A3_60d_Comments_2004

Attachment 3

CDC Responses to comments.

April 27, 2005

Re: Response to the National Surveillance for Severe Adverse Events Associated with Treatment of Latent Tuberculosis Infection (LTBI), Federal Register, Volume 69, No. 228; November 29, 2004

Comments from:

Tuberculosis Control Branch, California Department of Health Services, and

California Tuberculosis Controllers Association

Methodologic limitations: This passive surveillance system will likely result in an underestimate of the number of adverse events associated with treatment for LTBI. Lack of a denominator will mean that the risk of these events cannot be calculated.

Can these data be better collected in conjunction with prospective studies? Alternatively, can an investigation be stimulated in response to patterns of events noted through the FDA Medwatch system?

CDC response: CDC is initiating the second phase of Task Order #13- Factors associated with acceptance of, adherence to, and toxicity from treatment for latent TB infection which is a prospective study that will obtain data on toxicity from treatment for latent TB infection. Also, with the established CDC and FDA collaboration, there is a greater possibility that an investigation will be initiated in response to patterns of events noted through the FDA MedWatch system.

Burden of reporting: The Federal Register notice estimates 1 hour average time burden per case of adverse event. This is a vast underestimate of the time and burden it would take for this reporting process. The initial report made by the reporting agency will take much more time in locating and reviewing records and recording the events. Even if CDC project officers can assist, coordinating access to relevant information will be time consuming. Additional time by the state will be spent to support the surveillance system, to respond to queries by local health departments (LHDs) regarding the protocol, and to coordinate communications and response. Without additional funding, some local jurisdictions will not have the ability to implement and participate in the surveillance system. Competing activities at the state and local level may be prioritized.

CDC response: The one-hour average time burden per case of adverse event is the amount of time the reporter of the event spends in filling up the basic information about the patient. CDC does not want to place too much burden on the reporting agency and that is one of the main reasons why the CDC medical team is sent to the reporting site to investigate the adverse event. The rest of the data on the form is filled out by the CDC medical team during telephone calls or onsite investigation. The collective time burden on the reporting agency can probably be one or more hours depending on the condition of the patient. So, based on your comment, we are changing this average time burden per case to eight hours.

Reporting flow and coordination: In California, reports are most likely to originate from LHDs. Traditionally, TB surveillance has proceeded from LHD to the State to CDC. Surveillance instructions suggest that local health departments and private providers can report directly to CDC. While CDC will coordinate with the state, reporting flow should follow current mechanisms.

CDC response: Historically, the reports that CDC have received and investigated so far have come from local health departments coordinated through the state and we anticipate that this practice will continue. We will encourage anyone who reports an adverse event to CDC to report the event to the local health department and we will follow up with the local and state health departments.

Potential negative consequences of the surveillance system: Collection and dissemination of information on these adverse events may discourage implementation of targeted testing and treatment for LTBI. This is a potential detrimental outcome since case reports can not provide sufficient evidence basis for this decision. Local health departments have reported that case reports of INH-related hepatitis have created significant barriers to implementing appropriate LTBI treatment.

CDC response: While reports of adverse events associated with treatment of LTBI may create barriers to LTBI treatment, we think that this possible negative consequence does not outweigh the benefits of monitoring these severe adverse events. The intent of the surveillance system is to provide data that will assist public health officials, policy makers, and healthcare providers in preventing severe adverse events associated with treatment of LTBI. The data will be the basis in supporting periodic evaluation of guidelines for treatment of LTBI and revision of these guidelines as needed.

Relationship of Medwatch and CDC surveillance systems: It is not clear how the FDA Medwatch and the CDC surveillance systems will intersect. If Medwatch is notified of an adverse event associated with treatment of LTBI, will DTBE be notified? And vice versa?

CDC response: CDC and FDA are developing a memorandum of understanding where both agencies will notify each other of any report of hospitalization or death associated with treatment of LTBI.

Exclusion of serious adverse events that do not result in hospitalization or death: It is likely that there are other adverse events of importance that may not result in hospitalization or death. Serious events as defined by the FDA include life-threatening conditions in addition to those leading to hospitalization or death.

CDC response: The national surveillance system receives reports of serious adverse events but collects data, through onsite investigation by a medical team, on hospitalization or death associated with treatment of latent TB infection. The CDC Medical Board decided to conduct onsite investigation only on hospitalizations or deaths to maximize use of staff resources.

Dissemination of findings: FDA should be included in the partners for dissemination of findings

CDC response: FDA will be included in the partners for dissemination of findings.

Process for comment review and response: The process by which these comments will be reviewed and addressed is unclear.

CDC response: The process by which these comments are reviewed and addressed is the following: The OMB Clearance Group sends for review all the comments they receive to the CDC project officer who develops the CDC response to these comments. The CDC response will be sent to those who commented and also will be attached to the OMB protocol.