Drug Safety & Pharmacovigilance - GDU Clinical Trials Consulting, LLC

Regulatory History of the FDA

FDA’s modern regulatory functions began with the passage of the Pure Food and Drugs Act of 1906 [i], which prohibited interstate commerce in adulterated and misbranded food and drugs; preventing the manufacture, sale, or transportation of adulterated or misbranded or poisonous or deleterious foods, drugs, medicines, and liquors.

The Food, Drug, and Cosmetic Act of 1938 [ii] required that drugs be labeled with adequate directions for safe use, mandated pre-market approval of all new drugs, such that a manufacturer would have to prove to FDA that a drug was safe before it could be sold, and prohibited false therapeutic claims for drugs. Public outcry over the Elixir Sulfanilamide incident led to the passage of this Act. The solvent in this untested product was a highly toxic chemical analogue of antifreeze; over 100 people died, many of whom were children.

The Kefauver-Harris Amendments in 1962, which mandated efficacy as well as safety before a drug could be marketed, averted the therapeutic disaster with thalidomide of grossly deformed newborns, by not allowing its approval in the United States [iii].

In the 1970’s, reports of pacemaker failures and hearings on Dalkon Shield injuries in thousands of women (after decades of strained FDA resources to remove widely distributed quack machines and gadgets) led to the Medical Device Amendments of 1976 [iv].

Prescription Drug User Fee Act (PDUFA)

The Prescription Drug User Fee Act (PDUFA) was enacted in 1992 and renewed in 1997 (PDUFA II), 2002 (PDUFA III), 2007 (PDUFA IV), and 2012 (PDUFA V). It authorizes FDA to collect fees from companies that produce certain human drug and biological products.

FDAAA (FDA Amendments Act) 2007 and FDASIA (FDA Safety and Innovation Act) 2012

Ensuring the safety, effectiveness and quality of human drugs is an increasingly complicated regulatory task, requiring expert consideration of a multitude of complex factors. The passage of the Food and Drug Administration Amendments Act (FDAAA) of 2007 provided FDA with additional requirements, authorities, and resources with regard to both pre- and post-market drug safety, and directed FDA to develop a systematic, scientifically sound approach to managing the risk-benefit ratio of a drug throughout its lifecycle, with an explicit focus on post-approval safety. The act required increased activities for active post-market risk identification and analysis particularly those related to tools and methods for data access and analysis. [v]

FDA [vi] can thus require manufacturers to:

conduct safety studies and clinical trials upon or after drug approval. Prior to FDAAA, these studies were conducted by manufacturers as voluntary commitments. Since 2008, FDA has required more than 385 postmarketing drug safety studies;
change a drug’s label to include new safety information. Prior to FDAAA, FDA did not have authority to order such label changes. Since 2008, FDA has required new safety labeling 65 times;
implement special risk management programs called Risk Evaluation and Mitigation Strategies (REMS) for its product if FDA believes it is necessary to assure that the drug’s risks do not outweigh its benefits. Many of these programs have a simple requirement to provide information sheets, called Medication Guides, to patients; others have more complex requirements such as patient registries, prescriber education, and restricted product distribution. Since 2008, FDA has required 64 REMS programs with these more complex requirements.

With FDASIA, FDA continues to enhance the structured approach to benefit-risk assessment in regulatory decision-making for human drug and biologic products, and commits to its further development. FDA is now required to implement a structured benefit-risk framework in the new drug approval process.

Information from FDA website:

The FDA Amendments Act of 2007 granted FDA the authority to require REMS, if FDA becomes aware of new safety information and determines that such a strategy is necessary to ensure that the benefits of a drug outweigh its risks. In PDUFA V, we have committed to publishing a draft guidance on how to apply this statutory standard for determining whether a REMS is necessary to ensure that the benefits of a drug outweigh its risks. FDA has formed a working group to address our commitment to publishing the draft REMS guidance. Because the benefit-risk framework was developed with our postmarket risk management authority in mind, there is a link between the framework and this PDUFA V commitment, and we anticipate that the benefit-risk framework effort will inform development of the draft guidance. [vii]

Ensuring the safety, effectiveness and quality of human drugs is an increasingly complicated regulatory task, requiring FDA’s expert consideration of a multitude of complex factors. Over the past several years, FDA has developed an enhanced structured approach to benefit-risk assessment in regulatory decision-making for human drug and biologic products. [viii]

The Benefit-Risk Assessment Framework was developed through extensive review and analysis of previous and ongoing regulatory decisions. PDUFA V commitments include further development and implementation of the Framework into FDA’s human drug and biologic review process. Section 905 of the FDA Safety and Innovation Act also requires FDA to implement a structured benefit-risk framework in the new drug approval process.

[i] http://www.fda.gov/AboutFDA/Whatwedo/History/default.htm

[ii] http://www.fda.gov/AboutFDA/WhatWeDo/History/Origin/ucm054826.htm

[iii] http://www.fda.gov/AboutFDA/WhatWeDo/History/Origin/ucm055118.htm

[iv] http://www.fda.gov/aboutfda/whatwedo/history/productregulation/medicaldeviceandradiologicalhealthregulationscomeofage/default.htm

[v] http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FoodandDrugAdministrationAmendmentsActof2007/ucm184271.htm

[vi] http://www.fda.gov/downloads/Drugs/DrugSafety/UCM300944.pdf

[vii] http://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm329758.pdf Draft PDUFA V Implementation Plan

[viii] http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm326192.htm

References