FDA Gives a “Nudge Nudge Wink Wink” in Denial of NORD Petition on Special Treatment of Orphan Drugs

By Kurt R. Karst –

In a September 10, 2015 Response to a September 2, 2011 Citizen Petition (Docket No. FDA-2011-P-0657) submitted by the National Organization for Rare Disorders (“NORD”), FDA refuses to add a statement to guidance documents concerning orphan drugs that the Agency’s official policy is to afford “special flexibility” to the regulatory review of marketing applications for products for rare diseases.  Despite FDA’s refusal, however – and in what might be characterized as the regulatory equivalent of a “nudge nudge wink wink” – the Agency assures NORD that FDA “remains sensitive to NORD’s concerns and will continue to encourage and support the development and availability of treatments for rare diseases” and outlines the numerous ways in which the Agency addresses the unique concerns related to rare diseases. 

NORD’s petition was triggered by a provision included in the Fiscal Year 2010 FDA Appropriations Act (Pub. L. No 111-80).  As we previously reported, Section 740 of the law required FDA to, among other things, develop “internal review standards” no later than 180 days following issuance of a report by the Agency’s internal expert committee on the review of articles for the diagnosis or treatment of rare diseases.  FDA issued the Report to Congress on June 27, 2011, making the Agency’s “internal review standards” guidance due for issuance no later than December 27, 2011 (see our previous post here).  NORD’s petition requests that FDA’s guidance explicitly include three items: 

• Acknowledgement that the conduct of clinical trials for most orphan drugs is qualitatively and quantitatively different from the conduct of trials for drugs that treat common conditions.
• Acknowledgement that FDA review of marketing applications for most orphan drugs is accordingly qualitatively and quantitatively different from FDA review of applications for articles that treat common conditions.
• In recognition of the above, and notwithstanding the unchanged requirements that articles for rare diseases must demonstrate both efficacy and safety, we request a statement that it will now be FDA official policy to afford special flexibility to the regulatory review of submissions for all orphan drugs.

According to NORD, “[t]his petition does not request any itemization of past actions – rather, through the language of forthcoming guidance, we request the establishment of a policy to direct future actions.”  In addition, NORD requests that FDA “incorporate mandatory training in this new policy and other matters related to orphan drug development for all full-time FDA review professionals”  by making the course administered by CDER’s Associate Director for Rare Diseases, titled “Meeting the Challenges of Rare Disease Drug Review,” a requirement for all CDER and CBER reviewers.

Citing the Agency’s January 2013 final guidance on Humanitarian Use Device Designations (see our previous post here) and FDA’s August 2015 draft guidance on “Rare Diseases: Common Issues in Drug Development” (see our previous post here) – which “acknowledges that certain aspects of drug development that are feasible for common diseases may not be feasible for rare diseases” – FDA says in the petition response that the guidances meet the publication provisions of Section 740 of the Fiscal Year 2010 FDA Appropriations Act, and that with their issuance, FDA grants the guidance publication request in NORD’s petition.  (FDA also notes that other related guidances are in the near-term pipeline.)  But that’s the extent to which FDA explicitly grants any of the requests in NORD’s petition. 

Moving on to NORD’s request for “explicit acknowledgements” in guidance that both clinical trials and FDA application reviews for orphan drugs are “qualitatively and quantitatively different” from clinical trials or application reviews for products treating prevalent diseases or conditions, and NORD’s request for a statement in guidance on the “special flexibility” FDA applies to the review of applications for orphan drugs, FDA takes an interesting tack.  FDA denies both requests, saying that “the language you suggest may inadvertently limit FDA’s decision-making flexibility or mislead others regarding the standards required for orphan drugs;” however, the Agency then goes on to note the various ways in which the Agency has accorded flexibility to orphan drug reviews, including citing a landmark report authored by Hyman, Phelps & McNamara, P.C.’s Frank J. Sasinowski on his findings of flexibility in FDA’s review of potential treatments for patients with rare diseases (see our previous posts here and here).  According to FDA:

Although the Agency will not make explicit the suggested acknowledgements in future guidances, FDA has assessed, and will continue to assess, orphan drug development programs on an individual basis, taking into account disease manifestations, the expected results of the intervention, the population under study, and other factors. . . .

For products treating rare diseases, FDA’s record of flexibility during the approval process is indisputable.  Between 2006 and 2015, FDA approved almost 200 such products in multiple therapeutic areas and indications.  In doing so, the Agency assented to a wide variety of clinical development programs, accepted trial populations as low as less than 20, approved treatments that in some instances relied on only one study, and accepted a diverse array of study designs.  For approved products, such factors such as the disease being treated, the intervention proposed, and the population under study can affect the quantity and quality of evidence available.) [sic] In each case, FDA exercised its scientific judgment to determine what level of information would be sufficient to demonstrate compliance with applicable statutory and regulatory standards.

FDA also declines to change the content of the Agency’s “Meeting the Challenges of Rare Disease Drug Review” training course as NORD requested, saying that “in its current iteration, this annual course sufficiently addresses your concerns regarding the unique challenges of orphan drug development.” 

But FDA’s petition response is not done yet.  FDA takes this opportunity to tick off some of the recent ways in which the Agency “has been proactive in addressing the unique concerns related to rare diseases”: 

• Hiring additional staff to the OND Rare Disease Program
• Forming a Rare Disease Council that meets monthly and discusses cross-cutting issues relating to rare diseases (see here at page 60)
• Developing a comprehensive regulatory science database and evaluation tool that allows the Agency to identify best practices and gaps for rare disease development
• Holding public workshops and Patient-Focused Drug Development (PFDD) meetings that address specific topical areas and particular diseases, where approximately 50% of these meetings have been focused on rare diseases (see our previous post here)
• Holding a PDUFA V- and FDASIA-mandated three-day public meeting entitled “Complex Issues in Developing Drugs and Biological Products for Rare Diseases and Accelerating the Development of Therapies for Pediatric Rare Diseases” on January 6- 8, 2014
• Publishing the draft guidance for industry entitled “Rare Pediatric Disease Priority Review Vouchers” in November 2014 (see our previous post here)
• Publishing the guidance for industry entitled “Expedited Programs for Serious Conditions – Drugs and Biologics” in May 2014 (see our previous post here)
• Establishing and participating in numerous conferences, committees, and work groups related to rare disease issues and topics

So, despite FDA's reticence to explicitly state as official Agency policy that FDA affords special flexibility to the regulatory review of submissions for orphan drugs, it seems pretty clear that the flexibility is implied.  That seems to me the messaging going on in FDA's petition response to NORD.  And it's a message repeated by FDA’s Associate Director for the CDER Rare Diseases Program, Dr. Jonathan Goldsmith, who commented in a recent FDA Voice blog post that it is “important to note that FDA regulations provide flexibility in applying regulatory standards because of the many types and intended uses of drugs. Such flexibility is particularly important for treatments for life-threatening and severely-debilitating illnesses and rare diseases.”