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  • Explain the concepts of interchangeability and bioequivalence for generic drug products in the United States, Canada, and Europe.

  • Explain why a generic drug product evaluated to be therapeutically equivalent and interchangeable in one region may not be a therapeutic equivalent in another region.

  • Describe what “branded generics” are and why they are more prevalent in developing countries.

  • Define the differences between products classified as “AA” versus “AB” in the FDA Orange Book.

  • Explain the differences between bioequivalence and a single PK equivalence study.

  • List the requirements for clinical generic drug product development for the United States, European, and Canadian markets.

  • Define the term biosimilar.

  • List the main differences associated with the clinical development of a biosimilar versus that of a generic drug product.

  • Describe what are called “locally-acting” drug products by regulators, and explain what particular challenges are associated with their clinical development from a bioequivalence point of view.


The clinical drug development process involves the scientific investigation of the safety and efficacy of drug products that may receive marketing approval by a regulatory agency. The United States (US), European, and Canadian regulatory agencies are responsible for the US, European, and Canadian drug market. Three highly regulated regions will be the focus of this chapter in terms of generic clinical drug development, and the following (Chapter 30) for new drug clinical development. These agencies regulate the needs in terms of scientific/research testing and minimum equivalence requirements, compliance, and audit. The study requirements for a generic product are much abridged versus those of a new entity because they will rely on the previous safety and effectiveness declaration associated with the latter, so most if not all animal and clinical studies will not need to be repeated. Because of this, generic application/submissions include the term “abbreviated” in the US (Abbreviated New Drug Application [ANDA]) and Canada (Abbreviated New Drug Submission [ANDS]). At the core of generic submissions, the “test” or generic product will need to be shown to be pharmaceutically equivalent (see Chapter 26) and therapeutically equivalent to the marketed “reference” product in the country or region where the generic product will be made available. The establishment of clinical therapeutic equivalence (TE) or bioequivalence (BE) is the focus of this chapter. In general requirements will include both in vitro dissolution and in vivo PK equivalence studies between the proposed generic and its associated marketed reference product. Once approved and declared to be bioequivalent and interchangeable by the regulators, a generic drug product will be able to be substituted to its associated marketed reference product by the pharmacist, because of its established equivalent safety and efficacy.

In this chapter, the regulatory pathways, scientific policies, and requirements for generic drug products in terms of clinical studies1 will be explored between the US, Canada, and the European Union (EU) for the clinician. Equivalence metrics between generic drug products (ie, ...

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