Ensuring Timely Approval Of Generic Drugs

By Ameet Sarpatwari and Aaron S. Kesselheim

Cross posted from Health Affairs Blog

Having saved US consumers over $1.5 trillion in the past decade, generic drugs are one of the most cost-effective interventions in our entire health care system. Using generic drugs instead of brand-name drugs, when a generic is available, has been shown to increase medication adherence and improve health outcomes for chronic conditions.

Importantly, generic drugs offer these advantages without sacrificing quality; the Food and Drug Administration’s bioequivalency standards are met and often exceeded by generic-name manufacturers, and no randomized controlled trials—the gold standard of medical evidence—have identified clinically significant variations in outcomes between brand-name and FDA-approved interchangeable generic drugs.

However, to perform the tests the Food and Drug Administration (FDA) requires before approving a generic drug, manufacturers need access to one vital component: the brand-name product. Samples of the brand-name version of a drug can be used as a comparator to demonstrate the similarity of the molecular structure, or even the clinical outcomes from the generic product. Physico-chemical details about the brand-name drug, such as its molecular structure, stability, and cross-reactions, can be even more helpful in ensuring that the generic version adheres to the highest quality standards.

Risk Evaluation and Mitigation Strategies

Unfortunately, there has been a growing trend in the pharmaceutical market of brand-name manufacturers actively seeking to prevent generic manufacturers from getting their hands on these samples and information. For example, some brand-name manufacturers have taken advantage of risk evaluation and mitigation strategies (REMS), a relatively new post-approval requirement that the FDA can impose on drugs with known or potential toxic side effects. REMS components can range from medication guides and communication plans, which aim to educate patients and providers, respectively, to more complex “elements to assure safe use.”

Many drugs subject to this more complex REMS component cannot be purchased in the standard way; rather, they must be distributed by specially-certified prescribers and pharmacists, may have limits on the amount of drug dispensed, and can include mandatory enrollment and monitoring of patients within registries. Brand-name manufacturers have argued that they cannot provide generic manufacturers with samples of such REMS-covered products necessary to conduct the FDA-required bioequivalency testing because doing so would be outside the restricted distribution pathway.

Other brand-name manufacturers have even patented their REMS as new and useful methods of conducting business, artificially extending the market exclusivity period of their products. Celgene, for example, patented its REMS for thalidomide (Thalomid), an old drug now used to treat multiple myeloma (a form of cancer) but that also causes birth defects. The patent for the active ingredient of thalidomide expired decades earlier.

But Celgene sued Barr Laboratories in 2007 to prevent the marketing of a generic version on the basis that Barr’s use of the same or similar REMS would infringe Celgene’s REMS patent, and that allowing Barr to use a different REMS would “compound the confusion and burdens associated with thalidomide risk management and make it more likely that the system would be compromised.” Matrix Global Advisors estimates that anti-competitive uses of REMS result in a staggering $5.4 billion in lost savings annually from the delayed market entry of generic drugs.

To tackle this problem, the FDA has proposed draft guidance that would enable generic manufacturers to obtain an Agency letter vouching for safety protections in bioequivalence testing protocols, assuring brand-name manufacturers that product sharing for such testing would not constitute a REMS violation. While laudable, this proposal is ultimately insufficient; it lacks enforcement power.

FAST Generics Act

A better solution was proposed by Congressmen Steve Stivers (R-OH) and Peter Welch (D-VT), who introduced the Fair Access for Safe and Timely (FAST) Generics Act during the last Congress in September 2014. The FAST Generics Act would create a pathway for generic manufacturers to obtain FDA authorization to secure a brand-name drug from its maker, wholesaler, or specialty distributor regardless of whether the product was subject to a REMS, and impose stiff penalties for non-compliance. Brand-name manufacturers would not be responsible for the conduct of generic manufacturers during equivalency testing on the remote chance that some of the brand-name product ended up in the hands of patients. These measures would help eliminate unnecessary delays in the approval of generic drugs.

Although the FAST Generics Act languished in committee, the causes it champions—free-market enterprise and affordable medications—are worthy of bipartisan support. The proposed legislation would be even stronger if it also confronted the impact of REMS patenting. To eliminate confusion and undue burdens among prescribers and pharmacies, and to promote patient safety, brand-name and generic versions of a drug should share a single REMS.

To make this possible, congress should create a safe harbor that would prohibit patent infringement claims from being brought against a generic manufacturer for replicating the REMS of a brand-name drug for a bioequivalent product. A similar safe harbor already exists for medical procedures, which are patentable; congress has shielded physicians performing such procedures from enforcement actions.

Every year, the FDA imposes a growing number of REMS on new and currently available drugs. With such growth comes greater need to facilitate the smooth sharing of products between brand-name and generic drug manufacturers for appropriate bioequivalency testing. Until we do so, many REMS will continue to stand in the way of patients’ access to low-cost, safe, and effective generic drugs.

Ameet Sarpatwari

Ameet Sarpatwari is an Instructor in Medicine at Harvard Medical School, an Associate Epidemiologist at Brigham and Women’s Hospital, and Assistant Director of the Program On Regulation, Therapeutics, And Law (PORTAL) within the Division of Pharmacoepidemiology and Pharmacoeconomics. His research draws upon his interdisciplinary training as an epidemiologist and lawyer and focuses on the effects of laws and regulations on therapeutic development, approval, use, and related public health outcomes.

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