Final guidance on expedited regulatory pathways suggests FDA is open to accelerated approval for some acute conditions; agency also provides examples outside of HIV/cancer arena where surrogate and intermediate clinical endpoints have supported approval.

FDA’s final guidance on expedited programs for drugs and biologics takes a more welcoming approach to the use of accelerated approval in some acute disease settings than did an earlier draft version of the document.

The final guidance, “Expedited Programs for Serious Conditions – Drugs and Biologics,” suggests the accelerated approval pathway may allow for smaller studies in some acute conditions than would be required for regular approval. The guidance was posted on FDA’s website May 29; a notice was published in the Federal Register May 30.

The document also includes a host of examples of surrogate and intermediate clinical endpoints that have been used to support accelerated approval outside HIV and oncology, where the expedited pathway traditionally has been used.

The guidance lays out the criteria and features for FDA’s four expedited regulatory programs – “breakthrough therapy,” fast-track, accelerated approval and priority review – that are aimed at facilitating and speeding development and review of new drugs to address unmet medical needs in serious or life-threatening conditions.

Intended to serve as a desktop reference for the regulatory pathways, the document fulfills requirements under the FDA Safety and Innovation Act (FDASIA) of 2012, pursuant to which the breakthrough program was created.

The final guidance also clarifies the types of “preliminary clinical evidence” to support a breakthrough designation, as well as the process for requesting and rescinding a designation (““Breakthrough” Designation: FDA Clarifies How To Get It – And How It Can Be Lost” — “The Pink Sheet” DAILY, May 29, 2014).

Regulatory Flexibility Reinforced

Congress included language in FDASIA aimed at encouraging use of accelerated approval beyond oncology and HIV/AIDS, although the statutory language was largely viewed as codifying FDA’s existing approach and regulatory flexibility under its accelerated approval regulations (see box).

The agency’s June 2013 draft guidance on expedited programs emphasized its flexibility in determining when an “unmet medical need” exists and when there is sufficient evidence for granting accelerated approval (“FDA Envisions Flexible Approach To Expanded Use Of Accelerated Approval” — “The Pink Sheet,” Jul. 1, 2013).

In comments on the draft, both the Pharmaceutical Research and Manufacturers of America and the Biotechnology Industry Organization suggested FDA understated the degree of enhanced flexibility that Congress provided through FDASIA to grant accelerated approval (“FDA “Available Therapy” Determination Is A Moving Target, Industry Groups Say” — “The Pink Sheet,”Sep. 2, 2013).

The final guidance retains the draft language stating that the FDASIA provisions facilitate somewhat broader use of accelerated approval and provide additional flexibility concerning the implications of available therapy on eligibility for accelerated approval.

The legislation also provides clarification regarding use of intermediate clinical endpoints as a basis for accelerated approval and makes clear that the agency has the authority to consider pharmacologic or other evidence developed using biomarkers or other scientific methods or tools, in conjunction with other data, in determining whether an endpoint is reasonably likely to predict clinical benefit, the guidance states.

However, the final guidance includes a special nod to the rare disease community, some members of which said the draft did not go far enough in promoting the use of accelerated approval for orphan drug development (“FDA Accelerated Approval For Rare Diseases Again Under Congressional Pressure” — “The Pink Sheet” DAILY, Jul. 30, 2013).

“By indicating that FDA should take into account, ‘… the severity, rarity, or prevalence of the condition …’ in considering whether to grant accelerated approval, FDASIA reinforces the agency’s longstanding commitment to regulatory flexibility regarding the evidence required to support product approval for the treatment of serious or life-threatening diseases with limited therapeutic options.”

Chronic Vs. Acute Diseases

The June 2013 draft guidance noted that accelerated approval has been used primarily in settings such as cancer and HIV, where the disease course is long and an extended period of time would be required to measure the intended clinical benefit, such as survival.

The draft went on to say that accelerated approval “is generally less useful in more acute disease settings in which therapy is intended to provide a more near-term clinical benefit” because “there may be little or no time advantage for studies evaluating a surrogate or intermediate endpoint compared to studies evaluating the intended clinical benefit.”

In contrast, the final guidance sees a role for accelerated approval as a means for conducting smaller studies.

“Accelerated approval is also potentially useful in acute disease settings where the intended clinical benefit can be demonstrated only in a very large study because the clinical event that would need to be evaluated to demonstrate clinical benefit occurs rarely,” the final guidance states. “For example, accelerated approval could be used for an acute condition where an effect on a surrogate endpoint could be shown in a small number of patients, but a much larger study would be needed to show the effect on a clinical outcome, such as survival.”

Surrogate And Intermediate Clinical Endpoints

In comments on the draft guidance, BIO requested FDA include a list of potential criteria or a framework for determining when surrogate or intermediate clinical endpoints are predictive of clinical benefit and therefore appropriate for use in accelerated approval.

While the final guidance does not go as far as BIO would like, it does provide numerous examples of surrogate and intermediate clinical endpoints that have been used to support accelerated approval.

Moving beyond the draft’s single example of a surrogate endpoint – HIV viral load suppression as predictive of survival – the final document now includes four other examples of surrogate endpoints(see chart).

Increasing the use of intermediate clinical endpoints to support accelerated approval has been suggested as one way of accelerating biomedical innovation (“Accelerated Approval Could Be Even Faster With Intermediate Clinical Endpoints” — “The Pink Sheet” DAILY, May 20, 2014).

However, the guidance makes clear that accelerated approval based on intermediate clinical endpoints will only be considered when it is essential to determine effects on irreversible morbidity or mortality, or other clinical benefit, to confirm the predicted clinical benefit that led to approval.

While the agency concedes it has limited experience with accelerated approval based on intermediate clinical endpoints, it does cite two examples where they have been used under the expedited pathway (see chart).

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