FDA Official Stresses "Flexibility" On Speeding Approval Of Drugs That Truly Stand Out

Four-year study of cancer drugs shows tyrosine kinase inhibitors commonly get cleared based on Phase II data in both accelerated and regular approvals. Emerging new classes could find faster paths.

SAN JOSE, CALIF.-- Industry can expect more, not fewer, accelerated drug approvals in the future, despite some disappointments of drugs failing to live up to their early clearances in the past, according to a presentation by an FDA official at the meeting of the Regulatory Affairs Professionals Society on Oct. 25.

A four-year review of FDA oncology marketing applications and clearances from 2006 to 2010 shows that about 30% of drugs were cleared via accelerated approval and 70% took the regular route.

"As long as there are new novel therapeutics emerging that display activity and are clearly better than what is available for a particular condition, there will be a need to utilize this [accelerated approval] pathway," Albert Deisseroth, medical officer for the Division Of Hematology Products in CDER's Office of Oncology Drug Products, said in an interview at the RAPS meeting.

Sub-categories of drugs - tyrosine kinase inhibitors in particular - are taking advantage of fast approval processes more often, according to Deisseroth's presentation, which was titled "Regulatory Flexibility in Drug Development." During his talk, the official stressed that the presentation reflected his own views and not necessarily the views of the agency.

Accelerated approval allows drugs to get clearance more quickly, based on earlier-stage data but typically requires a confirmatory trial be performed subsequently and this can be a high bar for some sponsors.

Roche/Genentech's Avastin was cleared early for a first-line metastatic breast cancer indication based on progression-free survival benefit. The company was not required to show an improvement in overall survival. But the Oncology Drugs Advisory Committee later voted overwhelmingly to withdraw this approval, concluding that the delay to disease progression was not clinically meaningful. The agency could make a decision on withdrawing that indication later this year (Also see "Roche Gets Reprieve On Avastin For Breast Cancer With Delay At FDA" - Pink Sheet, 17 Sep, 2010.).

Deisseroth declined to comment on any particular drugs, but strongly reaffirmed the need for faster approval pathways, including accelerated approval. "When a new class of drugs emerges and displays activity in an area where no prior therapy class has, that really creates a need to respond by trying to accelerate the delivery of that particular drug to the marketplace so that the public good is served," he said in the interview after his presentation.

Accelerated approval is one of the tools at the disposal of the regulator for making oncology drugs available to the public sooner, along with expanded access, new types of study designs (such as adaptive trials), orphan drug designation and biosimilars.

Via accelerated approval, drugs may be approved based only on Phase II data. To qualify for accelerated approval, drugs must meet certain requirements, including targeting a life-threatening condition, offering an advantage over available therapy and using a surrogate endpoint to predict benefit.

Tyrosine Kinase Inhibitors Pave Their Own Way

Despite some disappointments in confirmatory trials of some drugs, the trend is clearly on the side of accelerated approval.

Since 2006, oncology marketing applications to the FDA have been divided into subcategories of chemicals/cytotoxics (classic), tyrosine kinase inhibitors (new), antibodies to unique receptors (new) and peptides/recombinant proteins.

Deisseroth's presentation highlighted the differences in types of approvals, as well as trial design and endpoints for the various drug types.

In the last four years, 86 oncology applications were submitted to the FDA, of which 79% were approved. Out of the four sub-categories, applications for antibodies more commonly were supplemental filings as opposed to being for new molecular entities. Specifically, 88% of the antibody applications were supplemental, versus 60% for peptides, 57% for TKIs and 42% for chemical drugs.

By category, 19% of chemical drugs were cleared via accelerated approval, compared to 39% of TKIs and 37% of antibodies.

Use of Phase II data is common for accelerated approvals. But when it comes to tyrosine kinase inhibitors, earlier stage data also often are acceptable for regular approvals.

Overall, 70% of regular FDA approvals are based on Phase III data. However, for TKIs, 45% of approvals were supported by Phase III data. That compares to 83% for antibodies and 76% for chemical drugs.

There also were differences in endpoints based on drug type.

Overall survival was used in 17.1% of FDA drug actions, overall response rate in 39.5%, and progression-free survival in 39.5%.

For the TKIs, survival was used in only 9% of cases. Response rate was commonly used, followed by PFS (39%). Antibodies more commonly used PFS (54%) followed by response rate (25%) and survival (17%). Chemical drugs commonly involved response (43%) as a measure of efficacy, followed by PFS (29%) and with greater use of survival as an endpoint (21%).

Overall, tyrosine kinase inhibitors had a higher percentage of applications approved compared to antibodies and chemical drugs, more frequent use of overall response rate as an endpoint and more frequent use of Phase II trials to support approval. The willingness of regulatory authorities to approve these drugs based on Phase II data shows the magnitude of effect shown in Phase II and confidence in the endpoints used, Deisseroth said.

"The type of drug is really driving the trial design and regulatory response," he said. "The data suggest they are showing much more dramatic initial activity in trials, otherwise they would not be getting approvals."

In contrast, antibodies had the highest usage of Phase III trials of all three types of drugs, more frequent use of progression endpoints (PFS or TTP) and a very much higher ratio of supplemental versus NME applications.

New drugs clearly have been utilizing different trial designs, endpoints and the regulatory pattern has been different. And in Deisseroth's view, the data for four years show that regulators are acting more quickly for drugs that are novel, address a fatal disease, and show ability to halt progression of disease or reduce mortality.

Deisseroth said he can't predict what the next breakthrough will be, but as new types of drugs are developed that show unusual activity, the regulatory system will need to adapt. For example, some cancer treatments do not make tumors shrink but rather they stop cancer cells from multiplying and relieve patient symptoms. Such therapies may require changes in endpoints, design and review processes.

"Change in regulatory practices and clinical trial design may occur in the future and will be dependent on new drugs that emerge," he said.

-Emily Hayes ([email protected])

[Editor's note: This story has been revised to clarify that Roche/Genentech was not required to show an overall survival benefit for Avastin following accelerated approval in metastatic breast cancer. Nor did reconsideration of accelerated approval hinge on overall survival data ('Avastin Breast Cancer Approval Debate Pits Benefit Versus Statistics,' 'The Pink Sheet,' DAILY, July 26, 2010).]