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Independent Evaluation of FDA's Prescription Drug User Fee Act III – Evaluations & Initiatives

Contract No.  223-04-8100 Task No. 4

Postmarketing Commitments Study Final Report

Note: This version of the report was modified from its original format to accommodate Federal website Section 508 compliance requirements.  To view the original format of the report, refer to the link to the PDF version of the document.

January 2008

TABLE OF CONTENTS

1. Executive Summary

2. Background, Objectives, and Scope

2.1 Study Objectives
2.2 Study Scope

3. Methodology

4. Findings

4.1 Study Cohort Overview
4.2 PMC Development
4.3 PMC Rationale

4.3.1 Issue/Data Gap
4.3.2 Study Timing
4.3.3 Best Practices Observed

4.4 PMC Milestone Submission, Tracking and Review

4.4.1 Status of PMCs in Study Cohort
4.4.2 Factors Responsible for Delayed PMCs
4.4.3 PMC Tracking and Communication
4.4.4 Timeliness of Sponsor Submission and FDA Review
4.4.5 Best Practices Observed

4.5 Public Health Impact

5 Recommendations

5.1 PMC Development and Rationale Recommendations
5.2 PMC Tracking and Review Recommendations

EXHIBITS

Exhibit 3-1. High-Level PMC Study Approach
Exhibit 5-1: Sample PMC Development Template

Tables

Table 1: PMC Study Cohort by NDA/BLA and NME/non-NME Status
Table 2: Distribution of PMCs across BLAs and NDAs by NME/non-NME status
Table 3: Study Cohort Products and PMCs by Fiscal Year
Table 4: PMC Category Distribution
Table 5: PMC and Product Distribution by Division, Office, and Center
Table 6: Average Number of PMCs per Application by Division/Office
Table 7: PMC Development by GRMPs Phase
Table 8: Sponsor Involvement in PMC Development
Table 9: Factors that Influence FDA's Decision to Request a PMC
Table 10: Actual PMC Rationale for FY 2002-2005 Cohort
Table 11: Study Type Requested When Additional Data or Analysis Needed for Expected/Submitted Study
Table 12: PMC Study Rationale by Review Division
Table 13: Primary Rationale for Postmarketing Study Timing
Table 14: Influence of Product Review Factors on PMC Decision
Table 15: Status of PMCs
Table 16: Status of PMCs by Study Type
Table 17: PMC Status by Fiscal Year of Product Approval
Table 18: Reasons for Delayed PMC Status
Table 19: PMC Status by GRMPs Phase of PMC Notification
Table 20: Consistency in PMC Status Between FDA Databases and Interviews
Table 21: Timeliness of Sponsor PMC Submissions
Table 22: Timeliness of FDA Review of PMC Submissions
Table 23: Fulfilled PMC Impact on Label Changes
Table 24: Label Changes by PMC Study Category
Table 25: Label Changes by Study Subcategory
Table 26: Sponsor Perspectives on R&D Impact of Conducting PMCs and Potential Enforcement Options
Table 27: Summary of PMC Recommendations

1. EXECUTIVE SUMMARY

The Food and Drug Administration (FDA) evaluates new drug and biological products prior to approval for marketing in the United States, in order to ensure the products’ safety and efficacy for human use. However, in some cases, even if FDA approves a product, some issues may remain unresolved. In these instances, FDA may request that a sponsor seeking approval of a new drug or biological product conduct a postmarketing study to provide additional information that is important but not necessary for market approval. In certain situations, postmarketing studies are required by FDA (e.g., clinical benefit studies for products subject to accelerated approval, clinical benefit and safety studies for products approved based on animal efficacy data, and safety and effectiveness studies in pediatric patients). Studies that FDA requires sponsors to conduct, or which sponsors agree to conduct, after FDA has approved a product for marketing are referred to as postmarketing study commitments (PMCs) or phase 4 commitments. [1] Typically, PMCs are identified during the application review process and, while these issues are important to define, they do not represent major unaddressed safety and efficacy concerns, but instead are intended to further refine the safety, efficacy, or optimal use of a product, or to ensure consistency and reliability of product quality. Other postmarketing studies that are conducted by sponsors on their own initiative, typically to seek approval for new indications or formulations, are not PMCs.

Under section 506B of the Federal Food, Drug and Cosmetic Act (the act) [2] , sponsors of approved drugs and biological products that have entered into an agreement to conduct a postmarketing study must report to FDA annually on the status of the study until the study is completed or terminated. These status reports must be submitted annually until FDA notifies the sponsor, in writing, that the agency concurs with the sponsor’s determination that the study commitment has been fulfilled or that the study is either no longer feasible or would no longer provide useful information. [3] Section 506B of the act also requires FDA to develop and publish in the Federal Register annually a report on the status of postmarketing studies that sponsors have agreed to conduct and for which they have submitted reports.

The FDA commissioned this study to identify possible improvements to its existing PMC processes. [4] This report includes a retrospective analysis of agreed-upon PMCs and the processes associated with their development, tracking, and review.

Study Overview

Although FDA and most sponsors are complying with the reporting requirements for PMCs under the Food and Drug Administration Modernization Act of 1997 (FDAMA), the Agency believes that it should proactively evaluate PMCs as an important component of its Critical Path Initiative. Of significance, PMCs may identify important postmarketing adverse events. FDA decides whether additional studies are required to support approval or whether they can be performed after marketing begins. To this end, the Agency commissioned this evaluation to determine if FDA is consistent in its PMC decision-making process. The objectives of this study were to:

• Conduct a retrospective analysis of PMCs associated with New Drug Applications (NDAs), Biologic License Applications (BLAs), and supplements
• Evaluate the consistency of the PMC processes (requiring, requesting, facilitating, and reviewing) within divisions/offices, across divisions/offices, and across centers
• Identify process inefficiencies or inconsistencies
• Evaluate the value of PMCs with respect to public health objectives
• Develop recommendations for improving the quality of the PMC processes.

The study was based on a cohort of all 245 original product and supplemental applications approved with agreed-upon PMCs between FY02 and FY05.  These applications contained a total of 743 unique PMCs. [5] Data were collected from FDA systems and through interviews with FDA reviewers (e.g., Regulatory Project Managers (RPMs), Medical Officers) and sponsor companies.  The cohort consisted of 184 NDAs (118 original and 66 supplements) and 61 BLAs (29 original and 32 supplements).  Thirty percent of the applications had at least one PMC, with an average of three per product (range was from 1.2 for the Office of Nonprescription Products and the Division of Metabolism and Endocrinology Products, to 5.0 for the Division of Anti-Viral Products).

PMC Development

The NDA/BLA review process is divided into five phases, under the Good Review Management Principles and Practices (GRMPs) guidance: [6] 1) filing determination and review planning; 2) review; 3) advisory committee meeting preparation and conduct; 4) action; and 5) post-action. The PMC lifecycle spans the review phases, usually beginning when FDA identifies an issue or data gap in a product application and determines that the gap can be resolved through a PMC.  After notifying the sponsor of the need for a postmarketing study and receiving agreement, the PMC is documented, usually in an approval action letter.  After the product is approved, sponsors submit protocols for the PMC studies [7], annual reports, and final study reports.  FDA tracks, monitors and reviews these submissions until the PMC is fulfilled or released.

PMCs can be developed throughout the product life cycle (from pre-submission to post-marketing), but development most often occurred during the product application review.  Reviewers often identified issues leading to PMCs early in the review process, during the filing and planning or review phases.  However, sponsors were typically not informed of PMC requests until the action phase, sometimes only days before the action date.  The timing of sponsor notification sometimes left insufficient opportunity for sponsors to evaluate study feasibility, clarify rationale and/or propose alternative study designs to achieve the desired objective.  Consequently, a sponsor's input was sometimes limited to proposing or modifying goal dates rather than study design.  Further, late sponsor notification was associated with a greater number of delayed, terminated, or released PMCs.

For PMC development, FDA should encourage reviewers to aim to meet the current GRMPs milestone that PMC discussions begin three weeks prior to division sign-off. Encouraging reviewers to meet this milestone would provide sponsors the opportunity to properly assess feasibility and propose alternative study designs that may be more effective. If feasible, FDA should notify sponsors of potential PMCs sooner. For PMCs known early in the review, the mid-cycle review would be an appropriate goal for notifying sponsors of those PMCs requiring clinical studies.  Early notification of PMCs would allow time for sponsors to develop a workable approach or prepare evidence regarding the necessity or feasibility of the study, without any commitment from FDA to drug approval or to PMC request.

PMC Rationale

PMCs were most often requested based on a need for additional data or analysis for an expected or submitted study in the application (21 percent) that did not significantly impact the overall assessment of safety and efficacy to warrant delaying approval. The next most common rationales for PMC requests were potential safety signals (13 percent), underrepresented subpopulations (12 percent) and drug-drug interaction concerns (10 percent). Divisions/offices had a similar set of reasons for requesting PMCs, but therapeutic area differences influenced which reasons were cited most frequently in each division.

Divisions/offices understand what is appropriate for a PMC, despite a lack of formal guidance. Most sponsors and FDA reviewers indicated that the PMCs they were involved with were appropriately deferred to phase 4, rather than required as part of the original marketing application. This timing decision was often based on the product safety profile in conjunction with the target population for the therapy. Review designation was also a factor in the decision to request PMCs. In particular, those applications that were designated for priority review were more likely to have PMCs requested than standard review applications.  The most frequent reason given for requesting a PMC rather than requiring a completed study for approval was that the issue required further definition but did not affect the determination of safety and efficacy (33 percent of PMCs). The next most common reasons were that the issue was only a theoretical concern (16 percent) and that long-term data were required (14 percent).  There was no significant difference in the probability of having PMCs requested on applications that were approved in single or multiple review cycles, further supporting the notion that FDA review teams have applied consistent standards for issues that can be resolved as PMCs.

While both FDA and sponsors agreed on the justification for most requested PMCs, increased transparency of the PMC process would provide other stakeholders (e.g., public interest groups, Congress) the same insights. As part of the existing GRMPs program, FDA should create and publish guidance regarding PMC requests. This guidance would ensure the appropriate level of  process consistency across divisions/offices, while still allowing for the variability associated with different therapeutic classes. As part of this guidance, FDA should also ensure that reviewing, approving, and workload allocation responsibilities are assigned and performed consistently at the division level.  These practices would likely reduce the number of requested PMCs, relieve workload pressure and allow more time and flexibility for remaining PMC activities.

PMC Milestone Submission, Review and Tracking

PMC tracking and review is an important part of the PMC process, ensuring successful and timely completion of these commitments. For each PMC, FDA and sponsors agree upon significant milestones for study completion. For PMCs that are clinical studies, typical milestones include: protocol submission, patient accrual, study start, study completion, and final report submission. Sponsors submitted their protocols and final study reports by the milestone date 76 percent and 60 percent of the time, respectively. FDA reviewers met their goal dates for completing annual status report reviews (3 months) 53 percent of the time, and final study report reviews (12 months) 61 percent of the time. The main reason for failure to meet review goal dates was competing workload priorities.

The current status of a PMC is characterized by the progress made by the sponsor against the original study schedule and milestones. A PMC that is conducted entirely on schedule proceeds through the following general study lifecycle. All PMCs are initially classified as pending, which indicates that the study has not started and the patient accrual date has not yet passed. Once the study has begun, it is classified as ongoing until the FDA receives the final study report, at which time it is classified as submitted. At the time that FDA has reviewed the report and notified the sponsor that the commitment has been satisfied, the PMC is categorized as fulfilled. There are also three additional status categories for classifying PMCs that do not proceed on schedule or to completion. If the PMC misses a milestone date on the original study schedule, it is identified as delayed until the milestone is met, even if FDA and the sponsor have agreed to a revised timetable.  The commitment is considered terminated if the sponsor discontinues the study before its completion.  If FDA agrees that the study should no longer be conducted or is no longer feasible and notifies the sponsor, the PMC is classified as released.

Among PMCs in the study cohort, 34 percent were completed and 66 percent remained open.  Of the open commitments, 81 percent were progressing on schedule,[8] while the remaining 19 percent were delayed. The most common reason for delayed PMC status was difficulty with patient enrollment in clinical trials (29 percent of delayed PMCs). As mentioned earlier, late sponsor notification of PMCs was associated with delayed study status, likely due to insufficient time to assess feasibility and/or clarify study objectives or design.  In some instances, FDA and sponsor companies agreed to revise the original study schedule due to unanticipated delays such as difficulties in developing an agreed-upon study protocol.  However, the original PMC milestones were used to determine PMC status.  This means that some PMCs were classified as delayed despite proceeding according to a schedule agreed to by both FDA and sponsor.  Moreover, it gives the appearance of a greater number of PMCs for which the sponsor is not putting forth sufficient effort and FDA is not adequately ensuring compliance.

The FDA has taken limited action to address delayed PMCs and reviewers have generally not contacted sponsors regarding delayed PMCs in order to determine the reason for the delay.  Until the FDA Amendments Act of 2007 (FDAAA) was enacted, there was limited enforcement authority available to deal with sponsor noncompliance in addressing certain PMCs, which FDA reviewers interviewed claim has led them to place a reduced emphasis on PMC activities compared to other priorities, such as meeting PDUFA goal dates.  Review team staff turnover (e.g., Regulatory Project Managers, Medical Officers) also affected timely review because it significantly impacted the level of knowledge of and responsibility for PMC tracking and review. Finally, the status tracking systems are passive and can fall out of date when FDA review teams do not submit updates in a timely fashion. For example, there is no consistent mechanism to determine when a PMC should move from pending to ongoing status, and renegotiated PMC schedules were inconsistently noted in the internal databases, each of which may result in inaccurate assessment and limited awareness of PMC status.

In the current environment, improving PMC development practices is anticipated to have the largest impact on increasing PMC compliance among sponsors, because clearly-articulated feasible PMCs are more likely to be fulfilled in a timely manner.  Beyond PMC development, there are several other potential opportunities for improvement related to PMC tracking and review.  First, adopt a quality systems process to ensure PMC responsibilities are met and document monitoring occurs.  Second, monitor the frequency of PMC database updates and prompt non-responsive teams to submit updates, including any renegotiated PMC schedules.  Finally, capture renegotiated PMC study schedules in existing database fields accompanying the current status assessment to give a more accurate representation of PMC status.  This could be accomplished by requiring reviewers to notify the PMC database manager when a new schedule has been agreed to, and displaying this new study schedule in the internal PMC database.  Other options that should be explored include displaying the revised schedule on the public PMC website [9], and releasing a PMC after its study schedule is renegotiated, and creating a new one with the revised milestone dates.

PMC Public Health Impact

FDA promotes and protects the public health by evaluating new drug and biologic products to ensure they are safe and effective.  PMCs can play a critical role in promoting the public health by providing additional safety, efficacy and optimal use data while the product is available to the general public.  Alternatively, PMCs could be detrimental, if they do not provide meaningful results that impact the use of the product and divert resources that could be used for other drug development by sponsors and review of other products by FDA.  The public health impact was first assessed in this study by determining the number of PMCs that resulted in label changes, which have tangible benefit in expanding the education of risks, benefits, and optimal usage of marketed drugs.  For those PMCs that did not result in a label change, the public health impact was assessed through FDA interviews.  More than half (51 percent) of fulfilled PMCs assessed in the study cohort resulted in a label change.  The most common reasons for the label change were validated safety and efficacy concerns (30 percent of fulfilled studies with a label change), validated drug-drug interaction concerns (18 percent), and expanded use in subpopulations (16 percent).  Additionally, for those studies that did not result in label changes, there was a discernible public health benefit, such as confirming safety (33 percent of fulfilled studies without a label change), confirming both safety and efficacy (10 percent) or satisfying safety concerns (9 percent).

Sponsors generally agreed (86 percent) that the PMC program has a positive public health impact, through studies enhancing clinical safety, clinical efficacy, or optimal use of products.  However, 50 percent of sponsors questioned the value and/or rationale of specific PMCs. These sponsors noted that in some cases, the studies were ongoing at the time of approval of the product, and the PMC was simply a mechanism to ensure the results were submitted to FDA.  Others reported that the PMC supported a reviewer's academic interests. Sponsors were divided on whether or not conducting studies to fulfill PMCs impacted their ability to conduct new product research and development (R&D). They indicated that additional FDA enforcement would neither change the sponsor's approach to PMC fulfillment, nor increase the priority with which PMCs were addressed.  Overall, evidence indicates that the PMC program positively impacts public health, but PMCs need to be used judiciously to ensure that only studies addressing important issues regarding safety, efficacy and optimal use are requested.

2. BACKGROUND, OBJECTIVES, and SCOPE

Studies may be conducted by a sponsor after FDA has approved a product for marketing. These studies can be:

• Required by FDA
• Agreed to by FDA and sponsor

The circumstances under which FDA would require a sponsor to conduct a postmarketing study include:

• Confirmatory trials to demonstrate the clinical benefit of a product following accelerated approval
• Pediatric studies for products not adequately labeled for children, required as part of the Pediatric Research Equity Act (PREA)
• Studies needed to confirm safety and efficacy in human subjects for products approved under the Animal Efficacy Rule.

Agreements with sponsors to conduct postmarketing studies can be reached either before or after FDA has granted approval to a sponsor to market a product.  These PMCs are intended to further define the safety, efficacy, or optimal use of a product, or to ensure consistency and reliability of product quality (chemistry, manufacturing and controls (CMC) commitments).  Under section 506B of the act, [10] sponsors of approved drugs and biological products that have entered into an agreement to conduct a postmarketing study must report to FDA annually on the status of the study until the study is completed or terminated. These status reports must be submitted annually until FDA notifies the sponsor, in writing, that the agency concurs with the sponsor's determination that the study commitment has been fulfilled or that the study is either no longer feasible or would no longer provide useful information. [11]

An agreed-upon PMC is typically derived from a gap in product information that FDA identifies in an application, but determines through a carefully deliberated process that resolving the gap is not a condition of approval.  FDA notifies the sponsor of the issue prior to the completion of the product review—before the action letter is issued.  The sponsor must notify FDA in advance of their agreement to conduct the study before it is described in the action letter, and once the sponsor agrees to the PMC, a submission date schedule is usually established.  These dates typically address:

• Protocol submission
• Patient Accrual
• Study start
• Study completion
• Final study report submission

The sponsor is required to report the status of the PMC in their annual report to FDA, which is due within 60 days of the anniversary of the product approval each year. [12]  FDA reviews the annual report (typically within 3 months) and then updates the status in the PMC database.  A final study report submission (which is typically reviewed within one year of receipt) will also trigger an update to the PMC database.  FDA uses the PMC database status to display certain information on a public PMC Web site in order to meet its obligations for public disclosure of information under FDAMA.

2.1 Study Objectives

FDA commissioned this PMC study as part of its continuous improvement effort to the drug and biologic review process.  The objectives of the study were to:

• Conduct a retrospective analysis of PMCs associated with NDAs, BLAs, and supplements
• Evaluate the consistency of the PMC processes (requiring, requesting, facilitating, and reviewing) within divisions/offices, across divisions/offices, and across centers
• Identify process inefficiencies or inconsistencies
• Evaluate the value of PMCs with respect to public health objectives
• Develop recommendations for improving the quality of the PMC processes.

This study reviewed the PMC development process (i.e., when issues are identified in a review and how they become PMCs).  The purpose of this evaluation was to identify ways to improve the decision-making process that results in requested PMCs.  The study also assessed the PMC tracking and review process (i.e., once a PMC is issued, how is the status tracked and how are submissions reviewed) to determine improvements to these processes that may result in better status tracking or an improved PMC completion rate.

2.2 Study Scope

The source of the PMCs included in this evaluation were all NDAs, BLAs and supplements approved between FY2002 to FY2005.  The study only focused on agreed-upon clinical efficacy, clinical safety, clinical pharmacology, and non-clinical toxicology PMCs in these approved applications (i.e., PMCs reportable under 21 CFR 314.81(b)(2)(vii) and 601.70.  The decision to include only these PMCs was based on the assumption that they would provide the most relevant and useful additional information about the risks, benefits, and optimal use of an approved drug or licensed biological product.  The study cohort excluded approved products that had only required PMCs or PMCs pertaining to CMC issues. For products with both required and agreed-upon PMCs, only the agreed-upon PMCs were reviewed, since the rationale for required studies is well-established in legislation.

3. Methodology

To ensure that the correct FDA systems and data sources were being accessed for the study, a preliminary analysis of ten product applications (seven NDAs and three BLAs) was conducted.  After FDA reviewed and approved the preliminary analysis approach, the next step was to conduct the full analysis on the complete cohort of products.  Data were gathered from FDA systems, FDA review team interviews and emails, and sponsor interviews and surveys.  The findings from the preliminary and full analysis project phases were integrated for this final report.  The high-level PMC study approach is illustrated below (Exhibit 3-1).

Exhibit 3-1. High-Level PMC Study Approach
D

FDA documents and databases were the initial source of information collected for each product and the associated in-scope PMCs.  Many basic product and PMC attributes were consistently available from these sources, including:

• Product review details (e.g., approval date, sponsor company, FDA review division)
• Product review designations (e.g., priority/standard review, orphan designation)
• PMC descriptions and goal dates.

Some data that were found in FDA systems required further validation or was inconsistently available, such as:

• Rationale for requesting the study
• Description of why the review issue could be addressed as a PMC instead of a pre-approval requirement
• Timing of communication with sponsor to discuss potential PMCs
• PMC status
• Public health impact of completed PMCs.

FDA and sponsor interviews were conducted to confirm information found in FDA systems and to collect additional data.  Interviews, both in-person and via teleconference, and surveys, via email, were used to collect data in a structured format that facilitated aggregation and comparability between products and PMCs.  To select the sponsors, FDA RPMs were asked to identify the appropriate sponsor point of contact with whom to discuss PMC development and status for their respective product.  Of 110 sponsor companies represented in the study cohort, 51 companies were contacted via email to complete a customer satisfaction survey and 20 submitted responses to the survey. [13] Of these 51 sponsors, 39 were also invited to participate in a teleconference interview.  A total of 18 sponsor interviews (i.e., nine biologic and nine drug products) were conducted in compliance with the Office of Management and Budget (OMB) guidelines.  An interview handout or an OMB-approved customer satisfaction survey was provided to the sponsors who were interested in participating.

4. Findings

The findings from this study are discussed in this section, organized by study cohort characteristics, PMC development, rationale, and tracking and review.  These findings were derived from a combination of the data sources mentioned in Section 3, unless a particular source is noted.

4.1 Study Cohort Overview

The cohort contained all 245 original and supplemental applications [14] that contained agreed-upon PMCs, for both BLA and NDA products.  Applications without agreed-upon PMCs were excluded from the analysis. The study cohort consisted of 48 percent original NDAs, 27 percent NDA supplements, 13 percent original BLAs, and 12 percent BLA supplements (Table 1).  Nearly half of the original NDAs were classified as New Molecular Entities (NMEs), while all original BLAs were considered NMEs. All BLA supplements were considered non-NMEs. The total number of unique [15] agreed-upon PMCs in this group was 743, for an overall average of 3.0 per application [16].  For both NDAs and BLAs, the average number of PMCs per application was significantly greater for NMEs than for non-NMEs.

Table 1: PMC Study Cohort by NDA/BLA and NME/non-NME Status

The number of PMCs per application was more broadly distributed for NME applications than for non-NME applications (Table 2).  NME applications also had more outliers with significantly more PMCs than average.

Table 2. Distribution of PMCs across BLAs and NDAs by NME/non-NME status

The number of product applications approved by year was relatively consistent, although the number of applications with PMCs dropped in FY05 after a steady increase during FY02 through FY04 (Table 3). The number of PMCs by year followed a similar pattern as the number of products with PMCs, demonstrating that the average number of PMCs per application remained consistent through the study cohort years.

Table 3: Study Cohort Products and PMCs by Fiscal Year

A. Total Approved Products (Original Applications and Supplements) by Fiscal Year

B. Total Unique Reportable PMCs by Fiscal Year for Original Applications and Supplements

The PMCs in the study cohort were broadly categorized by study type.  In addition to the four common types of PMCs described in the Code of Federal Regulations [17], two other study commitment types (immunogenicity and microbiology) were identified through interviews with FDA reviewers.  The most common study category was clinical safety, which accounted for 40 percent of the PMCs in the cohort (Table 4).  The distribution of categories varied depending on the application type and NME designation.  For example, clinical safety studies were more common in BLAs than NDAs and were more common in non-NME than NME applications.  Non-clinical toxicology study commitments were more common in NDAs than BLAs.  The proportion of clinical pharmacology commitments was greater in NME than non-NME applications, and they were much more common for NDAs than BLAs.  As expected, microbiology studies were limited to antimicrobial NDAs, while almost all immunogenicity studies appeared in BLAs.

Table 4: PMC Category Distribution

The number of products reviewed and PMCs assigned varied considerably by FDA review division/office.  Divisions with the most PMCs in the study cohort were Anti-Viral Products, Dermatology and Dental Products, Biologic Oncology Products, and Neurology Products (Table 5).  Those with the fewest products and PMC requests were Nonprescription Products and Cardiovascular and Renal Products.  Divisions/offices with the most NMEs also tended to have more PMCs.

Table 5: PMC and Product Distribution by Division, Office, and Center

Legend for Tables 5, 6, and 12

The average number of PMCs per application ranged from a low of 1.2 for the Office of Nonprescription Products and the Division of Metabolism and Endocrinology Products, to a high of 5.0 for the Division of Anti-Viral Products (Table 6).

Table 6: Average Number of PMCs per Application by Division/Office [18]

4.2 PMC Development

The analysis of the PMC development process in this study focused on three primary concepts:

• The general implementation of the PMC development process
• The consistency in timing of each step in the process
• The impact of this timing on study outcome and status.

The NDA/BLA review process is divided into five phases, defined in the GRMPs guidance: 1) filing determination and review planning; 2) review; 3) advisory committee meeting preparation and conduct; 4) action; and 5) post-action. The PMC development process typically occurs during the application review, but in some cases begins prior to submission.  In general, the process involves the following high-level steps: 1) the sponsor is notified of the issue/gap, 2) FDA decides that the gap can be addressed as a PMC, 3) the sponsor is notified of the PMC request, 4) the sponsor agrees to the PMC, and 4) the commitment is documented in the action letter (Table 7).

The PMC development process is initiated when a data gap or issue is identified, which typically happens early in the review process.  Eighty-two percent of issues were identified after application submission and before the end of the review phase.  Twelve percent of issues were discovered prior to the submission and were inadequately addressed by the sponsor at the time of submission.  Once an issue was identified, FDA occasionally notified the sponsor of the issue before making the decision to address it as a PMC; however, in many cases FDA did not discuss the gap in product information with the sponsor until after the PMC decision point.  The PMC decision point occurred most often in the review phase (59 percent), but also occasionally in the action phase (23 percent).  Despite this relatively early PMC decision point, sponsors were more likely to be notified of the PMC late in the review, during the action phase (65 percent), than in the review phase (33 percent).  Late notification appears to have negatively impacted PMC progress and outcome, and is discussed further in Section 4.4.2.

Table 7: PMC Development by GRMPs Phase

Over 60 percent of the 18 sponsors interviewed requested that PMC discussions occur earlier in the review process to provide for sufficient time to evaluate the feasibility of a requested study or to verify and discuss the rationale in order to inform their study objectives and design. Sponsors indicated that they usually agreed to the studies in order to receive approval by the action date, but that rushed agreement had occasionally led to difficulties in subsequent study design and trial execution, with corresponding delays in PMC progress. More than three-quarters of FDA review teams interviewed reported that sponsors provided some input to the PMC, usually during the action phase. Sponsors were most often involved in setting goal dates but less frequently contributed in study trial design, usually because the timing of the interaction did not provide for adequate discourse with FDA (Table 8).

Table 8: Sponsor Involvement in PMC Development

A. Sponsor Involvement

B. Type of Sponsor Involvement

4.3 PMC Rationale

In addition to analyzing the overall PMC development process, this study included an analysis of the rationale for assigning the PMCs.  The rationale for each PMC in the cohort was characterized in two ways:

• What is the issue or data gap that needed to be addressed?
• What is the reason the issue/gap was appropriate for a PMC, instead of a requirement for approval (i.e., study timing)?

The goal was to capture the nuanced thinking that occurs during a review and the breadth of factors considered during the decision-making process.

4.3.1 Issue/Data Gap

When FDA reviewers were asked to generalize, the most commonly cited reasons for PMC assignment were: potential safety signals in submitted studies, underrepresented subpopulations, and drug-drug interaction concerns (Table 9).

Table 9: Factors that Influence FDA's Decision to Request a PMC [19]

Review team perceptions were supported by the actual rationale given for individual PMCs in the study cohort.  Interviewees most frequently cited that the rationale for assigning a specific PMC was a need for additional data or analysis for an expected or submitted study in the application (Table 10) [20].  The next three most common reasons for requesting actual PMCs were potential safety signals in submitted studies, subpopulation studies needed, and drug-drug interaction concerns.

Table 10: Actual PMC Rationale for FY 2002-2005 Cohort [21]

To further define the finding that a need for additional data or analysis for an expected or submitted study led to a PMC, the type of issue/gap was analyzed (Table 11).  Non-clinical toxicology studies were the most common study type to be requested based on this rationale, followed by clinical safety, immunogenicity, and clinical pharmacology.

Table 11: Study Type Requested When Additional Data or Analysis Needed for Expected/Submitted Study

While rationales were similar across review divisions/offices, the mix of rationales for PMCs within each division varied (Table 12). Interviewees attributed these differences to therapeutic area differences or product-specific issues, rather than an inconsistency due to different decision-making processes.  For example, resistance studies were typically requested for antimicrobial products, but are not relevant for other therapeutic areas.  Similarly, assay validation was requested for immunogenicity studies for biologics, but almost never for drug products, which explains part of the reason for the greater number of PMCs associated with approved BLAs. Drug-drug interaction studies were more likely to be requested for products targeting conditions in which patients are likely to be taking several therapies at the same time, such as HIV and cancer. In general, the rationale for most PMCs, across all review divisions/offices, was determined by factors specific to each product application.

Table 12: PMC Study Rationale by Review Division