Maggie Mahar writes on healthcare, economics and public policy. Her work has appeared in The New York Times, Barrons, Institutional Investor and may other publications. A regular contributor for THCB, her most recent book is "Money-Driven Medicine: The Real Reason Healthcare Costs So Much." She was recently named a fellow at The Century Foundation.
Only in America do physicians
who evaluate new drugs need bodyguards.
You may have read about the
brouhaha surrounding Provenge, a vaccine designed to extend the lives
of men suffering from late-stage prostate cancer. In March, a Food and
Drug Administration (FDA) advisory panel voted 13 to 4 to recommend
approval. The next day, shares of Dendreon, the drug’s sponsor, doubled.
But shareholders did not celebrate
for long. Two of the dissenting votes were cast by the panel’s two
prostate cancer specialists: Sloan-Kettering’s Howard Scher and the
University of Michigan’s Maha Hussain. And they did not just vote
“no”—following the hearing, both wrote to the FDA arguing that
Dendreon offered no solid evidence that Provenge works.
The FDA listened. And in May
it told the company it wouldn’t approve the drug until it had more
data. That is when the two oncologists began receiving threatening e-mails,
phone calls, and letters. Many were anonymous.
No doubt much of the hate mail
came from investors who had watched Dendreon’s shares climb from $5
in early January to $25.25 in late March—before plunging to $3 and
change. One Alabama shareholder expressed his feelings on his MySpace
page, where he asks “Hey, Hey, FDA, How Many Dads Did You Kill Today?”
while images of Hussain and Scher flash across a backdrop of crooked
crosses. Mozart’s “Requiem” plays in the background.
The response illustrates how,
in a money-driven health care system, those who view health care as
a profit center strive to dictate social policy. From their point of
view, the FDA should approve any product that Wall Street finds attractive—and
then let the market decide whether or not the drug is both safe and
effective. What they ignore is that, unlike other consumers, sick patients
are not in a good position to comparison-shop. They must rely on the
doctors and scientists who serve on FDA panels to sort through the hundreds
of offerings that drug makers hope to bring to market. For even if a
drug makes it to Phase III trials, this is no assurance that it is safe—or
that it will work. Indeed, a recent study shows that fully 40 percent
of new drugs fail in that final stage of testing.
So far, the FDA has not bowed
to investor pressure regarding Provenge, but the e-mails and phone calls
were too menacing to be ignored. When Hussain and Scher attended the
conference of the American Society of Clinical Oncology last month,
both asked for extra security guards. At that point, Hussain began wondering
whether she should continue as an FDA adviser.
Patients also protested the
FDA’s decision. Many had pinned their hopes on Provenge because it
is one of a group of new cancer drugs under development that uses the
patient’s own cells to create a vaccine designed to mobilize the patient’s
immune system to attack the cancer. The notion that the body might “heal
itself” is enormously seductive. For more than a century, oncologists
have dreamed of such a solution. But thus far, as Dr. Steven A. Rosenberg
of the National Cancer Institute confirmed in an e-mail to me last week,
“there are no therapeutic vaccines that have been shown to be effective.”
This is not what patients want
to hear. But while many were crushed by the FDA’s decision, patient
advocates such as PSA Rising disown the hate mail. "Folks, this is not grassroots
cancer patient activity, it’s . . . naked grassroots investor activity,”
wrote Jaqueline Strax, the editor of PSA Rising, in her newsletter for
prostate cancer survivors. “Ironically, some investors have whined
that prostate cancer patients are not helping THEM on behalf of Dendreon.” Roman">
Meanwhile, shareholders charged
that Sloane-Kettering’s Scher nixed the drug because he is the lead
investigator for a rival product. To drive this point home, earlier
this month Provenge activists raised $24,000 on the Dendreon message
board at Investor Village to buy a half-page ad in the Washington
Post headlined
“Prostate Cancer Victims Face Needless Suffering and Premature Death.”
Could this be true? Knowing
how much misinformation swirls around any new cancer drug, I decided
to take a close look at the transcript of the FDA hearing and find out
more about the scientific evidence behind Provenge.
This is when my skepticism
turned to shock. First, I learned that Dendreon has done two clinical
trials attempting to show that Provenge slows the progress of the cancer.
And that both failed. That’s right—the studies offered absolutely
no proof that the drug put a brake on the disease.
“It’s not clear why the
FDA panel was even voting on the drug—Provenge had already been check-mated,”
says Paul Goldberg, who broke the story by printing Scher’s letter
to the FDA in The Cancer Letter, a weekly newsletter about the
politics of cancer. . . .
In the meantime, “the stock
has become the momentum trading vehicle of 2007,” TheStreet.com’s
Adam Feuerstein wrote earlier this month. “A stock that will be pumped
and dumped based on the flimsiest of rumors and lowest-common denominator
reporting.”
Inevitably, the Wall Street
hype spills over into the mainstream media, where dying patients, willing
to grab at any thread of hope, read about a drug and begin to believe
that, if they could just get access to the “newest new thing,” it
might save their lives. (In fact, even the company claims only that
the average patient might win an extra 4½ months.) Those who
“pump” the stock do patients a cruel disservice.
Ultimately, Scher and Hussain
were not the only ones who would be intimidated by the Wall Street community.
I’ve written the full story of Provenge, discussing how it passed
the FDA panel, and whether individual patients should have the right
to gamble their lives on an unproven drug at http://www.tcf.org
Read the extended version of the story at http://www.tcf.org/Publications/HealthCare/healthbeat.pdf. Please return here to comment
Categories: Uncategorized
Any more comments? You got shut down with your silly article and lack of factual data to back up your position. IMO
I did not mean for a “personal attack” on you. If I had, I would have said: you “were” rather than “I think” as I was trying to realize and understand why you would take such a position without being educated on the statistics. I however think Walldiver summed it all up fairly well why you psotion yourself as you did.(see below)
I would seriously like to see an intelligent rebuttal to the real facts such as those presented by Walldiver , tallhoriz, Paul and others that you conveniently avoided. All thus far have been strongly refutted by Scher , Hussain , Flemming and others.
And I highly doubt that there were any real threats made upon Dr. Scher and Hussain. Where is the proof? Show me the proof in the police reports? I found none in the public record. Sure the NY times etc reported but they failed to site any proof other that from a spokesperson from MSKCC. Who of course virtually works for Scher.
It makes for great news headlines thus I see why a reporter would like to report it. To bad that the news is based on no known public facts. And even you try to spin it; you are spinning rumors. (really helps your validity as a journalist; NOT)
I would also like to add that I have no investment in Dendreon . I know Provenge should have been approved and that it will in the interim in 2008. But men are dying earlier than thy need be. No one ever thought of Provenge as a cure! I have people that love me and I know they would not mind if I was dying to have a few extra months with me as I would with them.
So we can all laugh at those who say we will see at the interim if Provenge really works. If you knew anything about biostatistics you would already know that it does work. But I suppose if your ignorance of the statistical facts was not clouding your judgement that you would have nothing to bitch about.
CD
From Walldiver:
http://investorshub.advfn.com/boards/read_msg.asp?message_id=21928141
OT-Nmstav, sometimes I’m disappointed in my fellow progressives. The truth should take precedence over all issues. One shouldn’t reflexively take a political position on an issue based solely on what one’s ideological counterparts are saying, without looking objectively at the underlying facts. Right now, the FDA is under attack from some right-wing think tanks for not allowing limited approvals of some cancer treatments…so people on the left like Maggie automatically start out with the opposite view, use specious arguments that confuse “median” with “average,” and then change the subject when you call them on it…and then say that an extremely close miss on an endpoint means that there was “no effect” on that endpoint.
Uh, Maggie; I wouldn’t want to be called a cold lonely woman either (wtf??!!), but in the name of using precise terminology, there is no cure for prostate cancer with distant metastasis – not all prostate cancer. I know you know this. Interestingly, Lance Armstrong had practically the only solid cancer that CAN be cured when widely metastatic – testicular – but he is still a lucky man.
Care to comment on the lawsuit?
http://www.pharmalot.com/2007/07/provenge-group-files-lawsuit-against-fda/
Bev M.D.–
Thanks–you make the best point about why investors
are inevitably biased, like anyone else with a financial interest in the outcome of a FDA decision.
I’d urge everyone to look at http://www.aamc.org/research/coi/science.htm on conflict of interest.
I also think that FDA reform is coming, and that ultimately physicians and scientists with a financial interest will no longer be sitting on panels.
The piece on hospital architecture (on the same site)
also is interesting. I can see the argument that private rooms make medication mix-ups less likely. But I’m still concerned that too much money is being spent on hospital amenities while too few hospitals have the healthcare IT that they need . . . Also, hospitals are
being built in some parts of the country where we don’t need more hospital beds. (Southern California is a good example.) But once they are built, the beds will be filled. (Build them and they will come.) And often they will be filled by patients who don’t really need to be inpatients, exposing those patients to all of the risks of being in a hospital while also wasting billions of dollars that could be used for preventive medicine, heatlhcare IT, etc. . .
Carey D. I don’t see any point in going round and round over the same issues. I suggest that everyone wait for
results from the randomized controlled trail that the company is now doing. Then we will find out how effective Provenge is. At this point, no one knows for sure–including me.
It is true that while we are waiting, people will die of
Prostate cancer. BUT THOSE PEOPLE WOULD HAVE DIED OF PROSTATE CANCER ANYWAY. THERE IS NO CURE FOR PROSTATE CANCER. EVEN THE COMPANY DOES NOT PRETEND THAT PROVENGE WILL SAVE LIVES. THE COMPANY CLAIMS ONLY THAT PROVENGE MAY GIVE PATIENTS A MEDIAN AVERAGE OF AN EXTRA 4.5 MONTHS.
Finally, Carey D. I don’t respond to personal attacks.
But I’d like to thank everyone else for your comments and opinions.
Carey D.;
The reason why investors should have no say in this process, among other reasons, is found in the American Association of Medical Colleges link I cited above:
“The (scientific) evidence suggests that self interest has a tendency to bias independent judgement in unconscious ways.”
You may fairly argue that the two docs are in no better position than investors due to their own purported conflicts of interest. But don’t set investors up as people with a right to sit at the FDA’s conference table. Much less threaten the people who do sit there.
I agree the FDA has been fairly hopelessly politicized in the past several years and that must be changed. This includes COI on the part of physicians (see the link I cited.) But it must also be changed to keep Wall Street OUT, not let them in!
Maggie,
You seem to be a great writer. You are so wonderful.
However you seem to only be trying to prove the only reason people are actively trying to change the “non-approval” of provenge is because they are all bitter investors.
“I’d also note that once again, it turns out that many of the most vociferous critics of the FDA decision are not patients, but investors” M.Mahar
So what? Investors are more informed than any other group when it comes to the many aspects of Provenge and it CR letter.
The investors are not just investors, they are among others things Cancer survivors, Prostate cancer patients,doctors, Nurses, Professors,lawyers, professional biotech traders, other healthcare professionals.
It is these investors that are well informed of not just the science but also the workings of Wall Streets hedge funds, the sec and the FDA. They study all angles thoroughly. (now they must study COI’s thoroughly)
How many PC patients do you know? I know more than a few and the ones that are not investors just think they have been screwed over by the FDA (the others know it) but know nothing about how the stock has been manipulated and the implications of virtually half the sock (~40M shares) being shorted.
They also are in no condition to fight , they depend on the fairness of the FDA to make decisions for them. They do not count on the FDA letting doctors with extremely blatant Financial Conflicts of Interest sitting and persuading the outcome of the drugs they depend on. They have no energy to fight the likes of you who only wishes to see the investors suffer rather than the patients survive longer.
Why do you not reply to walldivers post’s intelligently rather than choose to pick away at parts superficially?
Why do you not dispute the points he has made?
You said you would get back to the other points? when .
All of the posts have been saved and are there for others to look back at and see that you never have debated the real facts but rather keep coming back with lame rebuttals about investors.
I think I know why, because all you want to do is try and make the story 100% about disgruntled investors that cannot accept the decisions of the FDA.
You most likely feel the same way all the investors, advocates do and know that the patients and future patients have been screwed over and think the FDA made a serious mistake. However,I think you are a cold lonely woman that is actually the bitter one and must find a fight.
I think maybe someday you can actually write an intelligent piece that is from your heart and not your kulo.
Maggie;
I found a link to the American Association of Medical Colleges which cited a symposium on the “science of conflict of interest”. It won’t solve everyone’s assertions on this particular issue, but it does indicate the profession is taking notice. Change will no doubt follow, after a lot of kicking and screaming.
http://www.aamc.org/research/coi/science.htm
In addition, Maggie, regarding the issue of private rooms, which you and I both thought wasteful, here is information from the same organization that has changed my mind:
http://www.aamc.org/newsroom/reporter/june06/patients.htm
Data is everything; not just throwing around opinions.
Here are the main points that Maggie can’t address inteligenly.
1)Missed end points have nothing to do with Provenge’s FDA review. The FDA knew about the failed end points but still encouraged DNDN to file the NDA and gave it fast track priority. Provenge was to be judged on survival data.
2)The FDA appointed a panel of expert with great expertise in oncology, immunology, statistics etc… voted overwhelmingly to approve Provenge 13-4 efficacy for survival and 17-0 safety.
3)This is the first time in its history that the FDA went against the apointed panel recommendation for a drug adressing terminaly ill patient.
4)Two oncologist with documented professional and financial conflict of interest were allowed on the panel.
5)The two oncologist werent satisfied with voting no. They launched an unprecedented campagne to influence the FDA final decision in doing so they highjacked the process from the other member of the panel and wrongly affectd the FDA decision.
6)On survival, which is what provenge was supposed to be judged on. There is subtantial evidence of efficacy as the stats indicate and as the panel voted.
7)Oncologist have a vested interest in defeating Provenge. They have done that in the past (see NY times article that I posted earlier). Scher and Hussein are the worst example of such oncologist.
8) Maggie has yet to tell me why I should beleive her rather then the panel of experts in imunotherapy, oncology and statistics that voted 13-4 for efficacy and 17-0 for safety.
9)Maggie has yet to articulate why she is siding with the conflicted minority of experts.
10)Maha Husein, Maggie Mahar, relationship??? LOL
Tall
Hang it up Maggie, you are on the wrong side of the argument. You have no conterpoints to the very reasoned arguments that a few of the posters have put in front of you. My total investment in DNDN at the height of the PPS was less the 1% of my portfolio. I explained to you my interest in Provenge, but of course you chose to ignore that and again you refuse to respond to my main question / point. It is apparent that you have no interest in intelligent debate.
Wall,
Thank you for your contributions to this discussion. But please don’t waste anymore of your time responding to Maggie. She will never admit that she’s got it wrong.
Tall
Maggie, from your last couple of posts it appears that this subject is starting to push your emotional buttons. Perhaps the oncologists in the thread who weighed in on the side of Provenge were the tipping point.
To address a couple of your points: when Dr. Fleming strongly came out against Iressa approval for third-line non small-cell lung cancer (NSCLC) back in 2002/03, he did have a strong biostatistical case. The ODAC panel had recommended approval based on the 10% objective response rate (ORR) surrogate endpoint in one or two single-arm trials. The ORR was much lower than Astra Zeneca expected, or hoped for. In addition, Iressa was being tested in an ongoing, randomized Phase 3 trial with an enrollment target of over 750 patients. Results were expected in late 2004/early 2005. However, ODAC members voted thumbs up because 3rd-line NSCLC patients are extremely sick (already having failed two previous treatments), and typically only live 4 to 5 months. Pazdur stalled as much as he could after the panel meeting, actually ruling it should not be approved. The nonapproval went up the line to FDA Commissioner McClellan, who overruled Dr. No. Iressa was granted accelerated approval for marketing under Subpart H, with ultimate final approval contingent upon the overall survival results in the ongoing Phase 3.
That ongoing Phase 3 failed to attain stat sig in Dec 2004 (p=0.11, median survival benefit of only 2 weeks). So, Drs. Fleming and Pazdur were “vindicated.” Iressa was effectively pulled from the market by the FDA. There had been another approval of an EGFR inhibitor (Tarceva) in 2nd/3rd-line NSCLC a few weeks before, so Pazdur felt there was no longer an unmet medical need in this indication. However, despite my already owning stock in Tarceva’s developer OSI Pharma (which went up 20 points on the Iressa trial news), I believed it was a mistake a few months later when Pazdur pulled Iressa from being marketed to new patients. He should have kept it on the market for patients refractory to Tarceva treatment. Iressa did work, and work well, for approx 10% of those who received it. Oncologists would know within a month or less if their patient would respond to Iressa, so cost would not be a major issue. Again, a p value of 0.11, while a miss, isn’t chopped liver. Especially if you’re one of those patients who responds to Iressa but don’t respond to Tarceva. Despite their being similar molecules with similar methods of action, different people react differently.
You also seem stuck on the Provenge primary endpoint of TTP. You labeled the 0.052 p value in time to progression as a “fact that the trials showed absolutely no sign that Provenge slowed the course of the disease…” So, how is it that a 0.050 p value is absolutely a sign of slowing the course of the disease, but a 0.052 p value is absolutely not a sign? A little bit stark, but this is the logic that you’re using when you equate an extremely close miss on statistical significance in slowing the course of the disease with “absolutely no sign that it slowed the course of the disease.”
As for the crossover, there is considerable pressure from regulators and patient advocacy groups on companies testing oncology treatments to incorporate crossover designs into their trials. A crossover component is not a “poor design” as you label it, but rather ethical and compassionate behavior. And, it does make it more difficult for a survival trial to achieve statistical significance if the product being tested is effective. The two recent biologics approved for kidney cancer (Sutent and Nexavar) both had crossover designs into the trial, and most patients in the control arms were allowed to cross over after progression when the trials were unblinded and PFS had been proven significant. Both of these drugs had p values in the PFS endpoint with multiple zeroes to the right of the decimal. Crossover severely weakened the overall survival p values in the trials.
All this shows is that if you can still achieve stat sig survival in a randomized Phase 3 with a crossover component built in to the design, then you have a very effective drug.
Let’s start with The Cancer Letter. No, it’s not Barron’s or The New York Times.
Barron’s and The New York Times turn to The Cancer Letter as an expert source. See for example, the Times
quoting The Cancer Letter in this story: ANDREW POLLACK, “Studies Show Anemia Drugs May Harm Cancer Patients”, New York Times, February 27, 2007,
Link: http://www.nytimes.com/2007/02/27/health/27drug.html?em&ex=1172725200&en=b255f2891d666d3c&ei=5087.
I’d also note that once again, it turns out that many of the most vociferous critics of the FDA decision are not patients, but investors (tallwhenhorizontal).
To be fair, some physicians also feel that FDA was mistaken. (Though most haven’t disclosed whether they own the drug or would profit by administering it–so that’s still a bit of an open question.)
I’d also note that the members of the FDA panel who voted for Provenge were hardly universally enthusiastic (as some commenting here have suggested.) As The New York Times reported at the time:
“The advisory panel to the Food and Drug Administration voted 13 to 4 that there was “substantial evidence” that the treatment was effective in men with advanced prostate cancer and 17 to 0 that the therapy was safe.
The votes increase the likelihood of F.D.A. approval for the therapy, Provenge, by the agency’s May deadline. *****Still, even panel members who voted for the drug expressed some reservations about the strength of the data. That could leave the door open for the agency to reject Provenge until a bigger trial, now under way, is completed in 2010.” http://www.nytimes.com/2007/03/30/health/30vaccine.html?ex=1185768000&en=fcc2eacc67e87282&ei=5070.
So it was hardly a great surprise when the FDA decided to ask for more information. If you read the NYT, you knew that was likely to happen.
But some investors just
can’t admit it when they have lost money–and so they go into denial. (For stories, Google “TheStreet.com” and Provenge)
Maggie,
As expected you didn’t answer my main question. Why I should beleive you rather then 17 people that are far more skilled then you are in imunotherapy, oncology and statistics that voted 13-4 for efficacy and 17-0 for safety??? I even add flemings and make it 13-5…Why?
You say that the panel composition was to blame for the positive vote. Who would be more expert on judging an imunology drug, imunologist or oncologist with an agenda to protect their turf?
Here is an article from the NY times that illustrate the foolishness of your argument.
****
2 potent cancer drugs works, but rarely used
By Alex Berenson
NEW YORK TIMES NEWS SERVICE
July 14, 2007
The patients’ stories sound nearly impossible.
After an hourlong infusion, Linda Stephens, 58, has been cancer-free for seven years. Dan Wheeler, three years. Betsy de Parry, five years. Before treatment, the trio had late-stage non-Hodgkin’s lymphoma, a cancer of the immune system, and a grim prognosis.
All three recovered after one dose of Bexxar or Zevalin, both federally approved drugs for lymphoma. And all three can count themselves as lucky.
Not just because their cancers responded so well. But because they got the treatment at all.
Non-Hodgkin’s lymphoma is the fifth-most common cancer in the United States, with 60,000 new cases and almost 20,000 deaths a year. But fewer than 2,000 patients received Bexxar or Zevalin last year – about 10 percent of candidates suitable for the drugs.
“Both Zevalin and Bexxar are very good products,” said Dr. Oliver W. Press, a professor at the University of Washington and chairman of the scientific advisory board of the Lymphoma Research Foundation. “It is astounding and disappointing” that they are used so little.
The reasons that more patients don’t get these drugs reflect the market-driven forces that can distort medical decisions, Press and other experts on lymphoma treatment say. The result can be high costs but not necessarily the best care.
Although the two drugs have not been clinically proven to prolong survival compared with other therapies, patients are more likely to respond to them than to standard treatments. Trials to test whether Bexxar and Zevalin do have a survival benefit are nearly complete.
Other, more thoroughly tested lymphoma drugs are preferred as first-line treatments. But doctors often repeatedly prescribe such drugs after they have lost their effectiveness – and when Bexxar and Zevalin might work better.
“Oncologists use everything in their cupboard before they refer,” Press said. “At least half the patients who get referred to me have had at least 10 courses of treatment.”
When Bexxar and Zevalin were approved, analysts expected they would be used widely. But the drugs have run into an obstacle that so far has been impassable. Because they are radioactive, they are almost always administered in hospitals, not doctors’ offices. As a result, cancer doctors are not paid by Medicare and private insurers for prescribing the drugs, as they are when they give patients a much more common treatment, chemotherapy.
In addition, most oncologists outside academic hospitals treat many different cancers and may be only vaguely familiar with the drugs, said Dr. Andrew D. Zelenetz, chief of the lymphoma service at the Memorial Sloan-Kettering Cancer Center. “There are a number of barriers,” Zelenetz said.
Press and Zelenetz acknowledge they have financial incentives to support the drugs. Press has been paid to speak at medical education seminars sponsored by the makers of the drugs, and Zelenetz is paid when the companies sponsor clinical trials at Memorial Sloan-Kettering.
Both said the money was a fraction of their overall income and had not colored their views.
Some patients say they would not have received Bexxar and Zevalin if they had not demanded them. Wheeler, of Kalamazoo, Mich., said he received Bexxar in April 2004 only after insisting on it when his lymphoma recurred.
“I told my local oncologist, ‘I want Bexxar; you give me a referral,’ ” Wheeler said. “I’ve been a real pain.”
Zevalin and Bexxar are the first in a new class of drugs called radioimmunotherapies. They deliver radioactive particles directly to cancerous cells to kill them. Idec, a San Diego company that is now part of Biogen Idec, invented Zevalin. Corixa, a Seattle company bought by GlaxoSmithKline, developed Bexxar. Both drugs are expensive, costing about $25,000 per treatment. But one dose is usually sufficient. The cost of the drugs is similar to a full four-month regimen of chemotherapy and Rituxan, another lymphoma treatment.
For decades, lymphoma has been treated with chemotherapy, drugs that attack cancer cells but that can have severe side effects. Alongside chemotherapy, most patients receive Rituxan. It was discovered by Idec, the same company that found Zevalin, and is marketed in the United States by Genentech, the world’s largest biotechnology company.
Since it was approved in 1997, Rituxan has become standard treatment for newly diagnosed lymphoma patients, based on clinical trials showing that it makes chemotherapy more effective.
Rituxan is the top-selling cancer drug worldwide, with sales in 2006 of $4 billion. A typical course of treatment costs $20,000.
Doctors agree that Rituxan is an excellent drug, with only minor side effects for most patients. Still, the few head-to-head clinical trials that have been conducted show Bexxar and Zevalin are as effective as Rituxan, if not better.
The Food and Drug Administration approved Zevalin in 2002 and Bexxar in 2003 for the treatment of slow-growing lymphoma that had failed previous treatments.
Wall Street analysts projected that Zevalin would reach $100 million in sales in 2003. But the drug hit roadblocks immediately. Its five-figure price caused insurers to balk, and its radioactivity made some oncologists worry it might prevent them from giving other treatments later.
Prescribing Zevalin also requires oncologists to coordinate care with the hospitals that administer it. To get either Zevalin or Bexxar, patients first receive a low-radiation diagnostic dose, then imaging scans, then a high-radiation therapeutic dose, which comes a week after the first dose. Over the next weeks, the patient’s red and white blood cell counts must be monitored.
The back-and-forth makes the treatment complicated to oversee, said Dr. Joseph M. Connors, a lymphoma specialist in Vancouver, British Columbia. “The doctors looking after people tend to turn to tools that they themselves know how to use and are familiar with,” Connors said.
For most oncologists, infusions of chemotherapy, Rituxan and other drugs remain their primary source of income. Even so, Connors said, doctors might turn to Bexxar and Zevalin if the drugs are proven to extend survival over older treatments. While preapproval trials showed the drugs shrank tumors more frequently than Rituxan and suggested patients would survive longer, the test groups were too small to confirm it.
Connors said Idec and Corixa should have designed their clinical trials to prove – not suggest – the drugs increased survival.
Two clinical trials meant to answer that question are under way, but their results have not been reported. Until they are, doctors will be reluctant to use Bexxar and Zevalin, Connors said.
Meanwhile, patients who have benefited from Bexxar and Zevalin say they cannot understand why they are not more widely used.
Betsy de Parry received Zevalin in 2002, when she was 52. She had already failed chemotherapy and Rituxan.
But she responded quickly to the injection and has remained cancer-free.
“It’s not that I believe that radioimmunotherapy is right for everybody,” she said. “I just think that patients, all patients, should know their options.”
******
The other agument that you make or I should say Flemming makes and you repeat is that Provenge in both trials missed the end points. Well as I already said, everyone in the world and their dogs already knew that going in, including the FDA. In fact the FDA, knowing all this granted them Fastrack status and accepted their NDA. The panel was to review the data and render an opinion on the merrit of the survival data and they did by an overwhelming majority. To go back and argue the missed endpoints is worthless. Move on and judge the survival data. A majority of experts already have and deemed it substantial.
tall
Ps: Your standard reply to anyone that questions your logic is that they must own DNDN? Well big surprise, you caught me I own DNDN, as I do a bunch of other stocks.
For the record, I am happily retired and my DNDN holdings have little to no impact on my finacial well being. I got interested in the stock becasue my Fathere in Law has prostate cancer. It came back twice already and he is on hormone therapy now. If that’s unsuccesfull or if it comes back again, he will have no option. He is a very proud man and didn’t even want to take the hormone therapy. I know he will not put up with the toxicity of Taxotere. SO I was hoping that Provenge would have been approved by know and wanted to see it applied for even earlier stages.
SO Maggie, please grow up. Thanks.
1. AIPC patients are typically elderly TERMINAL cancer victims with an approximate 18 month expected life-span and often other compounding illnesses.
2. SURVIVAL trumps all surrogate endpoints in clinical trials as several oncology meetings this year have espoused which is a substantial CHANGE from the “old” ways of looking at cancer treatments (chemo) and their results such as TTP.
3. IMMUNOTHERAPY cancer treatment signs and symptoms appear to be significantly different from CHEMOTHERAPY treatments. Our nations best and brightest–including Federal government physicians and researchers–are currently recommending that IMMUNOTHERAPY be assessed differently from Chemo… something that is NOT being done presently.
4. THREATS to Drs Scher and Hussain: No question, such tactics are immoral and illegal and, if true, should be investigated and punished to the full extent of the law whether they come from cancer patients (and families), investors, advocates or whomever.
You report Sloan Kettering reports some are email. Those are more than easily traceable across the internet by law enforcement personnel. Have those two physicians made police/law enforcement reports of these alleged threats? No one–reputable or not–in the media has reported from either physician any call for law enforcement investigation.
If not, why not?
If anyone received such alleged multiple death threats and took them seriously enough to comment about them publicly in the media as Scher and Hussain have as well as to secure bodyguards, doesn’t common sense suggest that one would also discuss the matter with law enforcement?
5. SCHER COI: This topic, while talked about in generalities herein seems to be lacking in specifics.
Scher seemed to represent to the FDA via his Feb 2007 Application for a Waiver to serve on the Provenge Advisory Committee that he has 1 stock ownership (between $5,000 and $100,000) and 2 “Grants (Related)” each between $100,000 and $300,000.
Publicly available information shows these apparent Scher COIs (so far): [Particular attention is directed to items 1, 2 and—especially–15, but ALL—in totality– are important and telling, imo]
1. Novcea: STUDY CHAIR of DN-101; Grants & Research support
2. Medivation, Inc: PRINCIPAL INVESTIGATOR MDV3100;
3. Innovive Pharmaceuticals: PRINCIPAL INVESTIGATOR
4. Infinity Pharmaceuticals: PRINCIPAL INVESTIGATOR
5. Cougar Biotechnology: PRINCIPAL INVESTIGATOR; Advisory Board
6. Department of Defense: PRINCIPAL INVESTIGATOR PC Clinical Trials-P1 and P2
7. Bristol Myers Squibb: Consultant, Grants & Research support
8. Millennium Pharmaceuticals: Grant of Research support
9. sanofi-aventis: Grants & Research support
10. Genta: Scientific Advisory Board (as of March 6, 2007; since removed from web, but cached)
11. Biogen-Idec: Joint stock with spouse
12. Pfizer: Joint stock with spouse
13. Pharmion: Financial Conflict of Interest per Scher quote in MedPage
14. GPB Biotech: Financial Conflict of Interest per Scher quote in MedPage
15. PROQUEST INVESTMENTS: Consultant, Scientific Advisory Board; Limited Partner FINANCIAL interest
Go back and read #15 again…. He’s reported to be a “LIMITED PARTNER” in a Proquest partnership; doesn’t that suggest FINANCIAL investment?????
=========
6. CONDITIONAL Approval could (and should after full 500 patient enrollment) be granted by the FDA with the follow-up 500 patient trial as a requirement for full Approval. Provenge is clearly a substantially safe treatment and patients need PROVENGE NOW; the current alternatives for cancer victims are do nothing and die sooner or chemo.
7. You stated why would anyone want a 50-50 chance of receiving Provenge by being in a trial? It’s not 50-50; the Provenge arm will have 2/3’s of the patients and the placebo arm will have 1/3. Chances are 67% of getting Provenge.
8. QUALITY of LIFE: This horse has been well detailed above. Suffice it to re-state that Provenge is a 3 treatment immunotherapy similar to a blood infusion given over the course of a month with mild flu-like symptoms for 1 or 2 days following each treatment.
Chemo is an extended treatment (over a year?) refused by 50% or more of those recommended to take it and results in about 1 to 2% of the TERMINAL cancer patients who take this treatment dying from the treatment itself and NOT from their disease. Hospitalization and added drug treatments (all expensive) to treat the horrible side-effects of chemo are often required.
EACH patient’s Provenge treatment is specifically designed for that sole patient. This is not a cookie-cutter, one-size fits all treatment such as pills or chemo which only vary in the dosages (i.e. 2 pills/day for patient A and 3 pills/day for patient B) or treatment length—but all take the same meds.
The treatment I would receive is based solely on immuno-activation given to my own blood. It cannot be used in anyone else’s body; their individual blood needs to be treated and then re-infused into themselves only.
9. Mr. Edwardo Garcia of San Diego, a Provenge patient who has survived more than 5 1/2 years since treatment testified both in favor of Provenge and about his Quality of Life, especially with his grandchildren, at the FDA AC on Provenge.
Mr. Kenneth Agnor of Chesapeake, Virginia, another Provenge treated patient, credits Provenge with arresting his prostate cancer diagnosed in 1992.
You talk about Fleming (a Ph.D., if memory serves) and his being a cancer patient. Here’s another MEDICAL doctor and his results with MORE THAN 30 patients reported in media.
The Norfolk, VA newspaper also reported, “Dr. Paul Schellhammer, a Norfolk urologist, oversaw the treatment of more than 30 local patients on Provenge in clinical trials several years ago and now has patients in a third study that the FDA will use to inform its decision. Schellhammer said he had been paid in the past by Dendreon for serving as an advise r [sic].”
“When a drug improves survival, it’s a hallelujah event,” Schellhammer said. He said he has patients who were treated with Provenge “who are still alive with minimal other therapies, which just defies the odds.””
“And, the treatment seemed to be especially patient-friendly, Schellhammer said, with little of the harshness of some chemotherapy drugs.”
“No patient withdrew because of the side effects, which is virtually unheard of in an advanced cancer treatment trial,” said Schellhammer, who is director of the Virginia Prostate Center at Eastern Virginia Medical School and incoming president of American Urological Association.”
This not from a statistician who crunches cold, hard numbers, but from a Physician actually working in the trenches with real, live patients!
10. THE CANCER LETTER – It’s reportedly:
A. NOT peer-reviewed
B. Is run from Mr and Mrs Goldberg’s home basement in the Washington, DC area.
C. They “are” the staff of this publication; previously, Mrs Goldberg’s father ran it.
I believe all can agree that this is no BARRON’S- or THE NEW YORK TIMES-type publication.
i. The 3 doctor’s anti-Provenge letters published in THE CANCER LETTER were CONFIDENTIAL letters purportedly written by them to the FDA which appeared almost evenly spaced about 1 week apart prior to the FDA’s May 9th decision.
ii. I know, at least, the Scher and Hussain letters began with a long, detailed CV in the opening paragraph. Does it strike anyone as odd they would re-inform the FDA of their qualifications before their post-AC meeting attack on Provenge? The FDA has to be more than well-acquainted with their work and educational history; after all, didn’t the FDA invite them to serve on this important committee as “temporary government employees” as the FDA’s own paid consultants?
Could it possibly be that these letters were NOT intended to be CONFIDENTIAL and, instead, for public consumption?
iii. How did THE CANCER LETTER acquire copies of these 3 CONFIDENTIAL FDA letters?
iv. Why hasn’t any law enforcement agency investigated how these CONFIDENTIAL letters to the FDA were “leaked” to THE CANCER LETTER?
v. Such a public letter writing campaign has to be unheard of in the FDA history. Doesn’t this strike anyone as more than unusual to have 3 such letters conveniently leaked 1 week apart? Doesn’t it smack of intentional sabotage?
ENDING:
No matter which camp one resides in, this is a genuine tragedy for prostate cancer victim of which some 27,050 men–according to the American Cancer Society and the National Institutes of Health–will succumb to their TERMINAL prostate cancer in the next 12 months alone! It appears interim data will be at least 12 additional months away. In the event it takes the full 2 or 3 years for the complete data to be submitted to the FDA and for the FDA to act, the Death Tally will be between 54,000 and 81,000 men who will die prematurely from the FDA’s current actions.
Is it no wonder patients, families and advocates are making this cause known to media, Congress and the FDA? Such a horrendous death toll, if noted daily by the media just like the Iraq war casualties are, would create a firestorm and clamor from the general public as well for this product to be released to those suffering such TERMINAL cancer.
The DAILY Death Total is 82 (EIGHTY-TWO-emphasis added) men each and every day, 24 hours per day and 7 days per week and that, to me, is totally unacceptable when a “safe” product exists which will help a significant portion of these men EXTEND their lives and do so with excellent Quality of Life with the family and friends!.
Provenge satisfied 100% of the 17 voting and FDA-invited and imminently qualified members (including Scher and Hussain) at the March 29th FDA AC meeting that it is “substantially safe” and 13 of those 17 positively voted that Provenge shows “substantial evidence of efficacy”.
FINALE:
September is Prostate Cancer Awareness month. Be sure that you’ve had your prostate cancer screening and insist the same for your brothers, fathers, and any other male family and friends! The life you save may be your own or that of a loved/esteemed one.
Clearly this issue has ardent supporters on both sides; Thank You! for bringing this issue to public attention!
Maggie,
I wanted to respond to several flaws in your logic that exemplifies the problem with provenge. I am not a shareholder in the maker of provenge. I am a physician and the MD’s I know who are familiar with provenge feel, like those on the FDA panel, that it is safe and effective. Benign immunotherapy like provenge, as a part of combination therapy is almost certain to become the next dramatic evolution in standard of care treatment for cancer patients. Regardless of what the good Dr. Rosenberg emailed you I would suggest you peek at the dramatic data presented by either Drs. Jeffery Schlom of the NCI or Daniel Petrylak.
If you think the FDA just saved us a bunch of money, think again. While there will indeed be short term savings, the FDA has just placed rigid requirements for the development of these very benign medicines on par with lifethreatening chemotherapies that will cost us many times what we have saved in the short run. Who do you think will end up paying for this? I treat cancer patients on a daily basis struggling to relieve their suffering from, among other things, side effects of chemotherapy; people with anorexia, burning up with fever. Every day we hold up immunotherapy is another day we prolong suffering and run up huge,expensive bills. Who will end up paying for this?
You stated: “The egregious part, to me, is that investors in the company should have any say at all, or even the right to comment, on the scientific deliberations.” While you qualify your statement by saying the FDA should avoid conflicts of interest it is troubling, to say the least how you and most others gloss over the real issue here. The issue, believe it or not isn’t investors in provenge raising a fuss. In fact, activism is a part of democracy. The real issue is the fact that likely the largest investor involved here is Dr Howard Scher, a highly placed advisor for a hedge fund that is heavily invested in a potential competitor to provenge and who weighed heavily in the FDA’s decision to reject provenge. This is akin to a defendant’s sibling being on a jury resulting in a hung jury. Now you can say that the jury made the correct decision all you like but, really now, surely you see the travesty even if you don’t admit it.
One final thought. The notion that the few naysayers were oncologists who, unlike the rest of the AC panel, actually treat prostate cancer patients and therefore are inordinately qualified is incredibly insidious, particularly in light of the conflicts of interest. All MD’s go to the same medical schools, take the same statistics courses, the same licensure exams. Most importantly, we are all trained to finally ask ourselves: what would we want if we were the patient?
Chuck Bennett, MD
Thanks for the comments.
Tall when horizontal points out that Spike and I are not statisticians. I have studied statistics, and it’s obvious that Spike also has real knowledge of the subject.
But let’s go back to what Fleming, a biostatistician with a national reputation says. (See my long response to Walldiver on July 25–Fleming also wrote a long letter to the FDA saying that it should not approve Provenge without further evidence.)
What is signifiant, I think is that Fleming actually Has Prostate Cancer–which gives him quite a bit of credibilty in my mind.
One would expect that, as a prostate cancer patient, he would be eager to have Provenge approved as soon as possible. But he understands the science behind
randomized controlled trials, and is able to look beyond his own narrow self-interest to take a broader view when he says:
“I strongly disagree that all patients want is a ‘choice.’ Patients want an ‘informed choice.’ How would pre-mature approval of Provenge that could diminish the likelihood of obtaining reliable results from the larger trial be in the best interests of prostate cancer patients?”
I would also note that, not long ago, Fleming warned the FDA about another drug that they were approving. He turned out to be right. Maybe that is why the FDA felt it had to listen to him this time around.
I also wonder why some investors are so anxious to have Provenge approved immediately. If they had faith in the drug, one would think that they would be willing to wait until the middle of next year when results from the larger, well-designed trial begin to come in. (The FDA has indicated it may approve the drug then if the results are good.)
Perhaps some investors want to see the drug approved this year so that they don’t have to risk bad results from the larger trial? IF the drug were approved this year, the stock would soar, and they could dump it and pocket the profit witout worrying about what happens in the more definitive trial. If I sound cynical, it is because I covered Wall STreet for Barron’s for about 12 years. (I may have made this suggestion above; if so I apologize for the repetition.)
Moreover, when Fleming says that you can’t change the end-point of a study after the fact, he is entirely right. As Spike points out above:
“it is not appropriate to dumpster dive for new findings when the tested hypothesis failed to pan out. From everything that’s been written, Provenge was designed to slow the progess of the disease, which it did not do. So, it did something else, and nobody understands the mechanism by which it happened, and that result only was discovered after the intended study failed and the researchers had to come up with something else to make the drug look good.”
“That’s fine,” Spike continues, “we all understand that’s how science works. But, after the unintended consequence with no understood mechanism is determined, the scientific approach is to run another study that intends to measure that specific variable and see if the result can be replicated.”
Tall-when-horizontal–I am wondering why you are so outraged by Spike’s arugment (and my argument). Do you
happen to own the stock (or have you ever had a financial interest in the company.)
Ciarin and Walldiver–
While the FDA usually follows the advice of an advisory committee, sometimes it doesn’t. This is not
unprecedented.
What is very unusual is the fact that the majority of people on the panel were not oncologists. In the past, when a cancer drug was being evaluated, most of the members of the panel were oncologists, many of whom
worked directly with patients. The composition of the panel may help explain why it took so little interest in the quality of life that the average patient enjoyed
during those extra months of life. Perhaps they just didn’t realize how painful late-stage prostate cancer can be.
Walldiver– As you know, in everyday language “average” is commonly used to mean “median”, but you are absolutely right, here it’s a median average: half of the patients who received Provenge gained more than 4.5 months– half gained less.
What’s important is that we don’t know whether the Provenge CAUSED increased survival. The fact that the trials showed absolutely no sign that Provenge slowed the course of the disease or the onset of pain (no lowering of PSA levels, etc.) seems to contradict the notion that it was the Provenge that caused the patients to live longer. The placebo was not inert, so there is the possibility that it harmed the patients in the control group. Or the extended survival could just have been chance. We’ll just have to wait for the results from the larger trial.
As for the crossovers, there is another factor that
makes the results uncertain. People like Fleming say that this is another example of how the trial was poorly designed. .
Spike,
What is your point?? The whole world knows that provenge didn’t meet the original end points, and so did the FDA. They granted fast track status and accepted the NDA. SO the FDA was already past that, it’s time you do the same. The original endpoints essentially tried to measure disease progression by measuring tumor size. Well imunotherapy takes a lot longer to work then threrapies that kill all the cells in sight regardless whether they are cancer cells or good cells (as in chemo). If they had waited a little longer before taking the measurements we probably wouldn’t be here discussing the merrits of provenge. So anyway all that is water under the bridge, the FDA agreed to that by accepting the NDA. The new basis for approval was supposed to be survival. So at least, lets discuss the proper endpoint, survival. Are you arguing that provenge did not show subtantial evidence of survival? If you are then you are disagreing with a panel of experts that voted 13-4 that provenge did show subtantial eveidence of extending life.
Come on you and and Maggie show me your credentials, tell me why I should beleive you rather then the panel of experts in imunotherapy, oncology and statistics that voted 13-4 for efficacy and 17-0 for safety. Tell me why you are siding with a couple of doctors that had everything to lose by approving provenge.
you have nothing to say, don’t you…
tall
Spike, please read my posts again. The p value for the primary tested hypothesis was 0.052 for time to progression. The FDA claimed it was 0.085. Either way, that was the primary endpoint, and the 0.21 p value for time to symptomatic pain was the secondary endpoint. One additional important point to make is that this trial was designed in 1999 and conducted from 2000-01 when much less was known about the chronology of hormone-refractory prostate cancer. The subsequent Taxotere trials and all of the other Phase III trials being run by other companies are designed with the pioneering Provenge trial in mind.
Dendreon, its investors, and many patient advocates have been fully aware the whole time that its Phase 3 trials are not statistically pristine. The filing was based on the premise that for a terminal condition, Provenge showed a statistically significant survival benefit, plus every remaining endpoint that was a surrogate for survival trended in a beneficial direction. The company, its investors, and patient advocates were hoping for a positive, common sense, non-conflicted decision from the FDA in the best interests of terminal patients and their doctors, instead of one based on (1) rigid biostatistical criteria and (2) fear that the oncology cooperative groups would fund adjuvant immunotherapy trials instead of adjuvant chemotherapy trials, thus taking grant money away from the employers of prostate cancer oncologists/academicians (whose funding share increased after 2004 Taxotere approval) and putting it in the hands of urology groups (who dominated the treatment of the asympomatic stage of HRPC prior to Taxotere).
tall,
If you read the full article, she lays plenty of the blame at the feet of the FDA for allowing such a compromised person to make the decision. Plenty. But that doesn’t change the fact that the drug failed to meet the standard it said it was going to meet and the standard the trial was designed to measure: slowing the progress of the disease.
These days, it’s a miracle the FDA turns down anything. So comparing this drug’s treatment to the treatment other drugs receive isn’t very meaningful, either.
Maggie, maggie, maggie… Please take a statistics course or design of experiment course at your local city college prior to making any other comments on whether provenge will help or not. If you refuse to do so, at least side with the majority of scientists that reviewed the data (13-4 for efficacy and 17-0 for safety). For you to choose to side with the minority w/o any statistical creds to offer any inteligent points or counterpoints is useless.
Scher has huge conflict of interests, the approval of provenge would have impacted impacted him professionaly to say nothing of his pocket book. His unprecedented campaign to influence the FDA decision given his conflicts was sickening.
Finaly and most importantly you have failed to address the main issue. Why did the FDA, for the FIRST time in its history (for terminal diseases) go against the advise of its own panel of expert when they voted overwhelmingly in favor of Provenge aproval? Why did they allow a couple of individulas with huge COI’s to highjack the process?
Given your previous work, I don’t expect you to rise to the challenge of answering these questions, but I thought I’ll give you a chance anyway. Thanks for the vine.
tall
walldiver,
All conclusions seem valid once they attain significance. But someone as well-versed as you in research should know that it is not appropriate to dumpster dive for new findings when the tested hypothesis failed to pan out. From everything that’s been written, Provenge was designed to slow the progess of the disease, which it did not do. So, it did something else, and nobody understands the mechanism by which it happened, and that result only was discovered after the intended study failed and the researchers had to come up with something else to make the drug look good.
That’s fine, we all understand that’s how science works. But, after the unintended consequence with no understood mechanism is determined, the scientific approach is to run another study that intends to measure that specific variable and see if the result can be replicated. Then, you can say whether there is a real effect or not.
A .21 p value for the tested hypothesis isn’t that great. It’s something, but it’s still very possible that random chance generated that outcome and with such a small sample size, it doesn’t say much at all.
Run another study that’s designed to test survival, and if it pans out, then go with it. Pharma companies bemoan how much they have to spend on clinical trials, and use that as an excuse to price-gouge consumers. This time, the consumers should at least get their money’s worth.
Ugh. I see I am going to have to provide some basic biostatistical education here, as a number of the Provenge detractors keep mentioning something along the lines of “but the Provenge patients only lived an average of 4.5 months longer than those in the control arm” when making a financial or statistical argument against approval. The 4.5-month benefit in the 9901 Phase 3 trial is the MEDIAN survival benefit, not the AVERAGE survival benefit. The median survival is calculated by the measuring the number of months alive for the patient in the 50th percentile of the treatment arm, vs the # of months alive for the 50th percentile patient in the control arm. So, Provenge’s MS was 4.5 months better than the control arm’s MS.
However, the average survival of the Provenge arm patients is likely 9 to 12 months longer than the average survival of the control arm patients. Why? Because 34% (28/82) of the Provenge arm patients survived the full 36 months of the formal followup included in the trial protocol, while only 11% (5/45) of the control arm patients did. In addition, it appears that 20/28 of those in the Provenge arm who survived the full 36 months after formal followup was stopped, went on to survive a total of least 66 to 84 months by the time of the advisory panel meeting in March 2007, according to the FDA briefing documents. So in summary, it’s quite apparent that the average survival benefit from Provenge treatment is substantially greater than its median survival benefit.
Another point I haven’t made yet is the beneficial effect of salvage Provenge after progression for those patients in the control arm who opted to receive it. Approximately 75% (34/45) of the patients in the control arm opted to receive cross over and receive salvage Provenge after their cancer progressed, and their survival results were still counted as part of the control arm. Dendreon did not do a final, 36-month breakdown of the entire control arm between the crossovers and the non-crossovers…the only breakdown we have is from Sept 2003, one full year before the final 36-month survival numbers were calculated. Here are the Sept 2003 numbers for median survival:
26.3 months Provenge arm
23.9 months control arm crossovers
19.3 months control arm non-crossovers
That’s a 7.0-month median survival benefit for the Provenge arm patients vs the control arm patients who, upon enrollment in the trial, opted not to receive salvage Provenge after progression if they were to be randomized into the control arm. Thus it appears that Provenge achieved its statistically significant survival benefit despite having to compete with a substantial percentage of patients who received later Provenge.
Finally, to answer Maggie’s point about the basis of Fleming’s biostatistical argument against approval: this isn’t just some random endpoint…it’s survival. Provenge showed a survival benefit at the point of each unblinding. In addition, while the progression and pain endpoints failed to reach statistical significance, Provenge did not “fail to show a benefit in these endpoints.” The median TTP was 11.7 weeks Provenge vs 10.0 weeks control (p=0.052 to 0.085), while the p value for time to pain was 0.21. Provenge in both endpoints showed a benefit and trended toward statistical significance, but did not attain it.
The FDA advisory committee for Provenge voted 17-0 on safety and 13-4 on substantial evidence of efficacy. It is unprecedented in the history of the FDA that this level of support for a new treatment would not be approved. Therefore, there must be unknown factors at play in this case that led to the denial by the FDA. These factors need to be unearthed in a thorough investigation.
Sincerely
Ciaran N. Cronin PhD