Is Fda Advisory Committee Tightening The Rules For Drug Approval?

Cancer Decisions ^ | 10.08.06 | Ralph Moss, Ph.D.

[Coleus]

In September, the FDA's Oncologic Drugs Advisory Committee (ODAC) refused to approve Abraxane, a new drug for the treatment of breast cancer, because of the weakness of the supporting data that was presented to the committee.   It is by no means certain that the FDA will go along with this decision. At one time, the FDA bowed unquestioningly to the decisions of ODAC, the agency's top scientific advisory committee on cancer, but this is no longer the case. For example, in July, 2006, ODAC recommended against the approval of Gemzar (gemcitabine) for the treatment of advanced ovarian cancer because of a lack of evidence of its effectiveness. However, the top leadership of FDA (under acting head Andrew C. von Eschenbach, MD) overrode the committee's decision and granted approval for this indication in spite of the absence of evidence of substantial patient benefit from the drug.

In the case of Abraxane, it remains to be seen whether FDA officials will abide by the decision of ODAC, or whether it will once again override the committee, and grant approval to a drug for which there is scant evidence of effectiveness.  Abraxane is already approved for use in patients with advanced, metastatic breast cancer for whom all other treatments have failed. Although Abraxane has been shown to cause temporary tumor shrinkage in a larger percentage of patients than the very similar drug, Taxol (24 percent versus 11 percent), there is no evidence whatever that Abraxane prolongs life in these patients. Abraxis BioScience, Inc., the drug's manufacturer, is strongly motivated to obtain approval for the drug as a treatment for node-positive breast cancer in its earlier stages since approval for use in this setting would greatly increase the market for the drug. And at $4,200 per dose, the drug stands to make a great deal of money for Abraxis BioScience.

Because of investor enthusiasm for Abraxane, the stock market value of Abraxis is currently $4.6 billion. The company had a profit of $86 million last year on sales of $519 million. According to the New York Times, Patrick Soon-Shiong, MD, the company's chairman, who owns 84 percent of the stock, is now worth about $3.8 billion, and annual sales of Abraxane could reach $1 billion within the next four years (Berenson 2006). ODAC's refusal to expand approval for Abraxane without further clinical trials therefore represents an unwelcome setback for Abraxis. ODAC concluded that although Abraxane is closely modeled on Taxol (paclitaxel) it is basically a separate and new entity, and should therefore not be approved without the same clinical trial procedure that is required for all new drugs. This ruling came despite the intensive lobbying effort conducted by Abraxis, employing the help of at least one top name in American oncology. Arguing on behalf of the drug before the committee was Clifford Hudis, MD, chief of the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, New York. The panel, however, rejected his argument that since Taxol is known to be active in breast cancer, Abraxane should be approved as well. By a vote of 13-1, ODAC ruled that Abraxane was indeed a separate drug that will require independent proof of safety and efficacy.

Dr. Soon-Shiong remains staunchly enthusiastic about his company's product, despite the lack of evidence of its ability to prolong life. "We have a breakthrough," he is quoted by the New York Times as saying. In its excellent analysis the Times points out that in at least one way, Abraxane is indeed a breakthrough, if only in that it costs about 25 times as much as Taxol. "Because of the odd economics of the cancer drug market, though, Abraxane's price does not seem to be hurting its popularity. About 20,000 people have now been treated with the drug, and Dr. Soon-Shiong expects its sales to approach $200 million this year" (Berenson 2006). Worldwide, the money spent on cancer drugs is skyrocketing and is expected to more than double from 2004 to 2009, to $55 billion, with most of that in the United States (ibid.). 

The FDA's Oncologic Drugs Advisory Committee (ODAC) also recently rejected approval of the drug Genasense (oblimersen sodium) for use in combination with two standard drugs, fludarabine and cyclophosphamide, as a treatment for chronic lymphocytic leukemia (CLL). While acknowledging that Genasense somewhat increased the rate of complete responses (CR), as well as so-called nodular partial responses by 10 percent, the high-level committee questioned the clinical significance of such regressions. ODAC members pointed out that Genta, Inc., Genasense's parent company, had sponsored a randomized controlled trial (RCT) that failed to show an improvement in (a) overall survival, (b) time to progression, or (c) duration of the response. (Note: these are three commonly used measurements of actual clinical benefit). Susan O'Brien, an M. D. Anderson Cancer Center, Houston, investigator who worked on the Genasense trial and served as one of the company's presenters, countered that the company was being "penalized" for performing a randomized trial.

If approved, Genasense would have been among the first of the so-called "antisense" drugs to come to market. Scientists have thus considered Genasense to be one of an exciting new generation of "smarter" targeted drugs, attacking cancer more specifically than did the first generation of targeted therapies (such as Avastin). However, the failure of Genasense to achieve much in the way of clinical improvement in several kinds of cancer, as well as ODAC's proper recommendation against approval, is a setback for this much-hyped kind of treatment. Previously, the same company had sought approval of Genasense for treating another kind of cancer, advanced melanoma. In 2004, ODAC similarly voted against recommending approval for that use, in the words of some commentators, "clobbering" the company.

According to a report in the well-informed Cancer Letter, M.D. Anderson's O'Brien felt that Genta could have been better served in its leukemia trial by performing a less rigorous study. "I think we are penalizing the sponsor for the fact that they did a randomized trial," she commented. Furthermore, in a revealing statement, she claimed: "Every drug that has been approved in leukemia so far has been approved based on response rate, mostly from single-arm trials. If this were a single-arm trial that showed a benefit in response, compared to historical data, nobody would be raising this issue of time to progression. It's only because this is a randomized trial where we have these two groups, that this would even come up."

I find this to be an extraordinary argument, and ODAC members may have felt the same way, since the committee voted 7-3 against approval. What Dr. O'Brien seems to be saying is that the FDA and its advisory committees have in the past lowered the standard of proof for new cancer drugs by repeatedly allowing agents to be approved based on inadequate phase II trials, and sometimes accepting clinically dubious endpoints (such as apparent changes in response rates). It appears that she is taking ODAC to task for being inconsistent and unfair when the committee should in fact be praised for reverting to the FDA's earlier, and higher, standard of proof, i.e., increased overall survival as demonstrated in randomized controlled trials.  Luckily, there was a patient advocate present at the committee's public hearing session, who understood the importance of maintaining high standards of proof. "We want to make sure that inferior drugs don't start creeping into the standard of care," said Helen Schiff, of the Center for Medical Consumers. "We want to make sure that newly diagnosed women have the very best shot at preventing a recurrence and not dying of breast cancer. It is important to remember that therapy in the adjuvant setting is curative for some women. We want to increase the number who survive, not decrease them. The stakes are very high. Once a drug becomes a standard of care, it can be used as the comparator arm in a registration trial. This is an advocate's worst fear. If the drug in the comparator arm is inferior, you can end up replacing one inferior drug with another inferior drug."

Avastin Also Takes a Hit

In another sign that FDA may be tightening its requirements for anticancer drugs, the biotechnology firm Genentech announced in mid-September that the government agency had delayed a request for the approval of Genentech's widely used colon cancer drug, Avastin, as a treatment for breast cancer, asking for more data on its safety and efficacy. The company said it was confident that it could gather the necessary data by the middle of 2007. But if FDA once again requires proof of actual life prolongation (as they should) this might be a tall order. Ironically, the company blamed the delay on its collaborators at the National Cancer Institute. According to a report in the New York Times:

"Genentech applied for approval of Avastin as a treatment for metastatic breast cancer based on a trial organized by academic researchers sponsored by the National Cancer Institute. Such academic trials, Genentech said, do not collect and audit data as rigorously and in as organized a form as trials typically run by companies." This reverses the assumption, common to most observers, that NCI and other unaffiliated scientists generally attain a high level of objectivity in their work, while reports emanating from drug companies are typically presented in a way that distorts both the safety and efficacy of new drugs. "We're very confident the data is there," Dr. David Schenkein, vice president for clinical oncology at Genentech, said in an interview. Still, he said, "We certainly were surprised and disappointed" by the FDA request.

According to the company, the NCI-sponsored trial had shown that the addition of Avastin to a standard drug, paclitaxel (Taxol), had doubled the median time that it took for breast cancers to worsen, from six months (with paclitaxel alone) to one year (with added Avastin). However, readers should be aware that a delay in the doubling time of a tumor does not by any means translate into an increase in overall survival. And unless the company can show through reliable studies that Avastin-added patients actually lived longer, FDA may decide to continue to withhold approval for this indication. Wall Street reacted with disappointment to the news and Genentech lost some 5 percent of its valuation. Geoffrey C. Porges of Sanford C. Bernstein & Company wrote that if by some chance Avastin were not approved for breast cancer in 2007, "the revenue loss would be substantial." He is forecasting that use for breast cancer will account for $1.4 billion of Avastin's $5.6 billion in sales by the year 2010. The generally poor performance of Abraxane, Avastin and Genasense in the latest clinical trials is a cautionary tale about the limitations of both chemotherapy and the supposedly more effective ‘targeted' therapies. While these drugs may eventually find a broader niche in cancer treatment, they have not yet even begun to live up to the wildly exaggerated claims that were being made for them in the mainstream media just a few short years ago.

[Jaysun]

I hate the FDA. And the EPA. And the IRS. And God knows how many other three letter organizations. They're more a nuisance than a help.