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.
Drug
Safety
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.
Major Provisions
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 biologics could 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 PREA and
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.
Legislative History
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.
Possible Amendments
The
DPC will publish information on amendments when it becomes available.
Administration Position
As of the time of publication,
the Bush Administration has not issued a Statement of Administration Policy regarding
this bill.
