- Brief History of Pharmaceutical Regulation
- The United States is the global leader in biopharmaceutical research and development, accounting for around one-third of the world’s pharmaceutical market. In exploring the nuances of drug innovation and regulatory approval, it can be helpful to review how the current state of pharmaceutical regulation came to be. From the Pure Food and Drug Act of 1906 to the 1962 Kefauver-Harris Amendments, numerous events in our pursuit of a balance between patient safety and market innovation have shaped the regulatory and intellectual property world we know today.
- Hatch-Waxman Amendments
- The 1984 Hatch-Waxman Amendments arose from the legislature’s attempt to enhance the availability of lower-cost generic drugs while simultaneously maintaining incentives for research-based pharma companies to expend the resources necessary to develop new drugs. Today, if generic manufacturers demonstrate a product’s bioequivalence to the pioneer drug, FDA can rely on its finding of safety and efficacy for the innovator product to expedite approval of the generic version. The Amendments provide for patent listings, patent certifications, and a regulatory stay of approval permitting parties to resolve patent disputes before generic drug market entry. Understanding the regulations governing today’s drug approval pathways, bioequivalence requirements, Q1/Q2 requirements for parenteral drugs, and safe harbor provisions is vital to optimizing the product lifecycle and market value. Drug sponsors should be familiar with concepts surrounding innovator intellectual property protections, including new chemical entity exclusivity, Orange Book listings, use codes, patent certifications, Section VIII label carve-outs, and ANDA litigation.
- Pharmaceutical Market Exclusivities
- Various market exclusivities have been designed to increase incentives for new drug innovation and development for high-priority conditions and diseases. Approved drug products with previously unapproved active moieties receive five-year new chemical entity (NCE) exclusivity. The approval of a new indication or condition of use that required a new clinical investigation essential to approval of the change receives three-year new product exclusivity. And the generic applicant that is the first to file a substantially complete ANDA containing a paragraph IV certification with respect to a patent that the NDA holder asserts claims the referenced brand drug receives 180 days of marketing exclusivity with respect to other paragraph IV filers. Drug manufacturers and sponsors should understand the benefits, limitations, and regulatory requirements for available pharmaceutical market exclusivities.
- Biologics and Biosimilars
- In 1997, Congress established a biologics license application (BLA) under §351(a) of the Public Health Service Act for biological products containing full data on product safety, purity, and potency. Subsequent growth in biologic drug applications urged the 2010 enactment of the Biologics Price Competition and Innovation Act (BPCIA), shaping a regulatory and legal pathway for the approval of biosimilar and interchangeable biological products, exclusivities for innovator biological products, and procedures to resolve patent disputes. Today, the 351(k) application offers an abbreviated pathway for biological products shown to be biosimilar or interchangeable with a licensed biological reference product. Understanding the details of 351(a) and 351(k) applications, including biosimilarity and interchangeability requirements, is vital for biologic and biosimilar developers.
- Biological Product Market Exclusivities
- Like the Hatch Waxman Amendments, BPCIA offers numerous exclusivities for biologicals and biosimilar drug products. These include patents, patent term restoration (PTR), orphan drug exclusivity, and pediatric exclusivity. In addition, innovator biological products may be eligible for reference product exclusivity and biosimilars can be eligible for interchangeability exclusivity under BPCIA. It is helpful to be familiar with the various exclusivity durations, eligibility requirements, incentives, and exceptions in preparing for product development and commercialization.
- Patent Term Restoration (PTR)
- The Hatch-Waxman Act includes provisions to restore patent life lost during pharmaceutical product development and approval. Any approved product covered by a composition, method of use, or method of manufacture patent may be eligible for patent term restoration (PTR). Sponsors of small molecule products, biologics, biosimilars, and combination products should be familiar with PTR eligibility criteria, PTR term duration, and any impact of existing exclusivities.
- Orphan Drug Exclusivity
- The Orphan Drug Act of 1983 urges sponsors to develop drugs to prevent, diagnose, or treat rare diseases and conditions. FDA orphan drug designation is available for products intended for use in fewer than 200,000 patients in the U.S. per year or products unlikely to recover the costs of research and development. With orphan drug exclusivity, FDA will not approve a subsequent sponsor of the same drug (active moiety) for the same use or indication for 7 years. Examples of orphan drug products include single-entity products for new orphan indications, fixed-dose combination products, and co-packaged products. Significant variation exists in “drug sameness” eligibility among small molecules, polysaccharide drugs, polysaccharide drugs containing two or more distinct nucleotides, complex partly definable drugs, monoclonal antibodies, and fusion proteins. Multiple orphan drug exclusivity periods for one drug may be possible.
- Pediatric Exclusivity
- Under the FD&C Act §505A, FDA can issue written requests for pediatric studies if it agrees that a drug’s pediatric use may produce health benefits. As an incentive to conduct these studies, §505A offers a six-month period of marketing exclusivity known as pediatric exclusivity. Eligibility for pediatric exclusivity does not require a demonstration of safety or efficacy in the studies performed. Drug sponsors should be able to navigate the impact of pediatric exclusivity on existing exclusivity periods, §505(b)(2) applications, 351(k) applications, and §505(j) submissions containing paragraph IV certifications. It is helpful to compare the rules and regulations surrounding pediatric exclusivity for monotherapies, combination products, biologics, and biosimilars. For example, pediatric exclusivity has no patent-related effect on the timing of biosimilar product approval.
- Expedited Review Programs
- FDA has developed four expedited review programs to facilitate the development of new drugs that address unmet medical needs in treating serious or life-threatening conditions. These include fast-track designation, breakthrough therapy designation, an accelerated approval pathway, and priority review designation. Drug sponsors seeking expedited review should become familiar with the eligibility criteria, FDA guidelines, benefits, and limitations of the available expedited review programs.
- Specialized Incentives
- Congress and FDA have designed several incentives to help encourage investment and streamline drug development in urgent need areas and conditions with low patient populations. Qualified Infectious Disease Product (QIDP) designation and the Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD) are in place to help combat current antibiotic resistance issues. Regenerative Medicine Advanced Therapy (RMAT) designation is available for drugs aimed at treating patients with unmet medical needs. In addition, Competitive Generic Therapy (CGT) designation aims to expedite the development and review of drugs with inadequate generic competition. Priority Review Vouchers are available for drugs designed to treat neglected diseases like rare pediatric and tropical diseases. Drug sponsors seeking these specialized incentives should be familiar with these programs’ eligibility criteria, benefits, and limitations, and FDA guidelines.
- Special Circumstances
- Advances in medicine bring several challenges to a clear understanding of pharmaceutical regulation and approval, namely, how new and innovative concepts fit into specific regulatory categories. In this section, we have compiled several special circumstances for which clarifications may be necessary, or exceptions to general rules exist. These special circumstances include gene therapy products, combination products, drug-device combinations, fixed-combination drug products, antibody-drug conjugates, fusion proteins, and complex products.
- End-of-Lifecycle Strategies
- Most of the life cycle management tools discussed in this book serve to facilitate the research, development, and protection of prescription pharmaceutical innovations. A variety of post-marketing strategies exist to help diminish the effect of impending competition for the prescription product, including strategic pricing, new formulations, new indications, or combination products. Certain strategies are generally implemented at the end of the life cycle, such as performing an Rx to OTC switch or launching an authorized generic. There is no standard solution to mitigate the impending revenue decline of patent expiration. Pharmaceutical companies and researchers must become familiar with available options and make proactive, informed decisions to fit each specific product.
