When Fear Intimidates Science

I did something the other day that has bothered me for the past 72 hours: I decided not to publish a comment in my blog because of fear of retribution or possibly retaliation.


 


Today, I decided to correct that decision and discuss my concerns.


 


Although it may not be a momentous piece of information, it nonetheless made me think long and hard about why I made the decision I did at that time, and what the implications were for providing information to the public about current controversies in oncology.


 


The topic of my blog this past Saturday was about the changing face of oncology, as reflected in the annual American Society of Clinical Oncology meeting.


 


What has concerned me were the comments in my draft about an investigational cancer vaccine called Provenge.


 


As I noted in that blog draft, we live in a different world today than we did years ago when it comes to public knowledge and influence on the drug approval process.


 


We have more information readily available, with many more people having access to that information.  I call this phenomenon the “democratization of information.”


 


Along with that democratization (if there is such a word) comes the sense among many that they want information provided to them so that they can make up their own minds regarding the validity, value and implications of that information.


 


It is one thing to have that information about, for example, a presidential candidate or a new car.  It is something else, in my personal opinion, when it comes to a new medicine or a new treatment. 


 


I agree with my colleagues that it is important that people have access to the information, but the subtleties of interpretation do require knowledge, training and expertise that are not possessed by most people who have not had training in medicine.


 


This brings us to the Provenge story.


 


I will admit that I am not privy to all of the information and primary data related to Provenge, an investigational vaccine being studied in the treatment of men with advanced prostate cancer. Much of what I do know comes from other sources that have reported on this topic.


 


That said, in a nutshell the story is that several years ago the company that has been working on this vaccine reported that their clinical trial intended to demonstrate that Provenge was useful in the treatment of advanced prostate cancer did not meet its goal.


 


Subsequently, on reanalysis, they concluded that there was some information in that “failed” trial which suggested that the vaccine may have in fact increased the lifespan of the men who received the vaccine.


 


The company then supplied the data to the Food and Drug Administration for review and possible approval of the vaccine.


 


Within the past several weeks there have been several news reports about the developments surrounding the FDA’s analysis and decision.


 


First, one of the FDA’s outside advisory committees suggested the vaccine be approved, despite some problems with the quality of the statistics that are normally used to determine whether or not in fact a drug (or vaccine, in this case) is effective for the disease in question.


 


A report in a widely followed cancer newsletter called The Cancer Letter reported that the advisory committee meeting was apparently raucous, with the advocates present in the audience making their opinions known very vocally when someone agreed or disagreed with their position that the vaccine should be approved for general use in the treatment of prostate cancer.


 


Subsequently, as again reported in the Cancer Letter, some highly respected cancer specialists wrote the FDA regarding their concerns about possible approval of the vaccine.  They felt that the data did not support effectiveness, and pointed out that there were ongoing clinical trials that would directly answer these questions, without the statistical problems of the current data.


 


The FDA decided to not approve the vaccine, and await the results of the ongoing clinical trial.


 


That apparently led the advocates in favor of vaccine approval to develop a series of actions with the goal of changing the FDA’s mindset. 


 


The advocates had posted an announcement on a website that they were planning a rally for Saturday morning at ASCO. They also planned a rally in Washington yesterday and today to meet with Congress and the FDA. 


 


Their position is that someone who wanted access to Provenge should be able to receive the vaccine.  The argument they make is that if it appears the vaccine may be effective, then why should men who are facing a fatal disease be denied the opportunity to receive the vaccine when it may improve their survival?


 


This is the question that piqued my interest in this topic, and how our standards may be changing when it comes to the decisions we make in caring for our patients.


 


For years, much of what we did as doctors—in treating ALL types of illnesses—was based as much on tradition and expert opinion as it was on science.  Now, as physicians, we are trying to move our care into more of an evidence based model, where we develop the science to back up our actions.


 


But with the spread of the internet—and the democratization of information—we find patients and others are beginning to influence our treatment choices, much as is the case with DCA and now with Provenge.  (Other alternative therapies are also driven by this “word-of-mouth” (or perhaps “word-of-internet” would be a more apt description) phenomenon, and are now very much a part of the landscape of cancer treatment.)


 


So that is what interested me.  I also had expressed in the blog draft my personal opinion that based on what I had read, waiting for the results of the clinical trial was the appropriate thing to do. 


 


We have seen too many examples in cancer medicine and other areas of medical treatment and practice where the initial thoughts have proven wrong—and even harmful—to ignore good science in this particular situation.  (The current discussions surrounding the potential harms of erythropoietin come to mind as an example.)


 


On my way to the ASCO meeting, I heard that the situation may have become even more serious than I had realized.


 


What made me pull my comments from that draft blog was a message I received that serious personal threats had been made against two physician scientists who had urged the FDA to delay approval of Provenge, pending the results of the clinical trial. And, I was told, these were threats of the most serious type.


 


Because of the risk, I decided not to say anything publicly.  Although I had written my blog on this topic, I edited the comments regarding Provenge out of the final posting which you may have read on Saturday.


 


For your background, what you see on my blog is generally what I write.  I may make some editorial edits, or perhaps tighten up some comments.  But I have never removed a “theme” from one of my blogs under pressure—either real or perceived–since I started writing it almost two years ago.


 


But this time was different. 


 


As I spoke with some reporters who attended ASCO, a common theme emerged. 


 


They, too, had become reluctant to cover the story because of fear of retaliation.  One reporter said that in their opinion you had to “steel yourself” if you intended to report an opinion or comment in support of the FDA’s conclusion.


 


Frankly, this troubles me a great deal. 


 


On Saturday afternoon I decided to give an interview to a major business journal and basically say that this is not the way we should do our science. 


 


What I said was that we may not always agree on the science, but intimidation is not the answer to making evidence-based decisions regarding drug approvals.  (As I write this, I don’t know if those comments have been published.)


 


Then, yesterday, the New York Times went public with confirmation that threats of physical harm had in fact been made against the experts who opposed approval of Provenge.  The Times reported that one of the physicians actually had bodyguards with him as he presented at ASCO.


 


In that interview, the physician indicated his concern that more of his colleagues had not come out publicly to support him in his time of need.  I suspect that, like me, many of his colleagues have been intimidated, and are frankly afraid to make a public comment.


 


As it turned out, the rally on Saturday had a small number of participants and nothing untoward occurred.


 


There were no meetings invaded, no sessions disrupted, and no one harmed.


 


As I said above, my personal opinion based on the information I have read is that it is appropriate to await the results of the current clinical trial to determine whether or not in fact Provenge improves survival in advanced prostate cancer before approving the vaccine for general distribution.


 


The question of access to investigational drugs is an important one, and one that is currently being debated in multiple forums.  When it comes to drug (or vaccine) approval, we must have the best evidence possible that the drug is effective, and a valid understanding of what risks may be associated with the drug.


 


But to threaten established, knowledgeable investigators who honestly express their well-reasoned opinions, which in turn “chills” rational discussion is, from my point of view, simply unacceptable.


 


We will always be subject to those who try to influence our comments, decisions and recommendations.  I personally try to limit those outside influences, and try my best to declare when I perceive there may be a conflict of interest that people should know about when I make a statement in a public forum.


 


Public debate and discussion is appropriate. Intimidation is not.  Disclosure is essential.


 


Ultimately, I am hopeful that our decisions whether or not a particular drug should be approved will be based on the best evidence available, and the best quality interpretation of that evidence. 


 


Yes, there are problems with the system currently in place.  Every human system is subject to personal interpretation and potential error.


 


That does not mean that those involved in making those decisions and making comments on those decisions are not trying to do the best they can under the circumstances.


 


Fear and intimidation should not make us hold back the expression of our legitimate scientific concerns. 


 


I know that the perception of potential intimidation influenced me a couple of days ago, and I hope that sharing these thoughts with you will help assuage the nagging guilt that has bothered me since I made that decision.


 


In the meantime, I hope that those who disagree with my position will be rational—and, non-threatening.

11 thoughts on “When Fear Intimidates Science

  1. Dr. Len – Thank you for having the courage to be honest. Life is full of challenges that we may not always know how to face, and fear is a compelling decision-maker. I applaud your sincerity and humility in the face of fear, and your effort to make things right.

    I have had the pleasure of hearing you speak, and I love reading your blog. Thanks for making complicated science tangible for the rest of us!

  2. I agree with you that threats are disturbing at the very least.I think Dr Scher’s credibility has been called into question due to his COI in this case.The FDA panel voted 17-0 on safety and 13-4 on its efficacy.Then you have Dr Scher with a financial stake raise questions about its safety and effectiveness.I would this is an important part of the story.Here is a link to his COI.
    http://www.fileupyours.com/files/104862/Scherfinalpdf.pdf

  3. Appreciate your candor. The threats (by one or two) were unacceptable, but should not distract us from scrutinizing the FDA’s mistake. The expert panelists included some of the nation’s leaders in immunotherapy, from such institutions as Moffitt, MD Anderson, NIH, Harvard, Stanford, Duke, UCLA, U. of Wash., all of whom voted that the data presented showed “substantial evidence” (the legal standard) of efficacy. Never before that I know of has the FDA failed to follow the overwhelming approval recommendation of its panel for and end stage disease, especially when safety is not in question and the only available treatment has such a severe side effect profile and marginal benefit that many patients forego it. The data is there per those who understand how immunotherapy works (Drs. Scher and Hussain lack such expertise), and delay will mean about 60-90K patients will die prematurely. Shameful.

  4. The real story here is not that a couple of doctors received threats from possibly only one individual…at most a few? Any person in the public eye who expresses opinions will tell you that they routinely receive such threats from the lunatic fringe.

    The real story here is that the FDA denied a treatment, to end-stage prostate cancer patients, which demonstrated remarkable evidence of efficacy and which received a unanimous vote in the Advisory Committee attesting to its safety. These men (AIPC patients)have pretty much stopped responding to previously effective treatments…they have approx. 20 months to live. Their only FDA approved treatment is a chemotherapy of such limited efficacy (median survival increase of approx. 10 weeks) and such severe side effects(one being death)that apparently a majority of potential recipients refuse to take it.

    In the 9901 P-3 trial, 34% of Provenge recipients were alive at 36 months compared to 11% for the control group. The primary endpoint for TTP was missed by .002!!! I thought ‘overall survival’ was the “Gold Standard”. Aren’t all these endpoints mere surrogates for survival? What about the renowned Dr. Petrylak’s findings of GREATLY increased survival when Provenge is combined with Taxotere?

    Are you aware that some trial participants who received Provenge in 2001 are still alive and well?

    You should be asking yourself ‘and others’, “how does the FDA justify denying a treatment to terminal patients who have no acceptable alternative, which has been demonstrated safer and superior to the currently approved treatment”? BTW, ALL subsequent trials support that evidence of efficacy.

    The FDA’s decision was unprecedented, unjustified and morally indefensible. Even former FDA Deputy Director Dr. Scott Gottlieb recently alluded to the FDA’s unusually high bar of statistical certainty which FDA used to deny Provenge.

    Why don’t you do some research, and then come back and write a new entry in your blog which addresses the really important questions?

  5. Provenge and Our F.D.A.’s Overt Absent Of Loyality

    Terminal patients are those who are not expected to live due to usually illness such as advanced cancer. If the patient has 6 months or less to live, those patients are considered terminally ill. Regardless, if a patient is terminal, they are without a cure or tolerable treatment for their illness. Since such patients will likely die in a short period of time, treatment options, even if unproven, are often desired by such patients. This is understandable, because at such a severe stage of illness, such as prostate cancer, possible extension of their lives with comfort is worth it to them, regardless of lack of evidence of proof of whatever treatment that may be advantageous to them regarding these issues. The FDA, however, claims authority on the treatment options of such patients, although that administration has proven itself over the years to be rather inadequate with its frequent drug recalls and black box warnings, and they do these things only under pressure from the public, usually.

    Prostate cancer is a rather frequent occurrence- with between 10 to 20 percent of men predicted to acquire the disease during their lifespan, resulting in about 30,000 deaths a year from this disease. Furthermore, there are different stages of prostate cancer, and the more severe the prostate cancer cases are which is determined by such methods as bone scans and Gleason’s scores, the more difficult it is to treat such patients.

    Yet innovation still exists in medicine. A few years ago, a small Biotechnology company called Dendreon was working on a conceptually new treatment for the worst prostate cancer patients, and this treatment therapy created by Dendreon was named Provenge. Provenge is the first immunotherapy biologic treatment for the progressed prostate cancer patients. Usually, these patients are unresponsive to usual treatment methods for prostate cancer, and are left with chemotherapy as their only treatment option at such a traumatic stage of prostate cancer. Understandably, most patients at this stage refuse treatment entirely, largely due to the brutal side effects of such chemotherapy treatments as taxodere. The immunotherapy method developed by Dendreon required the removal of white blood cells of the diseased patient and, after altered, are re-injected into this patient now designed to attack what is called PAP, which is on prostate cancer cells only. This treatment required only three such injections in a period of six weeks. This resulted in life extension twice that of chemotherapy treated prostate cancer patients of this severity, and without the concerning side effects of chemotherapy. The medical community and survivors of prostate cancer were elated and waited with great anticipation for access to this treatment method.

    Fortunately, as the years passed, Provenge, by 2007, had convinced others of its safety and efficacy in its benefit for severe prostate cancer patients. This caused great joy to such patients and their families. Perhaps greater elation was experienced by the caregivers and specialists of such a disease, such as Urologists and Oncologists who treat such patients. While Provenge was on fast track status at this time at the FDA, the FDA panel recommended with clarity the approval of Provenge based on its proven and substancial efficacy and safety demonstrated in its trials, as they announced in March of 2007.

    Now for the bad news: With great shock and surprise, the FDA agency rejected the approval of this great treatment for very sick patients due to, they said, ‘lack of data’ in May of 2007. This contradicts their favorable opinion of Provenge weeks before delivering this terrible news. Especially when one considers the FDA Commissioner is a prostate cancer survival himself!

    Soon after this judgment was passed by the FDA, conflicts of interest were discovered by others. For example, a member of the FDA agency w

  6. The real story is about the stock, labeled DNDN. Because there is so much speculated money involved, and because many will want a “piece of the action” (including institutions), the FDA will be under enormous pressure in this case. Approving this medicine may result in profits to some, but with losses to others (“shorters”, large funds, and others) – according to my understanding of the situation (please correct me if I’m wrong). There is a huge expectation on the stock market for developments, and the whole situation is extremely volatile.

  7. Did it ever occur to someone that maybe not everybody is happy if they would find a cure for any type of cancer? There is much more money to be made the way it is in place right now by a lot of people involved.

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