Background and Summary
On April 24, 2007, the Committee on Health, Education, Labor, and Pensions (HELP Committee) approved S.1082, the Food and Drug Administration Revitalization Act. As reported by the HELP Committee, S.1082 reauthorizes the Food and Drug Administration’s prescription drug and medical device user fee programs, and also includes provisions to improve drug safety, track clinical trials, publicize clinical trial results, and increase data on the safety and efficacy of drugs and medical devices used by children.
Prescription Drug User Fee Act
The Prescription Drug User Fee Act (PDUFA) allows the Food and Drug Administration (FDA) to accept fees paid by pharmaceutical manufacturers to supplement, but not supplant, the agency’s direct appropriations. Any time a company wants the FDA to approve a new drug or biologic prior to marketing, it must submit an application along with a fee to support the review process. In addition, companies pay annual fees for each manufacturing establishment and each prescription drug product marketed. Prior to PDUFA, product reviews were paid for solely with money appropriated by Congress. Under PDUFA, the drug industry provides funding in exchange for the FDA’s agreement to meet drug-review performance goals, which emphasize timeliness.
PDUFA was first enacted in 1992 and has been reauthorized twice since (referred to as PDUFA II and PDUFA III). The impetus behind this legislation was the significant length of time it took for the FDA to approve New Drug Applications (NDAs) and Biologics License Applications (BLA’s), a problem that the FDA attributed to limited resources. These delays in FDA approval affected both drug manufacturers and patients.
The goals of the original PDUFA were to diminish the FDA’s backlog of NDAs and BLAs, and to shorten the time from application submission to FDA decision. PDUFA II expanded these original goals to include activities related to the investigational phases of a new drug’s development; it also added the goal of increasing FDA communications with industry and consumer groups. PDUFA III authorized additional activities both at earlier (pre-clinical development) and later (post-drug-approval) stages of drug research and development.
In implementing PDUFA, the FDA set specific performance goals in coordination with drug manufacturers and the Secretary of Health and Human Services (the “Secretary”). The Secretary submits annual PDUFA performance and financial reports to Congress. As a result of PDUFA, the FDA has increased its review staff and decreased its application review time. Based on its stated goals, PDUFA has generally been viewed as successful.
PDUFA III is set to expire on September 30. S.1082 would reauthorize the prescription drug user fee program; increase the fees the agency charges companies seeking approval for drugs; and expand the use of user fees for post-approval drug safety programs.
Members of Congress and the public have been increasingly concerned about the ability of the FDA to ensure that drugs sold in the United States are safe and effective. S.1082 would strengthen the FDA’s ability to make sure that drug manufacturers appropriately design and conduct post-market studies, and disclose the results to the public. The bill would achieve this by establishing a system of routine active surveillance for post-market drug safety.
Medical Device User Fee Act
In 2002, the Medical Device User Fee and Modernization Act (MDUFMA) accomplished for devices what PDUFA did for drugs: authorized the FDA to collect fees from manufacturers for reviewing Pre-Market Approval Applications (PMAs) and pre-market notifications (510(k)s) and established performance goals for reducing review time. Specifically, MDUFMA: 1) established user fees for pre-market reviews of devices; 2) allowed facility inspections to be conducted by accredited third parties; and 3) instituted new regulatory requirements for re-processed single-use devices.
Under MDUFMA, the FDA also set specific performance goals in coordination with industry groups and the Secretary. The agency is required to provide periodic reports on its progress towards meeting these goals to its stakeholders and Congress. The FDA is also required to provide an annual financial report to Congress to help ensure transparency and accountability of its use of the additional funds provided by MDUFMA.
In the years preceding the enactment of MDUFMA, the FDA’s medical device program resources had been decreasing, undermining the program’s capacity and performance. In particular, new device applications were delayed because the individuals who performed the application review were either stretched thin or not available. The primary goal of MDUFMA was for the FDA to approve safe and effective medical devices more rapidly, thus benefiting device manufacturers as well as patients. The FDA has met most of the modest MDUFMA goals for improving device review times.
Like PDUFA, MDUFMA is set to expire on September 30. S.1082 would reauthorize the medical device user fee program and would increase the fees the agency charges companies seeking approval for medical devices.
Best Pharmaceuticals for Children Act
The Best Pharmaceuticals for Children Act (BPCA) was first enacted in 1997 and reauthorized in 2002. The legislation provides incentives for drug manufacturers to develop pediatric drugs; gives pediatric medications priority status for FDA evaluation; and promotes the dissemination of information related to pediatric drugs. Since enactment of BPCA, the FDA has requested nearly 800 studies involving more than 45,000 children in clinical trials. Pediatric information is now part of the product labeling for 119 drugs. In contrast, in the seven years prior to passage of BPCA, only 11 pediatric studies of marketed drugs were completed. BPCA is set to expire on September 30. Earlier this year, Senator Dodd introduced the Best Pharmaceuticals for Children Amendments of 2007, which would reauthorize BPCA and improve its provisions in order to make it more effective at ensuring that drugs are safe for children. The provisions of the Best Pharmaceuticals for Children Amendments of 2007 are included in S.1082.
Pediatric Research Improvement Act
In 1998, the FDA issued a regulation known as the “Pediatric Rule,” which allowed the agency to require companies to perform pediatric clinical trials on medications used by children. After a U.S. District Court found that the FDA had exceeded its statutory authority in promulgating the Pediatric Rule, Congress passed the Pediatric Research Equity Act (PREA) in 2003, legislation that codified the Pediatric Rule.
Since 2003, over 100 drugs have been evaluated under PREA – and since 1998, more than 1,000 drugs have come under the authority of the Pediatric Rule. PREA is set to expire on September 30. Senator Clinton has introduced the Pediatric Research Improvement Act (PRIA), which would strengthen PREA’s provisions to make it more effective at ensuring that drugs are safe for children. The provisions of PRIA are included in S.1082.
Pediatric Medical Devices Safety and Improvement Act of 2007
The Pediatric Medical Devices Safety and Improvement Act of 2007 was introduced by Senator Dodd in March of this year. This legislation would provide a comprehensive approach to ensuring that children are not left behind as cutting-edge research and revolutionary technologies for medical devices advance. Like drugs, where for too long children were treated like small adults who could just take reduced doses of adult products, many essential medical devices used extensively by pediatricians are not designed or sized for children. According to pediatricians, the development of new medical devices suitable for children’s smaller and growing bodies can lag five or ten years behind those for adults.
The Pediatric Medical Devices Safety and Improvement Act would lower the barriers manufacturers face in developing and producing medical devices that are safe and effective for children and infants. The legislation would provide incentives for companies to develop medical devices for children; enhance the FDA’s ability to track the availability and effectiveness of pediatric devices; and help coordinate investors with researchers in order to facilitate the development of new devices. The provisions of the Pediatric Medical Devices Safety and Improvement Act are included in S.1082.
TITLE I – PRESCRIPTION DRUG USER FEES
Title I of S.1082 would reauthorize PDUFA by codifying the user fee agreement reached by the FDA with the drug and biotechnology industries. It would establish an overall amount for user fees of nearly $393 million for 2008 (which would be adjusted upward based on 2007 workload). It would include the expansion of the use of drug user fees by nearly $30 million for post-approval drug safety programs.
Title I would also codify the FDA-industry proposal to provide for a voluntary user fee program under which drug companies could submit direct-to-consumer advertisements to the FDA for review before they are distributed.
TITLE II – DRUG SAFETY
Subtitle A: Risk Evaluation and Mitigation Strategies
This subtitle would establish a system of routine active surveillance for post-market drug safety through a public-private partnership. The partnership would aggregate data from federal and private health databases and support the analysis of utilization and safety data from these databases. Active surveillance would occur for every newly-approved drug. The aggregated data is expected to produce better drug safety information more quickly.
Risk evaluation and mitigation strategy. Using a risk-based approach, drugs and biologicscould be approved with a risk evaluation and mitigation strategy (REMS). The REMS would be tailored to fit the safety profile of the drug in question. For drugs with new chemical entities, the REMS would be reviewed at 18 months and three years. For other drugs, review would occur at three years, although for all drugs, the FDA would have the authority to require a review if there were public health reasons to do so. Personnel from offices responsible for drug safety would be integrated into the REMS review process.
The following would be the minimal elements of a REMS: 1) FDA-approved professional labeling; and 2) a timetable for periodic assessment of the REMS. For
drugs with out-of-the-ordinary risks, the REMS could include additional elements to protect patient safety, such as special training for doctors who prescribe the drug, and additional studies conducted after approval.
S.1082 would also allow the FDA to impose certain restrictions on advertising of a drug. First, the FDA would be able to require all advertisements (both professional and direct-to-consumer (DTC)) to be submitted for review (not clearance) 45 days before distribution. (This review is the same sort of review for which drug companies would pay user fees on their DTC television ads.) Second, the FDA would be able to require certain disclosures in an advertisement including, for example, that the drug was recently approved and its safety profile isn’t known, or that there is a serious risk or safety protocol listed in the labeling of the drug. Third, if the disclosure that a drug was recently approved is inadequate to protect public health, the FDA would be able to prohibit DTC ads for up to two years after approval. The FDA would impose these requirements only on a case-by-case basis, and the moratorium would only be used in the rare circumstances where the warning would not be effective. (Note that the HELP Committee is currently evaluating whether requiring expanded safety information in DTC ads, coupled with fines for misleading ads, may be an alternate way of achieving the goal of ensuring accurate information is conveyed to consumers; accordingly, the these advertising provisions may change.)
Enforcement. An applicant who knowingly fails to comply with any component of a REMS would be subject to civil monetary penalties of not less than $15,000 and not more than $250,000 per violation, and not to exceed $1 million for all violations adjudicated in a single proceeding. The FDA would also use its traditional enforcement tools, such as seizure of drug products or court injunctions.
Resources. This subtitle would increase user fee revenue by $50 million from the agreement between industry and the FDA to fund drug safety activities, and would authorize $30 million of that amount for the routine surveillance of drugs once marketed. Increased drug user fees would be used to review REMS and for FDA’s general drug safety surveillance.
Transparency. S.1082 includes important measures to promote transparency, such as posting of the action package for approval for drugs (including scientific commentaries), requiring notice of the actions of the Drug Safety Oversight Board, and a report on the involvement of safety staff in drug review activities at the FDA.
Improving science. This bill includes measures to improve science at the FDA, including the establishment of an Office of the Chief Scientist and a required consultation with the Drug Safety and Risk Management Committee on priority drug safety questions and on the effectiveness of aspects of the REMS process.
Subtitle B: Reagan-Udall Foundation for the Food and Drug Administration
This subtitle would establish a foundation to lead collaborations among the FDA, academic research institutions, and industry directed to improving the process of drug development and evaluation. Collaborative research projects would be selected that are designed to bolster research and development productivity; provide new tools for improving safety in drug evaluation; and, in the long term, make drug development more predictable and manageable. This institute would be financially supported by both industry and the government.
Subtitle C: Clinical Trials
Clinical trials registry. To enhance patient enrollment and provide a mechanism to track subsequent progress of trials, clinical trials of late Phase II, Phase III, and Phase IV drugs would be required to register in a publicly-available database. Certain basic pieces of information would be placed in fields in the database entry, while the bulk of the information would be in summary documents.
Clinical trials results. To ensure that results of trials are made public, and that patients and providers have the most up-to-date information, publicly-available information (including the FDA’s action package on a drug) would be deposited in a publicly-accessible database. Device clinical trials to support FDA approval or clearance would also be included, as well as data regarding pediatric post-market surveillance. The FDA would be given regulatory authority to require inclusion of results for trials that are not publicly-available information. Violators of these requirements would be subject to civil monetary penalties.
Subtitle D: Conflicts of Interest
This subtitle would require pre-disclosure of conflicts of interest of members of advisory committees that advise the Secretary regarding activities of the FDA, and greater efforts by the FDA to identify non-conflicted members.
Subtitle E: Other Drug Safety Provisions
Database for authorized generic drugs. S.1082 would require the FDA to compile data on “authorized generics,” which are generic drugs that are manufactured or contracted out by the brand company under a generic label, and make the data available in electronic form. The data would be used by the Federal Trade Commission in a study of the effects of the use of authorized generics on the prices of true generics and the marketplace.
Medical marijuana. S.1082 would subject “medical marijuana” to review by the FDA to ensure its safety and efficacy.
TITLE III – MEDICAL DEVICES
S.1082 reauthorizes MDUFMA by codifying the agreement between the FDA and the medical device industry groups. Although the bill reported out by the HELP Committee reflected only a place holder for the final FDA-industry agreement, the managers’ amendment to be brought up for consideration by the Senate includes a complete agreement. In addition to reauthorizing the user fee program, S.1082 (as modified by the managers’ amendment) would streamline the FDA’s third-party inspection program and allow for electronic registration of device manufacturing facilities. The FDA would receive approximately $287 million from user fees during the five-year period covered by the reauthorization.
TITLE IV – PEDIATRIC MEDICAL PRODUCTS
Subtitle A: Best Pharmaceuticals for Children
Subtitle A would reauthorize BPCA for five years and improve its provisions in order to make it more effective at ensuring that drugs for children are safe for children. As described above, BPCA provides increased market exclusivity to drug manufacturers to encourage the determination of safety and efficacy of drugs in pediatric populations. Currently, BPCA gives six months’ market exclusivity to pharmaceutical companies that invest in research and development of pediatric uses of drugs. S.1082 would cap exclusivity at three months where the annual U.S. sales of a drug exceed $1 billion at the time the written request for pediatric studies is accepted by the drug manufacturer. Products earning less than $1 billion annually would continue to receive six months of exclusivity.
S.1082 would also improve BPCA by implementing the following changes to the program:
- Increasing the amount and quality of pediatric drug information by streamlining BPCA and PREA at the FDA and ensuring that labeling changes that occur as a result of BPCA are communicated to physicians;
- Improving transparency and accountability by making exclusivity determinations and written requests for them public within 30 days of FDA’s awarding of exclusivity; and
- Improving the accuracy and speed of labeling changes by requiring them to be made within the FDA’s timeline and ensuring that they reflect the results of the applicable BPCA study that was conducted.
Subtitle B: Pediatric Research Improvement
Subtitle B would reauthorize PREAand improve its provisions in order to make it more effective at ensuring that drugs for children are safe for pediatric populations. In order to improve coordination with the pediatric exclusivity provisions of BPCA, S.1082 would expand an internal FDA committee to review all issues of pediatric-related labeling and assessments. Doing so would ensure that drugs under both PREA and BPCA are reviewed by individuals with pediatric expertise.
Currently, if a company chooses not to pursue pediatric exclusivity for an already-marketed drug under BPCA, the Secretary has the authority to require the submission of pediatric data for the drug. This authority has never been used, in part due to the lengthy administrative process required to invoke the authority. S.1082 would streamline this administrative process and help acquire essential pediatric data for important drugs, while preserving the ability of companies to meet and discuss testing with the agency. The legislation would also expand the ability of the Secretary to use this authority in cases where such data would represent a benefit to a large number of children, or help us to learn more about the risks associated with certain drugs.
The bill would require two reports – one from the Institute of Medicine and one from the Government Accountability Office – that would allow Congress to have better data on the number and ways in which the Pediatric Rule is used, and evaluate its contributions to ensuring overall pediatric drug safety.
Subtitle C: Pediatric Medical Devices
S.1082 would improve incentives for the development of pediatric devices for small markets – while still preserving the ability to ensure the safety of new products once on the market. It would provide assistance to innovators, streamline regulatory processes, and elevate pediatric device issues at the FDA and the National Institutes of Health (NIH). Specifically, S.1082 would:
- Modify the existing humanitarian device exemption (HDE) for medical devices to allow profit for HDE-approved devices specifically designed to meet a pediatric need. (Under current law, device manufactures may request an HDE from the FDA’s effectiveness requirements, when a device is designed to treat conditions that affect fewer than 4,000 individuals in the United States per year.) The bill would maintain the existing requirement that a humanitarian use device is limited to one that treats and diagnoses diseases or conditions that affect fewer than 4,000 individuals in the United States per year. No profit will be allowed for a device used in more than 4,000 individuals. The HDE exemption expansion would sunset in 2013 and a GAO report assessing the HDE exemption expansion and its impact on patients and manufacturers would be required.
- Establish a mechanism to allow the FDA to track the number and types of devices approved specifically for children or for conditions that occur in children, as well as the approval times for pre-market applications and HDEs.
- Require the NIH to designate a contact point or office to help innovators and physicians access existing funding for pediatric medical device development and direct the NIH, FDA, and Agency for Healthcare Research and Quality to submit a plan for pediatric medical device research that identifies gaps and proposes a research agenda for addressing them.
- Establish demonstration grants for non-profit consortia to promote pediatric device development, including “matchmaking” between inventors and manufacturers and connecting innovators and physicians to existing federal resources, including the FDA, NIH, Small Business Administration, the Department of Veterans’ Affairs, and others.
- Grant explicit authority to the FDA’s Pediatric Advisory Committee to monitor pediatric devices and make recommendations for improving their availability and safety.
- Incorporate several recommendations of the Institute of Medicine, including improving the post-market surveillance of medical devices used in children and expanding public access to post-market studies of pediatric medical devices.
S.1082 was reported out of the HELP Committee on April 18, 2007, by a vote of 15-6. All Democrats, and several Republicans voted to approve the bill. The Committee approved several amendments to the bill, including the following: 1) an amendment offered by Senator Brown to require the FDA to assist the Federal Trade Commission with an investigation into “authorized generics” – drugs licensed by brand-name drug companies to compete with the generic versions of their products; 2) an amendment offered by Senator Burr to set deadlines for negotiations between the FDA and drug companies over labeling changes for drugs; and 3) an amendment offered by Senator Coburn to subject “medical marijuana” to FDA approval, including a review of its safety and efficacy.
The DPC will publish information on amendments when it becomes available.
As of the time of publication, the Bush Administration has not issued a Statement of Administration Policy regarding this bill.