What an Expedited FDA Review Pathway Changes

Answer first: three of these change the process, one changes the evidence

Section 356 of Title 21 is titled "Expedited approval of drugs for serious or life-threatening diseases or conditions," and it contains several distinct mechanisms that are often lumped together in coverage.

Breakthrough therapy designation and fast track designation are about how a drug is developed and reviewed. They change meetings, communication and review sequencing. Accelerated approval is different in kind: it changes what an approval may be granted on the basis of, by permitting an effect on a surrogate endpoint rather than a directly measured clinical benefit.

The threshold for all of them is the same phrase: a serious or life-threatening disease or condition. None of these provisions is available for a product simply because its sponsor would like to move faster, and every one of them applies to a drug that is still going to be approved, if at all, under the ordinary approval statute.

Breakthrough therapy: a request, a 60-day answer, and a list of actions

The criteria are written into the statute. FDA shall, at the request of a sponsor, expedite development and review of a drug "if the drug is intended, alone or in combination with 1 or more other drugs, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on 1 or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development."

The request may be made concurrently with, or at any time after, submission of an investigational application. The answer comes on a clock: "Not later than 60 calendar days after the receipt of a request... the Secretary shall determine whether the drug that is the subject of the request meets the criteria."

What designation buys is spelled out as a list of possible actions rather than a promise of approval: holding meetings with the sponsor and the review team throughout development; providing timely advice and interactive communication to make the development program as efficient as practicable; involving senior managers and experienced review staff in a collaborative, cross-disciplinary review; assigning a cross-disciplinary project lead; and taking steps to make trial design as efficient as practicable, including "by minimizing the number of patients exposed to a potentially less efficacious treatment."

Every item on that list is about process. None of them lowers what the drug must eventually show.

Fast track: unmet need, and a review that can start before the file is complete

Fast track designation is available at the sponsor's request where a new drug "is intended, whether alone or in combination with one or more other drugs, for the treatment of a serious or life-threatening disease or condition, and it demonstrates the potential to address unmet medical needs for such a disease or condition," or where the drug is designated a qualified infectious disease product.

Its most concrete consequence sits in a separate subsection. If FDA determines, after preliminary evaluation of clinical data, that a fast track product may be effective, it "shall evaluate for filing, and may commence review of portions of, an application for the approval of the product before the sponsor submits a complete application." That is the mechanism usually described as rolling review.

It comes with two conditions on the applicant: providing "a schedule for submission of information necessary to make the application complete," and paying any applicable user fee. And it comes with a trade-off the statute states plainly — the agreed review-time goals do not apply to an application submitted this way "until the date on which the application is complete." Starting earlier does not start the review clock earlier.

Accelerated approval: a different endpoint, and a study that has to follow

The statutory description is precise. FDA may approve an application for a serious or life-threatening disease or condition "upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments."

The implementing regulation says the same thing in the language of trials: approval may be granted "on the basis of adequate and well-controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely... to predict clinical benefit," subject to the requirement that the applicant study the drug further "to verify and describe its clinical benefit," and that any such postmarketing studies also be adequate and well-controlled and carried out with due diligence.

The obligations are specified in the statute. Approval may be conditioned on the sponsor conducting a postapproval study to verify and describe the predicted effect, and on submitting copies of all promotional materials during the preapproval review period and, after approval, at least 30 days before dissemination. Not later than the date of approval, FDA must specify the conditions for any required study, "which may include enrollment targets, the study protocol, and milestones, including the target date of study completion." If no postapproval study is required, FDA "shall publish on the website of the Food and Drug Administration the rationale for why such study is not appropriate or necessary."

The regulation adds a separate tool for safety rather than evidence: where a product "shown to be effective can be safely used only if distribution or use is restricted," FDA will require postmarketing restrictions such as distribution limited to certain facilities or physicians with special training or experience, or distribution conditioned on the performance of specified medical procedures.

The obligations that outlast the approval

Accelerated approval is the only one of these mechanisms that comes with an expedited way to undo it. The statute permits withdrawal using expedited procedures if the sponsor fails to conduct a required study with due diligence, if a required study "fails to verify and describe" the predicted effect or benefit, if other evidence demonstrates the product is not shown to be safe or effective under the conditions of use, or if "the sponsor disseminates false or misleading promotional materials with respect to the product."

Those expedited procedures are themselves defined, and they are not summary. Before withdrawal, the sponsor gets due notice, an explanation, an opportunity for a meeting with the Commissioner or a designee, and an opportunity for written appeal to the Commissioner or to a designee who did not participate in the proposed withdrawal. There must be an opportunity for public comment, publication of a summary of comments and FDA's responses, and — if the sponsor requests it and no committee has already advised on the issues — the convening of an advisory committee.

The regulation's own withdrawal list runs parallel and adds two grounds tied to restrictions: that use after marketing demonstrates the postmarketing restrictions are inadequate to assure safe use, and that the applicant fails to adhere to the restrictions agreed upon.

Promotional-material submission is written into the regulation as well: for products being considered for approval under this subpart, applicants must submit all promotional materials intended for dissemination within 120 days following approval during the preapproval review period, and after that first 120 days must submit them at least 30 days before initial dissemination or publication.

None of this is permanent. If FDA later determines that the restrictions, withdrawal-procedure conditions or promotional submission requirements "are no longer necessary for the safe and effective use of a drug product, it will so notify the applicant" — and for products approved on a surrogate endpoint, those requirements ordinarily end when the required postmarketing study verifies and describes the clinical benefit and the product would be appropriate for approval under traditional procedures.

How to read a claim that a drug was expedited

The word expedited in a press release can mean any of four different things, and they are not interchangeable. A breakthrough or fast track designation is a statement about the development and review process, granted on preliminary evidence, and says nothing final about whether the drug will be approved. An accelerated approval is an approval, but one resting on an endpoint reasonably likely to predict benefit, with a verification study attached.

The checkable questions follow from that. Which mechanism is being described, and does the source name the statutory or regulatory provision. If it is an accelerated approval, has a required postapproval study been specified, and has it reported. And if a source claims no study was required, FDA is directed to publish its rationale for that, which means the claim is verifiable rather than a matter of belief.

This article does not say which pathway any particular product used. That is a fact about a specific approval, and it belongs in the approval documents FDA publishes rather than in a general description of the law.