OOPD Clarifies Orphan Drug Designation Policies for Scleroderma and Pulmonary Hypertension

By Kurt R. Karst –      

FDA’s Office of Orphan Products Development (“OOPD”) recently revised its Standard Operating Procedures and Policies (“SOPP”) concerning review of orphan drug designation requests to provide the Office’s policies on designating products for two diseases: scleroderma and pulmonary hypertension.  The second version of the SOPP (available here) updates the first version of the document from November 2010 (see our previous post here), and is the first update since FDA issued issued a final rule on June 12, 2013 amending the Agency’s 1992 orphan drug regulations (see our previous post here).

As we previously reported, the SOPP is used by FDA’s OOPD for the review of orphan drug designation requests and provides some interesting (and useful) insight into the Office’s policies.  The appendicies to the SOPP are particularly useful.  Several of the appendicies describe OOPD policy on general issues such as “Scientific Rationale Supporting a Request for Orphan Drug Designation” (Appendix B), “Medically Plausible or Orphan Subsets Supporting a Request for Orphan Drug Designation” (Appendix C), and “Recombinant Products and Orphan Drug Designation” (Appendix E).  The 2010 version of the SOPP included a single disease-specific appendix: “Lymphoma as the Subject of a Request for Orphan Drug Designation” (Appendix D). 

The second version of the SOPP adds two disease-specific appendicies: “Scleroderma as the Subject of a Request for Orphan Drug Designation” (Appendix F), and “Pulmonary Hypertension as the Subject of a Request for Orphan Drug Designation” (Appendix G).  Both diseases have been the subject of dozens of orphan drug designation requests submitted to OOPD (at least 18 for scleroderma and 36 for pulmonary hypertension) and  several designations, according to OOPD’s Orphan Drug Designations and Approvals Database.  Interestingly, both additions to OOPD’s SOPP point to the European Medicines Agency’s (“EMA’s”) orphan drug designation policies (see here) as supportive of OOPD’s decisions.  This might signal greater cooperation between FDA and EMA on orphan drug issues and an effort to have consistent views on rare diseases.

Scleroderma as the Subject of a Request for Orphan Drug Designation.  According to the National Institute of Arthritis and Musculoskeletal and Skin Diseases, although scleroderma “is often referred to as if it were a single disease, scleroderma is really a symptom of a group of diseases that involve the abnormal growth of connective tissue, which supports the skin and internal organs.”  This group of diseases falls into two main classes: localized scleroderma and systemic sclerosis.  Systemic sclerosis has two main types: limited disease and diffuse disease. 

OOPD states in the SOPP that prior to 2009, the Office “designated products for the treatment of systemic sclerosis because the combined prevalence for both localized and systemic sclerosis was under 200,000.”  In 2009, however, the National Institutes of Health noted that the U.S. prevalence of scleroderma was 300,000, and thus over the 200,000 person prevalence threshold for orphan drug designation purposes.  From that point forward, explains OOPD, the Office “has asked sponsors requesting orphan drug designation for the use of their product for the treatment of systemic sclerosis why the product could not be used to treat localized scleroderma and to include that population in their prevalence estimate if there was no reason to exclude them.”  In other words, to obtain designation, a sponsor needed to explain what aspects of the drug product resulted in an orphan subset of a non-rare disease or condition.  As FDA explained in the preamble to the Agency’s 2013 final rule, “[u]nder FDA’s longstanding approach, eligibility for orphan subsets rests on whether use of the drug in a subset of persons with a non-rare disease or condition may be appropriate but use of the drug outside of that subset (in the remaining persons with the non-rare disease or condition) would be inappropriate owing to some property(ies) of the drug, for example, drug toxicity, mechanism of action, or previous clinical experience with the drug.”

Despite OOPD’s post-2009 orphan subset approach to scleroderma, the SOPP states that “one could make the case that localized scleroderma is a different disease than systemic sclerosis,” as “[l]ocalized scleroderma does not progress to systemic sclerosis.”  Morover, the SOPP notes that “the EMA considers systemic sclerosis to be distinct from localized scleroderma for the purposes of orphan drug designation.”

Given these considerations, OOPD states the Office’s current policy that “for the purposes of orphan drug designation, OOPD will now consider systemic sclerosis to be a different disease or condition than localized scleroderma.”  As such, “[s]ponsors requesting orphan drug designation for the use of their products for the treatment of systemic sclerosis will no longer be required to make the case that their product would not be effective in treating localized disease or include the patients with localized disease in their prevalence estimate.”  This policy went into effect on April 3, 2013.  Several weeks later, on May 14, 2013, OOPD designated Sanofi’s 2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indan-2-carboxylic acid for the treatment of patients with systemic sclerosis.  The designation followed the EMA’s March 12, 2013 orphan drug designation of the product for the treatment of systemic sclerosis (see here). 

Pulmonary Hypertension as the Subject of a Request for Orphan Drug Designation.  The World Health Organization (“WHO”) describes pulmonary hypertension as “a condition in which there is high blood pressure in the lung arteries,” and has divided the disease into five groups based on the cause of the condition and treatment options.  Historically, OOPD has designated products for the treatment of Pulmonary Arterial Hypertension (“PAH”), generally; however, as the Office notes in the SOPP, “it was not clear if PAH was treated as a different disease or condition from the other WHO groups of pulmonary hypertension or if PAH was treated as an orphan subset of pulmonary hypertension.”

After consulting the review division in FDA’s Center for Drug Evaluation and Research concerning what constituted the disease or condition when discussing pulmonary hypertension, “[i]t was determined that the results of studies of products intended for the treatment of pulmonary hypertension were not generalizable from one WHO classification of pulmonary hypertension to another,” and it was noted that the pathologies and treatments were different between groups.  As a result, OOPD clarifies in the SOPP that the five WHO classifications of pulmonary hypertension represent different diseases or conditions for orphan drug designation purposes.  “This clarification does not affect prior designations of products for [PAH] (WHO classification group I),” notes OOPD.  As with scleroderma, OOPD refers to its European orphan drug counterparst to support its decision, stating that in Europe PAH is considered “to be a different disease or condition from other WHO classification groups of pulmonary hypertension,” and that products have been designated for PAH and for chronic thromboembolic pulmonary hypertension (WHO group 4).  Moreover, says OOPD, European officials have “opined that it was supportable to consider the 5 groups that comprise the WHO classification of pulmonary hypertension to be different diseases or conditions for the purpose of orphan drug designation.”