FDA Issues New “Critical Path” Report Highlighting Research Needed to Foster Generic Drug Development

On May 2, 2007, FDA announced the availability of a report, titled “Critical Path Opportunities For Generic Drugs.”  The report identifies several unanswered scientific questions that FDA believes impede the development of generic versions of commonly used brand name drugs, and is part of FDA’s broader Critical Path Initiative launched in March 2004.  FDA’s Critical Path Initiative is the Agency’s long-term “effort to stimulate and facilitate a national effort to modernize the sciences through which FDA-regulated products are developed, evaluated, and manufactured.”

The goal of FDA’s new Critical Path report “is to bring the critical path challenges related to generic drugs to the attention of interested parties and to stimulate additional discussion and collaboration about the science needed to meet these challenges, with a goal of facilitating generic product development.”  To this end, the report identifies four areas of opportunity where the collaborative activities of FDA, the generic drug industry, and other government institutions (e.g., the National Institutes of Health) could advance the public health by more efficient development of high quality generic products:

·        Improve the science underlying quality by design for the development and manufacture of generic drug products

·        Improve the efficiency of current methods for assessment of bioequivalence of systemically acting drugs including products that use complex and novel drug delivery technologies

·        Develop methods for the assessment of bioequivalence of locally acting drugs such as topical and inhalation products

·        Develop methods for characterizing complex drug substances and products

According to FDA, “[p]rogress in these areas will accelerate approval of generic drug products.  More importantly, it will expand the range of products for which generic versions are available, while maintaining high standards for quality, safety, and efficacy.”  FDA’s findings in each of the four areas are summarized below.

(1)       Quality by Design (“QbD”)

The current drug development and manufacturing paradigm primarily determines drug product quality and performance by endproduct testing. Under a QbD paradigm, however, “quality is built into the final product by understanding and controlling formulation and manufacturing variables: testing is used to confirm the quality of the product.”  FDA’s report encourages QbD implementation for all drug products, but notes that “there are unique issues in the application of QbD to generic products. To use QbD to develop a product that is bioequivalent to a reference product, a generic applicant must understand attributes of the formulation and manufacturing process that have the potential to change the bioavailability of a particular active ingredient.”

(2)       Bioequivalence Methods for Systemically Acting Drugs

For systemically acting drugs (i.e., drugs that have their effect on the body as a whole, following distribution around the body in the blood), FDA’s critical path goal “is to increase the efficiency of a process that is already providing safe and effective generic drugs to the public.”  To do this, FDA recommends expanding the use of “biowaivers,” improving dissolution methods, and improving the methods of assessing bioequivalence.

(3)       Bioequivalence Methods for Locally Acting and Targeted Delivery Drugs

For locally acting drugs (i.e., drugs that have their effect on the tissues onto or into which the drug has been delivered) and targeted delivery drugs (i.e., drugs whose pharmacological activity is localized to the site or organ of action), FDA notes that the assessment of bioequivalence “has presented scientific challenges to the approval of generic products.”  Specifically:

Currently, it may be difficult to demonstrate the bioequivalence of locally acting drug products when drug concentration profiles in the plasma or in vitro dissolution are not appropriate surrogates of pharmacological activity. The current method of comparative clinical trials can be prohibitively expensive and is the least efficient way to detect differences in product performance (as well as being relatively insensitive).

As such, FDA identifies new bioequivalence methods and approaches for specific product categories, including inhalation products, nasal sprays, dermatological products, gastrointestinal products, and liposome products. 

(4)       Characterization of Complex Drug Substances and Products

Certain drugs, such as botanicals and other natural source products, because of their complexity, present unique and difficult characterization challenges for generic applicants, as opposed to products containing small molecules.  As such, FDA recommends the development of improved analytical methods for identity and statistical methods for profile comparisons.