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Dendreon (NASDAQ:DNDN) may have to conduct an additional trial before FDA approval of Provenge, despite recent results showing that the company met its primary endpoint of overall survival (OS) based on one study, physicians and industry sources speculated.
A Phase III clinical study named IMPACT showed that Provenge improved overall survival in patients suffering from advanced prostate cancer, pushing Dendreon’s shares up 136%, reports Pharmawire.
The first Phase III studies for Provenge, named D9901 and D9902A, both failed to meet their primary endpoint and also failed to demonstrate statistical significance on other pre-specified endpoints. When the data from the two trials was pooled and analyzed retrospectively, Dendreon found that there was a difference in OS between the active and placebo arms. The current IMPACT trial is designed with OS as the primary endpoint in accordance with positive OS data generated from the original Phase III trials.
Dr CK Wang, an oncologist at the Cancer Institute of Dallas, said Provenge will receive scrutiny from the FDA, based on the failure rate of previous cancer vaccines. This is the first vaccine immunotherapy up for FDA approval. Cell Genesys’ (NASDAQ:CEGE) GVAX vaccine failed in late-stage clinical trials last year.
When asked whether the company would be asked to conduct a confirmatory trial, Wang said that is always ideal. A lot of times when drugs are approved, there are usually two concurrent trials published at around the same time to confirm the data.
Asked if it would be clinically significant if Provenge showed a four-month survival benefit, Wang said it would be, but the cost-benefit of treatment will be the next area of debate. ”More of these vaccines are getting approved with a much higher cost, compared to the older chemotherapies,” he said.
An industry executive agreed that the initial Phase III studies that pooled data from two studies together to form a larger trial is a point of concern, and would not be considered a second Phase III trial. The only Phase III trial that has OS as an endpoint is the IMPACT trial, and nothing will settle the question of whether the results can be reproduced, unless another well controlled Phase III trial is conducted, he said.
”If you combine two different studies, or studies with different patient criteria, you run into statistical problems and more scrutiny,” Wang said.
A second executive, who is familiar with Dendreon’s management, said it is quite unusual for a company to change the trial design in the middle of the game. ”In my experience, the FDA scorns such attempts as manipulative since these are agreed upon prospectively,” he said. On the other hand, if the results are dramatic enough, the FDA might show some flexibility, but that’s a real gamble, he added.
The standard that the FDA has always set is two well controlled large-scale studies, the first industry executive said. ”We have to be very careful interpreting results from a single study, particularly with immunotherapy since we don’t have any other data on this type of therapy,” he noted.
”My guess is it will get back to ODAC [the Oncology Drugs Advisory Committee], and at that point, depending on who is on the ODAC committee, the reproducibility of the study will be called into question,” the first industry executive said. At this point, it remains uncertain whether the FDA will ask Dendreon to conduct another trial, he agreed.
Dendreon did not respond to repeated requests for comment.
A biotech investor said that FDA almost always requires multiple Phase III trials, making rare exceptions for drugs that are already on the market for different indications. The investor identified health outcomes of high unmet need as an area where the agency might be more flexible as well. He added that as a bureaucracy, the agency would choose caution over risk, following rules and regulations as closely as possible with very few exceptions, and that in the case of a new chemical entity, it is expected that extra care would be taken to ensure that the proper decision is made.
Dendreon would not have been granted a Special Protocol Assessment (SPA) for IMPACT unless the agency found logic with pooling the trial data, but as this is a contesting BLA, the company will likely have to go back to ODAC, the first industry executive said. Although the main factor preventing the drug’s use in the market may be cost considerations, the FDA can only consider safety and efficacy in their approval decision regarding Provenge, he added.
A third industry executive, at another immunotherapy company, said the FDA will be in a quandary because in one sense, Dendreon has complied with the agency’s requests outlined in the letter for approval. But on the other hand, the FDA is now forced in a position where they will have to ”bend a couple of rules” if they approve Provenge.
One issue will be the quality control regarding the manufacture of Provenge, the third industry executive said. The FDA is now in a position where they may have to approve a vaccine, where the quality control is ambiguous, since every dose is a different drug, he explained.
The FDA manufacturing hurdles to produce Provenge will be high, added another industry investor. Since Provenge is a tailored immunotherapy, isolating an individual’s dendritic cells is not an easy procedure. Taxotere’s results showed a two month survival benefit, and if Provenge shows a four-month survival benefit, it is still ”not going to knock people’s socks off,” he said.
Dr Mark Scholz, of Prostate Oncology Specialists in California, said he would use Provenge in his clinic, if approved, although only some patients respond to the treatment. The measured overall survival in clinical trials is only an average of all the patients - where some men get no benefit - but since the toxicity is low, there is no reason not to use it, he said.
In many cases, immunotherapies are drugs that do not have specific dose response relationships, the third industry executive said. ”We don’t know why some immunotherapies work in some patients and not in others,” he said. It remains unknown what the correlates of response are, and maybe the response is based on the patient’s unique genetics.
If the FDA requires another confirmatory trial before approval, there is no way to align the two patient populations from the two different trials, since it still remains unknown why the patients in the IMPACT trial responded to Provenge, the third industry executive noted. In another cohort of patients, even with the same exclusion/inclusion criteria, there is no way to ensure that the patient population in a second, confirmatory trial will respond to Provenge in the same way, he stated. ”It’s an unfair burden from the FDA, to insist that the manufacturer has to show how the drug works,” he added. The current FDA structure and model used to evaluate drugs may not fit with immunotherapies, so something has to change, he added.
The first industry executive said whether the positive results released today will result in FDA approval is a whole different story, since the company just has one positive prospective trial.
But the FDA may be facing a lot of political pressure from prostate cancer groups to approve Provenge, the second biotech investor said. ”Prostate cancer groups are very politically active, and now that Dendreon has met their SPA endpoint, it’s going to place a lot more pressure on the agency [to approve this drug],” he said. But whether Provenge will be a commercial success, if approved, remains the key question, the industry executives added.
Dendreon has a current market cap of USD 1.68bn.
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