FDA Breast Cancer Guidance Paves Way for Accelerated Approval With One Trial

[Hopeful]

The Pink Sheet Daily. 2012 May 29, E Hayes

FDA’s draft guidance on use of pathological complete response to support accelerated approval of drugs for neoadjuvant treatment of breast cancer lays the groundwork for using only one clinical trial, with response rate as a surrogate endpoint and an extension to look at survival to fulfill the requirement for confirmatory evidence.The draft guidance issued May 29 addresses accelerated approval of drugs for early-stage, high-risk breast cancer in the neoadjuvant setting (before surgery) as add-on treatment to regimens typically given post-operatively, with the goal of enabling sponsors to use pathologic complete response rate (pCR) as a surrogate endpoint to help save time and expense in development of drugs for early breast cancer.
FDA’s accelerated approval program typically requires a separate post-approval clinical trial to confirm the benefit seen on the surrogate endpoint in the pivotal trial. But in the draft guidance, FDA recommends a double-blind, randomized pivotal trial with pCR as the surrogate endpoint for accelerated approval; to confirm clinical benefit, sponsors would have the option of using the same study to assess traditional endpoints of disease-free survival or overall survival after approval.

“We believe that use of pCR as an endpoint to support accelerated approval in high-risk populations in the neoadjuvant setting has the potential to help address unmet need in these populations in a far shorter time frame than would be required via the conventional approach to breast cancer drug development,” according to the guidance, titled “Pathologic Complete Response in Neoadjuvant Treatment of High-risk Early-stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval.”

The ongoing I-SPY 2 trial, which has a novel adaptive design and makes full use of biomarkers to guide development, uses pCR as an endpoint for assessing multiple investigational drugs in early-stage, high-risk breast cancer in the neoadjuvant setting.

Currently, no drugs are FDA-approved for use in neoadjuvant treatment of early-stage breast cancer, but increasingly, systemic chemotherapy post-operative regimens are increasingly being used prior to surgery for a variety of reasons, for example it may help with breast conservation.

Traditionally, drugs have been evaluated first in the metastatic setting and then later tested in adjuvant trials, so it could take more than a decade between the time a drug is approved for metastastic cancer and cleared in an adjuvant setting, the guidance document notes.

The release of the breast cancer accelerated approval guidance fits with the agency’s overall push to speed development of promising drugs and ease use of its accelerated approval program, which was launched in 1999. Some lawmakers had been looking to reform the program and make it easier for drugs to get approved as part of the latest review of the Prescription Drug User Fee Act. But while more aggressive options, like adding alternate approval pathways, were discussed, in the end the PDUFA bill attempts to work with the existing accelerated approval program.

In recent meetings, FDA officials have repeatedly stressed the agency’s intent to make better use of the accelerated approval program. At a March media briefing, Center for Drug Evaluation and Research Director Janet Woodcock said that the pathway was “underutilized in many areas”. The agency has indicated that upcoming guidance on pCR in high-risk breast cancer trials was a good example of how accelerated approval could be improved. The coming guidance was also cited in October 2011 when FDA unveiled its biomedical innovation initiative, which addressed ways to speed drug development.

Trial Design How-To’s

Randomized trials have shown that preoperatively and postoperatively, pCR may predict disease-free survival (DFS) or overall survival (OS) in patients with early-stage breast cancer treated with preoperative systemic therapy. However, this link comes from responder analyses, which have limitations. Further research is ongoing to “clarify the association” between pCR and survival endpoints, the new guidance acknowledges.

A high pCR rate in a single-arm trial may reflect biologic characteristics of tumors in the population enrolled, the efficacy of an investigational drug, efficacy of conventional therapy delivered, or a combination of those factors. Therefore, FDA recommends a double-blind, placebo-controlled randomized superiority trial design. Sponsors should focus on patients with a high risk of disease recurrence and mortality, despite use of optimal modern local and systemic therapy.

The randomized trial should test the investigational drug on top of standard adjuvant regimens used preoperatively. However, depending on the particular circumstances, the document states that alternative approaches for accelerated approval will be possible in some cases and could allow testing of an investigational drug alone against a standard-of-care adjuvant regimen. For example, this may be possible if extensive prior clinical data is available, for drugs approved for other breast cancer indications, and for candidates showing “unprecedented efficacy” in early breast cancer trials.

Median follow-up for efficacy with pCR will be “brief at the time of accelerated approval,” but then it will take several years of follow-up to confirm clinical benefit using DFS and OS measures, the guidance notes. A confirmatory trial with DFS or OS endpoint should be ongoing at the time of approval, but FDA offers sponsors the option to “follow the patients entered into the original randomized neoadjuvant trial that supported the accelerated approval until DFS or OS data are mature.”

“This approach may enable a single randomized trial, if adequately powered and with sufficiently compelling results, to serve as the basis for both accelerated and regular approval, saving time and resources in drug development and expediting patient access to breakthrough therapies for high-risk early stage breast cancer,” the guidance states.

Alternatively, clinical benefit could be confirmed in another breast cancer setting.

For those taking the one-trial option, the pivotal study needs to be powered for the survival endpoints, which would mean the trial would be overpowered for the pCR surrogate endpoint. Sponsors should avoid interim efficacy analysis of pCR, though the FDA says interim analyses for futility are acceptable.

Since many patients won’t get a pCR prior to surgery, sponsors need to ensure that post-operative systemic therapy is delivered consistently and should avoid designs that allow patients in control groups to cross over to treatment arms post-op. Otherwise, they could compromise the ability to measure DFS or OS.

The guidance document stresses that trials of drugs for neoadjuvant treatment of early-stage breast cancer should compare pCR and DFS between treatment arms, using the full intent-to-treat population and not just those patients who achieve pCR, the latter of which represents a “nonrandomized patient subset determined by outcome subsequent to randomization.”

“It is expected that a large difference in pCR rate between treatment arms will be needed to produce a statistically significant difference in DFS or OS in the overall trial population that is also clinically meaningful,” the guidance document adds.

Comprehensive Safety Analysis Required

On the safety front, FDA acknowledges the risks of making drugs available with only limited data at the time of approval. Consequently, the agency stresses that the trials should be limited to populations with the highest unmet medical need and drugs that show a “substantial magnitude” of effect over available therapy.

“We wish to emphasize that we are concerned about the risk of granting an initial approval in the setting of limited long-term efficacy and safety data from a neoadjuvant trial,” the guidance states.

The risk may be acceptable in women with a poor prognosis despite available therapy, such as those with high grade tumors lacking estrogen, progesterone and HER2 receptors (triple-negative breast cancer) still have a poor prognosis, despite available adjuvant systemic therapy, but unlikely to be worth taking in those with a better outlook. “We strongly recommend that patients with hormone receptor-positive tumors lacking high risk features generally not be enrolled in neoadjuvant trials intended to support accelerated approval,” FDA says.

Regulatory decisions would consider a drug’s known and unknown risks and the pCR improvement for the particular population studied. Trials in the neoadjuvant setting should be designed to collect long-term safety data on the scale of what is required for adjuvant trials, according to the guidance. Following accelerated approval, additional safety studies may be needed.
Sponsors must create a safety database that tracks incidence and severity of treatment-emergent adverse events, and long-term data on the outcome of adverse events and incidence of rare and late toxicities, such as malignancies.

“Such a comprehensive safety assessment is critical in an early stage breast cancer population, in whom long-term survival is common and indeed may be the result of local therapy alone,” the document states.

Hopeful