Accelerating – and maintaining – drug approvals in the U.S.

Bringing a drug to market is the ultimate milestone for any pharmaceutical firm that has invested significant effort, not to mention time and resources, into developing its product. But all that work and outlay does not stop at marketing approval—this achievement must be maintained.

There can be various regulatory requirements that a firm must meet in the post-marketing stage, often relating to continued demonstration of product efficacy and safety as well as additional testing that may not have been initiated or completed ahead of approval. When requirements are not met, withdrawal from market may result. Such was the outcome for Mylotarg (gemtuzumab ozogamicin [GO]) from Wyeth Pharmaceuticals Inc. (Wyeth), a subsidiary of Pfizer Inc., in 2010.

Mylotarg had received accelerated approval under a new drug application (NDA) in May 2000 and, at the time, was the first antibody-targeted chemotherapy agent approved by the U.S. Food and Drug Administration (FDA). It was indicated as monotherapy (2 doses of 9 mg/m2 given 14 days apart) to treat patients aged ≥60 years who have CD33-positive acute myeloid leukemia (AML) in first relapse and who are not considered candidates for cytotoxic chemotherapy.

For its post-marketing confirmatory trial, Wyeth was required to evaluate the addition of GO to standard chemotherapy (daunorubicin and cytarabine) versus the chemotherapy alone as induction therapy in patients with de novo CD33-positive AML. The primary efficacy endpoint was complete remission. That trial was terminated early when it failed to show a clinical benefit, and the rate of fatalities as a result of treatment-related toxicity was significantly higher in the Mylotarg arm. In May 2010, the FDA requested that Wyeth voluntarily withdraw Mylotarg from the market.

More than 17 years after its original approval, thanks to steadfast interest in developing an improved therapy for patients with an unmet need, Mylotarg is back.

Regulatory background
As noted by Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research (CDER) at a public meeting in July – The Hatch-Waxman Amendments: Ensuring a Balance Between Innovation and Access – the agency has several expedited pathways “that are intended to help promising therapies get into the hands of doctors and patients as quickly as possible.”

Toward that end, the FDA has developed four distinct programs, one of which grants marketing authorization (accelerated approval) and three of which award product designations (fast track, breakthrough therapy and priority review). Each of these programs aims to facilitate and hasten the development and review of new therapies to address unmet medical need in the treatment of a serious or life-threatening condition.

The accelerated approval regulations – 21 Code of Federal Regulations (CFR) part 314, subpart H (for drugs) and 21 CFR part 601, subpart E (for biologics) – were codified in 1992. In 2012, Congress passed the Food and Drug Administration Safety and Innovation Act (FDASIA), of which section 901 amended the accelerated approval provisions found in section 506 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) to allow the FDA to base accelerated approval of drugs for serious conditions that fill an unmet medical need on whether the drug has an effect on a surrogate or an intermediate clinical endpoint (see “Settings of Use”).

Congress noted as its findings under section 901 that “remarkable” advances had occurred in the medical sciences during the two decades since the accelerated approval mechanism was established. These developments “provided an unprecedented understanding of the underlying biological mechanism and pathogenesis of disease,” the findings stated. For these reasons, Congress urged the FDA to pursue improved processes for expediting the development and review of critical new medicines using a broad range of surrogate or clinical endpoints and modern scientific tools, applied earlier in the drug development cycle when possible.

Products that receive accelerated approval are required to be further evaluated by the sponsor in adequate and well-controlled trials, conducted with due diligence, to verify and describe clinical benefit. The FDA may withdraw approval of a product or indication for reasons including that the post-marketing trials fail to confirm clinical benefit or do not demonstrate sufficient clinical benefit to justify the risks associated with the product’s use. For example, the trials may show a significantly smaller magnitude or duration of benefit than was anticipated based on the observed effect on the surrogate.

Settings of use
In its May 2014 final guidance for industry, “Expedited Programs for Serious Conditions—Drugs and Biologics,” the FDA stated that accelerated approval has been used primarily in settings in which the disease course is long and an extended period of time would be needed to measure a drug’s intended clinical benefit. Examples of such settings include the approval of drugs to treat various cancers and human immunodeficiency virus (HIV). In these cases, effect on tumor growth or viral load can be evaluated quickly, but demonstrating an effect on survival or morbidity generally requires lengthy and sometimes large trials due to the duration of the typical disease course.

The guidance elaborates on the two types of endpoints that can be used as a basis for accelerated approval: 1) surrogate endpoints and 2) intermediate clinical endpoints. A surrogate endpoint is a marker – such as a laboratory measurement, radiographic image, or physical sign – that is thought to predict clinical benefit, but is not itself a measure of clinical benefit. An intermediate clinical endpoint is a measurement of a therapeutic effect that can be assessed earlier than an effect on irreversible morbidity or mortality and is considered reasonably likely to predict the drug’s effect on irreversible morbidity or mortality or other clinical benefit.

In the FDA’s May 2007 final guidance for industry, “Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics,” the agency outlined the types of commonly used endpoints in oncology, including the following surrogate endpoints to support accelerated approval: disease-free survival, objective response rate, complete response (also called complete remission) and progression-free survival or time to progression. These surrogate endpoints, the FDA stated, can also support regular approval – that is, the longstanding route of drug approval based on the demonstration of clinical benefit. However, the particular approval route taken (accelerated or regular) is highly dependent on other factors, such as effect size, effect duration and benefits of other available therapy.

Return to market
In November 2016, Wyeth submitted a new product application for GO, this time a biologics license application (BLA), proposing a lower-dose fractionated regimen of GO (3 mg/m2 on days 1, 4, and 7) in combination with standard chemotherapy (daunorubicin and cytarabine) to treat adults with previously untreated, de novo CD33-positive AML. The pivotal trial’s primary efficacy endpoint was event-free survival (EFS – a measure of how long patients went without certain complications, including failure to respond to treatment, disease relapse or death, from the date they started the trial).

The BLA was reviewed by the FDA’s Oncologic Drugs Advisory Committee (ODAC) at a public meeting on July 11, 2017. ODAC members in the majority agreed that use of EFS as the primary endpoint was a reasonable choice. Although the results did not correlate well with overall survival (OS) – the gold standard endpoint for direct measurement of benefit for oncology drugs – and there was no demonstration of OS benefit in the trial, members pointed to advantages observed with GO treatment, including delayed relapse in patients who achieve remission, a manageable level of risk, and an improved safety profile conferred when using the fractionated dosing.

With a vote of 6-1, the ODAC concurred that the results of the pivotal trial for GO supported a favorable risk/benefit profile in the proposed indication. Panelists were aware of the potential safety risks associated with use of the agent, including veno-occlusive disease (VOD) (a type of hepatotoxicity) and hemorrhage, but agreed that the potential advantages with treatment outweigh any risks.

The FDA approved Mylotarg on September 1 for the following two indications:
• treatment of newly diagnosed CD33-positive AML in adults; and
• treatment of relapsed or refractory CD33-positive AML in adults and in pediatric patients aged ≥2 years.

This latest Mylotarg approval was accompanied by a boxed warning in the label stating that hepatotoxicity, including severe or fatal VOD, has occurred in some patients who took Mylotarg as a single agent or as part of a combination chemotherapy regimen. The original label also housed a boxed warning, but it concerned the risk of severe myelosuppression.

Once again, Wyeth must work hard to keep its product on the market. Although this recent approval was not via the accelerated pathway, the firm has several required post-marketing commitments to fulfill, including various non-clinical studies and a clinical trial to assess a signal of increased hepatic VOD in pediatric patients.

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