On September 27, 2007, President George W. Bush signed into law the Food and Drug Administration Amendments Act of 2007, significantly amending the Food, Drug, and Cosmetic Act. The new Amendments will have far-reaching effects, though some of the more controversial aspects of the proposed legislation – for example, provisions involving so-called follow-on biologics - were eliminated during the extensive compromise negotiations that occurred over the past several months. In brief, the major provisions of the new legislation include:

• User Fees. A renewal and expansion of the user fee program under both the Prescription Drug User Fee Act (PDUFA) and the Medical Device User Fee and Modernization Act (MDUFMA).
• Pediatric Incentives. Creation of incentives for medical device manufacturers to target conditions affecting pediatric subpopulations; an elaboration on the requirement for drug companies to submit pediatric data assessments with their New Drug Applications (NDAs); and a call for the formation of an internal Food and Drug Administration (FDA) committee to focus on pediatric issues.
• Reagan-Udall Foundation. Establishment of a nonprofit Reagan-Udall Foundation to support FDA's mission and the Office of the Chief Scientist within FDA to coordinate intramural research efforts.
• Clinical Trial Bank. Expansion of the National Institutes of Health (NIH)-maintained clinical trial data bank by requiring the registration of all device trials and all drug trials from Phase II onward, as well as requiring study protocols and trial results to be incorporated into the database.
• Greater Safety Oversight. Addition of provisions strengthening FDA’s authority over postmarketing studies and risk evaluation and mitigation strategies, and the establishment of reporting systems for human and pet foods that may cause harm to humans or animals.

TABLE OF CONTENTS (Please click on a Title to go to the corresponding text)

Title I - Prescription Drug User Fee Amendments Of 2007
Title II - Medical Device User Fee Amendments Of 2007
Title III - Pediatric Medical Device Safety And Improvement Act Of 2007
Title IV - Pediatric Research Equity Act Of 2007
Title V - Best Pharmaceuticals For Children Act Of 2007
Title VI - Reagan-Udall Foundation
Title VII - Conflicts Of Interest
Title VIII - Clinical Trial Databases
Title IX - Enhanced Authorities Regarding Postmarket Safety Of Drugs
Title X - Food Safety
Title XI - Other Provisions

Title I – Prescription Drug User Fee Amendments of 2007

Under the “Prescription Drug User Fee Amendments of 2007,” FDA will receive additional user fees from pharmaceutical companies totaling approximately $392.8 million per year through FY 2012. The new legislation significantly increases user fees – the agency will receive an additional $225 million from the pharmaceutical industry to help pay for drug safety initiatives, including postmarket safety programs, created under the new legislation. These new fees will be phased in with an additional $25 million collected beginning in Fiscal Year (FY) 2008, with increases of $10 million per year through FY 2012. The new amendments also permit FDA to assess and collect fees from companies that voluntarily submit to the agency direct-to-consumer television advertisements for advisory review.

Title II – Medical Device User Fee Amendments of 2007

Under the “Medical Device User Fee Amendments of 2007,” FDA is authorized to collect approximately $287 million in user fees from medical device manufacturers during fiscal years 2008 through 2012. While the new amendments decrease fees associated with Pre-Market Approval (PMA) and 510(k) Notification submissions, they create two new annual fees -- a registration fee and a fee for filing periodic reports concerning PMA-approved devices. The new amendments also create fees for 30-day device modification notices and device classification requests. Finally, they authorize an additional $39 million in appropriations over five years for FDA’s postmarket surveillance program.

In addition to user fees and appropriations, the Medical Device User Fee Amendments of 2007 also require the promulgation of regulations to establish a unique device identification system for medical devices. The new regulations must establish a system under which a unique device identifier is included on the label of a device and “adequately identifies the device through distribution and use.” No deadline, however, is established for FDA to implement this new system.

Title III – Pediatric Medical Device Safety and Improvement Act of 2007

The “Pediatric Medical Device Safety and Improvement Act of 2007” seeks to improve the research, manufacture, safety, and approval processes for pediatric medical devices. New device applications submitted to the agency must include a description of the pediatric subpopulations suffering from the condition targeted by the device, as well as the total number of affected pediatric patients. FDA is required to report annually to Congress on the progress made in the availability of pediatric medical devices.

Further, the new Pediatric Medical Device Safety and Improvement Act of 2007 expands the existing humanitarian device exemption (HDE) that permits a device to be marketed with minimal efficacy data if it also targets a condition affecting fewer than 4,000 persons. Until now, a company with an HDE was prohibited from making a financial profit on the device. The new language creates an incentive for manufacturers to develop devices for pediatric subpopulations by expressly permitting those companies to profit from devices covered by HDEs and intended to treat or diagnose conditions that affect fewer than 4,000 minors.

The Pediatric Medical Device Safety and Improvement Act also encourages pediatric medical device research by requiring FDA to develop a research agenda, in consultation with experts in the field, within 180 days. In addition, FDA must issue a request for proposals within 90 days for “demonstration grants” to support the activities of nonprofit consortia in promoting and facilitating the development of pediatric medical devices. The Act authorizes an annual appropriation of $6 million for fiscal years 2008 through 2012 to fund these demonstration grants. Further, the Act gives FDA’s Pediatric Advisory Committee the ability to recommend improvements to the pediatric device system, and, finally, also gives FDA the authority to order manufacturers to conduct postmarket surveillance on pediatric devices for more than 36 months, if necessary.

Title IV – Pediatric Research Equity Act of 2007

A second pediatric-related provision – the “Pediatric Research Equity Act of 2007” – reauthorizes and expands upon the Pediatric Research Equity Act. Currently, a manufacturer of a drug or biologic that submits an application to market a new active ingredient, a new indication, a new dosage form, a new dosing regimen, or a new route of administration must include a pediatric data assessment. The new law continues to allow for sponsors to request full or partial waivers from the pediatric assessment requirement, but requires specific documentation be submitted detailing why a pediatric version of the drug or biologic cannot be developed.

The Act also requires FDA to establish an internal FDA committee within 30 days of enactment of the law to review all pediatric assessments, deferral and waiver requests, and labeling. The internal committee is “expected” to conduct a retrospective review of a representative sample of these waiver requests after one year. The Act also orders FDA to coordinate two outside studies evaluating progress in pediatric drug research – one from the Institute of Medicine, to be initiated within three years, and another from the Government Accountability Office, the results of which must be sent to Congress no later than January 1, 2011.

Title V – Best Pharmaceuticals for Children Act of 2007

A third pediatric provision – the “Best Pharmaceuticals for Children Act of 2007” – reauthorizes FDA’s authority to grant market exclusivity for drugs if safety and efficacy studies are provided for pediatric populations. The time limit established for FDA to determine whether the statutory standard is met and exclusivity may be granted is increased from 90 days to 180 days after the submission of the reports from the studies. New language is included to inform the public about pediatric study data and information regarding labeling changes. The authority of the Pediatric Advisory Committee is expanded under the legislation to allow the Committee to review adverse event reports submitted for pediatric studies undertaken by manufacturers. Moreover, the new internal FDA committee will be responsible for reviewing requests for market exclusivity and accompanying study data. Other newly-added provisions direct FDA to develop a priority list of needs in pediatric therapeutics and to award grants supporting pediatric studies. Congress authorizes $200 million for FY 2008 to fund the pediatric studies program, as well as necessary funding for the subsequent four years. Further, an Institute of Medicine study is authorized to assess the market exclusivity requests and a representative sample of study data. The new legislation also provides incentives to perform pediatric research on products that are off-patent or whose manufacturer declines to conduct such studies.

Title VI – Reagan-Udall Foundation

Title VI of the Food and Drug Administration Amendments Act of 2007 creates a new, nonprofit corporation not affiliated with the government to be known as the Reagan-Udall Foundation for the Food and Drug Administration. The purpose of the Foundation “is to advance the mission of the [FDA] to modernize medical, veterinary, food, food ingredient, and cosmetic product development, accelerate innovation, and enhance product safety.” To help FDA achieve these goals, the Foundation will establish priorities, award grants or enter into contracts, coordinate research projects, oversee the patent application process and the licensing of Foundation inventions, and organize and sponsor meetings. Title VI also establishes the Office of the Chief Scientist within FDA to oversee, coordinate, and advocate for the agency’s intramural research programs, as well as to ensure that research efforts are not being duplicated by FDA scientists and the Reagan-Udall Foundation grantees. Finally, this Title grants authority to enter into collaborative agreements, known as Critical Path Public-Private Partnerships, to implement FDA’s Critical Path Initiative.

Title VII – Conflicts of Interest

Title VII includes new provisions that define the recruitment process for FDA advisory committees and the evaluation of individuals nominated to serve on advisory committees. Although waivers of conflicts of interests to allow a member of an advisory committee to participate in the meeting, either as a voting or non-voting member, continue to be permitted under the Title, the new legislation establishes a limit on the number of waivers and other exemptions that may be granted annually.

Title VIII – Clinical Trial Databases

Title VIII of the Food and Drug Administration Amendments of 2007 significantly increases the scope of the HHS clinical trial data bank, accessible on the ClinicalTrials.gov Web site, by expanding the clinical trial registry and requiring results be reported to the data bank for certain clinical trials. The existing system only required the registration of trials of drugs for serious or life-threatening diseases. The new legislation has expanded this requirement so that all ongoing trials of drugs and devices, except for preliminary studies, must be registered. Trials that are initiated after the date of enactment, or are ongoing 90 days after the date of enactment, must be registered not later than 90 days after enactment of the law, 21 days after the first patient is enrolled, or, for a trial that is not for a serious or life-threatening disease, one year after enactment (whichever is later). Moreover, the results of clinical trials that form the primary basis for efficacy claims or are conducted after a drug or device is approved or cleared must be posted to the data bank. This requirement will be phased in over the next three years; FDA is instructed under the legislation to promulgate implementing regulations during this period. The Title includes various details regarding the features to be incorporated into the expanded data bank, including particular search functions and data elements, links to FDA advisory committees that reviewed a study protocol, approval packages for studied drugs, and Medline citations to primary research articles discussing the trial results. Congress provided for a civil monetary penalty of no more than $10,000 for a failure to comply with the registration requirements, although additional penalties may accrue if a trial sponsor does not correct the violation within thirty days. These federal provisions preempt any state or local government from establishing or maintaining clinical trial databases.

Title IX – Enhanced Authorities Regarding Postmarket Safety of Drugs

Title IX broadens FDA’s authority to monitor and improve drug and biologic safety. The Title empowers the agency to require postmarket studies and clinical trials, changes to product labeling, a “Risk Evaluation and Mitigation Strategy” (REMS), pre-review of television advertisements, and additional statements included in direct-to-consumer (DTC) advertisements. Further, Title IX requires FDA to develop a system to identify and analyze postmarket drug safety risks.

• Subtitle A – Postmarket Studies and Surveillance

Postmarket Studies and Clinical Trials

Under the new Title, FDA can require the sponsor of an NDA for a prescription drug or Biologic License Application (BLA):

1. To assess a known serious risk¹ related to the use of the drug involved.
2. To assess signals of serious risk related to the use of the drug.
3. To identify an unexpected serious risk² when available data indicate the potential for a serious risk.

FDA may require studies based on scientific data, including information regarding chemically-related or pharmacologically-related drugs. In the case of approved applications, however, FDA can only require such studies if it becomes aware of new safety information after approval.

The Title provides certain limitations on the authority to require such postapproval studies – there must be a determination that existing postmarket reporting requirements and the active postmarket risk identification and analysis system (described below) will not be sufficient to meet the above three purposes and there must be a determination that postapproval studies will not be sufficient to meet the above three requirements.

Finally, the Title includes provisions for the establishment of timetables for completion of the studies, the submission of periodic reports during the course of the studies, and dispute resolution proceedings.

Changes to Labeling

Title IX requires FDA promptly notify the holder of an approved drug product, or generic drug product if the innovator drug is not currently marketed, if new safety information becomes available that FDA believes should be included in the drug labeling. If such a notification is made, the application holder within 30 days must either submit a supplement to FDA proposing changes to the labeling to reflect the new safety information or notify FDA that it does not believe a labeling change is warranted. If FDA disagrees with the proposed changes to the labeling, or the reasons why the application holder believes no labeling change is necessary, then FDA is to initiate discussions with the application holder. The Act provides a timetable for such discussions as well as provisions for dispute resolution.

Risk Evaluation and Mitigation Strategy

The Title also provides FDA with the authority to require a Risk Evaluation and Mitigation Strategy for new drug and biologic license applications if FDA determines it is necessary to ensure that the benefits outweigh the risks of the drug involved. FDA may also require a REMS for approved drug and biologic license applications if the agency becomes aware of new safety information and makes a determination that a REMS is necessary to ensure that the benefits of the drug outweigh the risks of the drug.

Once an applicant or sponsor is notified of FDA’s decision, the applicant or sponsor must submit a REMS to FDA within 120 days or within another “reasonable” timeframe as required by FDA to protect the public health. These provisions codify FDA’s specific authority to require postmarketing risk minimization plans (RiskMAPs) and other restricted distribution plans.

Direct-to-Consumer Advertising

The Title empowers FDA to require the submission of any television advertisement for a drug for review not later than 45 days prior to dissemination of the advertisement. FDA may recommend changes to the advertisement that the agency deem necessary to protect the “consumer good and well-being” or that are consistent with the approved prescribing information for the product. Further, the agency may also recommend, if appropriate and if information exists, the inclusion of statements to address the specific efficacy of the drug as it relates to specific populations groups, including the elderly, children, and racial and ethnic minorities. However, FDA may not require such changes to an advertisement unless it determines that the advertisement would be false or misleading without a specific disclosure about a serious risk listed in the drug product labeling. Finally, FDA is given authority to require advertisements for new drugs or biologics disclose the date of FDA approval for up to two years after approval if the agency determines that the advertisement would otherwise be false and misleading.

The new provisions require that the major statement relating to side effects and contraindications presented in direct-to-consumer (DTC) advertisements stating the name of the drug and its conditions of use and presented in radio or television format must be presented in a “clear, conspicuous, and neutral manner.” The provisions further direct FDA to promulgate regulations establishing criteria for determining whether a major statement meets the standard set forth in this provision.

In addition, this Title requires print DTC advertisements include the following statement in conspicuous text: “You are encouraged to report negative side effects of prescription drugs to FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.” FDA is also directed to conduct a study determining whether such a statement is appropriate for inclusion in DTC television advertisements. If FDA determines that such a statement is appropriate, then regulations are to be written requiring the implementation of such a statement in DTC television advertisements.

Provisions Related to Generic Drugs

The new legislation includes several provisions related to the submission of citizen petitions to challenge approval of generic drug applications. The Act prohibits FDA from delaying approval of a generic drug application on the grounds it has not completed its review of a citizen petition raising issues related to the application, unless such a delay is necessary to protect “the public health.” Further, FDA must take final agency action on the petition within 180 days of its submission and cannot delay action for any reason, including a determination that delaying approval of a generic application pending resolution of the petition is necessary to protect the public health, the submission of comments related to the petition or additional information from the petitioner, or the consent of the petitioner. Indeed, the new provisions state that any final decision on the petition within the 180 day period, as well as FDA’s failure to make a final decision within 180 days, shall constitute final agency action, allowing for an appeal to the courts. The provisions also authorize FDA to deny a citizen petition if the agency determines that the petition was submitted with the primary purpose of delaying the approval of a generic application.

Within nine months of enactment of the Amendments, FDA must publish a complete list on its Web site of all so-called “authorized generic drugs” – that is, all drugs approved under “full” new drug applications but sold under different labeling or packaging from the identified, listed drug. The list must be updated quarterly to include each authorized generic drug included in annual reports submitted by the sponsor of a pioneer drug. FDA must notify other federal agencies, including the Federal Trade Commission and the Centers for Medicare & Medicaid Services, that it has published the list and will update the information quarterly.

Active Postmarket Risk Identification and Analysis

FDA is directed to develop a system to identify and analyze postmarket drug safety risks. The system must collect drug safety data to identify postmarket risks and provide for advanced analysis of the drug safety data in order to: (1) to improve the quality and efficacy of postmarket drug safety risk-benefit analysis; (2) provide FDA with routine access to outside knowledge to study advanced drug safety questions; and (3) enhance the ability of FDA to make timely assessments based on drug safety data.

Reports to Congress and Studies

Title IX includes several reporting requirements for the Secretary of Health and Human Services and the Commissioner of Food and Drugs, including:

• • A report to Congress on DTC advertising and its ability to communicate to subsets of the general population, including elderly populations, children, and racial and ethnic minorities
  • A report on how best to communicate the public risks and benefits of new drugs and the role of risk evaluation and mitigation strategy in assessing such risks and benefits
  • A report on the ways in which the HHS Secretary has used the active postmarket risk identification and analysis system to “identify specific drug safety signals and to better understand the outcomes associated with drugs marketed in the United States”

Enforcement

Title IX includes an expansion of FDA’s authority to assess civil penalties, including penalties for the violation of the new drug safety requirements related to postmarket studies and clinical trials, revised labeling, REMS, and the dissemination of DTC advertisements that are false or misleading). Further, the scope of the definition of “misbranded” products is expanded to include the products that fail to comply with the new drug safety requirements.

• Subtitle B – Other Provisions to Ensure Drug Safety and Surveillance

Subtitle B of Title IX outlines several additional drug safety and surveillance provisions, including:

• Clinical Trial Guidance for Antibiotic Drugs – TheAct requires FDA to issue guidance for conducting antibiotic drug clinical trials. It also requires FDA review and update the guidance within five years to reflect developments in scientific and medical information and technology.
• Prohibition Against Food to Which Drugs or Biological Products Have Been Added – The Act prohibits the introduction or delivery for introduction into interstate commerce of any food to which has been added an approved drug or biologic, or a drug or biologic for which substantial clinical investigations have been instituted and made public. The prohibition allows for some exceptions, including foods that were marketed prior to FDA approval of the drug or biologic, or prior to the commencement of any substantial clinical investigations of the drug or biologic. Foods in which the drug or biologic is used to enhance the safety of the food, but which does not have an independent biological or therapeutic effect on humans, and where such use is in conformity with FDA’s regulation of food, are also exempt.
• Assuring Pharmaceutical Safety – FDA is directed to develop standards and identify and validate effective technologies for securing the drug supply chain against counterfeit, diverted, subpotent, substandard, adulterated, misbranded, or expired drugs. As part of this effort, FDA must develop a standardized numerical identifier that would be applied to a prescription drug at the point of manufacturing and repackaging in order to facilitate the identification, validation, authentication, and tracking and tracing of the drug. Further, FDA is directed to expand and enhance FDA resources and facilities to secure the drug supply chain against counterfeit, diverted, subpotent, substandard, adulterated, misbranded, or expired drugs, including biologics and active pharmaceutical ingredients, from domestic and foreign sources.

Title X – Food Safety

Title X includes several provisions intended to establish new systems that strengthen the monitoring, reporting, and publicizing of human and pet food safety issues.

The Title requires FDA within two years of the date of enactment of the Act to promulgate regulations establishing ingredient standards and definitions with respect to pet food, processing standards for pet food; and updated standards for the labeling of pet food that include nutritional and ingredient information. FDA is also required to establish within a year of enactment “an early warning and surveillance system to identify adulteration of the pet food supply and outbreaks of illness associated with pet food.”

Title X also adds several provisions aimed at improving FDA’s oversight of human and pet food safety. FDA is required to establish within a year of enactment an electronic “Reportable Food Registry” system to which reports may be submitted to the agency for a food product, other than infant formula, when there is a “reasonable probability” that use or exposure to the food “will cause serious adverse health consequences or death to humans or animals.” The Title imposes the reporting requirement on firms that manufacture, process, pack, or store food products (“responsible party”), as well as federal, state, and local public health agencies. Responsible parties must submit a report within 24 hours of becoming aware that the food product may pose a danger. If necessary to protect the public health, FDA must issue an alert or notification about the food. Also, if FDA believes that the food may have been intentionally adulterated, the Department of Homeland Security must be notified.

Notably, the new legislation strongly encourages, and in some cases, mandates, cooperation between FDA and other federal agencies, state and local agencies, and private organizations. For example, Title X includes provisions requiring FDA to work with states “to establish, continue, and strengthen” food safety programs. FDA is also instructed to work with state and local health agencies to monitor food safety in establishments that are not required to be registered with FDA and report adverse events involving food. In addition, the agency is to work with private organizations, such as companies and relevant professional organizations, during ongoing recalls of human or pet foods, as well as use existing networks of communication and to post information regarding the recalled foods on FDA’s Web site in a single location.

The Title specifically states that the regulation of dietary supplements under the Dietary Supplement Health and Education Act (DSHEA) and under the Dietary Supplement and Nonprescription Drug Consumer Protection Act is not affected.

Under Title X, FDA must make an annual report to Congress that includes with respect to the preceding year:

• The number and amount of food products regulated by FDA and imported into the United States, aggregated by country and type of food
• The number of FDA inspectors of imported food products and the number of FDA inspections performed on such products
• Aggregated data on the findings of such inspections, including data related to violations and enforcement actions taken with respect to the such findings and violations

Title XI – Other Provisions

Title XI includes several miscellaneous provisions, including those that:

• Require review and clearance by FDA of articles written by agency employees, including Staff Fellows or contractors who perform staff work, prior to publication.
• Establish a priority review program to encourage development and marketing of treatments for so-called “tropical diseases,” such as tuberculosis, malaria, and cholera.
• Require FDA to contract with the Institute of Medicine to assess the safety and quality of genetic tests and prepare a report if the Advisory Committee on Genetics, Health, and Society has not completed and submitted its report and action recommendations by July 2008.
• Encourage the development of antibiotic drugs that are intended to treat drug-resistant bacteria.
• Establish criteria for considering a drug containing a single enantiomer to be a new chemical entity eligible for five year marketing exclusivity.

The text of the full Food and Drug Administration Amendments Act of 2007 may be found here on FDA.gov.

If you have any questions about the Act, please do not hesitate to contact any member of the Arent Fox Food and Drug Group.

Stanley H. Abramson
abramson.stanley@arentfox.com
202.857.8935

Rachel G. Lattimore
lattimore.rachel@arentfox.com
202.857.8958

Wayne H. Matelski
matelski.wayne@arentfox.com
202.857.6340

Georgia Ravitz
ravitz.georgia@arentfox.com
202.857.8939

James R. Ravitz
ravitz.james@arentfox.com
202.857.8903

Paul M. Rudolf, MD
rudolf.paul@arentfox.com
202.775.5731

Brian P. Waldman
waldman.brian@arentfox.com
202.857.8971

Marsha C. Wertzberger
wertzberger.marsha@arentfox.com
202.857.6122

Sarah C. Beck
beck.sarah@arentfox.com
202.857.6036

Joanne S. Hawana
hawana.joanne@arentfox.com
202.715.8951

Amy M. Swift
swift.amy@arentfox.com
202.857.6338

Julia C. Tierney
tierney.julia@arentfox.com
202.828.3427

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1. The Act defines “serious risk” as “a risk of a serious adverse drug experience.”

2. The Act defines “unexpected serious risk” as “a serious adverse drug experience that is not listed on the labeling of a drug, or that may be symptomatically and pathophysiologically related to an adverse drug experience identified in the labeling, but that differs because of greater severity, specificity, or prevalence.”