FDA Proposes to Clarify and Update Orphan Drug Regulations

By Kurt R. Karst –   

On October 19, 2011, FDA issued a proposed rule to amend the Agency’s December 29, 1992 (57 Fed. Reg. 62,076) orphan drug regulations.  The proposal is not a whole-scale overhaul of FDA’s orphan drug regulations, but rather a group of amendments “intended to clarify regulatory provisions and make minor improvements to address issues that have arisen since those regulations were issued” and that are based on the Office of Orphan Products Development’s (“OOPD’s”) review of more than 3,350 orphan drug designation requests since December 1992.  FDA’s proposal is the latest development on the orphan drug front.  As we reported last week, the National Organization for Rare Disorders (“NORD”) released a landmark report (authored by Chairman of the NORD Board of Directors and Hyman, Phelps & McNamara, P.C. Director, Frank J. Sasinowski) on the flexibility in FDA’s review of potential treatments for patients with rare diseases.

FDA’s proposed rule addresses 13 specific issues (some of which we touched on earlier this week when we reported on an OOPD Standard Operating Procedures and Policies):

(1)  Demonstration of an appropriate “orphan subset” of persons with a particular disease or condition that otherwise affects 200,000 or more persons in the United States, for the purpose of designating a drug for use in that subset (21 C.F.R. § 316.20(b)(6));

(2)  Eligibility for orphan-drug designation of a drug that is otherwise the same drug for the same orphan indication as a previously approved drug (21 C.F.R. §§ 316.3(b)(3), 316.20(a), and 316.20(b)(5));

(3)  Eligibility for multiple orphan-drug exclusive approvals when a designated orphan drug is separately approved for use in different subsets of the rare disease or condition (21 C.F.R. § 316.31);

(4)  Requirement for demonstrating clinical superiority for the purpose of orphan-drug exclusive approval (21 C.F.R. § 316.3(b)(3)(iii));

(5)  Requirement for submitting the name of the drug in an orphan-drug designation request (21 C.F.R. § 316.20(b)(2));

(6)  Required drug description and scientific rationale in a designation request (21 C.F.R. § 316.20(b)(4));

(7)  Required information in a designation request relating to the sponsor's interest in the drug (21 C.F.R. § 316.20(b)(9));

(8)  Timing of a request for orphan-drug designation (21 C.F.R. § 316.23(a));

(9)  Responding to a deficiency letter from FDA on an orphan-drug designation request (21 C.F.R. § 316.24(a));

(10)  FDA publication of information regarding designated orphan drugs (21 C.F.R. § 316.28);

(11)  FDA recognition of orphan drug exclusive approval (21 C.F.R. § 316.34(c));

(12)  Miscellaneous terminology changes (21 C.F.R. Part 316); and

(13)  OOPD address change (21 C.F.R. § 316.4).    

Below we note some of the proposed changes and clarifications that we think merit special attention.

Demonstration of an “Orphan Subset” of a Disease or Condition.  One element of an orphan drug designation request is to explain the relevant “medically plausible subset” (“MPS”) of individuals (if any) affected by a particular disease or condition that is eligible for a therapy (21 C.F.R. § 316.20(b)(6)).  FDA’s orphan drug regulations do not clearly define the term “medically plausible subset.”  In fact, in the preamble to the 1992 regulations, FDA stated that it “declines to provide examples of medical plausibility or to further develop the definition of [an MPS].  Application of the concept is a matter of judgment based on the specific facts of each case.” 

Recognizing that the term “medically plausible” “has been misinterpreted to mean any medically recognizable or any clinically distinguishable subset of persons with a particular disease or condition,” and that “[i]nappropriate application of the concept of a [MPS] could result in the creation of subsets of non-rare diseases or conditions that are artificially narrow,” FDA proposes to remove the term “medically plausible” in 21 C.F.R. § 316.20(b)(6) “and instead provide a description of how an appropriate subset [(i.e., an ‘orphan subset’)] may be identified for the purpose of orphan-drug designation.”  Specifically, 21 C.F.R. § 316.20(b)(6) is proposed to state:

Where a drug is under development for only a subset of persons with a particular disease or condition that otherwise affects 200,000 or more people, a demonstration that, due to one or more properties of the drug, the remaining persons with such disease or condition would not be appropriate candidates for use of the drug

FDA goes on in the preamble to note that “[w]hen a sponsor has established that the selected population constitutes a non-arbitrary subset, e.g., by describing the scientific or medical basis for limiting the potential use of the drug to that population and demonstrating that such scientific or medical basis is reasonable, the target population is an acceptable orphan subset of persons with the particular disease or condition for the drug of interest.”  FDA also provides some useful examples of what the Agency says are appropriate and inappropriate orphan subsets, and recommends that sponsors ask themselves a few of questions to test whether a subset of patients within a larger disease or condition grouping that has a United States prevalence of 200,000 or more persons can be considered an appropriate orphan subset for purposes of orphan drug designation:

• Is the intended subset artificially restricted in any way with respect to the use of the drug to treat the disease or condition?
• Given that the drug may potentially benefit this particular subset of persons, is there a reasonable scientific or medical basis for believing that the drug would also potentially benefit the remaining population with the non-rare disease or condition or a larger subset of that population?  If not, why not?

Eligibility for Orphan Drug Designation of a Drug That Was Previously Approved for the Orphan Indication.  FDA’s orphan drug regulations at 21 C.F.R. § 316.20(a) state that “a sponsor of a drug that is otherwise the same drug as an already approved orphan drug may seek and obtain orphan drug designation for the subsequent drug for the same rare disease or condition if it can present a plausible hypothesis that its drug may be clinically superior to the first drug” (emphasis added).  Over the years, there has been confusion as to how FDA/OOPD interprets the term “orphan drug” in this regulation.  The term is specifically defined at 21 C.F.R. § 316.3(b)(10) to mean “a drug intended for use in a rare disease or condition as defined in section 526 of the act.”  But does this mean that an “orphan drug” is any previously approved drug for a rare disease or condition, regardless of whether or not it was designated and approved as an orphan drug?

FDA states in the proposed rule that “[i]n the absence of a clinical superiority hypothesis, the Agency does not interpret the orphan-drug regulations to permit orphan designation of a drug that is otherwise the same as a drug that is already approved for the orphan use, either where the approved drug received orphan-drug exclusive approval (even after such drug's exclusivity period has run out) or where the approved drug was not previously designated as an orphan drug and thus did not receive orphan exclusive approval” (emphasis added).  Accordingly, FDA proposes to amend certain regulations to delete the word “orphan” in the phrase “approved orphan drug” in order to “clarify that these provisions would be applicable to a drug that is otherwise the same drug as any previously approved drug for the same orphan disease or condition, regardless of whether such drug was designated as an orphan drug” (emphasis in original).

Eligibility for Multiple Orphan-Drug Exclusive Approvals.  For years now, we understand that FDA has adopted a “pie approach” to orphan drug designation, under which a single orphan drug designation can result in multiple periods of orphan drug exclusivity.  That is, an approval for each slice of the pie (i.e., the designation) can result in separate 7-year periods of exclusivity.  As FDA explains in the preamble to the proposed rule:

The scope of orphan exclusive approval for a designated drug is limited to the approved indication or use, even if the underlying orphan designation is broader.  If the sponsor who originally obtained orphan exclusive approval of the drug for only a subset of the orphan disease or condition for which the drug was designated subsequently obtains approval of the drug for one or more additional subsets of that orphan disease or condition, FDA will recognize orphan-drug exclusive approval, as appropriate, for those additional subsets from the date of such additional marketing approval(s).  Before obtaining such additional marketing approval(s), the sponsor in this instance would not need to have obtained additional orphan designation for the additional subset(s) of the orphan disease or condition.

This interpretation is proposed to be included in 21 C.F.R. § 316.31(b).  FDA also notes in the preamble what this interpretation means with respect to clinical superiority and subsetting, stating that:

After approval of the drug for one or more subsets of the orphan disease or condition, a subsequent sponsor may, without submitting a plausible hypothesis of clinical superiority, seek designation of the drug for the subset(s) of the orphan disease or condition for which the drug has not yet been approved.  FDA may designate the drug for use in the remaining subset(s) without requiring a postulation of clinical superiority.  To obtain such a designation, however, the sponsor must demonstrate that, at the time of its designation request, the entire population with the orphan disease or condition, not just the remaining subset(s) of the population, is under the prevalence limit, unless the sponsor can demonstrate that the remaining subset(s) is an orphan subset in accordance with § 316.20(b)(6).

Demonstration of Clinical Superiority.  FDA’s proposal is intended to clarify that merely because FDA/OOPD has granted orphan drug designation based on a plausible hypothesis of clinical superiority does not mean that clinical superiority has been demonstrated and the orphan drug can be approved or approved with a period of 7-year exclusivity.  FDA states in the preamble to the proposed rule that:

It is possible . . . that a sponsor that has obtained designation of its drug on the basis of a hypothesis that the drug will be clinically superior will be unable, upon submission of the marketing application, to demonstrate that the drug is clinically superior to the previously approved drug.  In that case, if the already approved drug has remaining exclusive approval, the subsequent drug would not itself be eligible for approval, because it is the same drug as the drug with exclusive approval.  If the approved drug does not have exclusive approval, the subsequent drug may be approved, but would not itself be eligible for orphan-drug exclusive approval.

FDA also states with respect to the “major contribution to patient care” (the so-called “MC-to-PC”) basis for clinical superiority (see our previous post here) that:

a drug that is otherwise the same drug as a previously approved drug, and for which a clear showing of greater effectiveness or greater safety has not been made, may still be considered clinically superior within the meaning of § 316.3(b)(3)(iii) if it makes a major contribution to patient care.  FDA believes that such clinical superiority is meaningful only when the subsequent drug provides safety or effectiveness comparable to the approved drug.  For example, to claim that a drug makes a major contribution to patient care through a new formulation or a different route of administration, the sponsor must also address whether the change renders the drug less safe or less effective than the approved drug.  (Emphasis added)

Timing of Request for Orphan-Drug Designation.  FDA’s proposal would amend 21 C.F.R. § 316.23(a) to clarify the timing of an orphan drug designation request.  According to FDA, “[i]t is not clear in the current regulatory language that one sponsor’s marketing application would not prevent a different sponsor from submitting a request for orphan designation for the same drug for the same orphan use and that this subsequent sponsor would not have to submit a plausible hypothesis of clinical superiority.” 

The proposed revisions to 21 C.F.R. § 316.23(a) would not only clarify that a sponsor may not submit an orphan drug designation request after the submission of a marketing application for the drug for the rare disease or condition, but also that “submission by a sponsor of a marketing application for the drug for the orphan indication does not prevent another sponsor from submitting a request for orphan designation of the same drug for the same orphan use.”  However, “[o]nce any sponsor’s marketing application for the orphan indication has been approved, with or without orphan exclusive approval, another sponsor may not obtain orphan-drug designation for the same drug and the same orphan indication or use for which the approval was granted absent a plausible hypothesis of clinical superiority.”

Responding to a Deficiency Letter From FDA on an Orphan Drug Designation Request.  Noting that “FDA regulations are currently silent on when sponsors must respond to a deficiency letter from FDA on an orphan-drug designation request,” and that while some sponsors respond promptly to deficiency letters, other sponsors “may take several years or more to respond without sending any interim communication to FDA,” the Agency proposes to amend 21 C.F.R. § 316.24 to require that sponsors respond to a deficiency letter within 1 year after issuance, unless the sponsor requests (in writing) an extension of time to respond within the 1-year period.  “Such a request would specify both the reason(s) for the requested extension and the length of time of the requested extension,” says FDA.  According to FDA, a “repeat request” for an extension may be granted if the sponsor submits a new extension request before expiration of the deadline as originally extended, and if such request states both the reason(s) for the request and the requested length of time of the extension.

In the event a sponsor fails to respond to a deficiency letter, fails to request an extension
of time within a year, or if FDA denies an extension request, the Agency says that it may consider the designation request voluntarily withdrawn.  FDA notes in the proposal that the Agency “will grant all reasonable requests for an extension”; however, FDA goes on to state that:

some deficiencies may be less suitable to extension requests than others.  For example, FDA generally expects that deficiencies involving an inaccurate or incomplete prevalence estimate will be readily addressed within 1 year.  Other types of deficiencies, however, may take longer to address.  For example, deficiencies involving the scientific or medical rationale supporting a designation request for only a subset of persons with a particular disease or condition may require sponsors to conduct research and develop additional data, which may take several years or more.  For the latter types of deficiencies, FDA generally anticipates granting extension requests to allow sponsors to develop necessary supporting data and information.

Electronic or written comments on the proposed rule (Docket No. FDA-2011-N-0583) are due by January 17, 2012.