The U.S. Food and Drug Administration has been picking the brains of some leading cancer experts to examine how its guidances on clinical trial endpoints can be revised to create a list of new markers for cancer researchers to aim at.
While disclaiming any attempt to loosen the FDA’s expectations on clinical data, the experts say that the steady development of new cancer drugs and biologics makes it imperative to define new endpoints that will speed the acceptance of much-needed therapies. And while the agency maintains it will continue to hold drugs to high standards, the move will create new ways for biotech companies to prove the therapeutic value of their products in a more timely — and less expensive — way.
“This is an effort to speed up the process and get more drugs available faster,” sums up Robert Ozols, MD, PhD, senior vice president at Philadelphia’s Fox Chase Cancer Center and the outgoing chair of the American Society of Clinical Oncology’s cancer research committee who has helped provide ASCO’s feedback to the FDA.
For years, the FDA has kept drug developers focused primarily on prolonging the survival of cancer patients. But the new guidances being developed for 2005–2006 signal an evolution of the rules away from survival as the primary goal of cancer research and toward new objectives, such as disease-free progression, hematological improvements, or as a bridge to transplantation. And as the field of cancer drug research continues to develop, Ozols says, you may see the emergence of other ways to determine a drug’s clinical benefit, such as the way in which certain drugs can influence a disease pathway.
Richard Pazdur, MD, a veteran oncologist and head of the newly established Office of Oncology Drug Products within the FDA’s Center for Drug Evaluation and Research, is careful to point out that the FDA is not interested in relaxing endpoint standards. But there has been a host of changes in cancer research in the last 15 years that demand a fresh approach.
“It brings clarity to what we will accept and why,” says Pazdur. “It’s always important to look at overall survival,” he adds, but new therapies and improvements in research techniques mean it’s “not necessarily the gold standard it once was.”
In some cases, time to disease progression may be a better indicator of a therapy’s value, he says. “Endpoints have some fluidity to them, not only in what we accept but also in terms of the stage of development of a compound.”
“ITS THE ISSUE”
There isn’t anything new about the FDA’s involvement in setting standards for endpoints. And any drug developer considering the multimillion-dollar gamble involved in trying to bring a new cancer therapy to the FDA for approval will carefully consider the primary and secondary endpoints they’re shooting for and try to make sure they can pass the FDA’s examination procedure. The company’s existence may depend on the outcome. Even in an early-stage trial of a cancer drug, proof of statistical significance in hitting the endpoint can send a company’s stock through the roof — or into the cellar if the compound fails to hit the endpoint — in a matter of minutes. Being sent back by the FDA to do an additional clinical trial beyond phase 3 can add years and millions of dollars in added cost to developing a new drug. Gaining the FDA’s initial nod about the endpoint is a vital part of the process, given the agency’s role as the country’s ultimate drug umpire.
For some drugs, inhibition of a disease pathway could be an important alternative to survival time as a trial endpoint, says Robert Ozols, MD, PhD, of the American Society of Clinical Oncology.
None of that is lost on Pazdur, who’s acutely aware of just how vital an issue the endpoint is.
“It’s essential,” he says. “That’s the primary analysis of the trial; that determines whether you win or lose. It’s not a side issue — it’s the issue.”
Several experts note that winning FDA approval should become easier once the new guidances are adopted.
“I think the FDA would like to see more drugs approved as long as they are safe and effective,” says Fred Appelbaum, MD, director of clinical research at the renowned Fred Hutchinson Cancer Research Center, in Seattle, who co-chairs a working group looking at leukemia endpoints. The issue at hand, he says, is to figure out a way for researchers to mount fast and efficient trials that can hit a biomarker “short of prolongation.”
Appelbaum points out that the FDA’s traditional focus on survival in cancer trials actually has made the job of drug development increasingly difficult. As cancer drugs have improved, studies showing better survival times are taking longer and longer. In one case — imatinib mesylate (Gleevec) — patients can already live beyond a decade. To prove a new drug could outperform imatinib would take more than 10 years of research.
UNINTENDED CONSEQUENCES
There is a flip side to this, however. Some drug developers fear that disease prevention as a clinical endpoint could force them into big trials that would extend beyond the life of their patents. As such, many biotechs may be inclined to steer away from attempting them at all.
“If [a drug] inhibits a pathway, that could be important for approval,” notes Ozols. “If you wait for the actual development of cancer to show you decreased instances of the disease, it could take 15, 20 years.”
New endpoints under discussion are within closer reach.
For example, if a cancer drug can demonstrate that a significant percentage of patients can rely on it as a “bridge to a bone marrow transplant” — with the therapy advancing them to a potentially life-saving procedure — that alone might be a good endpoint to shoot for, says Appelbaum.
Ozols finds the prospect of committee meetings on specific diseases especially “intriguing.” Endpoints may be tailored to meet the particular needs of ovarian, lung, or other cancers. Ovarian cancer, he says, may be particularly in need of new endpoints based on progression-free survival, as opposed to overall survival rates.
As new FDA guidances on trial endpoints are developed, expect to see many biotechs respond swiftly. Many are already testing therapies along the emerging endpoints.
Ozols believes that the guidance review should also consider other important endpoints, such as improvements in the quality of life. Any trial can gauge objective measurements of side effects, such as white cell counts, he notes — but it’s also important to consider more subjective data on a drug’s relative improvement in how patients feel while taking the new drug.
As the new guidances are adopted, expect to see many biotechs in the field respond swiftly. Many are already testing therapies along the emerging endpoints. And by redefining acceptable endpoints, he adds, they’ll be able to mount trials with fewer patients — at significantly less cost to reach their endpoint.
Appelbaum’s working group — composed of a experts from the FDA, cancer research centers, industry, and others — was to meet in late June to consider the draft guidances and hear from other experts in the field.
The FDA makes it clear that these working groups are not advisory panels, which play a key role in drug evaluation. The groups will produce recommendations, which go to the Oncologic Drugs Advisory Committee for final consideration. ODAC is an external committee made up of 13 cancer experts who advise the FDA on the adoption of experimental drugs. And while its own recommendations are not binding, they are frequently followed — on issues ranging from approval to speeding up the review process and getting a drug to market faster.
The FDA guidances on endpoints also are not intended as a mandate to drug developers. Researchers can use the guidances to refine their objectives, but don’t get any guarantees from following them.
Whatever emerges from the current round of meetings, says Ozols, other issues will also need to be addressed in time — such as the wisdom of evaluating cancer drugs against a placebo in double-blind trials, considering cancer patients’ reluctance to be involved in studies in which they could possibly receive nothing of any help to them.
And as cancer research continues to develop, he adds, endpoints will need continual refinement.