FDA Guidance Sheds (Some) New Light on 3-Year New Clinical Investigation Exclusivity

While 3-year new clinical investigation exclusivity has never been the holy grail of exclusivities—we reserve that for 7-year orphan drug exclusivity or 5-year new chemical entity exclusivity (with the plus-5-year GAIN and plus-6-month pediatric exclusivity additions!) because of the different lengths and scopes—it plays an important role in the Hatch-Waxman regulatory scheme, encouraging the development of follow-on products and/or new conditions of use.  But FDA’s interpretation and application of exclusivities can be confusing, and 3-year new clinical investigation exclusivity and its intricacies seem to raise questions for industry.  For that reason, FDA issued a new draft guidance document this week, New Clinical Investigation Exclusivity (3-Year Exclusivity) for Drug Products: Questions and Answers.  The guidance, in the form of FDA’s recently-preferred Questions and Answers format, addresses the statutory and regulatory criteria for eligibility for this exclusivity, as well as the content and format of requests.

As a primer, 3-year exclusivity is available under the federal Food, Drug, and Cosmetic Act where a 505(b)(1), (b)(2), and supplement seeks approval of a previously approved active moiety (or moieties in the case of a fixed-dose combination product) based on reports of new clinical investigations that are 1) not bioavailability studies, 2) essential to approval, and 3) conducted or sponsored by the applicant.  The draft guidance goes through each aspect of these requirements, including the types of applications for which exclusivity is available, the types of clinical investigations are eligible, the definitions of essential to approval, and the requirements for studies to have been sponsored or conducted by the applicant.

FDA’s draff guidance explores the types of applications eligible for 3-year exclusivity. Clearly, an original NDA is eligible, but questions have arisen in Citizen Petitions about supplements.  While supplements are eligible, the guidance clarifies that “changes that may qualify for 3-year exclusivity .  . . are typically submitted in an efficacy supplement”  (emphasis added).  FDA is also clear that the 3-year exclusivity is recognized only for the change associated with the supplement that is supported by the new investigations.

While the passage above focuses on efficacy supplements, there have been times when FDA awarded 3-year exclusivity for safety-related changes supported by new clinical investigations.   Typically, FDA grants 3-year exclusivity to efficacy studies rather than safety studies:

The agency believes that most studies qualifying for exclusivity will be efficacy studies. There may, however, be occasional clinical investigations qualifying for exclusivity that establish that a product is safer than originally thought and that permit broader use of the drug.  Studies that establish new risks will not be eligible for exclusivity because protection of the public health demands that all products’ labeling contain all relevant warnings.

54 Fed. Reg. 28,872, 28,899 (July 10, 1989).  However, FDA has been clear that it addresses 3-year exclusivity on a “case-by-case and product-by-product basis, depending on the particulars of the relationships between the information from the ‘new clinical investigation,’ the change approved to the drug product, and the scope of what an ANDA relies on.”  Letter to Covington and Burling re Seroquel (Mar. 27, 2012).

For example, FDA has granted 3-year exclusivity to several sponsors as a result of safety changes to labeling.  For example, in April 2003, FDA granted 3 years of exclusivity to labeling changes designed to enhance the safe use of Rapamune.  There, FDA approved efficacy supplements revising the labeling to include cyclosporine withdrawal procedures in patients at low to moderate risk for rejection.  FDA, Response to Citizen Petition, Docket No. 2003P-0518 (Sept. 20, 2004).  The labeling was revised to include extensive information from the cyclosporine withdrawal clinical study detailing the adverse event profile of cyclosporine withdrawal on Rapamune therapy patients.  This labeling change was necessary to safe use of the product because “continued use of cyclosporine with Rapamune is no longer an acceptable maintenance regimen in renal transplant recipients at low to moderate risk for rejection.”  Id.

Similarly, FDA granted exclusivity to a labeling change for Travatan replacing a statement that “Travatan had not been studied in patients with renal or hepatic impairment” with clinical findings showing that “no clinically relevant changes were observed” when patients with renal or hepatic impairment took the drug.  See Astrazeneca Pharms. LP v. FDA, Amended Memorandum Opinion, No. 12-00472 (Jul. 5, 2012).  Because the labeling changes were the subject of, and integral to, the approval of the supplement, FDA granted exclusivity.  Id.

And in 1997, FDA made a similar determination with respect to Diprivan.  After much internal deliberation, the CDER Director rejected OGD’s denial of 3-year exclusivity for the addition of EDTA to Diprivan.  OGD had reasoned that because the clinical studies submitted did not demonstrate substantial evidence of effectiveness for any indication, result in a change to the indications section, or provide safety information in a new patient population, the Diprivan supplement was not entitled to 3-year exclusivity.  Then-CDER Director Janet Woodcock overturned this decision and noted that “[t]he fact that the studies of the new formulation, once performed, provided considerable reassurance about the safety of the formulation, does not render them nonessential.”  FDA, Exclusivity Decision on Propofol Injectable Emulsion (Mar. 17, 1997).

FDA’s draft guidance provides a little more clarity on the safety study exclusivity issue, stating:

QB.5. Could an investigation assessing both PK/bioavailability and clinical safety and/or effectiveness qualify as a clinical investigation for 3-year exclusivity?

Yes. A study may have one or more purposes, including one or more primary purposes, which FDA may determine by examining, among other things, its endpoints, its design, and/or its role in the evidentiary package. For example, some studies may incorporate the assessment of a safety and/or effectiveness endpoint to support approval (for the purpose of demonstrating safety and/or effectiveness of the drug) in conjunction with a PK assessment.  Although the PK assessment is intended to characterize bioavailability, the Agency may find that the inclusion of the assessment of the safety and/or effectiveness endpoint in the study means that such a study meets the definition of a clinical investigation for purposes of 3-year exclusivity, notwithstanding the collection of PK/bioavailability data in the same study.  However, for example, studies that FDA concludes were conducted for the sole purpose of determining PK/bioavailability and merely incorporate routine safety monitoring of adverse events or reactions (as is generally required for all studies of drugs in humans, including bioavailability studies) would generally not be considered a clinical investigation for purposes of 3-year exclusivity.

The draft guidance also gets into the specifics of a new clinical investigation.  Clinical investigations must be real investigations: a placebo-only study would not qualify, nor would a bioavailability-only study (though a study that measures both clinical safety and efficacy in conjunction with a PK study may suffice).  And a “new” study is not necessarily a study that has recently been conducted—it simply must not previously have been relied upon by FDA to demonstrate substantial evidence of effectiveness or duplicate the results of a similar investigation.

Notably, FDA also addresses whether a cohort or treatment arm within a larger clinical trial can itself constitute a new clinical investigation for purposes of 3-year exclusivity. FDA explains that a cohort within a broader study may qualify even if the results of at least one different cohort or treatment arm were previously relined upon for approval of an application. Determining whether a cohort constitutes a new clinical investigation will be a fact-specific inquiry whereby FDA will consider whether there is an acceptable scientific or medical reason for the separate cohort or treatment arm, whether the separate cohort or treatment arm evaluates different patient populations and/or different drug products, and whether the separate cohort or treatment arm was prespecified in the protocol, among other things. This reflects the reality of modern clinical development, particularly in oncology and rare diseases, where basket, umbrella, and platform trials frequently evaluate multiple cohorts under a single protocol. FDA’s approach suggests that the Agency will look beyond the overall study design and instead focus on whether the cohort itself produced the clinical evidence supporting approval.

Essential to approval is also defined, meaning that “there are no other data available that could support approval of the NDA.”  The investigation must be “vital” to the application and no published studies or other information available to FDA would allow the Agency to approve the proposed drug product for the proposed conditions of use. This concept is closely intertwined with FDA’s cohort discussion described above. Even if a cohort could theoretically be viewed as its own investigation, it would still need to be essential to approval. In other words, FDA must actually rely on the data from that cohort in determining that the drug is safe and effective for the proposed indication. FDA therefore cautions that not every cohort within a trial will qualify as a new clinical investigation. If approval relies on pooled data across multiple cohorts, or if the cohort’s data are not independently necessary for approval, FDA may treat the broader trial as the relevant investigation for exclusivity purposes.

FDA also provides some procedural tips in the guidance. If an applicant believes its NDA is eligible for 3-year exclusivity, the applicant must submit a list of all published studies or publicly available reports of clinical investigations known to the applicant through a literature search that are relevant to the conditions for which the applicant is seeking approval; certification that the applicant has thoroughly searched the scientific literature, and to the best of the applicant’s knowledge, the list is complete and accurate, and in the applicant’s opinion, such published studies or publicly available reports do not provide a sufficient basis for the approval of the conditions for which the applicant is seeking approval without reference to the new clinical investigation(s) in the NDA.

Finally, an investigation is conducted by the applicant if the applicant was named in the Form FDA-1571; otherwise, the applicant must provide a certification stating that the applicant provided substantial support for the clinical investigations with information supporting the certification.  Such information should include either a certified statement from a certified public accountant that the applicant provided 50 percent or more of the cost of conducting the study or an explanation why FDA should consider the applicant to have conducted or sponsored the study.

If an applicant believes its drug is eligible for 3-year exclusivity, the applicant should submit a claim through the ESG identified as a “314.50(j) Exclusivity Claim” and placed in Module 1 at subfolder 1.3.5.3.  The guidance provides a handy template for a 314.50(j) exclusivity claim.  FDA will make a decision on exclusivity at approval, and such a decision will be reflected in the Orange Book.

One item the draft guidance does not delve into in any meaningful detail is the scope of 3-year exclusivity, which is effectively buried in an Orange Book exclusivity code.  Instead, FDA says:

QF.2. What is an exclusivity code and how does it relate to 3-year exclusivity?

The exclusivity code in the Orange Book provides notice of an application’s exclusivity.  Three-year exclusivity is described in the Orange Book with a letter (and sometimes numeric) code that may also be followed by a short description. The exclusivity codes are general shorthand descriptions and do not necessarily identify, with specificity, the actual scope of exclusivity.

Given that 3-year exclusivity scope issues are handled on a case-by-case basis and require extensive analysis, we understand why FDA decided not to opine on the issue.  But there are some helpful ground rules FDA could have communicated and that the Agency provides in various exclusivity memoranda (here and here).

Generally, the draft guidance does not add much information as to eligibility that could not be gleaned from the relevant regulations, but the process instructions and template will be helpful. FDA’s discussion of when a cohort within a larger trial may constitute a new clinical investigation essential to approval also provides some useful insight for sponsors employing modern multi-cohort trial designs.  Those of you submitting 505(b)(1)s, 505(b)(2)s, and supplements for approved moieties should get familiar with it and prepare those 314.50(j) Exclusivity Claims, along with all the requisite certifications, to secure any rightfully-earned exclusivity.