“New Chemical Entity Exclusivity Determinations for Fixed-Combination Drug Products”: Combo Drugs Now Eligible For 5-Year Exclusivity

 

The Food and Drug Administration (FDA) recently finalized guidance which allows fixed-combination drugs consisting of at least one new drug product to be eligible for a five-year “New Chemical Entity” (NCE) exclusivity period. FDA’s policy, entitled New Chemical Entity Exclusivity Determinations for Certain Fixed-Combination Drug Products, changes the Agency’s previous interpretation that rendered combination products with even one “previously approved moiety” ineligible for five-year exclusivity. While this policy is good news for manufacturers of combination products going forward, FDA’s new guidance does not apply retroactively.

What Are Combination Drugs?

Combination drugs are products that include two or more active pharmaceutical ingredients. Combination drugs may contain both new chemical entities and already approved chemical entities. For example, Gilead’s HIV treatment, Stribild, is a combination of four drugs combined into one pill (two previously approved active “moieties” and two that are new).

As FDA notes, combination drugs have become the “standard of care” in the treatment of certain cancers, cardiovascular disease, and infectious disease because the simplified medication helps promote adherence by patients, and may improve treatment outcomes and reduce drug resistance.

Exclusivity of Combination Drugs

The FDA grants “exclusivity” to New Drug Application (NDA) applicants if certain statutory requirements are met. Exclusivity provides the holder of an approved new drug application limited protection from new competition in the marketplace for the innovation represented by its approved drug product. The length of exclusivity depends on what type is granted. For orphan drugs, FDA grants 7 years exclusivity. For new chemical entities, FDA grants 5 years. For certain “changes,” FDA grants 3 years.

FDA explains its rationale as follows: “A 5-year period of exclusivity is granted to new drug applications for products containing chemical entities never previously approved by FDA either alone or in combination.” On the other hand, a “3-year period of exclusivity is granted for a drug product that contains an active moiety that has been previously approved, when the application contains reports of new clinical investigations (other than bioavailability studies) conducted or sponsored by the sponsor that were essential to approval of the application.” 

As Stribild illustrates, in combination drugs, one active ingredient may be a new chemical entity, while the other(s) may have already been approved.  Prior to FDA’s latest guidance, such a product would have to settle for a 3-year exclusivity period.

“Historically, FDA has interpreted these provisions such that a fixed-combination was ineligible for 5-year NCE exclusivity if it contained a previously approved active moiety, even if the product also contained a new active moiety (i.e., an active moiety that the Agency had not previously approved),” states the Agency.

FDA’s New Policy

In expanding its view of what products are elligible for 5-year exclusivity, FDA expressed its desire to incentive  development of certain combination drugs. “[F]ixed-combinations have become increasingly prevalent in certain therapeutic areas (including cancer, cardiovascular, and infectious disease) and [ ] these products play an important role in optimizing adherence to dosing regimens and improving patient outcomes.” 

FDA’s previous interpretation that combination drugs are ineligible for 5-year exclusivity stems from rather complex statutory interpretation. FDA initially interpreted the definition of the word “drug” in the term “new chemical entity” to mean “drug product.” FDA intends to now interpret “drug” here to mean “drug substance” or “active ingredient.”

This makes a big difference.

FDA’s new interpretation allows a drug substance that meets the definition of “new chemical entity” to be eligible for 5-year NCE exclusivity, even when it is approved in a fixed-combination with another drug substance that contains a previously approved active moiety.

In offering this language, FDA agreed with the arguments of three citizen petitions that pushed for interpreting the exclusivity language to include compounds. One such product was Gilead’s HIV treatment Stribild, the combination outlined above. For a full analysis of the petitions, FDA Law Blog provided a clear analysis earlier this year. 

Download Gilead Citizen Petition

However, despite agreeing with the petitioning manufacturers, one dark spot on FDA’s final guidance is their statement that the interpretation “will not apply to fixed-combination drug products that were approved prior to the publication of this guidance document.” 

While a number of drugmakers are likely disappointed by this–including the petitioners–two fixed-dose combinations came in at the right time. 

Regulatory Affairs has provided ongoing coverage of FDA activity in this area and reported that on the very day that FDA released this guidance, the Agency also approved two combination drugs that are eligible for the 5-year exclusivity. 

Just hours after FDA released its final FDC exclusivity policy, it announced the approval of Gilead’s Harvoni (ledipasvir and sofosbuvir), a FDC used to treat chronic hepatitis C virus genotype 1 infections, and Eisai’s Akynzeo (netupitant and palonosetron), an FDC used to treat nausea and vomiting in patients undergoing cancer chemotherapy.

Had the drugs been approved just one day earlier, neither would have been eligible for NCE exclusivity. Gilead’s Harvoni includes sofosbuvir, a drug approved in 2014 and marketed as Sovaldi. Eisai’s Akynzeo includes oral palonosetron, approved in 2008 under the brand name Aloxi.

RAPS notes that “[f]or both companies, the additional two years of market exclusivity could potentially be valuable.” Gilead’s drug Harvoni, for example, is “expected to become a blockbuster [link to Fierce Pharma], meaning Gilead will have at least two extra years to reap billions in revenue before it has to begin defending its patents on the drug in earnest.” Thus, while Gilead’s previous drug missed out on the 5-year exclusivity, they seem to be positioned well to capitalize on FDA’s new guidance.