Treatment for HIV/AIDS generally requires patients to take a large number of drugs. For HIV therapy, for example, at least three active drugs, usually from two different classes are required to suppress the virus, allow recovery of the immune system, and reduce the emergence of HIV resistance. As a consequence, medicines are being developed that combine these drugs into fixed dosages, thus providing a combination therapy that simplifies dosing and helps patient compliance.
Gilead Sciences ("Gilead") has developed a new fixed dose combination ("FDC"), STRIBILD®, which contains four distinct drugs: elvitegravir ("EVG"), cobicistat ("COBI") , emtricitabine ("FTC") and tenofovir disoproxil fumarate ("TDF"). EVG and COBI have not been approved before by FDA but both FTC and TDF have been.
Generally when a drug containing a new active ingredient is approved for the first time by FDA, it is considered a new chemical entity ("NCE"), which enables it to receive 5 years of market exclusivity, preventing third parties referencing that drug for their own applications for 5 years (or 4 years if their application includes a Paragraph IV certification / patent challenge).
Historically, FDA has interpreted sections Federal Food, Drug & Cosmetic Act ("FD&C Act") sections 505(c)(3)(E)(ii) and 505(j)(5)(F)(ii) to deny 5-year exclusivity to FDCs if any active moiety in the drug product as a whole had previously been approved by the agency. This interpretation dates back to the agency's early implementation of the Drug Price Competition and Patent Term Restoration Act of 1984 ("the Hatch-Waxman Act"). It pre-dates the agency's extensive Hatch-Waxman rulemaking proceeding, which concluded in 1994, and pre-dates the move in medicine where FDC therapies have been recognized as essential regimen for the treatment of HIV/AIDS and other critical diseases.
The effect is that up until now, a new combination of drugs, in which one or more of the active ingredients is new but also includes other already-approved active ingredients, these combinations do not obtain the 5 years of exclusivity but only the 3-year clinical data marketing exclusivity. The 3-year clinical data exclusivity does not prevent a third party from applying for a registration during those 3 years, unlike a drug with an NCE status. Since 1994, approximately 10 FDCs containing both new and old active ingredients have been denied NCE status.
Gilead, wishing to obtain an NCE status for STIBILD®, had petitioned FDA to reinterpret their position on NCE and FDCs. They argued that the previous FDA position should be re-examined in the light of the Hatch-Waxman Act and other case law by interpreting the word "drug" in the various statutes in a more context sensitive way. The effect being to assess whether the word "drug" in a particular document really refers to the active moiety or the drug product.
Gilead maintained that the interpretation given in 1988 is outdated. Here they are referring to when the Director of FDA's Center for Drug Evaluation and Research ("CDER") was asked if the 5-year exclusivity applies if any active moiety in the drug product had previously been approved. Carl Peck, Director, at that time issued a letter to all NDA or ANDA Holders and Applicants stating that the Agency considers a drug product eligible for the five-year period, if it contains no active moiety that was previously approved by the Agency. As a consequence and subsequently, if a drug product contained an active moiety that had previously been approved, no 5-year exclusivity was given. Gilead's point is that since that time, the Hatch-Waxman Act has undergone rulemaking proceedings, and with more recent case law, the term "drug product" should now be re-interpreted to mean either the active ingredient or drug product in its proper context.
Gilead pointed out in the Petition that as a consequence of the Peck letter, some sponsors appear to have crafted their development strategies and sought approval first for a new active moiety as a single entity drug product, to secure 5-year exclusivity, and then sought approval of an FDC incorporating that same moiety sometime thereafter. In some cases, the initial approval of (and grant of 5-year exclusivity for) the single-ingredient product has included labeling allowing for or even requiring, co-administration of the drug with other drugs.
Gilead stressed that since there has been no "definitive" FDA interpretation with respect to FDCs, they believe FDA could readily resolve the issue by "providing an adequate explanation for its departure from established precedent" and thus apply a "new" interpretation of the regulation.....preferably in favor of Gilead's STIBILD® then obtaining a 5 year exclusivity for its combination of ingredients.
[Note that in Europe, new fixed dose combination products obtain the same data exclusivity as new single active ingredient products, whether or not the active moieties involved are new or old.]