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Findings and Recommendations for FDA Evaluations Completed in FY 2010

Table of Contents FY 2012 OPA

1.      Safety and Transparency of Pediatric Drug Trials 

Purpose      Medication adverse events in children often differ from those in adults, particularly those that are neuropsychiatric in nature. Although this information is provided to FDA, it may not be disseminated in reputable journals. Therefore, FDA decided to quantify the frequency and type of new safety information arising from studies performed under the auspices of the Pediatric Exclusivity Program, to describe the dissemination of these findings in the peer-reviewed literature and compare this with the FDA review, and to describe their effect on pediatric labeling.

Findings     A total of 137 labeling changes were identified, with 8 selective serotonin reuptake inhibitors excluded from the review, for a total of 129 labeling changes evaluated.

Thirty-three products (26 percent) had pediatric safety information added to the labeling. Of these, 12 products had neuropsychiatric safety findings and 21 had other important safety findings. Only 16 of 33 of these trials (48 percent) were reported in the peer-reviewed literature; however, 7 of 16 focused on findings substantively different from those highlighted in the FDA reviews and labeling changes. 

Labeling changes for pediatric use demonstrate that pediatric drug studies provide valuable and unique safety data that can guide the use of these drugs in children. Unfortunately, most of these articles are not published, and almost half of the published articles focus their attention away from the crucial safety data.


No recommendations were presented in the study. 


2.      Final Report to the FDA Science Board: Research, Support Programs, and Alignment with Regulatory Responsibilities of the Center for Food Safety and Applied Nutrition (CFSAN) 

Purpose      The review of CFSAN’s science and research program was completed by the CFSAN Research Review Subcommittee of the FDA Science Board, with the results shared with the full FDA Science Board. The purpose of the review was to provide recommendations and observations to improve and strengthen CFSAN’s science and research program to increase its capacity to support CFSAN’s mission.

Findings    Non-laboratory research, especially in areas where food science, nutrition, and consumer areas integrate and connect, appears to receive lower priority and attention. Applied research areas related to food science, food processing, food technology and nutritional science with regulatory implications also appear to receive less attention. 

Risk, regulatory science, and consumer communication, including evaluation of the impact of communication on consumer understanding and behavior appear to lack the attention and resources required for the current challenges.          

Increased connectivity, interaction, alignment, and visibility within CFSAN and with other key external and professional organizations, at the national and international levels are essential, but insufficient within the current structure and focus.

Programmatic and regulatory outcomes related to CFSAN’s role and responsibilities for research prioritization appear to lack insufficient focus.

Since 2002, the number of research FTEs at CFSAN has remained essentially the same despite the fact that the Center’s responsibilities have continued to increase. Resources (number, depth, and subject matter expertise) are lacking at multiple levels, and will likely become more acute as the demand grows for expertise in areas of cutting-edge science.

There was insufficient support staffing in administrative and technical positions. The ratio of scientists to support staff was unbalanced and inefficient.

A separate review of the Office of Cosmetics should be done to address any outstanding issues and concerns (e.g., regulatory authority, framework). 


  • Create opportunities to meet with and participate in scientific exchanges with world experts from academia, other governmental organizations, and industry to consider topics relevant to the research agenda for CFSAN’s regulatory science mission.
  • Establish a formalized process for identifying and prioritizing emerging issues to include representatives from both internal and external stakeholders and include means to systematically capture and evaluate concerns that may arise from either scientific, regulatory, or societal challenges.
  • Create a Board of External Scientific Counselors to provide rigorous, ongoing review of science with CFSAN.
  • Develop a list of organizations against which to benchmark CFSAN’s research planning process.
  • Establish a competitive, nationwide extramural research program as part of the FDA budget request.
  • Build capacity to advance and lead new regulatory science in those areas key to CFSAN’s mission to include risk analysis, food safety, food science, food processing, nutrition, communication science, and regulatory science. 

3.      Risk Evaluation and Mitigation Strategies (REMS) Retrospective Regulatory Decision Analysis

Purpose      The Food and Drug Administration Amendments Act of 2007 (FDAAA) provided the United States Food and Drug Administration (FDA) with additional requirements, authorities, and resources in both pre- and post-market drug safety, including authorities to require Risk Evaluation and Mitigation Strategies (REMS).  REMS can include a Medication Guide, Patient Package Insert, a communication plan, or other elements to assure safe use (ETASU). This study, conducted by Booz Allen Hamilton (BAH), focused on REMS with elements to assure safe use due to their complexity and the unique decision-making challenges they pose.

Findings     Due to the small size of the study cohort, no conclusions were made about how these factors influenced FDA’s decision making or how these factors changed over time.

Based on the analysis of FDA’s review documents, the factors were grouped into six categories: 1) Specific adverse events, 2) Overall risk profile, 3) Ability to mitigate risk, 4) Efficacy and benefit, 5) Characteristics of the disease the product treats, and 6) Characteristics of the product.

In the process of analyzing the factors cited in the review documents, it was determined that the documents had not adequately captured all of the reviewers’ considerations.


  • Conduct further study to comprehensively identify reviewers’ considerations in determining whether or not to implement a REMS with ETASU. 

4.      Office of Generic Drugs Backlog Analysis

Purpose      Stakeholders have expressed concern about FDA’s backlog of unreviewed Abbreviated New Drug Applications (ANDAs), which appears to have grown dramatically in the past several years.

Findings     FDA’s old tracking system, COMIS, had undercounted the number of applications in the backlog by failing to count as part of the backlog those applications that had pending reviews in disciplines other than chemistry. 

FDA’s new tracking system, DARRTS, overcounted the number of applications in the backlog, as it did not permit reviewers to issue “complete response” letters as they had in the past. 


  • To help improve the tracking of DARRTS applications in the future, replace the existing backlog measure with two new measures: 1) Application Backlog: the number of applications with unfinished reviews, and 2) Review Backlog: the number of unfinished reviews.


5.      Office of Generic Drugs Consult Process   

Purpose      During the 2007 Generic Drug User Fee negotiations, industry sought goals for timelines to resolve Office of Generic Drugs (OGD) consults to Office of New Drugs (OND). The user fee negotiations were unsuccessful, and no timelines for consults were established. This study intended to study the OGD consults process and its performance to OND and other offices in preparation for new user fee negotiations.


Findings     Depending on the level of difficultly and the priority given to the consults, completing a consult can take anywhere from a few days to several years.

Generally, consultative reviewers have been responsive to consult requests, particularly when Abbreviated New Drug Applications (ANDAs) are close to approval. 

Median consult completion times range from 3 to 6 months. However, consults can slow the approval decision process when the need for a consult is recognized late in the review process, because the reviewer’s workload is so great, and because the reviewer has conflicting priorities.    


No recommendations were presented in the study.

6.      Task Force on the Utilization of Science in Regulatory Decision Making – Preliminary Report and Recommendations   

Purpose      The Task Force on the Utilization of Science in Regulatory Decision Making was convened in September 2009 to review how the Center for Devices and Radiological Health (CDRH) uses science in its regulatory decision making process, and to make recommendations on how the Center can quickly incorporate new science —including evolving information, novel technologies, and new scientific methods — into its decision making, while also maintaining as much predictability as is practical. 

Preliminary Findings 

It is difficult for CDRH staff to efficiently and effectively obtain complete information about the risks and benefits of regulated products across the total product life cycle. This can lead to unnecessary delays and burdens during premarket review and make it challenging for CDRH to identify and respond to postmarket trends quickly and appropriately. 

It is difficult for CDRH staff to share scientific knowledge across the Center, in part due to staffing limitations, and to tap meaningful external scientific expertise in a timely manner. 

CDRH has not yet articulated a business process to be followed across the Center for evaluating new scientific information and determining when that information warrants certain types of action, such as a change in premarket evidentiary expectations.

When new scientific information changes CDRH’s regulatory thinking, it is challenging for the Center to communicate the change and its basis to all affected parties in a meaningful and timely manner. 

Preliminary Recommendations

  • Take proactive steps to improve the quality of premarket data, particularly clinical data; address review workload challenges; and develop better data sources, methods, and tools for collecting and analyzing meaningful postmarket information.
  • Conduct an assessment of CDRH’s staffing needs to accomplish its mission-critical functions and prepare for anticipated scientific challenges.
  • Take steps to improve knowledge management within CDRH and make better use of experts outside of the Center, in part by developing a web-based network of external experts, using social media technology.
  • Establish a CDRH Science Council, comprised of experienced employees and managers and under the direction of the Deputy Center Director for Science, to help ensure consistency across the Center in responding to new scientific information.  
  • Make use of more rapid tools for broad communication on regulatory matters in addition to continuing ongoing efforts to streamline guidance development.
  •  Adopt a uniform template and terminology for such letters, including clear and consistent language to indicate that CDRH has changed its regulatory expectations, the general nature of the change, and the rationale for the change.

7.      510(k) Premarket Notifications Working Group – Preliminary Report and Recommendations   

Purpose      The 510(k) Working Group was convened in September 2009 as part of a two-pronged, comprehensive assessment of the 510(k) process. The other component of this assessment is an ongoing independent study by the Institute of Medicine (IOM) that is expected to conclude in the summer of 2011. The 510(k) Working Group was charged to evaluate the 510(k) program and explore actions the Center for Devices and Radiological Health (CDRH) could take to strengthen the program and improve the consistency of its decision making, with a principal focus on actions the Center could take in the short term under its existing statutory authority. 

Preliminary Findings  

Key terms in the statutory definition of “substantial equivalence” have not been consistently interpreted by CDRH. In particular, there is insufficient clarity about what constitutes the same versus a new “intended use,” and about when “different technological characteristics” raise “different questions of safety and effectiveness.” Ambiguity at these critical decision points, at times, has contributed to inconsistency in CDRH’s 510(k) decision making.

While the concept of “substantial equivalence to a predicate” is generally reasonable, CDRH’s application of this standard has, in certain cases, raised concerns. Concerns have been raised that current FDA regulations and practice may allow for some types of predicate comparisons that are insufficient to consistently provide such assurance, including the use of predicates that have been withdrawn from the market due to issues of safety or effectiveness and the use of so-called “split predicates,” a term that refers to using one predicate as the basis for a comparison with respect to “intended use” and another predicate as the basis for a comparison with respect to “technological characteristics.”

In general, most instances where concerns were raised by industry and CDRH staff about problems with the 510(k) program involved the small subset of devices for which staff requested clinical information, either to answer questions appropriate for a substantial equivalence determination. Also involved concerns sometimes in cases where the sponsor had no advance notice that such information would be needed or to answer questions more appropriate for the de novo classification process. Both scenarios have contributed to less predictability and longer time-to-decision in the 510(k) program.

CDRH has a need for more robust systems and tools for quality assurance in the 510(k) program. Quality and consistency depend on a highly qualified, well-trained, and well-supported review staff, and on appropriate oversight. 

There are insufficient tools and metrics in place to assess the consistency of decision making across the 510(k) program, and to track the program’s public health impact quantitatively. Although CDRH collects information on device performance in the postmarket setting, important limitations, including the inability to consistently link postmarket events to specific 510(k)s, make this information, in isolation, an unreliable measure of program effectiveness. 

Preliminary Recommendations

  • Clearly define what constitutes the same versus a new “intended use,” and about when “different technological characteristics” raise “different questions of safety and effectiveness” in guidance and training for review staff and industry.
  • Consider taking steps, through guidance, to set forth factors regarding when a device should not be used as a predicate. Such factors should be well-reasoned, well-supported, and established with input from a range of stakeholders, and unintended consequences should be carefully considered.
  • Explore the possibility of explicitly disallowing the use of “split predicates.”
  • Explore the possibility of developing guidance to define, as a heuristic, a subset of class II devices called “class IIb” devices, for which clinical information, manufacturing information, or, potentially, additional evaluation in the postmarket setting, would typically be necessary to support a substantial equivalence determination.
  • Enhance CDRH’s support for training and professional development for review staff.
  • Develop program metrics and better systems for continuous monitoring of 510(k) program performance and effectiveness, in part through the oversight of a new CDRH Science Council comprised of experienced reviewers and managers, under the direction of the Deputy Center Director for Science. 


Next page: GAO High Risk List Items FY 2012 OPA