Re: Docket No. FDA-2015-D-4562: Draft Guidance Safety Assessment for IND Safety Reporting

Transcription

1 February 16, 2016 Dockets Management Branch (HFA-305) Food and Drug Administration 5630 Fishers Lane, Rm Rockville, MD Re: Docket No. FDA-2015-D-4562: Draft Guidance Safety Assessment for IND Safety Reporting Dear Sir/Madam: The Biotechnology Innovation Organization (BIO) thanks the Food and Drug Administration (FDA) for the opportunity to submit comments on the Draft Guidance Safety Assessment for IND Safety Reporting (Draft Guidance). BIO is the world's largest trade association representing biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial, and environmental biotechnology products. BIO supports FDA s assertion that it is critical for sponsors to detect and report, as early as possible, serious and unexpected suspected adverse reactions and clinically important increased rates of previously recognized serious adverse reactions, and we appreciate the publication of this Draft Guidance to aid Sponsors in this responsibility. However, we are concerned about the prescriptive nature of this Draft Guidance and its emphasis on the Safety Assessment Committee (SAC). We are also concerned that FDA may not fully appreciate the time and resources required of Sponsors to implement the recommendations within the Draft Guidance. Overall, we recommend the Final Guidance allow for more flexibility for Sponsors in how safety assessments for IND safety reporting are performed. This flexibility should allow for accommodation of product-specific aspects of a development program, as well as the most efficient use of Sponsor resources, given pre-existing internal safety monitoring processes and governance. As currently written, the Draft Guidance s recommendations regarding the SAC, would present significant operational challenges, especially for small- and mid-sized companies. We also note that it is unclear whether the presence of an SAC will result in earlier detection of important safety information. As such, we believe it would be more beneficial and appropriate if this Draft Guidance focused on safety surveillance plans, which in some cases may include an SAC as part of the plan. A. Resourcing The resources needed to implement the recommendations in this Draft Guidance would be particularly problematic for small- and mid-sized companies. We note that in smaller companies,

2 there are fewer safety personnel and they often work closely with the development staff. Such companies would likely need to outsource the functions of the SAC, which may bring about issues regarding administration, oversight, and cost. In addition, if followed, we are concerned that the recommendations in the Draft Guidance could have the unintended, and undesirable, effect of detracting from the ability of the Sponsor safety team to comment on protocols and development plans with respect to safety. To minimize the number of personnel with access to unblinded study data, dedicated clinical experts, statisticians, and epidemiologists will be required to independently assess safety endpoints and carry out the safety analyses and background epidemiology. These individuals should not be part of the specific clinical trial safety assessment team, in accordance with current practice. The Draft Guidance recommends the SAC have responsibility for reviewing data from all relevant studies 1 ; implementation of this recommendation will require an expansion of the staffing and periodicity of meetings of the SAC, if formed. It may also require warehousing of external data, so these external data can be combined with internal data to assess serious adverse event (SAE) rates. The Draft Guidance recommends Sponsors conduct significant background or disease-state epidemiology such that certain SAEs are pre-defined as anticipated and the rate of such events are outlined in Safety Surveillance Plan, Investigator s Brochure (IB), and other study documentation. Additionally, it is difficult to obtain reasonable estimates of events in study populations where the event rate, without a drug effect, might reasonably differ substantially from the broad population estimates due to the particulars of the study population or due to sampling error. As such, this is another activity that would require resourcing and development of processes. Furthermore, the identification of additional resourcing, preparing data warehousing, and contracting external operations will impact the timeline for a company to comply with the Draft Guidance, as the set up will take many months. Utilization of processes in place for safety review can expedite the process and impact the plans to decrease submission of uninformative reports and identification of those safety concerns that are meaningful. There are concerns for redundancies in safety reviews, as most companies follow the concept of a Safety Management Team (SMT) as described in the CIOMS Working Group VI Report (2005) entitled Management of Safety Information from Clinical Trials. The document describes recommendations for the membership and roles and responsibilities: Good PV and risk management practices during clinical drug development includes the establishment of a multidisciplinary SMT. Excluding the clinical personnel most familiar with the product and the indication may eliminate those most qualified to provide medical judgment. Ultimately, to keep those involved in the study conduct from helping make the decisions may not be possible, as they must know the results to make the decisions and describe the content for updates to IBs, informed consent forms or other 1 See lines : The safety assessment committee should periodically review the accumulating serious adverse events across all trials. The safety assessment committee should also review findings from any clinical studies other than those reported under (c)(1)(i), epidemiological studies, and pooled analyses of multiple studies ( (c)(1)(ii)). Similarly, the safety assessment committee should review any findings from animal or in vitro testing that may suggest a significant risk in humans exposed to the investigational drug ( (c)(1)(iii)). The safety assessment committee will need access to the totality of safety information in the development program (i.e., completed and ongoing) because these data may contribute to the evaluation of serious adverse events. FDA Docket: FDA-2015-D-4562, February 16, 2016, Page 2 of 10

3 plans for protocol revisions. It is not likely the independent review committees and TA aligned person providing medical judgment cannot make recommendations about individual protocol conduct; most products have multiple indications and there may be need for more than 1 TA aligned person providing medical judgment. B. Harmonization Of key concern is the lack of alignment of FDA s recommendations in the Draft Guidance with the requirements of EMA and other major regulatory authorities. Because of this lack of alignment, it is challenging for Sponsors to use the same processes to conduct safety assessments to meet IND safety reporting requirements globally. While we understand that FDA is seeking to limit the reporting of uninformative adverse events and unnecessary followup information by putting forth criteria for reporting, other major regulatory authorities require that this information be reported (Section IV.E., page 15). However, in order to fulfill requirements of the different Agencies, significant resources and infrastructure are needed as the Sponsors are required to create subsets of reports that are needed to be sent to the FDA. For example, under this paradigm, a Sponsor would need to parse out a given subset of individual case safety reports (ICSRs) to accommodate FDA and Rest-of-World (ROW) requirements. It may be necessary for Sponsors to develop manual processes to produce certain reports within their global safety database that are non-reportable to FDA, but are otherwise reported to other regulatory authorities. Creating such a system of reporting introduces complexity, however the bigger challenge for the Sponsor is in identifying the cases reportable under this Draft Guidance. We request that FDA reconsider those recommendations that create a need for new processes or reports that may not be suitable for other major regulatory authorities. To harmonize, a listing from the Agency, suggesting examples of follow up information that should be considered not requiring submission as a follow up report can be helpful to negotiate with ex-us agencies. This would also help the Sponsors maintain internal consistency in single case reviews. We note that the net effect of the 2012 Final Guidance Safety Reporting Requirements for INDs and BA/BE Studies is that IND reporting in the US is done differently than in EU and other countries. We discourage FDA from implementing any processes that lead to further global divergence, rather than harmonization. We suggest the major regulatory agencies create a single consensus guidance for assessment of aggregate SAE data from clinical trials and criteria for reporting these events. C. Unblinding Data The Draft Guidance recommends development of therapeutically-aligned SACs with multidisciplinary expertise in reviewing aggregate safety data on a periodic and pre-specified basis. The purpose of the SAC review is to ascertain if SAEs observed from ongoing and completed trials represent a new safety concern and require IND reporting. Committee members are to review unblinded data and assess whether rates are higher than anticipated in FDA Docket: FDA-2015-D-4562, February 16, 2016, Page 3 of 10

4 the active treatment arm for pre-specified expected SAEs, and whether any unanticipated SAEs represent a new safety concern for the product in development. BIO believes the goal should always be to limit, to the extent possible, the numbers of people who have access to unblinded data within the company. Further, sending unblinded IND safety reports to investigators (see Line 502) should not be a routine practice. Awareness of unblinded trial results by SAC members could impact the integrity of the development program. Providing non-blinded reports to investigators has the potential for creating bias within a study at the site level, regardless of the phase or size of the study. Such bias has the potential of failure to recruit certain subpopulations into a study as well as not completing study requirements as outlined in the protocol for fear of causing harm to the patient. Given these concerns, we suggest, and ask FDA to confirm, that review of unblinded aggregate data only in situations where there is a signal from a review of blinded data is an acceptable approach. It is standard practice to do blinded aggregate reviews as described in a Sponsor s safety plans. The Draft Guidance states that unblinding of small numbers of serious and unexpected AEs should not compromise study integrity because the subject who experiences such events will often be withdrawn from the study at the time of the event. However, such a study withdrawal will not necessarily occur when a subject experiences events which may be expected to occur at a background rate in the study population, such as cardiac events, infections, depression, and cholecystitis/diverticulitis. There is some confusion as whether it is required to review the entire AE database versus only the SAE database. The December 2012 Guidance for Industry and Investigators Safety Reporting Requirements for INDs and BA/BE Studies seems to require reviewing the entire AE database. 2 If this includes nonserious AEs, many more subjects will be unblinded. Furthermore, combining the entire safety database including older studies adds the logistic complexity of compatibility of data from across trials. Are the data from trials to be combined regardless of study design, indication, durations, dosing schedule? Is the FDA recommending periodic analysis similar to a NDA clinical summary of safety? The subset analysis can be complicated programing. How would early data be used and should it include data from healthy volunteer trials, for example? The functioning and staffing of SACs will be complex and have to address issues of: unblinding the committee members while maintaining the blind for others; the scope of membership of the committee, and the ability to create these committees with internal staff or external staff; and the reporting of the committees findings to other internal governance groups. These committees may have to last for years for any particular product, and be a major repository for unblinded data. Accordingly, we recommend the addition of clarifying language to section C ( Unblinding Safety Data ), which begins at Line 500, to the effect that the submission of unblinded IND safety reports to regulatory agencies (where studies themselves are blinded) must be controlled and performed by staff that are not involved in the development of the product or decision making, so as not to compromise the integrity of ongoing blinded trials. 2 See page 12, the Guidance states, It is important to consider the entire clinical trial database in such analyses. FDA Docket: FDA-2015-D-4562, February 16, 2016, Page 4 of 10

5 The Draft Guidance states that IND safety reports submitted to FDA and all participating investigators should be unblinded FDA does not believe that unblinding single or small numbers of serious and unexpected suspected adverse event cases will compromise the integrity of the study. It also covers additional Sponsor concerns about unblinding for safety reporting beyond individual cases. However, in a study with a small number of subjects (e.g., Phase I or later Phase studies in a rare disease), sharing treatment assignments for one to two subjects openly could compromise the integrity of the study. Accordingly, BIO believes that it is imperative to limit, to the extent possible, access to unblinded data within the company in order to preserve study integrity, and asks the FDA to state that unblinded aggregate data are to be reviewed only where there is a signal from a review of blinded data or in the case where Sponsors have preplanned unblinded aggregated data reviews. The FDA is asked to provide guidance as to threshold setting regarding meaningful differences as compared to placebo and as compared to historical control rates. We also ask FDA provide guidance as to the criteria for a threshold that is acceptable to them to detect a safety signal from blinded data review (e.g., increased reporting rate as compared to historical control). D. Overlap with Existing Processes for Ongoing Monitoring The recommendations in this Draft Guidance overlap considerably with existing processes for the ongoing monitoring of clinical investigations. It will be challenging to integrate recommended SAC processes with those of other company safety and governance committees. For example, the Guidance recommends development of a Safety Surveillance Plan that describes the periodic review of aggregate data from ongoing and completed studies, and the means by which assessment of observed events will be done to identify IND reportable events. The need to combine ongoing and completed clinical trial data and look at these data unblinded, as recommended in the Draft Guidance, will require significant changes to current processes (such as the review by existing internal safety committees or external Data Monitoring Committees (DMCs)) and have significant impact on other processes within the company. It is also unclear how an internal SAC would interact with an External DMC (which would be in place for most registration studies). Most DMC charters do not contain language describing a responsibility to determine the need for expedited regulatory reporting of an event based on unblinded aggregate data review. If an internal SAC is reviewing unblinded data for the same study/studies for which an External DMC exists, then the interactions between these groups will have to be carefully considered, including arbitration for conflicting findings or recommendations. E. Additional Comments In some therapeutic areas, there are few experts that could serve on SACs. Many experts will already be investigators in studies, and we anticipate challenges in finding suitable external experts to serve on SACs, particularly given other reporting and conflict of interest issues. BIO appreciates that the Draft Guidance clarifies the reporting period: no later than 15 calendar days after determining that the information qualifies for reporting. In the past, there had been some ambiguity about whether the reporting period was 15 days from the Sponsor FDA Docket: FDA-2015-D-4562, February 16, 2016, Page 5 of 10

6 being informed about the event or 15 days from determination. We appreciate that FDA recognizes that there is a need for flexibility when receiving a report to have adequate time in determining its validity as a report. Oftentimes we are informed of a report, but further clarification is needed or collaboration between functions to determine if a report requires databasing. Additionally, BIO appreciates that the Draft Guidance provides some clarity about events that are not to be reported and encourages Sponsors to consider defining these events for each program s safety surveillance plan. --- BIO appreciates the opportunity to provide comments to the Draft Guidance Safety Assessment for IND Safety Reporting. We provide additional specific, detailed comments to improve the clarity of the Draft Guidance in the following chart. We would be pleased to provide further input or clarification of our comments, as needed. Sincerely, /S/ Cartier Esham, Ph.D. Executive Vice President, Emerging Companies Section & Vice President, Science & Regulatory Affairs Biotechnology Innovation Organization (BIO) FDA Docket: FDA-2015-D-4562, February 16, 2016, Page 6 of 10

7 SPECIFIC COMMENTS SECTION ISSUE PROPOSED CHANGE I. INTRODUCTION II. BACKGROUND A. Overview of Safety Reporting Requirements Lines 84-87: The Draft Guidance states, The process should include a method for comparing event rates across treatment groups, as needed, to detect serious and unexpected suspected adverse reactions and clinically important increased rates of previously recognized serious adverse reactions. Event rates represent only one option and when event rates are not available, planned unblinded reviews by an internal review group separate from the study team, either for target disease state associated SAEs or for study population anticipated SAEs are either for cause (when the observed incidence exceeds threshold rates prespecified in the IB or protocol) or at intervals specified in the protocol, IB, TLSR plan or PLSR plan (e.g., every 6 months, as each 20% of the recruitment target is achieved, or after each 20 events are reported) would represent additional options for the study as criteria for review. Finally, for studies involving combinations this recommendation may be challenging to implement, especially if treatment arms employ the same agent in multiple arms. Lines 87-90: The Draft Guidance states, An important component of such an approach is prospective identification of serious adverse events that the sponsor can foresee occurring with some frequency independent of drug exposure in the patient population, disease under study, or both (i.e., anticipated serious adverse events). The prospective list of events that could be foreseen for the population under study could be extensive and less prominent, but important, events could be overlooked. FDA Docket: FDA-2015-D-4562, February 16, 2016, Page 7 of 10

8 SECTION ISSUE PROPOSED CHANGE B. Rationale for Developing Guidance Lines The Draft Guidance states, For these reasons, this guidance provides recommendations intended to help sponsors meet their obligations under We recommend that sponsors develop a safety assessment committee and a safety surveillance plan as key elements of a systematic approach to safety surveillance. A safety assessment committee would be a group of individuals chosen by the sponsor to review safety information in a development program and tasked with making a recommendation to the sponsor regarding whether the safety information must be reported in an IND safety report (see section III of this guidance). A safety surveillance plan should describe processes and procedures for assessing serious adverse events and other important safety information (see section V of this guidance). As indicated above, BIO believes that the focus of the guidance should be on the creation of a safety assessment plan and not a safety assessment committee. Therefore, we suggest replacing the text with the following: We recommend that sponsors develop a safety surveillance plan as a key element of a systematic approach to safety surveillance. A safety surveillance plan should describe processes and procedures for assessing serious adverse events and other important safety information (see section V of this guidance). For development programs with large studies or multiple smaller studies or other programs where the regular review of unblinded safety data might be necessary, the safety surveillance plan should consider the creation of a safety assessment committee. A safety assessment committee would be a group of individuals chosen by the sponsor to review safety information in a development program and tasked with making a non-binding recommendation to the sponsor regarding whether the safety information should be reported in an IND safety report (see section III of this guidance). III. SAFETY ASSESSMENT ORGANIZATIONAL STRUCTURE A. Role of the Safety Assessment Committee Lines : The Draft Guidance discusses the role of the SAC. It is unclear whether the level of aggregate data review recommended in the Draft Guidance is needed prior to Phase 3 or for programs that have an accelerated/adaptive pathway or how this guidance would be applied to products with multiple INDs. BIO recommends the processes in the Draft Guidance apply to later stage compounds and suggest FDA Docket: FDA-2015-D-4562, February 16, 2016, Page 8 of 10

9 SECTION ISSUE PROPOSED CHANGE the following text be added to this paragraph: For early new molecular entity (NME) development, where the only information available is from a single, often unblinded clinical trial, the use of a SAC may be delayed until after the initiation of multiple clinical trials or of blinded trials. The Sponsor should have a process for the review and reporting of IND safety reports where aggregate information is not yet available." Lines : Lines : The Draft Guidance discuses that the SAC have responsibility for reviewing data from all relevant studies (including published studies, epidemiologic studies, and those conducted by other Sponsors). The Draft Guidance discusses the frequency of meetings. Implementation of this recommendation will require an expansion of the staffing and periodicity of meetings of the SAC. It will also require data warehousing of external data, so these external data can be combined with internal data to assess SAE rates. BIO notes that access to the totality of safety information in the development program may not necessarily be required in all cases but should be available as needed. As such, we recommend replacing lines with the following: There are instances where the SAC might require other safety information, including nonserious adverse events and results of investigations, to make the determination as to whether there is a safety signal requiring a recommendation for a change in the conduct of the study. If requested by the SAC, such information should be provided. Per our comment above regarding lines , BIO suggests this section should emphasize, that for compounds earlier in development, the SAC may be more effective once an understanding of the compound's safety profile is initially defined. As such, monthly or quarterly meetings of the SAC FDA Docket: FDA-2015-D-4562, February 16, 2016, Page 9 of 10

10 SECTION ISSUE PROPOSED CHANGE may allow appropriate assessments to be performed. B. Composition of Safety Assessment Committees Lines : IV. This section of the Draft Guidance discusses the disciplines of the SAC. SAFETY ASSESSMENT PRACTICES A. Anticipated Serious Adverse Events B. Aggregate Analyses of Safety Data Lines : C. Unblinding Safety Data Line 500: The Draft Guidance discusses the use of a historical control group. This section of the Draft Guidance discusses unblinding safety data. BIO recommends that Regulatory Affairs be added to the disciplines that participate in the SAC. It may be helpful for the Guidance to provide additional information on appropriate selection of historical controls in order to maintain consistency within therapeutic areas and across Sponsors. The functioning and staffing of SACs will be complex and may have to last for years for any particular. Accordingly, we recommend the addition of clarifying language in this section to the effect that the submission of unblinded IND safety reports to regulatory agencies (where studies themselves are blinded) must be controlled and performed by staff that are not involved in the development of the product or decision making, so as not to compromise the ongoing blinded trials. D. Reporting Thresholds for IND Safety Reporting E. Follow-Up Information V. PROSPECTIVE PLANNING: DEVELOPOING SAFETY SURVEILLANCE PLANS FDA Docket: FDA-2015-D-4562, February 16, 2016, Page 10 of 10