Patents on Risk Evaluation and Mitigation Strategies for Prescription Drugs and Generic Competition

Abstract

This cross-sectional study identifies the prevalence of patents on risk evaluation and mitigation strategies and their association with delaying generic competition.

Certain prescription drugs are associated with harms that the US Food and Drug Administration (FDA) concludes can be mitigated with safeguards, such as laboratory testing or prescriber and patient education. For these drugs, the FDA may require manufacturers to implement risk evaluation and mitigation strategies (REMS) encompassing such measures.¹

Some manufacturers have obtained patents on these REMS, which provide 20 years of market exclusivity and can frustrate generic competition. For example, Celgene sued a generic manufacturer of thalidomide for REMS patent infringement in 2007,² keeping generics off the market during years the drug earned billions.³ More recently, Jazz, the manufacturer of sodium oxybate (Xyrem), used REMS patents to forestall competition from a brand-name rival.⁴ We identified the prevalence of REMS patents and their effect on delaying generic competition.

Methods

We identified novel small-molecule drugs with active, non–class-wide REMS on December 31, 2022, from the FDA website, patents protecting the drugs in annual editions of the FDA’s Approved Drug Products With Therapeutic Equivalence Evaluations (Orange Book) through 2022, and patent litigation through 2011 using the database Lex Machina. For drugs with REMS patents, we classified the drugs’ other patents as protecting the active ingredient, a formulation, or a method of use.

Among drugs with generic competition by 2022, we compared the first generic marketing date with the expiration dates of REMS and non-REMS patents. For drugs lacking generic competition, we compared the expiration dates of the last-expiring REMS patent with the last-expiring active ingredient patent to estimate the maximum added exclusivity the REMS patents could provide.

For each drug, we identified the number of REMS patents the generic manufacturers challenged and the outcome of the challenges. Analyses were performed using Excel, version 16 (Microsoft).

Results

Of 24 novel small-molecule drugs covered by active, non–class-wide REMS, 5 (21%) had Orange Book–listed REMS patents: alvimopan (Entereg), lenalidomide (Revlimid), pomalidomide (Pomalyst), sodium oxybate (Xyrem), and thalidomide (Thalomid). There was a median of 10 (range, 2-14) REMS patents per drug, comprising a median of 33% (range, 32%-70%) of all patents per drug, which was higher than the median number of active ingredient (1 [range, 0-2]; 5% [range, 0%-17%]), formulation (3 [range, 1-6]; 17% [range, 5%-30%]), or method-of-use (5 [range, 2-15]; 33% [range, 20%-50%]) patents per drug (Table).

Table. Patent and Generic Entry Information for Drugs With REMS-Covered Patents.

Drug	Approval date	FDA-approved indications	No. of REMS patents (% of total Orange Book patent portfolio)	Last-expiring REMS patent expiration date	Last-expiring active ingredient patent date	First generic marketing date	Invalidated vs challenged REMS patents, No.
Alvimopan (Entereg)	5/20/2008	Bowel surgery	2 (33)	7/31/2030	3/29/2016	12/2/2020	0 vs 0
Lenalidomide (Revlimid)	12/27/2005	Multiple myeloma; mantle cell lymphoma, transfusion-dependent anemia; follicular lymphoma; marginal zone lymphoma	10 (33)	10/23/2020	10/4/2019	3/3/2022	2 vs 10
Pomalidomide (Pomalyst)	2/8/2013	Multiple myeloma; AIDS-related Kaposi sarcoma	10 (50)	10/23/2020	10/4/2019	NAa	2 vs 10
Sodium oxybate (Xyrem)	7/17/2002	Narcolepsy	7 (32)	12/17/2022	NAb	NAa	6 vs 7
Thalidomide (Thalomid)	7/16/1998	Leprosy; multiple myeloma	14 (70)	10/23/2020	NAb	NAa	2 vs 14

Abbreviations: FDA, US Food and Drug Administration; NA, not applicable; REMS, risk evaluation and mitigation strategies.

^a Generic entry had not occurred for pomalidomide, sodium oxybate, or thalidomide.

^b Sodium oxybate and thalidomide lacked active ingredient patents.

Generic entry had occurred for 2 drugs by 2022. For lenalidomide, the date of first generic marketing was 16 months after expiration of the last-expiring REMS patent and 28 months after expiration of the closest expired non-REMS patent. For alvimopan, the date of first generic marketing was more than 9 years before expiration of the last-expiring REMS patent and 3 days after expiration of the first method-of-use patent (Figure). Among drugs with no generic entry, only pomalidomide had an active ingredient patent, which expired 12 months before the last expiring REMS patent. Generic manufacturers challenged 10 lenalidomide, 10 pomalidomide, 7 sodium oxybate, and 14 thalidomide REMS patents, leading to invalidation of 6 sodium oxybate REMS patents and 2 REMS patents each for lenalidomide, pomalidomide, and thalidomide.

Figure. Orange Book–Listed Patents.

Some patents did not last 20 years because the patents were invalidated or because the manufacturer filed a continuation, in which minor clarifications or additions were added to an invention, resulting in a new patent that replaced the original patent. The dashed blue vertical lines indicate when generic entry occurred. REMS indicates risk evaluation and mitigation strategies.

Discussion

REMS patenting was observed for one-fifth of REMS-covered small-molecule drugs and constituted one-third to three-fourths of their patent portfolios. Generic entry occurred after expiration of the last expiring REMS patent for lenalidomide but a decade beforehand for alvimopan. REMS patents for alvimopan were not subject to challenges, while most REMS patents for lenalidomide, pomalidomide, sodium oxybate, and thalidomide were, with a few invalidations. Thus, the association of REMS patents with delaying generic entry has been variable.

Study limitations included not being able to evaluate biologics since they do not have the same system of listing their patents with the FDA.⁵ REMS can also complicate generic entry in other ways, such as when negotiations are needed to set up shared REMS between brand-name and generic manufacturers.⁶ Since some REMS patents may contribute to delays in generic marketing for emerging REMS-covered drugs, to the detriment of patients and the health care system, Congress should consider shielding generic manufacturers from REMS patent infringement claims.

Section Editors: Kristin Walter, MD, and Jody W. Zylke, MD, Deputy Editors; Karen Lasser, MD, Senior Editor.

Supplement.

Data Sharing Statement