US FDA Should Offer Formal Declaration Of Orphan Drug Flexibility, Attorney Says
Executive Summary
Attorney Frank Sasinowski says the agency should include new "boilerplate language" in official documents describing scientific flexibility for orphan drug approval requirements.
US Food and Drug Administration officials rarely shy away from an opportunity to trumpet the flexibility they allow with rare disease approval standards.
The FDA has approved drugs despite not having two adequate and well-controlled trials, as is usually required for conventional drugs, and made other concessions for rare diseases, which have small patient populations and where traditional clinical trials often are difficult or impossible to complete.
Yet the agency apparently is not conveying that flexibility with as much vigor in some official documents to sponsors. Attorney Frank Sasinowski, of Hyman, Phelps and McNamara, called on the FDA to declare that scientific flexibility is allowed as part of the legal statements of its approval standards.
"My sense is that if we can have this addition, it would allow the FDA to explain to the world the basis for its actions, it would allow the FDA to reserve to itself maximum discretion for exercising its scientific discretion," Sasinowski said during the 5 September EveryLife Foundation for Rare Diseases Scientific Workshop. He also is the foundation's vice chair.
Typically when the FDA issues preliminary comments in advance of a formal meeting or writes post-meeting minutes, officials include the legal basis for their statements, including approval standards.
The FDA's Statement Of Authority
Current Statement:
Even though the ODA did not amend 1962 law, a single positive [adequate and well-controlled] study may meet the statutory standard if it is either:
a. Highly statistically persuasive (p-value of at least less than 0.01) study with no other evidence of effectiveness as per May 1998 guidance, or
b. Conventionally positive (p-value less than 0.05) study with some form of confirmatory evidence (note: there is growing recognition of this alternative standard).
Proposed Addition:
In addition, the agency has long-established authority that “demands flexibility in applying the [statutory (1962 and 1997) and administrative (1998)] standards. Thus FDA is required to exercise its scientific judgment to determine the kind and quantity of data and information for a particular drug to meet the statutory [and administrative] standards.” 21 CFR 314.104(c).
As such, FDA is compelled to exercise its scientific judgment on a case-by-case basis in reviewing each therapy being investigated for a rare disease. That exercise of judgment can be affected by many factors, including among others, the rarity and severity of the condition and the relative availability of other satisfactory therapies.
When dealing with rare disease sponsors and their questions or stated intentions for a development program, the agency often will state in its responses that the Orphan Drug Act did not change the articulated standard of approval, which is that two adequate and well-controlled trials are necessary to show efficacy.
They also will state that updated laws and guidance allow the agency to accept one highly statistically persuasive study or a "conventionally positive" study with some form of confirmatory evidence. (See box for full statements.)
Sasinowski argued those statements do not fully describe the additional flexibility the agency has in determining whether a rare disease drug is effective and that while long-time observers understand the policy, it is not apparent to everyone.
"Every time the FDA records in its official minutes the current statement of its authority to act, it's used as a Rosetta Stone by corporate executives, by investors, by boards of directors to determine whether or not they're going to go forward and do the manufacturing, do the animal tests, do the clinical tests," he said. "Right now we have no metric for measuring how adverse the impact is when the FDA writes its current statement, which I don't think reflects its true authority."
The change could enhance agency predictability at a time when rare disease drug approvals are on the rise. In 2018, they constituted the majority of novel drug approvals for the first time. (Also see "Orphan Drugs Compose Majority Of Novel US Approvals For First Time Ever In 2018" - Pink Sheet, 3 Jan, 2019.)
Flexibility Statement Will Provide FDA More Coverage To Justify Decisions
The additional statement, which was proposed to be included along with other "boilerplate language," would indicate that the agency has long established authority that "demands flexibility" and that the agency is required to "exercise its scientific judgment to determine the kind and quantity of data and information for a particular drug" to meet legal standards.
"As such, FDA is compelled to exercise its scientific judgment on a case-by-case basis in reviewing each therapy being investigated for a rare disease," Sasinowski's proposed statement reads. "That exercise of judgment can be affected by many factors, including among others, the rarity and severity of the condition and the relative availability of other satisfactory therapies."
Sasinowski said that the additional language will provide more coverage for the agency to justify the many decisions it makes during a development program. He also said in presentation slides that "FDA would be preserving maximum degrees of freedom to act to promote the public health."
There have been attempts to better codify rare disease flexibility in FDA law and regulations which have not been particularly warmly received by the agency. Former Office of New Drugs Director John Jenkins has warned that describing flexibility in law or policy actually may limit it. (Also see "Regulatory Flexibility Staring Contest: Will Industry Or FDA Blink First?" - Pink Sheet, 24 Oct, 2011.)
Flexibility Well-Known In FDA Circles
The FDA's flexibility with rare disease drugs was recognized for many years, but had not been quantified.
Sasinowski and the National Organization for Rare Disorders published a report showing that either administrative or case-by-case flexibility had been used in a majority of non-cancer orphan drug approvals from 1983 through June 2010. (Also see "Orphan Products Mostly Approved With Regulatory Flexibility, NORD "Catalog" Finds" - Pink Sheet, 17 Oct, 2011.)
An update adding orphan drug approvals from July 2010 through June 2014 showed the agency maintained its rate of exercising flexibility. (Also see "FDA Orphan Approval Flexibility Remains Steady As Pressure Increases" - Pink Sheet, 27 Oct, 2014.)
Stakeholders also are interested in ensuring FDA assessors across OND understand the agency's flexibility policy and apply it consistently.
As part of the 2017 prescription drug user fee reauthorization, the agency agreed to have its rare disease staff integrated with assessors, in part to help improve consistency. (Also see "Rare Disease Integration Into FDA Reviews Will Grow Under PDUFA VI" - Pink Sheet, 18 Jul, 2016.)
Sasinowski and colleague James Valentine have proposed creating a rare disease center of excellence at FDA that would centralize expertise and enhance collaboration. However, Center for Drug Evaluation and Research director Janet Woodcock did not like the idea, saying a rigid framework may not be the best structure for the rare disease program. (Also see "Center Of Excellence Not Best Model For US FDA Rare Disease Program, Woodcock Says" - Pink Sheet, 13 Sep, 2018.)
Sasinowski and Valentine also proposed creating a standing advisory committee for rare diseases, though a pool of experts that would be added to existing committees when needed seems like more of a possibility. (Also see "US FDA May Create Rare Disease Expert Pool For Advisory Committee Reviews" - Pink Sheet, 29 Oct, 2018.)
In addition, the FDA has proposed creating a Division of Rare Diseases and Inborn Errors and Metabolism within an Office of Rare Diseases, Pediatrics and Women's Health as part of its pending reorganization of OND. The new flatter structure envisioned will be more disease-focused. (Also see "US FDA's Rare Diseases Program Not Expected To Change With Drug Office Reorg" - Pink Sheet, 27 Jun, 2018.)