Regulation and Testing of Vaccines in the US

Food and Drug Administration Modernization Act

Among other things, the FDAMA of 1997 included measures to modernize the regulation of biologics by synchronizing their review process with that of drugs and eliminating the requirement for an establishment license for biologics. Expedited approval mechanisms for life-threatening conditions also were authorized under FDAMA.

Pediatric Research Equity Act

The Pediatric Research Equity Act (PREA) of 2003 amended the FD&C Act by adding Section 505(B) to address product development for pediatric subjects from birth to 16 years of age. It requires that manufacturers submit a pediatric assessment with every application submitted under Section 505 of the FD&C Act or section 351 of the PHS Act for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration unless the applicant has obtained a waiver or deferral from the FDA. The pediatric assessment must contain data adequate to assess the safety and effectiveness of the drug or the biological product for the claimed indications in all relevant pediatric subpopulations and data to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

Food and Drug Administration Amendments Act

The FDAAA of 2007 includes 11 titles that added many new provisions to the FD&C Act. It reauthorized and amended several drug and medical device provisions and provided the FDA with additional responsibilities and new authorities. The provisions of FDAAA that have had a significant impact on the regulations of vaccines and the review process are contained in Title IV, the PREA, and Title IX, Enhanced Authorities Regarding Postmarket Safety of Drugs. The FDAAA reauthorized and revised the PREA, primarily to enhance FDA oversight and applicant accountability for the agreed-upon pediatric assessments. Of note, a new provision directed the FDA to establish the Pediatric Review Committee (PeRC), an internal review committee with pediatric expertise. This committee is required to provide consultation to FDA review divisions on all pediatric plans and assessments and on all deferral and waiver requests. Thus, early in the application review process the review team must assess whether PREA applies. If PREA applies, then a pediatric assessment must be presented to the PeRC.

Section 901 of Title IX of the FDAAA authorizes the FDA to require certain postmarketing studies and clinical trials for prescription drug and biological products approved under Section 505 of the FD&C Act or Section 351 of the PHS Act (42 USC §262). Section 901 of the FDAAA also created new Sections 505-1 and 505(o)(4) of the FD&C Act, authorizing the FDA, under certain circumstances, to require risk evaluation and mitigation strategies and safety-related labeling changes, respectively. The FDAAA also specifies adverse event reporting requirements for products with labeling changes that are a result of a pediatric assessment. Specifically, during the 12 months from the date that such a labeling change is made, all adverse event reports are reviewed by the FDA Pediatric Advisory Committee. Following review, the Pediatric Advisory Committee makes recommendations regarding whether the FDA should take action in response to such reports and whether the current pharmacovigilance plan is adequate.

Food and Drug Administration Safety and Innovation Act

The FDASIA was signed into law in 2012 and expanded the FDA’s authority by strengthening the agency’s ability to safeguard and advance public health by promoting innovation, increasing stakeholder involvement in FDA processes, and enhancing the safety of the drug supply chain. In addition to reauthorizing the prescription drug and medical device user fee programs, FDASIA established new user fee programs for generic drugs and biosimilar biological products. The provisions of FDASIA that impact the regulation of vaccines are contained in Pediatric Drugs and Devices (Title V) and Drug Approval and Patient Access (Title IX) . Title IX expands the scope of products that qualify for accelerated approval and creates a new “breakthrough therapy” program, among other things (see below). FDASIA also revised PREA to include a provision that requires vaccine manufacturers to submit a Pediatric Study Plan early in the drug development process. This initial Pediatric Study Plan must contain an outline of the pediatric study or studies that the sponsor plans to conduct, including, to the extent practicable, study objectives and design, age groups, relevant end points, and statistical approach, as well as any request for a deferral, partial waiver, or waiver. The FDA internal PeRC must be consulted for the review of the initial study plan, the agreed initial pediatric plan, and certain amendments to such plans. Both sponsors and the FDA must comply with prescribed timelines regarding submission, review, responses, and agreements reached regarding the Pediatric Study Plan, which are also described in applicable FDA guidance.

21st Century Cures Act

The 21st Century Cures Act (Cures Act) was signed into law in 2016 and strengthened the FDA’s ability to accelerate product development and promote innovative tools. The provisions of the Cures Act that impact the regulation of vaccines are contained in Title III (Development).

For example, the Cures Act revised and codified FDA’s qualification process to expedite the development of publicly available drug development tools (DDTs) and clinical outcome assessments. DDTs are methods, materials, or measures that can aid drug development and regulatory review, such as biomarkers. Once qualified, a DDT can be widely used across multiple drug and biologic development programs, including vaccines. The 21st Century Cures Act amends Chapter V of the Federal Food, Drug, and Cosmetic Act indicating that FDA “shall establish a program to evaluate the potential use of real world evidence (REW) (1) to help to support the approval of a new indication for a drug approved under section 505(c), and (2) to help to support or satisfy post-approval study requirements.” Although vaccines are licensed under the Public Health Service Act, the Office of Vaccines Research and Review (OVRR) at CBER has been contacted by regulated industry about the use of RWE to confirm the clinical benefit of vaccines and to support changes in labeling to include new comparative claims of vaccine effectiveness. In addition, evaluation of RWE may be essential as confirmatory effectiveness data to support accelerated approval of certain vaccines against other rare or emerging infectious diseases.

The 21st Century Cures Act defines “real-world evidence” as “data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than randomized clinical trials.” This can include data derived from prospective and retrospective observational studies and registries and may include use of electronic health records (EHRs) or claims data.

Food and Drug Administration Reauthorization Act of 2017

The FDA Reauthorization Act of 2017 (FDARA), signed into law on August 18, 2017, amends the Federal Food, Drug, and Cosmetic Act to revise and extend the user-fee programs for drugs, medical devices, generic drugs, and biosimilar biological products. It contains nine titles, including those reauthorizing the four user fee programs through FY2022. Many provisions of FDARA are not directly applicable to preventive vaccines and thus, are not further described here. Of note, FDARA also amended Section 505A the FD&C Act to require the Secretary to review and act on a proposed pediatric study request or proposed amendment to a written request within 120 days of submission and to provide to the internal review committee any response to a proposed pediatric study request.

Public Law 115-92

Public Law 115-92, enacted December 12, 2017, amended section 564 of the FD&C Act to allow for emergency uses of medical products for threats in addition to biological, chemical, radiological, or nuclear agent(s), to include other agents that may cause or are associated with, an imminently life-threatening and specific risk to the U.S. military forces. The legislation also authorized the Department of Defense (DoD) to request and FDA to provide assistance to expedite development and the FDA’s review of products to diagnose, treat, or prevent serious or life-threatening diseases or conditions pertaining to American military personnel. A joint program was launched by FDA and DoD on January 16, 2018, to prioritize the expedited development of safe and effective medical products including vaccines intended for deployed American military personnel.

Prescription Drug User Fee Act

Of note, these amendments to the FD&C Act also renewed the Prescription Drug User Fee Act (PDUFA) that was first enacted in 1992 and authorized the FDA to collect user fees from companies. These fees enabled FDA to hire additional reviewers and support staff and upgrade its information technology systems. In return for these additional resources, the FDA agreed to certain review performance goals, such as completing reviews of new drug applications and biologics license applications (BLAs) and taking regulatory actions on them in predictable timeframes. These changes revolutionized the drug approval process in the United States and enabled FDA to speed the application review process for new drugs and biologics without compromising the FDA’s high standards for demonstration of safety, efficacy, and quality. The PDUFA program has been reauthorized every 5 years, 1997 (PDUFA II), 2002 (PDUFA III), 2007 (PDUFA IV), 2012 (PDUFA V), and 2017 (PDUFA VI). It includes the 5-year review performance goals for drug and BLAs, supplements and resubmissions, meeting management goals, clinical holds, major dispute resolution, special protocol question assessment and agreement, electronic applications and submissions, discipline review, and complete response letters.