Biomarkers For Rare Diseases Get Scaled-Back Plea In New White Paper

EveryLife Foundation’s finalized white paper on using accelerated approval in rare diseases indicates that biomarkers don’t have to be discussed with FDA at the pre-IND stage, but should be done early enough to allow development process predictability.

A biomarker qualification meeting for a rare disease drug attempting to use accelerated approval need not be held in the pre-IND stage, a rare disease group decided, but early enough to deliver some certainty to the development process.

Conducting disease surveys early in product development also could better inform FDA about the flexibility needed to push the potential new treatment through the pathway, the EveryLife Foundation for Rare Diseases said in the final version of a white paper giving recommendations for rare disease drug development using accelerated approval.

The foundation continued its call for a process to have biomarkers approved for individual products before an IND is submitted. But, unlike a previous draft of the white paper, the foundation now is saying the biomarker qualification process could occur after the pre-IND stage.

“The only key goal is to help provide the option for earlier certainty in development, and the potential then to raise the sufficient funding to develop a rare disease drug when the pathway is clear,” the group wrote in the final white paper, which was submitted to FDA Aug. 25.

The document is intended to inform FDA efforts to write guidance clarifying the use of accelerated approval, including in rare diseases, mandated in the 2012 FDA Safety and Innovation Act.

FDA issued draft guidance on its expedited approval programs in late June that was intended to meet a requirement to clarify accelerated approval’s use in rare diseases. A final guidance is due in July 2014.

The foundation was not satisfied, however, saying it did not provide enough clarity about rare disease products’ use of the pathway. It rallied fellow advocates to push members of Congress to sign a letter asking FDA to provide a more workable solution (Also see "FDA Accelerated Approval For Rare Diseases Again Under Congressional Pressure" - Pink Sheet, 30 Jul, 2013.).

Foundation President Emil Kakkis said in an e-mail that the white paper “stands alone” and even if not added to the final guidance, can be cited as a reference and “still move the field forward in an organized direction.”

The foundation also submitted formal comments on the draft guidance that were based on the white paper, Kakkis said.

BIO, NORD Also Want More Detail

The Biotechnology Industry Organization and National Organization for Rare Disorders also said in its comments on the draft guidance that the document should specifically discuss accelerated approval for rare diseases and include a more formal mechanism for talking about surrogate endpoints and other issues.

BIO said the existing language “would seem to leave the current practice at FDA regarding accelerated approval for rare disease therapies essentially unchanged,” according to the comments.

The trade association asked for guidance on evidentiary standards for surrogate and intermediate clinical endpoints for rare diseases using the pathway. It also wants a “clear process to facilitate and document a discussion of an accelerated approval development program prior to and after … IND application submission,” including “the basis of approval and the selection of clinical trial designs and surrogate or intermediate clinical endpoints,” according to the comments.

BIO said the framework could outline data requirements for surrogate validation and evidentiary standards.

Industry groups also asked for more accelerated approval flexibility than was enumerated in the guidance (see related story, (Also see "FDA “Available Therapy” Determination Is A Moving Target, Industry Groups Say" - Pink Sheet, 2 Sep, 2013.)).

An analysis submitted as a guidance comment attempted to help sponsors and others better understand FDA accelerated approval policy by rating several products based on the factors used to determine whether they qualified for the pathway (see related story, (Also see "FDA Flexible With Accelerated Approval Evidence, Analysis Finds" - Pink Sheet, 2 Sep, 2013.)).

Review Divisions Would Manage Biomarker Qualification

The foundation white paper states the agency should allow rare disease sponsors to submit a briefing package that FDA could review to advise whether the proposed biomarker “could be used as a primary endpoint with a set of reasonable assumptions, or that it might be qualified if certain specified data were obtained or bolstered in the package,” according to the white paper.

The agency also could deny qualification under any circumstances based on the contents of the package.

The EveryLife Foundation pitched the biomarker qualification idea in a previous draft, but expanded on it in the final version (Also see "Biomarker Approvals At Pre-IND Stage Requested For Orphan Drugs" - Pink Sheet, 1 Jul, 2013.).

Under the proposal, FDA’s review divisions would handle the qualification process, as opposed to the Office of Translational Sciences, which handles general biomarkers that could be used across multiple drugs. OTS staff could consult, if necessary.

The agency’s existing biomarker validation process is separate from the application submission. Validated biomarkers are published on FDA’s website and available for anyone to use, unless designated for a specific product only. It also can take several years to gain approval.

The foundation wants a process in place to qualify a biomarker before the End-of-Phase II meeting, which could better direct research before large investments are made.

Whether the agency’s review divisions are willing or even capable of performing such a review is unclear. The process could end up having the opposite effect intended, slowing product development while waiting for the agency to decide on the biomarker qualification.

Kakkis said reviewers know about the diseases, but likely will have to work with OTS on biomarker questions.

Developing the pharmacological and other data necessary to convince FDA the biomarker is acceptable as a clinical endpoint also may not be as easy and quick as expected.

FDA’s draft expedited approvals guidance says pharmacologic activity alone is not enough for a surrogate endpoint to be used for accelerated approval (Also see "Biomarker Approvals At Pre-IND Stage Requested For Orphan Drugs" - Pink Sheet, 1 Jul, 2013.).

Surveys Replace Benefit-Risk Assessments

The group also says in the white paper that a disease survey could be used early in development to help qualify a rare disease product biomarker as well as give FDA an idea of the condition’s risk-benefit assessment.

Disease surveys could provide justification for an accelerated approval designation, as well as encourage FDA to be more flexible under its rules. They also could help find possible endpoints for clinical studies.

“The survey is intended to establish the burden of disease, the needs, and the substantial information about the important goals of therapy,” Kakkis said in the e-mail.

He said the surveys replaced benefit-risk assessment in the paper because they were confused with the possibility of “asking patients to decide if drugs were approved.” Kakkis said FDA preferred the paper not imply that patients should approve new drugs.

The white paper indicated the survey would allow stakeholders to “evaluate the disease and relevant benefit-risk by formally assessing the unmet need and risk-acceptance of affected patients.”

“This survey should consider whether and to what extent characteristics of the disorder targeted by the treatment meet the criteria of serious, life-threatening or rare or very rare, thus meriting flexibility for qualification of the biomarker under the [accelerated approval] pathway,” the white paper said.

The idea seems similar to the patient-focused drug development program FDA established under FDASIA. It has conducted a number of disease-focused meetings for patients to give opinions about the treatment armamentarium and unmet needs.

A September meeting will focus on narcolepsy (Also see "FDA Asks Narcolepsy Patients How Symptoms Change Over Time" - Pink Sheet, 18 Jul, 2013.).

Surveys could be designed with FDA’s help and also include patient groups, physicians and other stakeholders, according to the white paper.

“This information can be helpful in understanding the degree of flexibility appropriate for a rare disease and the relative impact of the disease relative to potential treatment,” the white paper said.

The EveryLife Foundation and other rare disease groups have asked FDA for specific criteria that it will use to evaluate surrogate endpoints, but FDA officials have said they will judge them on a case-by-case basis.

The agency said looking at prior biomarker approvals may be the best way to determine FDA practices (Also see "Biomarkers In Orphan Studies Still Need Past Experience, FDA Says" - Pink Sheet, 27 May, 2013.).