Talking with Capt. Martin Shimer, the former Deputy Director of the Division of Legal and Program Support, Office of Generic Drugs, CDER.

The FDA’s publication Approved Drug Products with Therapeutic Equivalence Evaluations, commonly referred to as the “Orange Book,” includes information about patents or exclusivities that apply to a particular drug product approved under the Federal Food, Drug, and Cosmetic Act (the Act).  Patents and exclusivities are two different forms of protection for qualifying drug products that may affect how and when certain generic versions of those drug products are approved. 

CAPT Martin Shimer, of CDER’s Office of Generic Drugs, discusses how patents and exclusivities for generic drug products usually function and intersect, and how they can impact the generic drug approval process.

What is a patent?

A drug patent is a property right granted by the United States Patent and Trademark Office (PTO) anytime during the development of a drug. Patents protect a drug manufacturer’s invention (for example, a new drug or a new use for a drug) and prevent other manufacturers from marketing products covered by the patent, among other things.

Generally, a patent term is 20 years from the date of filing with the PTO.  FDA does not enforce patents, or evaluate patent validity or infringement.  Rather, new drug application (NDA) holders for a “brand-name” drug product submit patent information to FDA for inclusion in FDA’s “Orange Book.”  This information, combined with information submitted in generic drug applications (known as abbreviated new drug applications or ANDAs) regarding these patents, informs when a generic drug application may be approved.

What is an exclusivity?

An exclusivity provides limited protection from new competition in the marketplace and precludes approval of certain ANDAs for prescribed periods of time. Certain exclusivities for qualifying brand name drugs and generic drugs were established in the Hatch Waxman Amendments as part of the Drug Price Competition and Patent Term Restoration Act of 1984.  Another type of exclusivity for brand-name “orphan” drug products was established by the Orphan Drug Act of 1983.  Moreover, exclusivity extensions are available for certain pediatric-related uses of drug products, and for qualifying antibiotic drug products.  The FDA administers all of these exclusivities.  

Exclusivities for brand-name drug products are intended to provide incentive for brand-name companies to develop new drug products and to find new uses for already approved drug products. Exclusivities for certain generic drugs provide incentive for generic drug companies to challenge brand-name companies’ patents.

What are the types of exclusivities?

There are several types of exclusivities or exclusivity extensions.

• Five-Year New Chemical Entity. This exclusivity applies to a brand-name drug that contains a new chemical entity (NCE), which is a drug substance that contains an active ingredient or moiety(ies) never previously approved by the FDA.  This exclusivity generally blocks the submission of any ANDA that contain the same active moiety for five years.  
• Three-Year New Clinical Studies. This exclusivity attaches to a brand-name drug approved for a new use for a previously approved drug product.  Applications for such new uses must be supported by information from new clinical investigations essential to approval of the new use, and conducted or sponsored by the applicant.  Such new uses could include changes in strength, dosage form, route of administration, or indication.  
• Orphan Drug. Certain drugs designated for the treatment of a rare disease or condition (e.g., one affecting fewer than 200,000 people in the United States each year) are eligible for orphan-drug exclusivity upon approval.  This exclusivity prevents approval of any other application (brand-name or generic) for the same drug for the same orphan-protected use during a seven-year period.   
• Pediatric. This type of exclusivity is granted to a brand-name drug for which pediatric clinical studies have been conducted in response to a written request for such studies from the agency.  Generally, pediatric exclusivity attaches to existing patents or exclusivities associated with the product line for the brand-name drug for six months.  
• GAIN.  The “Generating Antibiotic Incentives Now” (GAIN) exclusivity generally provides for an additional five years of exclusivity added to certain other exclusivity periods for a drug product that has been granted a “Qualified Infectious Disease Product” designation by FDA. 
• 180-Day. This type of exclusivity may be granted to the first generic applicant(s) to submit a substantially complete ANDA that contains a challenge to a patent listed in the Orange Book.  The generic drug applicant found to be eligible for this exclusivity has an exclusive right to market the generic drug for 180 days.  Only ANDAs are eligible for this exclusivity.

How common is it for a generic drug applicant to challenge a patent? What are typical outcomes when challenging a patent?

It is quite common in the very competitive generic drug market for generic drug applicants to challenge a patent listed in the Orange Book.  For instance, about 40 percent of the ANDAs we receive contain a patent challenge, which is referred to as a “paragraph IV certification” challenge.  After FDA notifies an ANDA applicant that its application containing a paragraph IV certification challenge is substantially complete and has been accepted for review, the applicant must notify the brand-name drug company and patent holder about the application and the patent challenge.  If the brand-name company or patent holder sues the generic applicant within 45 days of receiving the ANDA applicant’s notice, a stay goes into effect and generally blocks FDA’s approval of the ANDA for 30 months.  In many cases, the brand-name drug company/patent holder and the ANDA applicant reach a settlement agreement, resulting in dismissal of the litigation and lifting of the 30 month stay, if it is still in effect.  The FDA is not involved in these court cases or in any settlement discussions.

Before the Hatch Waxman Amendments, how did generic drugs get approved and on the market?

Prior to the Hatch Waxman Amendments, ANDAs had to go through an approval process that was similar to the NDA process.  Hatch Waxman created the abbreviated pathway through which an ANDA applicant can rely on FDA’s previous findings of safety and efficacy of a brand-name drug product.  Hatch Waxman also created the 505(b)(2) pathway through which an applicant can rely on FDA’s previous findings of safety and efficacy of a brand-name drug product as appropriate.  Hatch Waxman also established incentives in the form of exclusivities and patent term extensions to encourage innovation.  The passage of Hatch Waxman was intended to balance the interests of brand-name drug companies, generic drug companies, and the public.

If an ANDA meets all requirements for approval but a patent or exclusivity still prevents full approval of the ANDA, the ANDA holder may receive a tentative approval letter. Why is this important?

When an ANDA meets all requirements for approval, but patent protection or exclusivity prevents FDA from issuing a final approval to the ANDA applicant, the agency will issue a “tentative approval” letter to the applicant.  Tentative approval letters are important to industry because they indicate that the ANDA holder has met the requirements for approval, but cannot be fully approved due to a patent or exclusivity.  The tentative approval letter generally provides a date by which the generic drug may be approved and can be marketed (depending on the patent and exclusivity provisions involved). The FDA posts on the Drugs@FDA website when an ANDA has been tentatively approved.  However, a tentative approval letter does not automatically translate to a final approval.  For example, the length of time between a tentative approval and a final approval could be very long (e.g., it could be several years until a patent or exclusivity expires), so there may be instances where FDA needs additional information from the manufacturer before final approval, or the applicant’s manufacturing sites may need to be inspected again.

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