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SECOND THOUGHTS FROM SEKERES: Baby Steps or Giant Leaps for Cancer Drug Approval?

Sekeres, Mikkael A. MD, MS

doi: 10.1097/01.COT.0000371028.78164.28


There is a tension in the cancer drug approval process in the United States.

At odds are patient advocacy groups, who have argued for conditional approval of cancer drugs based solely on Phase I data, to make those drugs more widely available to patients with few other options; scientists, who support rigorous, stepwise clinical trials of rationally designed drugs, in which safety and then efficacy are demonstrated and ultimately compared with standard therapies or placebo; and regulatory agencies, such as the US Food and Drug Administration, which must balance the health of the public with the need for novel, active therapies for desperate populations.

In an interview he gave to the New York Times last September, Richard Pazdur, MD, the director of the FDA's cancer drug office, went so far as to comment, “You can't win in this job. If you approve a drug, they accuse you of lowering standards. And if you don't approve it, you're the worst thing since the Nazi death camps and should be killed.”

Wow—that's quite a statement. And Dr. Pazdur is not the type to make dramatic remarks solely to garner publicity. His observation emphasizes another aspect of drug approval, that is far more subtle than weighing safety and efficacy: Should we, as a cancer community, be supporting drugs that are safe enough, and effective enough, to advance the field forward, even if ever so slightly, through intermediate measures; or should we be patient and champion only those drugs that clearly improve survival in a clinically meaningful way, to be more vigilant guardians of what we and the public should view as minimal standards for acceptable outcomes criteria and tolerability?

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The Case of Azacitidine for MDS

The case for encouraging small advances can be made using myelodysplastic syndromes as an example. The first drug approved by the FDA specifically for the treatment of MDS was azacitidine (Vidaza), in 2004. At the time, therapies for MDS either had to come under the auspices of a clinical trial, or via off-label use, so a clear need in a terminal cancer population (the only cure for MDS is a bone marrow transplantation, a modality available to less than 5% of MDS patients) was established.

The drug was approved based on a complete and partial response rate of 16%, and on “improvement” in an additional 19% of patients, with no demonstration of a survival benefit. Serious adverse events occurred in 60% of azacitidine-treated patients, and in 36% of observation patients.

In sum, the drug was not a panacea, had appreciable toxicities, and could demonstrate disease impact only using intermediate endpoints. Years later, the results from a Phase III European study demonstrated a much more definitive advantage to azacitidine, with a doubling of survival at two years and of median survival compared with conventional care regimens, in higher-risk MDS patients.

In other words, the gamble paid off—MDS patients in the US received a life-prolonging therapy for four years longer than they would have if the FDA had waited for data demonstrating a survival advantage. In this case, baby steps worked.

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On the Other Hand: Decitabine for MDS

The case against allowing incremental benefits for drug approval can also be made within MDS, this time focusing on decitabine (Dacogen), the third MDS drug to be approved by the FDA, in 2006, based on Phase III data demonstrating an advantage in interim endpoints compared with best supportive care.

Similar to the situation for azacitidine, the complete and partial response rates were 17%, and an additional 13% of patients experienced a hematologic improvement, without a survival advantage. Grade 3 and 4 toxicities were higher in the decitabine arm.

This time, though, a subsequent Phase III European study failed to show a survival advantage for decitabine when it was compared with best supportive care in higher-risk MDS patients, when data were presented in preliminary form at the annual American Society of Hematology meeting in 2008.

Were patients in the US exposed for two years to a therapy with significant toxicities without any demonstrable survival advantage? Perhaps we should have waited for a “giant leap” in improved outcomes before allowing marketing of a drug with a modicum of efficacy measured using the ruler of response rates.

There are no easy answers, and no ways to determine in real time that one of these drugs would be proven successful based on interim endpoints, and another a failure. In a recent study from M. D. Anderson exploring anticancer drug approvals by the FDA from 1973 through 2006, the investigators identified 68 oncology drugs, of which 31 were approved without a randomized trial.

Of these drugs approved on earlier-phase data, 30 remain on the market, with subsequent formal FDA approval obtained for 11 drugs. The authors concluded that approval of drugs based on non-randomized data is justified given their long-term safety and efficacy.

Historically, then, baby steps have been good enough, and apparently safe enough. The majority of drugs approved with non-randomized data have been for indications in which other therapeutic alternatives were lacking, though.

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Moving Forward…

Moving forward, now that we have a number of drugs available for a variety of cancers, we should raise the bar and insist on giant leaps—survival data that are clinically meaningful—for drug approval in cancer indications for which therapies are available already.

If European patients have been willing to enroll in clinical trials in which there is no guarantee they will receive the latest and potentially greatest therapy, shouldn't we insist on the same from ourselves? After all, if we don't shoot for the moon, how else will we make major advances in cancer therapeutics?

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Hear More!

Hear Dr. Sekeres in an OT Broadcast News podcast available at (under the Podcasts link) and on iTunes.

© 2010 Lippincott Williams & Wilkins, Inc.
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