Office of Orphan Products Development SOPP Clarifies Orphan Drug Designation Policies

By Kurt R. Karst –      

A Standard Operating Procedures and Policies (“SOPP”) prepared and used by FDA’s Office of Orphan Products Development (“OOPD”) for the review of orphan drug designation requests was recently made public and provides some interesting (and helpful) insight into OOPD’s policies.  Of particular interest are several of the appendicies to the SOPP, including Appendix B (“Scientific Rationale Supporting a Request for Orphan Drug Designation”), Appendix C (“Medically Plausible or Orphan Subsets Supporting a Request for Orphan Drug Designation”), Appendix D (“Lymphoma as the Subject of a Request for Orphan Drug Designation”), and Appendix E (“Recombinant Products and Orphan Drug Designation”).  While we have seen the policies described in the SOPP implemented in product-specific sponsor correspondence (or know them through OOPD designation precedent), never before have we seen them discussed in a more general policy document like the SOPP.

Scientific Rationale Supporting a Request for Orphan Drug Designation – FDA’s orphan drug regulations at 21 C.F.R. § 316.20(b)(4) require that a designation request contain “[a] description of the drug and a discussion of the scientific rationale for the use of the drug for the rare disease or condition, including all data from nonclinical laboratory studies, clinical investigations, and other relevant data that are available to the sponsor, whether positive, negative, or inconclusive.”  FDA may refuse to grant designation on the basis that “[t]here is insufficient information about the drug, or the disease or condition for which it is intended, to establish a medically plausible basis for expecting the drug to be effective in the prevention, diagnosis, or treatment of that disease or condition” (21 C.F.R. § 316.25(a)(2)). 

In describing what constitutes an adequate scientific rationale for the use of the drug for the rare disease or condition when applying for orphan drug designation, the SOPP states that while “OOPD will accept data from clinical investigations as providing the strongest rationale for establishing a medically plausible basis for expecting the drug to be effective in the prevention, diagnosis, or treatment of the disease or condition,” animal data may also be acceptable.  According to OOPD:

[A]s evidence of a medically plausible basis for expecting the drug to be effective in the rare disease under consideration, OOPD requires sponsors seeking orphan drug designation to provide sufficient information about the drug from in vivo studies in a relevant animal model of the disease or from clinical studies in patients with the rare disease or condition treated with the drug.  Please note, the data must be generated from in vivo studies in a relevant animal model of the disease or from clinical studies in patients with the rare disease or condition in which the animals and/or patients are treated with the active moiety that is the subject of the orphan drug designation request.  In the absence of human data and when no animal model of the disease exists, OOPD may consider alternatives that include in vitro data, a description of the mechanism of action of the product, and the pathogenesis of the disease or condition. [(Emphasis in original)]

Medically Plausible or Orphan Subsets Supporting a Request for Orphan Drug Designation – 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)).  The orphan drug designation process has been designed to ensure that MPSs are groups of patients with special requirements or characteristics that distinguish them from the larger disease grouping.  Although a product may have a beneficial effect on the entire group of individuals with a particular disease or condition, to be designated as an orphan drug, the product must be able to treat a disease or condition that is distinguished in some aspect from the larger disease or condition.  FDA’s orphan drug regulations do not clearly define the term “medically plausible subset.”  In fact, in the preamble to the regulations, FDA states 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” (57 Fed. Reg. 62,076, 62,081 (Dec. 29, 1992)). 

OOPD’s SOPP takes a stab at defining an MPS:

A "Medically Plausible or Orphan Subset" of a more common disease or condition is defined by some characteristic of the drug or biologic that would limit its use to this subset of the disease or condition and would make the drug or biologic ineffective or too toxic to use in the complement of the subset of the disease or condition.  Examples of such characteristics would include mechanism of action of the drug or biologic or toxicity profile of the drug or biologic.  It is the policy of the Office of Orphan Products Development to apply this definition when faced with a request for orphan drug designation that targets a rare subset of a common disease or condition.

Lymphoma as the Subject of a Request for Orphan Drug Designation – What constitutes the disease or condition when the subject of a request for orphan drug designation is lymphoma?  That’s the question OOPD’s SOPP answers in Appendix D.  “At the crux of the issue,” says OOPD “is the question of ‘What is the disease?’”  The answer to this question has apparently changed over time.

Historically, OOPD has answered this question in different ways as the times have changed: it began with ‘lymphoma’; then was ‘Hodgkin’s disease and non-Hodgkin’s lymphoma” and subsequently progressed to “Hodgkin’s disease, non-Hodgkin’s B-cell lymphoma, non-Hodgkin’s T-cell lymphoma or non-Hodgkin’s null-cell lymphoma.”  With each iteration of OOPD nosology, sponsors were required to meet the statutory prevalence criteria for the disease terms that were put into effect.

As of the effective date of the SOPP – November 9, 2010 – OOPD says that the Office was “at a juncture where further splitting in the disease entities is well recognized by the medical community, and the terms ‘B-cell lymphoma’ and ‘T-cell lymphoma’ are thought not to be ‘diseases’ but rather to be agglomerations of distinct disease entities.”  To cut to the chase, OOPD states that the Office “recognizes the current [World Health Organization] classification of lymphomas as stipulating the diseases of record.” 

Recombinant Products and Orphan Drug Designation – The final appendix to the SOPP delves into the murky area of orphan drug “sameness” and “clinical superiority.”  (Clinical superiority is at the heart of one pending citizen petition – Docket No. FDA-2011-P-0213.)  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.”  FDA’s orphan drug regulations define a “clinically superior” drug as “a drug . . . shown to provide a significant therapeutic advantage over and above that provided by an approved orphan drug (that is otherwise the same drug)” in one of three ways:

(a) greater effectiveness as assessed by effect on a clinically meaningful endpoint in adequate and well controlled trials;
(b) greater safety in a substantial portion of the target population; or
(c) demonstration that the drug makes a major contribution to patient care.

With respect to the clinical superiority of recombinant products over tissue-derived products when determinations of orphan drug “sameness” are being considered, OOPD states in the SOPP that:

OOPD will adopt the policy that products of recombinant origin are inherently superior to those of human origin because they are safer regarding person-to-person transmission of infectious agents.  It is recognized that such safety may in fact be only theoretical safety, that is, OOPD would not require evidence of infectious disease transmission with a human-derived product in order to establish the superiority of a corresponding recombinant product.  Rather, it is acknowledged that current understanding may not include all potential agents of human disease; accordingly, this epistemological limitation may prevent the institution of processing procedures that render products free from agents not yet discovered.  This policy, that recombinant products are inherently superior, is a conservative judgment based on a lengthy history of medical iatrogenesis coincident to the use of human-derived products.  But it is acknowledged to be a judgment, and not founded on contemporary data.

The concept of “inherent clinical superiority” has also shown up in other places.  For example, in 1997, FDA determined that BENEFIX (coagulation factor IX) was clinically superior to MONONINE and ALPHANINE (both coagulation factor IX products) based on the fact that “BeneFix™ is inherently less likely to transmit human blood-born viruses and other infectious agents, and is also less likely to transmit animal-derived zoonotic agents.”  

In addition to the policies discussed above, the SOPP provides other helpful information, such as for purposes of documenting cancer prevalence “[t]he Surveillance, Epidemiology, and End Results program (SEER) database maintained by the National Cancer Institute has been adopted as OOPD’s standard source for cancer prevalence information.”  The SOPP also states OOPD’s “3 expert policy” for purposes of documenting disease/condition prevalence when medical literature does not yield prevalence information.  “In the event a search of the medical literature reveals no adequate sources of prevalence of a disease or condition,” says the SOPP, “the sponsor may enlist the statements of three independent experts in the disease in question.  These experts must provide an estimate of the prevalence of the disease or condition with a detailed reasoning or method by which they arrived at their aforementioned estimate.  All experts contacted must be identified by the sponsor if using this method.”