated Approval and Full Approval pathways; options for
consolidation of trial phases; clarification of when and what data from Phase 1 or early Phase 2
is acceptable; size of clinical trials, how substantial improvement over existing therapies will be
evaluated (for example, direct clinical trial comparisons not necessary) ; how to evaluate
“substantial” and clarification of what qualifies as an “existing therapy”; the
process/expectations for increased meetings between FDA and sponsors; and further details on
the expectations for the amount of data and whether there is a need for a full clinical
development plan in the application.
FDA should also elaborate upon what processes it will use to develop cross functional, senior
leadership teams across FDA, not just the review division, how it will facilitate interactive
communication with the Sponsor, and if/when external expertise or patient input can be imputed
14

to the process. This is expected to include expedited meeting requests (Type A or B) and
additional informal dialogue above and beyond what is expected for all PDUFA products and
Fast Track products. The creation of a Breakthrough Designation meeting type would facilitate
meeting requests for Breakthrough discussions and the identification of FDA employees required
to attend these meetings.
The Agency and industry should also engage in a dialogue in how to address the challenges
posed by manufacturing CMC and device-related bottlenecks and how to best harmonize the
expedited U.S. development program with other international regions, notably Europe, to
achieve a single harmonized development program for a Breakthrough Therapy designated
product or any product applicable for expedited development.
Lastly, there needs to be clarity on how this Breakthrough Therapy designation will integrate or
not with approval pathways (Accelerated/Full) and FDA processes such Priority Review, etc. In
other words, the Agency should clarify how increased communications and involvement of
senior level and cross functional FDA teams will actually expedite the development and approval
of these products.

III.

CONCLUSION

Under the FDASIA expansion of Accelerated Approval, Congress encouraged FDA to
“implement more broadly effective processes for the expedited development and review of
innovate new medicines… using a broad range of surrogate or clinical endpoints and modern
scientific tools earlier in the drug development cycle when appropriate.” In summary, FDASIA
provides FDA and Sponsors with greater flexibility under Accelerated Approval by:
• Enabling the eligibility of a combination of drugs
• Clarifying the distinction between Accelerated Approval and Fast Track designation
• Replacing the criterion for “unmet medical need” with an evaluation of other factors such
as “the severity, rarity, or prevalence of the condition”
• Promoting the use of “intermediate” clinical endpoints, as well as surrogate endpoints,
that can be measured earlier in drug development
• Facilitating the use of Accelerated Approval for serious rare diseases, including low
prevalence populations, low prevalence or enriched subpopulations, and genomic
subpopulations
• Modernizing the type of scientific evidence that can be used to support a determination
that a surrogate or clinical endpoint will be “reasonably likely to predict clinical benefit”
• Providing FDA and Sponsors with greater flexibility as to the type of studies that may be
used to verify clinical benefit in the post-approval setting
• Establishing a public process to develop and accept novel endpoints
• Establishing a new Breakthrough Therapies Designation process
The hope is that FDA will apply these authorities more broadly and in innovative ways to
leverage 21st century advancements in science and drug discovery to help ensure that patients
suffering from a broad array of serious and life-threatening condition have timely access to safe
and effective new therapies.
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