Monday, June 02, 2008

Criticism of Surrogate Endpoints in Whose Interests?

Last week, in an op-ed in the Wall Street Journal, Mark Thornton, lit into an inquiry launched by US Senator Charles Grassley (R-Iowa). Dr Thornton's concern was that Grassley was attacking the use of surrogate endpoints in clinical trials of drugs used to treat life-threatening conditions. Thornton was described as a "former medical officer in the Office of Oncology Products at the Food and Drug Administration," who also volunteers as "president of the Sarcoma Foundation of America."

Before discussing Dr Thornton's points, let me take a brief detour to explain surrogate endpoints. Ideally, physicians ought to prescribe treatments to alleviate pain and suffering, improve function, and delay death. So ideally treatments ought to be assessed on the degree they affect such endpoints. Often, however, trials designed to measure such endpoints are difficult, and often require prolonged observation of multiple patients. Thus, surrogate endpoints, which are those thought to correlate with such clinical endpoints, are studied instead.

Here is what Dr Thornton wrote about such endpoints:

At issue is the concept of 'surrogate endpoints' and the FDA's 'accelerated approval' regulations.

New laws and regulations ... created an accelerated approval mechanism by which a drug could be allowed on the market if it showed early evidence of an effect on a surrogate endpoint. For cancer, examples of surrogate endpoints are tumor shrinkage or a delay in the disease's progression.

This kind of measurement – as opposed to an assessment of a drug's impact on a patient's overall survival – has dramatically increased the pace of cancer clinical trials. It also has won near-universal acceptance within the cancer community.

The FDA does require follow-on studies to assure that a surrogate finding shows clinical benefit. But if all cancer clinical trials were required to show a survival benefit from the get-go, progress in cancer-drug development would slow to an absolute crawl.

The damage done by Mr. Grassley's decision to make an issue of this decision cannot be understated.

U.S. cancer-drug development stands on a precipice overlooking a new dark age in which each new product's development is longer and costlier than the last. Companies may decide it is not financially viable to even bother developing new drugs, and the pipeline for new products to treat cancer could slow even more. Mr. Grassley's legacy could be thousands of additional cancer deaths.

I cannot comment on the political or bureaucratic issues raised.

But I do question Dr Thornton's uncritical acceptance of surrogate endpoints, and his assertion that any questioning of the use of such endpoints could lead to death and disaster.

The problem with surrogate endpoints is that they are surrogates for the real thing. In many cases, a treatment may appear beneficial when measured by its affect on such endpoints, but not turn out to be beneficial when measured by its affect on real clinical outcomes, e.g., alleviation of symptoms, improvement of function, and prolongation of survival. There are many reasons why this may be the case.

Consider, for example, cancer "progression-free surival," cited by Dr Thornton in his article. Progression-free survival means the time a patient survives without measurable evidence that his or her tumor has gotten worse. There are some obvious reasons why progression-free survival may not correlate with overall survival. First, a tumor may progress but its progression may go undetected. Second, although a treatment may inhibit progression for a while, a tumor could escape its effects, and thereafter progress more rapidly than it did before. Third, a treatment might retard tumor growth, but cause severe adverse effects that hasten death on their own.

Thus, the FDA usually requires studies not only of progression free survival, but eventually of overall survival. Approving a drug only on the basis of its effects on progression-free survival risks allowing the use of a drug that may eventually prove to have no effect on overall survival, and hence whose benefits may not outweigh its harms.

So, regardless of the politics involved, Dr Thornton's dire warning that Senator Grassley's inquiry could lead to "thousands of additional cancer deaths" appears way over the top.

Incidentally, soon after the article came out, Ed Silverman on the Pharmalot blog reported that Dr Thornton, in addition to his voluntary post with the Sarcoma Foundation of America, serves as Senior Vice President of Product Development for the biotechnology firm GenVec, which is attempting to develop drugs to treat cancer. Also, the Sarcoma Foundation of America is supported in part by pharmaceutical and biotechnolgy companies including Ariad, Ziopharm, Bristol Myers Squibb, Ortho Biotech, and Novartis.

So readers of Dr Thornton's op-ed on health policy vis a vis how treatments for cancer and other life-threatening diseases are evaluated by the FDA deserved to know that Dr Thornton works for a biotech companies whose products could end up being evaluated by the FDA, and that Dr Thornton leads a not-for-profit organization which appears to be sponsored in part by other drug and biotech companies whose products also are being evaluated by the FDA.

Whether or not these firms' concerns that limitation of the use of surrogate endpoints in drug approval could affect their profts affected Dr Thornton's thinking is unknown. However, this question would not likely have even occurred to readers who did not know about Dr Thornton's ties, direct and indirect, to these firms.

In lieu of such disclosures, Dr Thornton's original op-ed, appears to be a new and prominent example of stealth health policy advocacy.

Health care is in crisis in many ways. Policy-level solutions deserve to be discussed widely by all sorts of people representing all sorts of opinions, with all sorts of expertise and backgrounds. However, the discussion would be a lot more productive if those taking part were completely transparent about who they are, for whom they work, and whose interests they may serve.


Anonymous said...

from today's WSJ, Sen. Grassley's response:

It doesn't help cancer patients or anyone else who has to rely on groundbreaking pharmaceuticals for a drug company executive with a financial stake in Food and Drug Administration approvals to attack independent review of the FDA ("Grassley's War on Cancer Patients," op-ed, May 29). The commentary by Mark Thornton, Senior VP of Product Development at GenVec, Inc., suggests that it's wrong to see if the FDA is carrying out its own policy of requiring follow-up safety studies on drugs that have been approved based on a method that uses narrow definitions of drug benefits. The FDA policy makes sense, and I asked the Government Accountability Office to see if the policy is being carried out. Cancer patients deserve no less.

Sen. Chuck Grassley (R., Iowa)

Marilyn Mann

Anonymous said...

Sen. Grassley's statement:

Anonymous said...

For some time I have felt that a large part of medicine reflects the corporate culture of pharma. Half truths, buried information, and other marketing "tricks" are the hallmark of this industry.

This point was made once again in the June 2 WSJ Health Blog posting on TriCor by Abbott Labs. I will let the doctors discuss the medical issues. The jest of the article is that Teva has tried for a number of years to copy this product, while Abbott makes minor changes, such as switching from a capsule to a table, changing the dosing, and legal suits intended to intimidate Teva.

From a business stand point what I see is a company, and an industry, bankrupt of new ideas and products. This op-ed piece only reinforces this concept through the lack of transparency on relationship and the questionable reliance on endpoints vs. actual patient outcomes. This is as if the whole Vytorin debacle did not exist.

Cancer is a hot button word and health issue. People simply are willing to pay anything to fight this terrible disease. Pharma has taken advantage of this with margins on these medications being astronomical. Now we see a published piece designed to maintain these business goals through fear, while enriching a small group of companies, without proven medical benefit.

While some would consider this good business practice. I consider it gaming the system and a waste of precious resources.

Steve Lucas

Anonymous said...

Provenge and Our F.D.A.’s Etiology For Not Being Approved

Terminal patients are those who are not expected to live due to usually illness such as advanced prostate cancer (cT3). 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 of the one million men who have prostate cancer in the United States. 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, which is a score that assesses prostate tissue after it is biopsied and if it is determined that the stage of cancer is severe by this and to estimate proper treatment options if proven to be malignant. Typically, the initial suspicion of prostate cancer is determined by the results of what is called a PSA blood test, as PSA is a protein produced by prostate cancer cells. If the PSA blood test is above normal limits, a prostate biopsy is performed to determine and confirm not only the presence of cancer, but also the severity of the disease on such a patient.
Yet fortunately, and as you will read, 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, and has proven to be a very novel and innovative treatment option for advanced prostate cancer patients who are terminally ill. 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 taxotere. 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 thankfully recommended with clarity the approval of Provenge based on its proven and substantial efficacy and safety demonstrated in its performance in past trials. The FDA announced this to the public in the early Spring of 2007, I believe.
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 who was evaluating Provenge, Dr. Scher, was found to have a financial commitment to a future competitor of Provenge that was being produced by a company called Novacea, and this company had signed a co-promotion agreement with Schering with this similar prostate cancer drug being developed by this company. Dr. Scher never disclosed this conflict during the approval process of Provenge. As it turns out, this anticipated prostate cancer drug made by Novacea was discovered to have serious flaws, and Schering pulled out of the agreement with Novacea. In addition to this incident and before May of 2007, baseless letters were anonymously delivered to the FDA stating negative qualities about Provenge that were without Merit and speculative claims about the treatment. Yet overall, the disapproval by the FDA of Provenge angered many, and a newly formed advocacy group called Care to Live filed a lawsuit against the FDA for their clear lack of protocol or knowledge about such complex treatment agents as Provenge at the end of last year.
Terminal patients, I surmise, desire comfort during their progressive disease that has placed them in the last chapter of their lives, and certainly should have a right to choose any treatment that possibly could benefit them. At this stage of such a patient, one could argue, safety of any treatment option is not of concern to these patients, because they are going to die anyway. Yet the FDA, with reckless disregard and overt harshness for these very ill patients, ultimately harmed others more by not approving Provenge with deliberate intent.
The FDA does in fact presently have the ability to grant what is called conditional approval for such treatment methods as Provenge, and why they have not expanded this approval process to all terminally ill patients remains completely unknown. What is known is that they are harming those they pledged to protect so long ago by depriving such patients in need of treatment, as no other options are viable presently that are as safe and effective with great tolerability associated with Provenge. So now the FDA appears to be a bought, corrupt, and incompetent administration without loyalty and dedication to the public and its health. This needs to be corrected in any way possible for the lives of others. A terminally ill patient has a personal right to obtain and access such treatments upon their own volition as well as the discretion of their doctor, just as a terminally ill patient is granted an individual right to die, if they choose to do so. It is an individual decision in such cases that should be void of interference from others.

“Facts do not cease to exist because they are ignored.” --- Aldous Huxley

Dan Abshear

David Hamilton said...

Although I realize I'm late to the party, I just wanted to point out that I noted Thornton's lack of disclosure in a WSJ op-ed way back in June of last year in a VentureBeat post. (It's a long post, so search on "Thornton" if you're interested; at the time he was complaining about the burden of having to meet statistical standards to prove that cancer treatments worked.)