Generic Drugs Face Regulatory and Scientific Challenges - Pharmaceutical Technology

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Generic Drugs Face Regulatory and Scientific Challenges
FDA funds research to further development of innovative generics.

Pharmaceutical Technology
Volume 37, Issue 8, pp. 24-26

Encouraging innovation

These and other complex regulatory policies stand to benefit from an important GDUFA initiative that supports research on issues affecting generic-drug testing and quality. The GDUFA Regulatory Science Plan for 2013 launched this $20-million program by identifying 13 research topics that warrant further study, ranging from quality-by-design (QbD) and postmarketing surveillance to bioequivalence (BE) and pharmacokinetic (PK) evaluation of complex dosage forms.

FDA held a meeting in June to update industry and the research community on studies funded by this program to date and to gain input for its 2014 science plan, which is due Oct. 1, 2013. The aim, explained Robert Lionberger, OGD acting deputy director for science, is to identify scientific issues that limit the availability of generic drugs and where regulatory science can improve the evaluation of therapeutic equivalence and post-approval assessment of generics. For example, FDA is seeking study proposals for developing in-vivo predictive dissolution methods for inhaled drugs to further establish BE standards for inhalation therapies and nasal sprays. There's interest in improving in-vitro release tests for topical products and new approaches to test gastrointestinal drugs with lower solubility. Research has begun on PK and BE studies for anti-epileptic drugs, with additional studies slated to build confidence among clinicians and patients in substitutability in this area.

Related studies may examine ways to identify those individual patients who have difficulty with generic drug substitution to better understand variability in patients and products. This touches on the hot topic of bioequivalence for Budeprion (bupropion). FDA was criticized at the June meeting for approving generic Budeprion XL 300 without adequate testing, and the agency is looking to examine why and whether different patients respond differently to a drug and how that relates to BE assessment.

Similar issues arise related to the equivalence of narrow-therapeutic-index (NTI) drugs and complex drug products such as iron colloids, liposomal products, and sustained release parenterals.

A related topic is whether human factors studies can expand understanding of switchability in drug-device combination products such as inhalers and auto-injectors. Other patient-use studies may explore physical attributes of drugs, such as how tablet size, color, and shape influence patient acceptance of generic drugs—or create confusion between brands and generics. FDA also is looking for more research on modeling and simulation methods as "enabling technology" for defining new equivalence methods.

Quality by design (QbD) for generic drugs is an important topic, Lionberger pointed out at the meeting noting that FDA would like manufacturers to move beyond standard dosage forms to apply QbD to more complex products. Gordon Johnston, representing the Generic Pharmaceutical Association (GPhA), noted that guidance on implementing QbD for added dosage forms could encourage more industry investment in this area. Manufacturers also would like further examination of how to leverage prior knowledge to reduce required testing and how manufacturing changes can support a less burdensome post-approval changes process, Johnson noted. And manufacturers of APIs seek to promote innovation in their field through research demonstrating that new production methods don't alter product bioequivalence, noted Carla Vozone of Hovione LLC, representing the European Fine Chemicals Group.

Postmarketing assessment and adverse-event monitoring of generic drugs also warrant further research. FDA is interested in switching studies on marketed drugs, as seen with transplant patients to assess equivalence of immunosuppressants. And there's continued interest in methods for evaluating whether new abuse-deterrent formulations actually reduce abuse in opioids.

The overall aim of manufacturers, said Johnson of GPhA, is to develop sound testing methods for generics that support a move away from clinical endpoint studies required for brands. Research evaluating immunosuppressants, liposomes, and sustained-release parenterals may not affect a high volume of generic products, but can help industry move forward in developing innovative, affordable therapies.

Jill Wechsler is Pharmaceutical Technology's Washington editor, tel. 301.656.4634,
Read Jill's blogs at


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