Department of Health and Human Services
`OFFICE OF
`INSPECTOR GENERAL
`
`FDA’s Review Process
`for New Drug Applications
`
`A Management Review
`
`JANET REHNQUIST
`INSPECTOR GENERAL
`
`MARCH 2003
`OEI-01-01-00590
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`Page 1 of 57
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`ICOS Exhibit 2005
`Mylan v. ICOS
`IPR2017-00323
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`OFFICE OF INSPECTOR GENERAL
`
`http://www.oig.hhs.gov/
`
`The mission of the Office of Inspector General (OIG), as mandated by Public Law 95-452, as amended,
`is to protect the integrity of the Department of Health and Human Services (HHS) programs, as well as
`the health and welfare of beneficiaries served by those programs. This statutory mission is carried out
`through a nationwide network of audits, investigations, and inspections conducted by the following
`operating components:
`
`Office of Audit Services
`
`The OIG's Office of Audit Services (OAS) provides all auditing services for HHS, either by conducting
`audits with its own audit resources or by overseeing audit work done by others. Audits examine the
`performance of HHS programs and/or its grantees and contractors in carrying out their respective
`responsibilities and are intended to provide independent assessments of HHS programs and operations in
`order to reduce waste, abuse, and mismanagement and to promote economy and efficiency throughout the
`Department.
`
`Office of Evaluation and Inspections
`
`The OIG's Office of Evaluation and Inspections (OEI) conducts short-term management and program
`evaluations (called inspections) that focus on issues of concern to the Department, the Congress, and the
`public. The findings and recommendations contained in the inspections reports generate rapid, accurate,
`and up-to-date information on the efficiency, vulnerability, and effectiveness of departmental programs.
`
`Office of Investigations
`
`The OIG's Office of Investigations (OI) conducts criminal, civil, and administrative investigations of
`allegations of wrongdoing in HHS programs or to HHS beneficiaries and of unjust enrichment by
`providers. The investigative efforts of OI lead to criminal convictions, administrative sanctions, or civil
`monetary penalties. The OI also oversees State Medicaid fraud control units which investigate and
`prosecute fraud and patient abuse in the Medicaid program.
`
`Office of Counsel to the Inspector General
`
`The Office of Counsel to the Inspector General (OCIG) provides general legal services to OIG, rendering
`advice and opinions on HHS programs and operations and providing all legal support in OIG’s internal
`operations. The OCIG imposes program exclusions and civil monetary penalties on health care providers
`and litigates those actions within the Department. The OCIG also represents OIG in the global settlement
`of cases arising under the Civil False Claims Act, develops and monitors corporate integrity agreements,
`develops model compliance plans, renders advisory opinions on OIG sanctions to the health care
`community, and issues fraud alerts and other industry guidance.
`
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`E X E C U T I V E S U M M A R Y
`
`PURPOSE
`
`To assess how well the Food and Drug Administration manages its new drug application review
`process.
`
`BACKGROUND
`
`The Food and Drug Administration (FDA) receives new drug applications (NDAs) from
`sponsors, typically pharmaceutical companies, and reviews these applications for scientific
`evidence pertaining to the safety and efficacy of drugs. Based on its assessments, the FDA
`determines whether drugs can be marketed in the United States.
`
`The Prescription Drug User Fee Act (PDUFA), enacted in 1992, authorized FDA to collect
`user fees from sponsors to help speed up the review of NDAs. It also established time goals
`for FDA’s reviews. In 1997, the FDA Modernization Act reauthorized user fees for another 5
`years. It shortened the time goals and called for FDA to work more collaboratively with
`sponsors. In June 2002, the Public Health Security and Bioterrorism Preparedness Act of
`2002 once again reauthorized user fees. The part of this Act addressing user fees is referred to
`as PDUFA III.
`
`This inquiry focuses on FDA’s Center for Drug Evaluation and Research (CDER), which
`reviews NDAs. This inquiry does not assess the scientific merit of the decisions that FDA has
`made. Instead, it examines how well FDA carries out its NDA review process. This report
`draws heavily on the opinions of CDER officials. We surveyed CDER reviewers, receiving an
`estimated 47 percent response rate (N=401) and interviewed about 80 CDER officials,
`including managers. In addition, we surveyed sponsors, receiving a 60 percent response rate
`(N=72), reviewed files for all 15 new molecular entities approved by CDER in fiscal year (FY)
`2001, analyzed CDER data regarding the number of advisory committees, observed 17 CDER
`meetings, interviewed 20 stakeholders, and reviewed relevant FDA policies and procedures.
`We also drew on data from an internal survey conducted by CDER of a random sample of 188
`reviewers that had a 72 percent response rate.
`
`We conducted this inquiry prior to the implementation of PDUFA III. Where appropriate, we
`indicate the potential impact of PDUFA III on our findings.
`
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`FINDINGS
`
`FDA’s new drug application review process has several strengths that contribute
`significantly to its effectiveness.
`
`Both FDA reviewers and sponsors have confidence in the decisions FDA makes. Our
`review underscored that FDA’s NDA review process is science-based and comprehensive.
`This is supported by the comments of both FDA reviewers and sponsors. Seventy-eight
`percent of FDA respondents and 86 percent of sponsors indicated in our surveys that they
`were confident in the decisions FDA makes with regard to a drug’s efficacy.
`
`FDA is highly responsive to the time goals required under the Prescription Drug User
`Fee Act and the FDA Modernization Act. In 1993, median total approval time for CDER
`was 27 months for standard NDAs classified as new molecular entities; in 2001, it was 19
`months. The reduction in approval times helps to ensure timely access to new medications that
`can benefit the public health.
`
`FDA works collaboratively with sponsors. In FY 2001, CDER conducted 1,021 formal
`meetings with sponsors. In these meetings, FDA provides valuable advice to sponsors that can
`help speed up the drug development process.
`
`FDA has taken numerous steps to improve efficiency and consistency. In 2000, CDER
`issued about 40 guidance documents, most of which it directed to sponsors. Between 1996
`and 2001, CDER issued about 140 policies to help guide reviewers. It also now accepts
`applications electronically.
`
`FDA relies on expert scientific reviewers. Both sponsors and reviewers agreed that
`FDA’s in-house expertise is a key asset of the review process. Funds from user fees have
`allowed FDA to increase the number of employees for drug reviews by about 700 employees
`over the past 10 years.
`
`But workload pressures increasingly challenge the effectiveness of the review
`process.
`
`Reviewers are under constant pressure to meet time goals. They not only review NDAs, but
`also other key documents submitted by sponsors, some of which also have time goals attached.
`At the same time, reviewers must provide advice to sponsors and stay abreast of the latest
`scientific advances in their fields. Below, we present the consequences of these workload
`pressures.
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`Reviewer concerns about time pressures. Forty percent of FDA survey respondents who
`had been at FDA at least 5 years indicated that the review process had worsened during their
`tenure in terms of allowing for in-depth, science-based reviews. Respondents cited lack of time
`as the main reason. According to 58 percent of FDA respondents, the allotted 6 months for a
`priority review is inadequate. This is considerably higher than the 25 percent of respondents
`who indicated that the allotted 10 months for a standard review is inadequate.
`
`Reviewer concerns about time constraints do not necessarily mean that there is a threat to
`public health. We have no evidence of a public health concern nor did we seek to obtain such
`evidence. Reviewers commented in interviews that they did not believe that they were ignoring
`key information or data contained in the applications in order to meet time goals. The FDA has
`also received the 4th highest composite score out of the 13 operating divisions within the
`Department of Health and Human Services on the 2002 Secretary’s Quality of Work Life
`Survey on Organizational Climate, which indicates a positive work environment. However, our
`survey data do indicate a significant management issue warranting attention.
`
`The PDUFA III should help to address reviewers’ concerns about time pressures, as CDER
`estimates hiring close to 300 additional employees over the next 5 years with funds from user
`fees.
`
`Less use of advisory committees. Advisory committees are comprised of independent
`scientific experts who provide advice to FDA during the review process. The number of
`advisory committee meetings CDER held for NDAs decreased from 40 in 1998 to 23 in 2001.
`Although the declining number of NDAs submitted by sponsors has contributed in part to this
`decline, FDA managers also pointed out that they have little time to hold these meetings.
`
`Insufficient time for raising scientific disputes. Pressure to meet time goals may inhibit the
`raising of disputes. Reviewers may be reluctant to raise disputes due to concerns about slowing
`down the process. Twenty-one percent of FDA respondents indicated that the work
`environment allowed for the expression of differing scientific opinions to a small or no extent.
`
`Contributing to staff turnover. The FDA data show that medical officers and
`pharmacologists had the highest attrition rates within CDER for FY 2001, 8.4 percent and 6.9
`percent respectively, compared to the overall rate of 5.5 percent. On an internal CDER
`survey, 50 percent of reviewers who responded indicated that their workloads are influential
`reasons to consider leaving FDA.
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`Less time for reviewers to participate in professional development and to conduct
`research to improve drug development. The FDA has policies and programs in place to
`encourage professional development, yet 59 percent of FDA respondents indicated that they
`have little time to participate in professional development activities. Similarly, reviewers have
`little time to conduct research on drug development using the clinical trial databases FDA has
`obtained from sponsors.
`
`Several factors have contributed to the workload pressures.
`
`Time goals have been beneficial, but at the same time they have created pressure on reviewers
`to work quickly. The FDA has little flexibility in reassigning staff to handle increased
`workloads. The FDA’s dual roles as advisor and reviewer demand substantial time and
`resources; the CDER held over 1,000 meetings with sponsors in FY 2001. Incomplete and
`disorganized applications can cause delays. The 15 new molecular entities we reviewed
`contained, on average, 38 amendments to the original application. Inefficiencies in the process
`also contribute to workload pressures.
`
`As we have already indicated, PDUFA III will provide FDA additional resources to hire more
`staff that should help address these workload pressures. It also calls for FDA to conduct
`several studies aimed at improving the efficiency of the process.
`
`Other factors also challenge the effectiveness of the review process.
`
`Rush to finalize drug labels at the end of the process. Although labeling negotiations must
`occur toward the end of the process, we found that negotiations were considerably
`compressed. Eighty-two percent of FDA respondents indicated that labeling negotiations
`contribute to delays. Twenty-seven percent of labeling amendments for the 15 new molecular
`entities we reviewed were submitted in the last 14 days of the review process. The rush to
`finalize labels at the end of the review process can be caused by the lengthy discussions that
`often occur between FDA and the sponsor regarding the information to include on the label.
`The FDA has numerous activities underway to help address this issue.
`
`Reviewers’ uncertainty about postmarketing commitments. Postmarketing commitments
`are made by the sponsor at the time of approval and can include additional studies to further
`define the safety and effectiveness of the drug. Reviewers indicated that they were often
`uncertain about what types of postmarketing commitments to request of sponsors. The
`PDUFA III calls for FDA to issue several guidance documents regarding risk management after
`the drug is approved. These documents should help to clarify the use of postmarketing
`commitments.
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`Limited public disclosure of FDA’s rationale for decisions. We reviewed the information
`on CDER’s website for 15 new molecular entities, and in no case did FDA provide a summary
`document that explained the overall basis for approval. The FDA does not routinely provide
`summary information for approved drugs, nor is it required to do so. We found it took 7.6
`months, on average, for FDA to post the technical information it does disclose on its website
`after a drug is approved. For drugs that FDA reviewed but did not approve, FDA disclosed
`almost no information regarding the basis for its decisions. The FDA’s regulations limit such
`disclosure.
`
`CONCLUSION
`
`FDA’s NDA review process has several strengths. However, reviewers face
`workload pressures that increasingly challenge the effectiveness of the process.
`
`Beyond these pressures, three other factors threaten the effectiveness of the process: the rushed
`review of drug labels that takes place toward the end of the review process, the limited
`guidance available to reviewers in determining the extent and type of postmarketing
`commitments to request of sponsors, and the limited information that FDA makes available to
`the public on the basis for its decisions concerning NDAs. Overall, these findings present a
`significant warning signal, one, that if not fully addressed, could jeopardize the gains that FDA
`has made in recent years.
`
`The enactment of PDUFA III presents significant opportunities to address many of
`the findings in this report.
`
`We recognize that FDA has already identified many of the concerns presented in this report
`and has numerous efforts underway to address them. In particular, the enactment of PDUFA
`III, which FDA played a critical role in developing with sponsors, presents significant
`opportunities to address many of our findings. It calls for an increase in user fees that CDER
`estimates will allow it to hire close to 300 additional employees over the next 5 years. Over
`time, this could help considerably in relieving the workload pressures that we have emphasized.
`In addition to resources, PDUFA III calls for FDA to conduct several activities aimed at
`improving the process. These activities will help to address many of the findings in this report,
`including efficiency, labeling negotiations, and the use of advisory committees. In addition,
`PDUFA III calls for significant attention to be placed on postmarketing commitments. For the
`first time, funds from user fees can be used to monitor drugs after they are on the market. It
`also calls for FDA to develop several guidance documents on risk management.
`
`Our first recommendation offers additional steps that FDA can take as it implements PDUFA
`III to ensure that it takes full advantage of these opportunities to address our
`
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`findings. We also make four other recommendations to FDA to improve the NDA review
`process that are not addressed in PDUFA III. We direct all our recommendations to CDER.
`
`RECOMMENDATIONS
`
`1. Take full advantage of the opportunities in PDUFA III.
`
`< Conduct a retrospective examination of recent NDA reviews to determine the capacity of
`reviewers to conduct in-depth, science-based reviews.
`< Evaluate the adequacy of current staffing levels and the workload distribution among the 15
`review divisions within CDER, and implement a system that in real time would indicate the
`status of an NDA and the time spent in reviewing its specific parts.
`< Assess how amendments to the original application, internal processing delays, and labeling
`negotiations affect FDA’s capacity to make timely, first-cycle review decisions.
`< Offer further guidance on the best way to handle scientific disputes that occur among
`reviewers, and how to balance the role of reviewing NDAs and the role of advising
`sponsors throughout the drug development process.
`Include case studies of past reviews as part of training programs for reviewers to illustrate
`good review principles and foster consistency among divisions.
`< Provide a list of the various postmarketing commitments that FDA reviewers can request of
`sponsors and suggestions for when each could be considered.
`
`<
`
`2. Determine whether the significant workload pressures discussed in this report
`justify any exceptions to the current time goals regarding new drug applications
`to allow for more in-depth reviews.
`
`As we have indicated, the Prescription Drug User Fee Act and the FDA Modernization Act
`have been positive forces for the review process. However, it is important that an appropriate
`balance exists between timeliness and the ability to conduct a comprehensive review. Our data
`show that reviewers face significant workload pressures. Therefore, FDA could examine if it
`would be beneficial to extend the review clock by 1 or 2 months when it chooses to use an
`advisory committee and to consider modifying the current 10-month time goal for standard
`NDAs by 1 or 2 months.
`
`3. Reject applications that are incomplete and of poor quality that can create
`delays in the new drug application review process.
`
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`A timely review process depends not only on FDA, but also on sponsors submitting complete
`and well organized NDAs. Toward that end, FDA could reexamine its policies for refusal-to-
`file and its guidance to sponsors on the content and format of applications to ensure that they
`make explicit FDA’s requirements.
`
`4. Provide the public with a clear and timely explanation of decisions on new drug
`applications.
`
`The FDA could provide on its website a succinct explanation of its rationale for approving an
`NDA. It could also provide the same explanation when it decides not to approve an NDA.
`Disclosing such information could help convey to the public the independent role that FDA
`plays in the review process and that FDA does not approve all drugs. Further, this could help
`sponsors gain a better understanding of the criteria FDA uses in its review process and could
`lead to improved NDAs in the future.
`
`5. Conduct or support research that takes greater advantage of its vast clinical
`trial databases to identify ways to improve drug development.
`
`The results of this research, over time, could be highly cost-effective, contributing to better
`clinical trial designs and more efficient drug development.
`
`AGENCY COMMENTS
`
`The FDA reviewed a draft of this report, and overall, it concurred with our conclusions and
`recommendations. In its comments, FDA outlined numerous activities it has underway or
`planned to address our recommendations. Specifically, FDA indicated that it is reviewing its
`workload distribution and has studies underway to examine delays in the review process. The
`full text of FDA’s comments can be found in Appendix A.
`
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`T A B L E
`
`O F
`
`C O N T E N T S
`
`EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . i
`
`
`INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
`
`
`PRIMER ON FDA’S NDA REVIEW PROCESS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
`
`
`FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
`
`
`Strengths of the Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
`
`Workload Pressures Challenge the Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
`
`Several Factors Have Contributed to the Workload Pressures . . . . . . . . . . . . . . . . . . . . . .14
`
`Other Factors Challenge the Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17
`
`
`CONCLUSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
`
`
`RECOMMENDATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
`
`
`APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
`
`
`Appendix A: FDA’s Comments on the Draft Report . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
`
`Appendix B: Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
`
`Appendix C: Time Goals For CDER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
`
`Appendix D: Highlights of PDUFA III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .32
`
`Appendix E: Rate of Withdrawn Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .35
`
`Appendix F: Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .37
`
`Appendix G: Endnotes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
`
`
`ACKNOWLEDGMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
`
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`I N T R O D U C T I O N
`
`PURPOSE
`
`To assess how well the Food and Drug Administration manages its new drug application review
`process.
`
`BACKGROUND
`
`The Food, Drug, and Cosmetic Act requires the Food and Drug Administration (FDA) to
`review and approve all new drugs before they can be marketed in the United States. The FDA
`evaluates new drugs based upon the scientific evidence obtained from clinical studies and other
`research conducted by a drug’s sponsor, typically a pharmaceutical company. Sponsors
`submit this information to FDA in a new drug application (NDA). Based on its review of the
`application, FDA assesses the safety and efficacy of the drug and determines whether it can be
`marketed in the United States. (We provide a primer that gives an overview of the review
`process on page 5. Appendix B contains a glossary of key terms.)
`
`The Prescription Drug User Fee Act and the Food and Drug Administration
`Modernization Act
`
`In response to the public’s demand for greater access to new drugs to treat life-threatening
`illnesses, the 1992 Prescription Drug User Fee Act, referred to as PDUFA I, was enacted. The
`main purpose of PDUFA I was to reduce the time it takes FDA to review new drugs for
`market approval. It authorized FDA to collect user fees from sponsors to be used towards
`speeding up the NDA review process. It also established time goals for FDA’s review of
`NDAs. The FDA reports annually to Congress on how well it has met these time goals (see
`Appendix C for a list of the goals).
`
`In 1997, user fees were reauthorized as part of the Food and Drug Administration
`Modernization Act. The section of the Act that addresses user fees, referred to as PDUFA II,
`tightened the deadlines in the goals. It also added new provisions to help speed up the entire
`drug development process. Most notably, it required FDA to meet with sponsors upon request
`and codified many existing FDA policies intended to bring life-saving treatments to market
`faster.
`
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`User fees have provided additional resources for FDA. The FDA’s Center for Drug
`Evaluation and Research (CDER) total costs in fiscal year (FY) 2000 for reviewing NDAs was
`$187 million, of which $86 million was paid for by user fees. The FDA primarily used the funds
`from user fees to hire more staff and to implement computer systems to speed up its review of
`NDAs.
`
`Prescription Drug User Fee Act III
`
`The PDUFA II expired on September 30, 2002. In June 2002, user fees were once again
`reauthorized, referred to as PDUFA III, as part of the Public Health Security and Bioterrorism
`Preparedness Act of 2002. The PDUFA III establishes time goals and outlines activities FDA
`will conduct over the next 5 years using the funds from user fees (see Appendix D).1 The
`PDUFA III went into effect on October 1, 2002.
`
`Most notably, PDUFA III increases user fees to help provide FDA with additional resources.
`According to a press release from the U.S. Department of Health and Human Services, “the
`law puts PDUFA III on sound financial basis.”2 In FY 2002, FDA, including both the Center
`for Biologics Evaluation and Research and CDER, estimates it collected about $160 million
`from user fees. Under PDUFA III, total funds from user fees should reach $223 million in FY
`2003, and gradually increase over the next 5 years to reach $260 million in FY 2007. With
`increased resources, CDER estimates it will hire close to 300 additional employees over the
`next 5 years.
`
`Concerns about the adequacy of FDA’s review process
`
`Critics allege that, in the rush to meet its time goals, FDA fails to identify key risks associated
`with drugs. Critics also raise concerns that FDA works too closely with pharmaceutical
`companies, lacks independence, has lowered its review standards, and conducts inadequate
`monitoring of drugs already on the market. Critics point to the recent drug withdrawals as
`evidence of their concerns. Between 1997 and 2001, sponsors voluntarily withdrew 13 drugs
`due to safety concerns. Five of them were approved prior to PDUFA, and one has since
`returned to the market. New molecular entities (NMEs) are drugs containing an active
`ingredient that has never been approved for marketing in the United States. According to
`CDER’s analysis, the rate of safety-based withdrawals for NMEs has remained relatively
`constant for periods prior to and after the enactment of the Prescription Drug User Fee Act in
`1992. According to CDER’s analysis, between FY 1983 and FY 1992, the rate of safety-
`based withdrawals for NMEs, based on the year of receipt, was 2.5 percent, and between FY
`1993 and FY 2002, it was 2.8 percent (see Appendix E for additional analysis). The FDA’s
`own review of many of these withdrawals concluded that they were not attributable to faster
`review times.3
`
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`Our Inquiry
`
`Our inquiry focuses on CDER, one of two Centers within FDA that reviews NDAs. We did
`not evaluate the Center for Biologics Evaluation and Research’s process for reviewing NDAs.
`Our inquiry focuses on how well CDER carries out its NDA review process. We did not
`examine the scientific merit of FDA’s decisions. We conducted this inquiry at the request of the
`director of CDER and prior to the implementation of PDUFA III. Where appropriate, we
`indicate the potential impact of PDUFA III on our findings. We also highlight activities FDA
`has underway to address our findings.
`
`We use the term “FDA reviewers,” broadly, unless otherwise specified, to refer to CDER
`officials involved in the NDA review process. This includes office directors, division directors,
`primary reviewers, secondary reviewers, and project managers within the Office of New
`Drugs, the Office of Pharmacoepidemiology and Statistical Science, the Office of
`Pharmaceutical Science, and the Office of Medical Policy.
`
`Methodology
`
`This inquiry is based on multiple data sources (see Appendix F). This inquiry draws heavily on
`a web-based survey of all CDER primary reviewers, secondary reviewers, and division
`directors. We received 401 responses for an estimated response rate of 47 percent. We
`conducted a mail survey of all 119 sponsors, excluding one federal agency, that had at least one
`NDA approved by CDER in the years 1999, 2000, or 2001. We received 72 responses from
`sponsors, resulting in a 60 percent response rate. We also drew on data from an internal
`survey conducted by CDER of a random sample of 188 reviewers that had a 72 percent
`response rate.
`
`We conducted a file review of all new molecular entities that CDER approved in FY 2001
`(N=15). For these 15 drugs, we analyzed CDER’s receipt dates for all amendments submitted
`to the application. We analyzed CDER’s data on advisory committees. We observed 17
`CDER meetings that occurred throughout the drug development process, including internal
`meetings and meetings between CDER officials and sponsors. We also reviewed relevant
`FDA laws, regulations, policies, and procedures.
`
`To enhance our understanding, we conducted numerous interviews. We interviewed CDER
`officials, including 17 office directors, 27 division directors, and 18 primary and secondary
`reviewers of NDAs, including project managers. We conducted 9 interviews with
`representatives from pharmaceutical companies and 15 interviews with other stakeholders, such
`as consumer advocates, patient advocates, and scientific experts.
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`FDA’s Review Process for New Drug Applications
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`We conducted this inspection in accordance with the Quality Standards for Inspections
`issued by the President’s Council on Integrity and Efficiency.
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`FDA’s Review Process for New Drug Applications
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`P R I M E R O N F D A ’ S N D A R E V I E W P R O C E S S
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`This primer refers to the review of NDAs conducted by CDER.
`
`Review Clock. The review clock is the time between FDA’s receipt of the application and FDA’s decision. The PDUFA II calls
`for FDA in FY2002 to review and act upon 90 percent of standard NDAs within 10 months and 90 percent of priority applications
`within 6 months. Priority applications are for drugs that are a significant improvement over drugs already on the market to treat the
`same condition. Standard applications are applications not classified as priority.
`
`Contents of a New Drug Application. A sponsor, typically a pharmaceutical company, submits the NDA to FDA to obtain
`marketing approval for a drug within the U.S. The application contains data regarding the safety and efficacy of the drug that the
`sponsor obtained during its research and development. Thesedatainclude the results of clinical trials, pharmacology and toxicology
`data, chemistry and manufacturing data, and proposed packaging and labeling information.
`
`Filing Review. When FDA receives an application, the review clock begins. The FDA assigns the application to the appropriate
`therapeutic review division, of which there are 15. The FDA has 60 days, from the receipt of the application, to determine whether
`it is adequate for review. If the application is deemed inadequate or incomplete, FDA can refuse to file it and the sponsor can
`resubmit it later. If the application is complete, FDA notifies the sponsor that the application has been filed.
`
`Reviews within Individual Disciplines. After the application is filed, FDA assigns the application to a team of multi-disciplinary
`reviewers. These reviewers are referred to as primary reviewers. They represent a variety of scientific disciplines, including
`medicine, pharmacology,statistics, and chemistry. The FDA also assigns a project manager that facilitates the review process and
`serves as a liaison between FDA and the sponsor. The reviewers, except for the project manager, evaluate the information in the
`application relevant to their areas. If necessary, the primary reviewer can request additional informati