Generic Drugs Face Regulatory and Scientific Challenges

Published on: 
BioPharm International, BioPharm International-08-01-2013, Volume 26, Issue 8
Pages: 40–45

FDA funds research to further development of innovative generics, while working to address review and approval issues.

Generic drugs have become the mainstay of pharmaceutical therapy, accounting for more than 80% of US prescriptions, as more blockbuster pharmaceuticals have lost patent protection. A range of legislative and regulatory actions have facilitated consumer access to safe, high-quality generic products, although manufacturing lapses and product quality problems have created critical shortages in important medicines, casting a shadow over the industry's success.

Jill Wechsler

FDA marked the one-year anniversary of the Generic Drug User Fee Amendments (GDUFA) of 2012 in June by noting that the agency collected $255 million in user fees—a little short of its $299 million goal for fiscal year 2013, but enough to hire 165 new staffers for the Center for Drug Evaluation and Research (CDER) and to expand the industry "self-identification" program to ensure accurate fee assessment and to improve generic industry supply-chain information.

A GDUFA steering committee, which includes representatives from CDER plus the FDA commissioner's office and the Office of Regulatory Affairs (ORA), is shifting focus to enhancing the generic-drug review program to meet GDUFA performance commitments. That assignment falls to Office of Generic Drugs (OGD) acting director Kathleen Uhl, who has made some progress in reducing the application backlog and enhancing review processes. But Uhl and her staff face considerable challenges, particularly in the face of further organizational changes slated for OGD.

Legal Controversies


Generic drugs also have been in the spotlight recently due to cases before the US Supreme Court involving pay-for-delay patent settlements and safety labeling issues. Manufacturers lost an important case in early June 2013 when the Justices made it more difficult for brands and generics to negotiate "reverse payment" patent settlements. A majority ruled in the Federal Trade Commission v. Activis case (docket no. 12-416) that the Federal Trade Commission (FTC) has the right to challenge these deals as anticompetitive and harmful to consumers. However, the Court stopped short of declaring these arrangements per se illegal. Both brand and generics firms have insisted that pay-for-delay agreements avoid costly litigation and actually permit generics marketing prior to patent expiration, but the ruling is slated to discourage these settlements in the future.

A majority of Justices, though, supported manufacturers and FDA in Mutual Pharmaceutical Co. v. Bartlett (docket no. 12-142). The case raised important questions for both brands and generics about whether lower courts can challenge FDA regulatory decisions, and whether generics makers should revise labels to reflect important new safety information when the brand does not do so. A patient who took Mutual's generic product and suffered adverse events sued and won a $21 million judgment based on the company's failure to warn of the drug's potential dangers. Mutual argued that the long-marketed anti-inflammatory and its label were approved by FDA, and the Justice Department agreed that states can't undermine the FDA approval process by overriding federal regulatory policy. A sharp dissent from some Justices in this 5-4 ruling, along with strong complaints from consumer activists, puts pressure on FDA to revise regulations to allow new warnings on generic drug labels, even if the information differs from that of the reference product.

The High Court is likely to revisit this issue as other cases emerge involving state versus federal consumer protection rules. In fact, one failure-to-warn suit has been brought against a brand manufacturer, even though injury was caused by a generic.

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 BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634, Read Jill's blogs at