Biomarker Approvals At Pre-IND Stage Requested For Orphan Drugs

Updated draft white paper on expanding use of accelerated approval suggests FDA approve the use of biomarkers as surrogate endpoints in the pre-IND stage, which could enhance sponsors’ abilities to raise funds for trials and manufacturing.

A rare disease group is pressing FDA for more systematic biomarker qualification, including a pre-IND stage approval process, arguing that it holds the key to expanding orphan drug development.

An updated draft white paper on the expansion of the use of accelerated approval (AA) continues to ask for more concrete criteria for biomarker qualification, in part to encourage more predictability and, by extension, more investment in rare disease drug development.

It also states FDA should create a “biomarker qualification request” process at a rare disease treatment’s pre-IND stage, when the potential surrogate endpoint could be reviewed and approved by the agency.

The latest draft of the white paper, released by the EveryLife Foundation for Rare Diseases June 25, indicates allowing biomarker approval before a sponsor would have to incur clinical trial and other costs could increase its ability to attract development funding.

“The review and approval of a potential biomarker endpoint at the pre-IND stage of development, before the investment in drug manufacturing and clinical studies, will help support the early investment in the most rare and difficult diseases,” the group wrote in the draft white paper.

“Without a biomarker that you could use to help demonstrate the drug’s effects, you may never be able to get the investment required for development.” – Emil Kakkis

“If this can be achieved, then greater investment in developing treatments in rare diseases, especially with small populations and complex disease pathophysiology, will occur and new treatments will finally be developed for so many untreated rare diseases using the AA pathway.”

Rare disease advocates and orphan drug sponsors are writing the white paper in the hopes of influencing FDA’s guidance development on using accelerated approval in rare diseases.

The EveryLife Foundation is receiving public comments on the draft until July 9. The group hopes to finalize it shortly thereafter.

The guidance was mandated in the FDA Safety and Innovation Act as part of an effort to expand the expedited approval pathway outside oncology and HIV, the disease areas where it is most commonly used. FDASIA also reauthorized the prescription drug user fee act and made other policy changes (Also see "FDASIA Is Signed, Not That White House Wanted Anyone To Notice" - Pink Sheet, 16 Jul, 2012.).

EveryLife Foundation President Emil Kakkis, who has been leading the effort to write the white paper, said his pre-IND qualification idea would involve biomarkers specific for one development program and was borne out of personal experience.

Kakkis said during a previous development effort FDA agreed to allow use of a biomarker early in the process, which allowed the sponsor to raise money to ultimately move the product along much faster.

He said the agency has backed away from that strategy in recent years.

“The challenge you see is that when you have a very rare disease and it’s very difficult to study, it’s very hard to raise money to invest in that treatment when the feeling from investors is that the disease is very hard to measure,” he said in a June 26 interview. “Without a biomarker that you could use to help demonstrate the drug’s effects, you may never be able to get the investment required for development.”

The challenge, Kakkis said, will be how comfortable FDA will be in deciding that the proposed biomarker will actually predict clinical development.

Biomarker Approval Possible At Pre-IND?

At the pre-IND stage, a potential rare disease treatment sponsor would have to provide FDA with a briefing book on the biomarker for review and approval.

The submission would include a risk-benefit assessment, analysis of the disease, drug or biomarker set using proposed criteria and verified with pre-clinical models, along with clinical survey or natural history data, according to the draft white paper.

Kakkis was unsure how long it may take the agency to approve the use of a biomarker if the envisioned system is implemented. But he said sponsors cannot afford to wait a long time for those decisions.

“I think their view is that biomarkers are difficult, therefore it takes them a very long time to do and they wouldn’t normally do it in a pre-IND package timeframe,” he said. “But the truth is they have to figure out a way to do that because people will not invest for a year or two years of fiddling around trying to figure out if they can use a biomarker or not. The decision to move forward or not is fairly prompt.”

The white paper proposal would be different from FDA’s existing biomarker qualification process, which is more focused on general biomarkers that could be used across multiple drugs.

The general biomarker process at FDA is separate from the application review and requires a two-stage process: data are submitted, and agency staff decide whether the marker can be used.

Once a biomarker is validated, it is published on FDA’s website, unless designated for a specific drug only (Also see "Biomarker Guidance To Encompass More Than Biomarkers, FDA Says" - Pink Sheet, 21 Jun, 2010.).

FDA reiterated in a June 27 statement that biomarker qualification and IND review are independent and that a biomarker does not need to be qualified for an IND to be submitted.

“Qualification may also be performed in parallel with IND drug development and is initiated through contact with the biomarker qualification program,” the agency said in the e-mailed statement.

FDA has listed three qualified general biomarkers on its website. The most recent, approved in February 2012, was for nonclinical qualification of circulating cardiac troponins T and I to be used as biomarkers of cardiac morphologic damage.

Ideally, having the biomarker approved prior to starting the clinical trials would improve the predictability and, presumably, speed up development dramatically in rare diseases.

Increasing the predictability of FDA approvals and requirements remains a common improvement suggestion among industry and patient advocates.

Kakkis has said regulatory predictability is more important than flexibility (Also see "Regulatory Freelancing: Rare Disease Group Hopes To Shape FDA Guidance" - Pink Sheet, 22 Apr, 2013.).

Specific Criteria Still Desired

The white paper still calls for more specific criteria for biomarker approval, even though FDA said it may not be ideal or possible.

A previous white paper draft asked for more specific criteria for biomarker and surrogate endpoint qualification so rare disease and other products would have an easier route through accelerated approval. But FDA officials said while general principles could be enumerated, creating very concrete rules about biomarker assessment may not be feasible.

The updated draft states a “scientific framework cannot substitute for good judgment or accommodate all the complexities of the science behind so many rare diseases.”

“But the framework does provide a more predictable structure for development and review of potential biomarker endpoints,” according to the new draft.

So far, FDA doesn’t seem persuaded. The agency recently released its anticipated expedited approval pathways guidance, which included a section describing accelerated approval and criteria for endpoints.

FDA maintained its position to judge surrogate endpoints on a case-by-case basis, seemingly against the idea of establishing specific criteria, but the agency encourages sponsors to look at the specifics of the already approved biomarkers to see how the agency weighs data (Also see "Biomarkers In Orphan Studies Still Need Past Experience, FDA Says" - Pink Sheet, 27 May, 2013.).

The standards for surrogate endpoints used in accelerated approval is that they are reasonably likely to predict clinical benefit.

The guidance indicates that surrogate endpoints will need clinical data to support the assertion; pharmacologic activity alone is not enough (Also see "FDA Expedited Programs Guidance: “Available Therapies” Depends On U.S. Standard Of Care" - Pink Sheet, 25 Jun, 2013.).

The industry-FDA agreement to reauthorize PDUFA included increasing staff for rare disease and biomarker development (Also see "PDUFA V: Final Recommendations Fund Proposals In Two Of Three Tiers" - Pink Sheet, 2 May, 2011.).

Hiring has been limited by sequestration, however. The agency lost millions and has not been able to add some of the new staff members that it wanted (Also see "PDUFA Communications Hurt By Sequestration As Late-Stage Meetings Begin" - Pink Sheet, 8 Apr, 2013.).