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
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,
Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634, email@example.com
Read Jill's blogs at http://PharmTech.com/wechsler.