The Complex Generic Drug Development Workshop is currently being held in Silver Spring, Maryland September 12‑13, 2018.  In her keynote address at the FDA’s Small Business and Industry Assistance (SBIA) workshop on complex generic drug development, Kathleen Cook Uhl stated that complex drug products are critical to the care of many serious medical conditions, such as multiple sclerosis, schizophrenia, metastatic breast cancer, osteoporosis, COPD, and diabetes mellitus.  Some of these drugs are costly and not easily accessible to patients.  Many complex drug products have relatively small market capitalization and are less enticing for generic drug developers.  These are contributing factors leading to a lack of generic drug product development and ANDA submission in this area.  As a result, there is little to no generic drug competition and, therefore, limited patient access to cheaper options.

The objectives of this workshop are to communicate how FDA research outcomes guide and facilitate complex generic product development and how to leverage GDUFA science and research on complex products to Product Specific Guidance (PSG) development.  Discussion on pre-ANDA meetings and review and how the FDA examines science related to complex products in various areas was also provided.  Additionally, the FDA offered a “deep-dive” to the complex generic drug development process and provided practical solutions to industry in submitting complete applications with a higher potential for first cycle approval.

In December 2017, Government Accountability Office (GAO) published a report on generic drugs.  GAO was asked to assess the FDA’s process for reviewing complex generics.  The report acknowledges that certain NonBiological Complex Drugs (NBCD) have a more complex chemical structure than most other drugs.  It can be more difficult to identify the physical and chemical properties of these complex drugs, and more difficult to demonstrate that generic versions of these drugs are equivalent to their innovative counterparts.  The GAO report identifies the scientific challenges related to the review of complex generics. GAO identified several steps that have been taken by the FDA to address the challenges associated with reviews to determine equivalence of a complex generic.  The FDA issued Product-Specific Guidance (PSG) documents to industry, providing recommendations on how to demonstrate equivalence for certain products.  While a PSG is helpful, it does not always adequately address the scientific complexities of these products.

Some of these guidance documents are revised numerous times without any advance notification to industry and have increased the workload and expense of drug development for the industry.  Although the FDA’s Good Guidance Practices regulation also specifies that the Agency will publish a list of possible topics for guidance development or revision for the next year, and the FDA publishes such a list annually, it does not include product‑specific guidance documents.  In addition, lack of advance communication on planned guidance issuance and subsequent revisions can create setbacks for generic drug sponsors.  It takes considerable time, effort, and other resources for the sponsors to update their applications or development program in response to unexpected changes in guidance.  These changes delay or prevent the entry of some of these generics to the market.  During the workshop, however, the FDA confirmed that it is working on making such a list of PSGs.

In October 2017, FDA Commissioner Scott Gottlieb announced the Drug Competition Action Plan to advance new policies aimed at bringing more competition to the drug market.  The FDA’s goal was to improve patients’ access to the medicines that they need.  Dr. Gottlieb believes that if consumers are priced out of the drugs that they need, that it is a public health concern that the FDA should address within the scope of the FDA’s mandate and authorities.  The plan includes a compilation of efforts to improve the efficiency of the generic drug approval process.  In addition, a group of policies aimed at making it easier to bring generic competition to a category of branded drugs known as complex drugs were rolled out.  One draft guidance was issued to assist ANDA applicants and prospective ANDA applicants in seeking pre-ANDA meetings so that the FDA can give better advice to sponsors looking to develop complex generic drugs.  Another draft guidance was issued to help applicants determine when submission of ANDAs for certain complex products, such as peptides, would be appropriate.

During the first day of the workshop, Office of Research and Standards (ORS) officials defined complex generic drugs as drugs containing complex active ingredients, complex formulations, complex routes of delivery, complex dosage forms, complex drug-device combinations, and other products where complexity or uncertainty concerning the approval pathway or other alternative approach would benefit from early scientific engagement.  Submission of a meeting request through the CDER Direct NextGen Portal, the Pre-ANDA Process, program metrics, and trends were presented as well.

One of the very valuable aspects of the workshop was the discussion on common deficiencies and possible solutions related to complex generic drug product applications.  This kind of presentation provides insight into what the Agency considers important information and its expectations related to these types of products.  As expected, API sameness for the complex generics was one of the important topics.  Emphasis was made on the totality of evidence.  The range of evidence includes starting material, reaction scheme, structural signature analysis, and physicochemical and biological properties/impurities.  Considerations for establishing Q1/Q2 sameness of complex formulations, in-vitro release testing of complex formulations, application and modelling, and simulation in establishing appropriate bioequivalence limits for complex formulations and equivalence testing of complex particle size distribution profiles based on earth mover’s distance were discussed.

This is a commendable initiative to provide the Agency’s perspective on such complex topics to the industry.  We have been following the conversation on complex generics for some time and participating in it at times.  We look forward to hearing more from the FDA and breaking these unique issues down to specific expectations and possible solutions during the remainder of the workshop.