Fast Times at FDA: Explaining Accelerated Approval to Ridgemont High’s Jeff Spicoli

The Food and Drug Administration recently approved a drug product to treat Alzheimer’s disease under the accelerated approval pathway, putting the spotlight back on what exactly is “accelerated approval?” This Bulletin will focus on this regulatory pathway and how drug companies might use it to their benefit. So, in a nod to the 1982 classic movie, “Fast Times at Ridgemont High,” we will try to explain the concept of accelerated approval plain and simple, as though we were talking to Jeff Spicoli, the character played by Sean Penn. This Bulletin will not discuss the specific drug approval.

What Is Accelerated Approval?

• In 1992, FDA issued regulations that allowed approval of drugs for serious or life-threatening conditions and generally provides a meaningful advantage over available therapies (i.e., unmet need) based on a surrogate endpoint (allowing for faster review and approval).¹

• In 2012, Congress passed the Food and Drug Administration Safety Innovation Act, which amended the Federal Food, Drug, and Cosmetic Act, to allow FDA to base accelerated approval on whether the drug has an effect on a surrogate or an intermediate clinical endpoint.
  • a surrogate endpoint is a marker that is expected to predict clinical benefit, but it is not itself a measure of clinical benefit;² 
  • a surrogate endpoint may be a laboratory measurement, radiographic image, or a physical sign, as examples;³
  • an intermediate clinical endpoint is a measure of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug, such as an effect on irreversible morbidity and mortality;⁴

• FDA will decide whether to accept the proposed surrogate or intermediate clinical endpoint on the scientific support for that endpoint.⁵

• Studies that demonstrate a drug’s effect on a surrogate or intermediate clinical endpoint must be “adequate and well-controlled.”⁶

• The accelerated approval pathway, by using surrogate or intermediate clinical endpoints, can save valuable time in the drug approval process.
  • e.g., instead of having to wait to see if a drug actually extends survival for cancer patients, the agency may approve a drug based on evidence that the drug shrinks tumors because tumor shrinkage is considered reasonably likely to predict a real clinical benefit (an approval based on tumor shrinkage can occur far sooner than waiting to learn whether patients actually lived longer).
    • it is important to note that the drug company will still need to conduct studies, known as phase 4 confirmatory trials, but this can occur after approval.

• So, if we put this all together: A drug that treats a serious condition and generally provides a meaningful advantage over available therapies and demonstrates 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 IMM that is reasonably likely to predict an effect on IMM or other clinical benefit (i.e., an intermediate clinical endpoint).⁷

• FDA may withdraw drug approval or change a labeled indication if the trial fails to confirm clinical benefit or does not demonstrate sufficient clinical benefit to justify the risks associated with the drug (e.g., a study that is required to verify and describe the predicted effect on irreversible morbidity or mortality of the product fails to verify and describe such effect).⁸

• Another unique feature of the accelerated approval program is that, if a company obtains approval, it must submit copies of all promotional materials to FDA’s Office of Prescription Drug Promotion (“OPDP”) prior to the intended date of dissemination or publication (after 120 days following marketing approval, unless told otherwise by FDA, at least 30 days prior to initial dissemination or publication).⁹

• As of December 31, 2020, FDA has approved more than 250 drugs and biologics through the accelerated approval pathway based on a surrogate endpoint.

AGG Observations

• In our experience working with clients on accelerated approval issues, a drug company should meet with FDA early if it believes its product might be eligible for accelerated approval review. FDA, not the company, is the final arbiter.

• The sponsor should consider that other aspects of the drug development process may need to be implemented at a more rapid pace, such as the creation of a potentially required companion diagnostic. Therefore, product quality and other teams should initiate early communication with FDA regarding development programs.

• A company should be prepared to show which planned endpoint it will use for approval and how it is expected to predict clinical benefit, as well as the confirmatory trials it will perform; the company is asking the agency to expedite review, so it must know FDA rules and the clinical data. It must anticipate the agency’s questions.

• A company should look at FDA precedents and see where the specific review division responsible for evaluating the drug has granted accelerated approval and on what basis. This point gets to preparation and anticipation.

• Remember that FDA will likely require phase 4 confirmatory trials, so an approval letter is not the end of the process. FDA may need to inspect clinical trial sites. Sponsors should be aware of, and prepare for, such inspections early in the application review process to ensure time to address any significant inspection results.

• Companies need to factor in the submission time of promotional materials to OPDP, which is not typical for non-accelerated approval drugs.

• Accelerated approval is not easy to obtain but, if a company can get it, to quote Mr. Spicoli, it’s “Awesome! Totally awesome.”

[1] 21 C.F.R. Part 314, Subpart H; 21 C.F.R. Part 601, Subpart E.

[2] 21 U.S.C. § 357(e)(9).

[3] Id.

[4] FDA, “DRAFT Guidance for Industry: Expedited Programs for Serious Conditions––Drugs and Biologics,” (May 2014), available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-serious-conditions-drugs-and-biologics; FDA website, Accelerated Approval, https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/accelerated-approval (last accessed June 18, 2021).

[5] FDA website, Accelerated Approval, https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/accelerated-approval (last accessed June 18, 2021).

[6] Id.

[7] FDA, “DRAFT Guidance for Industry: Expedited Programs for Serious Conditions––Drugs and Biologics,” (May 2014), available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-serious-conditions-drugs-and-biologics.

[8] 21 U.S.C. § 356.

[9] 21 C.F.R. § 314.550.