FDA Finalizes Expedited Product Guidance With Hundreds of Major, Minor Changes


FDA released the draft expedited programs guidance, Expedited Programs for Serious Conditions—Drugs and Biologics, in June 2013.  In the draft, FDA outlined how it says it planned to use four tools at its disposal designed to expedite the process of approving a drug intended to treat a serious or life-threatening condition:

– Fast track designation – A designation given to a drug application for which there is evidence that it has the potential to address an unmet medical need or one that has been designated as a qualified infectious disease product. Allows for a rolling review of an application by FDA and the ability to expedite certain aspects of development and review.

– Priority review designation – A designation given to applications (either new or supplemental applications) for which there is evidence that a treatment would provide a significant improvement in the standard of care for a patient. The designation shortens FDA’s timeline for reviewing the application from 10 months to six.

– Accelerated approval – An approval pathway through which a drug that provides a “meaningful advantage over available therapies” can obtain approval based on data in support of a surrogate endpoint. No change in the review timeline.

– Breakthrough product designation – An approval pathway first introduced into law under the 2012 FDA Safety and Innovation Act (FDASIA), breakthrough product designation is intended for first-in-class products that treat a serious condition based on preliminary clinical evidence that indicates the drug may demonstrate substantial improvement on clinically significant endpoints over available therapies.

The New Stuff: Breakthrough Basics

Unlike the other designations or pathways, breakthrough product designation isn’t meant to expedite development based on shortened timelines or surrogate markers, but rather to grant access to enhanced review tools such as all of the features of the fast track designation, as well as “intensive guidance” from FDA regarding the development of the product.  Much of FDA’s guidance on the breakthrough product designation is focused on the definitional details of evidence needed to support the indication, with FDA saying companies need to have data supporting preliminary evidence of an effect, as well as a rationalization that the effect would be a substantial improvement over the current standard of care. Clinical data is preferable, while certain pre-clinical data might also be used to support application of the designation.  As with the other two types of designations, FDA may withdraw breakthrough status if the product no longer meets the qualifying criteria for the designation.

Industry Response:  ‘Serious’ Problems

In comments submitted to FDA, some within industry expressed their concern that the draft guidance had “serious” problems.  Industry trade group PhRMA’s comments, for example, noted the absence of a preamble section that had been in the 2006 version of the guidance. The section had contained a statement that FDA would interpret the term “serious condition” consistent with how it had in the past. PhRMA called for its reinstatement.

PhRMA also said FDA had changed the criteria for priority review designations, which now require diseases to meet “a ‘serious’ standard”—a “significant change in Center for Drug Evaluation and Research Policy,” PhRMA added.  This change was not accompanied by any rationale or explanation, it continued.  The group argued that the term “serious condition” should have been broadened to be more consistent with federal law. For example, PhRMA says the guidance doesn’t include any text to say that a drug intended to mitigate a serious disease or condition—or its side effects—would get breakthrough designation consideration.  Neither is the guidance explicit on products intended to prevent a disease from progressing to additional stages or those that would “constitute a significant contribution to human health and fill an important unmet medical need.”  The comments propose text to remedy all three points.

Guidance Changes

FDA’s finalized guidance contains a substantial number of changes, a review by Regulatory Focus found.  For example, the preamble of the guidance now explicitly states that FDA recognizes the challenges of developing therapies for rare diseases, and that it will “continue to apply flexibility in these situations to address particular challenges posed by each disease.”

The same preamble also notes that doctors are willing to accept uncertainties about treatment benefit, but also now that they are willing to accept uncertainties about side effects as well in some cases (e.g. for life-threatening diseases).  Later in the document, FDA formally recognizes that “a product intended to prevent a serious condition or reduce the likelihood that the condition will progress to a more serious condition or more advanced stage of disease” is also eligible for expedited approval under FDA’s definition of “serious condition.” This addition appears to be directly in response to PhRMA’s above comments.  The guidance also introduces more nuance to its definition of “an available therapy,” which would preclude expedited program access for similar drugs. FDA says “an available therapy” is not one which has been granted accelerated approval based on a surrogate endpoint, but is one if the drug was granted accelerated approval based on its restricted distribution and the new drug’s intended population can already receive the other drug.

Another subtle yet potentially important change was made to FDA’s definition of “available therapy.” Previously, FDA said that “If no therapy exists for a serious condition, there is clearly an unmet medical need.” The new definition changes that to “if no available therapy exists…” The change could be important in areas where a drug once existed but has been discontinued, or if a drug is experiencing chronic shortages.

FDA has also explicitly indicated that if a therapy affects “disease progression,” then it may be eligible for expedited treatment if it meets an unmet medical need. It also added that if a therapy has “an effect on a serious outcome of the condition,” it similarly will be considered as treating an unmet medical need in some cases.

Breakthrough-Specific Changes

The breakthrough therapy designation section contains a massive number of changes.

One of the biggest:  FDA has now committed to rolling reviews for some breakthrough products, saying it has “determined that it is appropriate.” The measure allows FDA reviewers to review a submission in parts as they are submitted instead of waiting for the entire new drug application to be submitted. In a similar development, FDA said it will also grant breakthrough products access to priority review, but offered few details on this perk.

Another key development: FDA has removed a section committing the involvement of “senior managers” in the review of products given breakthrough product designation.  It will now rely more on “experienced review and regulatory health project management staff,” it said.

The final guidance also includes a new definition for the term “preliminary clinical evidence,” which FDA takes to mean “evidence that is sufficient to indicate that the drug may demonstrate substantial improvement in effectiveness or safety over available therapies, but in most cases is not sufficient to establish safety and effectiveness for purposes of approval.”  This evidence is generally obtained from Phase I or II trials, FDA said. Such evidence should indicate “a substantial improvement over available therapies.”  Drugs intended to treat a disease for which there is no currently available standard of care are also eligible for the designation, FDA wrote.  If a drug treats the underlying cause of a disease, it should have a “substantial and clinically meaningful effect” on it as well, FDA wrote.  Drugs, which inhibit disease progression, are also now eligible for the designation.

The guidance also contains a brand new part on the use of pharmacodynamics (PD) biomarkers, which FDA says “may be considered a clinically significant endpoint if it strongly suggests the potential for a clinically meaningful effect on the underlying disease.”  These will only be acceptable in “rare cases,” FDA noted, such as for areas where there are no approved therapies.

The guidance also now clarifies that just because FDA grants a product breakthrough therapy designation, that doesn’t mean it will obtain approval.  “The clinical evidence needed to support breakthrough designation is preliminary,” the agency wrote. All drugs need to undergo a more substantial review, it added.  If a product is later shown to not merit the designation, it will be rescinded so that FDA may focus its limited resources on other more promising drugs, it continued.

Other Various Changes

The guidance contains literally hundreds of changes. Some other notables:

– All sponsors must be prepared to ensure the “availability of quality product at the time of approval,” though FDA may “exercise some flexibility” on what information is needed on a case-by-case basis depending on the product’s characteristics and intended patient population.

– FDA will take into account the severity, rarity or prevalence of a condition being considered for its accelerated approval program

– FDA explicitly states that sponsors of an accelerated approval product need to start thinking early about drug manufacturing and development of any necessary companion diagnostics

– The guidance now contains new accelerated approval points aimed specifically at treating viral and bacterial infections, and which endpoints are acceptable for use

– FDA strongly emphasizes the role of confirmatory trials in the final guidance.

REFERENCE:  Regulatory Focus; Alexander Gaffney, RAC; 29 MAY 2014

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