What should be required for FDA new drug approval:
(1) Comparison with placebos or (2) Comparison with current “standard therapy?”
Dear Dr. Weisenthal:
I thought you'd like to read
these articles, if you haven't already. With your advocacy of revising the
chemotherapy drug concession (n.b. the system wherein oncologists are paid
for, in effect, running retail pharmacies, with a built-in incentive to choose
drugs for patient treatment based on the "spread" between actual
wholesale cost and reimbursement), I'm sure you are an advocate for
"comparative drug testing" instead of "comparing new drugs with
One of the commonest methods to test a new drug is not against an already effective treatment but against a placebo. However, what matters most to patients is not whether a company's drug is better than nothing, but whether it is better than established treatments. As this article explains, what a way to start off with comparative drug testing.
In reference to Taxol for ovarian cancer, I'm sure if it were tested against tried and true drugs already on the market (like melphalan or carboplatin alone), instead of against a placebo, it never would have made it as far as it did.
The percentage of patients that must respond to a drug before it is approved by the FDA varies from as high as 80% to as low as 20%. Thereafter, it is used routinely for "all" patients with the same form of cancer, though unfortunately a drug that helps one person does not necessarily mean it will help all patients with the same diagnosis. And the response rate for Taxol.....30%. Imagine if a patient knew beforehand that Taxol had only a 30% response rate, would that patient take the drug? This is all part of the "informed consent" (which most patients never get).
Celebrex (at $4 a pill), along with Thalidomide is utilized with small daily doses of standard chemotherapy to inhibit the formation of new blood vessels (Angiogenesis & Low Dose Chemotherapy). Now, Genentech just received approval from the FDA for their drug Avastin, to choke off the blood vessels that provide a tumor with oxygen and nutrients (at a cost of $4,400 a month). ImClone's Erbitux will cost about $10,000 a month. Go figure!
<Writer’s name redacted>
There are several overlapping problems.
The first problem is that there is seldom a "gold standard" therapy which has been proven to be superior to all other therapies. As discussed on my web site, nothing has been shown (in a definitive fashion) to be superior to single agent melphalan in treating ovarian cancer. A couple of individual studies did show superiority for platinum combinations. This convinced oncologists to make platinum combination therapy "standard." But when all of the studies were compared by meta-analysis, there was no difference. Ovarian cancer patients now live longer than they did in the past. But this is almost certainly owing to better and more aggressive surgery. By the time the meta-analysis had been completed, platinum-combination therapy had been used for so long as the "standard" treatment that there was no going back.
What is happening now is that so many new drugs are coming down the pike so fast that there is simply no way to evaluate them in randomized trials. Especially when you consider the precedent of ovarian cancer, where some trials are positive; some are negative, and it's only after 10 years have gone by and 8,000 patients have been enrolled on the trials that you can draw conclusions. And by then, what had been the "gold standard" treatment has now changed, owing to all the new drugs which have come out.
I agree with you on most things, but I personally wouldn't hold these new drugs hostage to the really unachievable standard of massive prospective, randomized trials. I want to see a "cure" for cancer in my lifetime. I think that "cures" are most likely to come the way it is happening for HIV/AIDS and not the way it happened for syphilis, where a single, non-toxic drug (penicillin) replaced complex combinations of toxic drugs (arsenic, mercury, etc.). I think that the best chance for discovering the correct "formula" is in having, for example, 1,000 drugs available to cancer doctors all over the world and allowing creativity and insight and the "art of medicine" to enter into the process. As an example, my own sister (whom I've told you about before) with advanced stage 3 ovarian cancer was treated with gemcitabine + carboplatin + vinorelbine + high dose tamoxifen, followed (treatment in progress now) by gamma interferon and then Doxil, followed (perhaps, considering this but not yet certain) by an anti-CA-125 monoclonal antibody. But this wouldn't necessarily be "standard" therapy for everyone...this is just based on having a lot of "tools" (drugs) available and making use of various tests (such as our own) to match treatment to patient.
But complete coincidence, the same week we tested my sister's specimen, we tested a non-small cell lung cancer specimen from another patient (by coincidence, a pharmaceutical company executive). By complete coincidence, the "in vitro best regimen" for this patient was quite similar to my sister, and he was treated with gemcitabine + carboplatin + vinorelbine + high dose tamoxifen + gefitinib (Iressa). I just received the e-mail reproduced below from him last week:
Back in May of last year at my insistence I had submitted a sample for screening prior to beginning chemotherapy for advanced NSCLC (diagnosed stage IIIB or IV). As a result of your screening I commenced a regimen of Gemzar, carboplatin, navelbine high dose Tamoxifen and Iressa! I completed 6 x 3 week cycles incorporating 2 doses per cycle with the exception of carboplatin which was administered only once per cycle. After two cycles the main mass in my lung had reduced 85% and lymph nodes were virtually undetectable. After 4 cycles the CT of my lung showed only a small residual mass which was not detected by PET. A small contrast in the MRI of my brain has remained unchanged throughout my treatment and is now thought to be unrelated to my cancer. I have just had my first scan since completing the IV chemotherapy in October 2003 (I have continued on Iressa at 250mg/day) and all appears unchanged and I am still considered a Complete Response by my oncologist.
First of all I would like to thank you for the service you provide and hope that in the not too distant future I get to thank you in person. Without the screen I firmly believe I would have been placed on standard therapy which would not have been nearly as effective and, according to my oncologist, I certainly would not have ever been treated with the combination that had shown activity in the screen. I am certainly grateful for my second chance at life and have been contemplating ways that I can help to pay back for the gift I have been given.
To that end I have several areas that I would like to get involved in that would include participation of your group. We had talked by phone briefly as I was going through treatment and you indicated a need to conduct a clinical trial to compare directed therapy with standard therapy. My oncologist, Dr <name redacted> at the Hospital of the University of <Name of institution redacted>, who now appears to be a firm convert to the benefits of your prescreening, has expressed an interest in being involved in conducting such a trial. I would like to help in any way I can in setting up such a trial using both my personal cancer experience as well as my professional background in pharmaceutical drug development.
Finally I have been surprised and dismayed at the lack of basic knowledge of these tests. In a large institution such as <Name of institution redacted> where they must treat thousands of patients the nurses there had told me I was the only patient they had seen that had had these tests done! Even experienced oncologists seem to have only a rudimentary understanding of the assays, if they even happen to know of their existence. I am trying to think of ways that I can become an advocate to raise awareness of the assays in the medical community who are after all the most important group to educate on their use. Hopefully my involvement and phenomenal result can help in convincing some of the skeptics as to the benefit these tests can have.
I would welcome the opportunity to speak with you on any or all of these topics. You can contact me by return e-mail or by phone at <redacted>.
Again thank you so much, and I look forward to speaking with you soon.
New York Times articles quoted in the first of the above letters:
Cancer Drugs, No Comparative Data
By GARDINER HARRIS
New York Times
February 25, 2004
Nearly two years into the planning of a head-to-head federal test of two expensive widely used cancer drugs, not a single patient has been enrolled in the study. But in a sense there is no hurry: Congress has barred the government from using the results in deciding how much to pay for the drugs.
<most of article is redacted, out of respect for copyright>
"If Medicare is going to spend more on a new drug, we need to establish that it is going toward something that provides significantly improved care for seniors," explained Dr. Sean Tunis, Medicare's chief medical officer.
But the drug industry, which counts on high-priced new drugs for its growth, persuaded Congress last fall to include a provision in Medicare legislation forbidding the program to use evidence that two drugs have "functional equivalence" in its payment decisions. The industry argued that such a balancing act would discourage makers from developing innovative drugs.
<remainder of article redacted>
Article # 2:
F.D.A Approves Cancer Drug
By ANDREW POLLACK
New York Times
February 27, 2004
The Genentech drug Avastin, which validated a decades-old theory about a new way to attack cancer while spurring investor enthusiasm for the biotechnology industry, won approval yesterday from the Food and Drug Administration.
The drug, approved for patients with colorectal cancer that has spread to other organs, is far from a cure. But in a clinical trial in which it was used with chemotherapy, people who received the drug lived a median of 20.3 months, almost five months longer than those who received only chemotherapy.
comes two weeks after the F.D.A. approved another biotechnology colorectal
cancer drug, Erbitux from ImClone Systems. Combined with the approval in 2002 of
Eloxatin, sold by Sanofi- Synthélabo, doctors now have almost a confusing array
"We have too many agents; we don't know how to mix them together in the right order," said Dr. Louis Fehrenbacher, an oncologist at Kaiser Permanente. "But that's an awfully nice luxury to have, because five years ago we didn't have much.
But since the
trials were done, many doctors have shifted their initial therapy to use
Sanofi's Eloxatin (oxaliplatin) instead of irinotecan.
So doctors will face a problem of whether to go back to irinotecan for initial therapy in order to use Avastin, or to stick with Eloxatin and forgo Avastin, or to combine Avastin and Eloxatin, even though there is no data yet showing that combination to be effective. But the F.D.A. approved Avastin for use with any chemotherapy combination containing 5-FU, not just for the combination of irinotecan and 5-FU. That would give doctors license to use Avastin with Eloxatin, though some doctors are still expected to wait for data.
Weisenthal’s editorial comments:
The above precisely illustrates how short sighted it was of clinical oncology (as a discipline) to abandon all interest in cell culture drug resistance testing (CCDRT or chemosensitivity testing) by the mid-1980s.