Honesty in clinical trials
Big chunks of this article are direct quotations from Dr. Terry Hamblin’s blog, where he has just reviewed the bendamustine clinical trial. Unless you are very newly diagnosed and have not had a chance to look around the CLL scene, you will need no introduction to Dr. Hamblin. It was Dr. Hamblin’s pivotal contribution that dawned the age of prognosis based on cellular understanding. Heard of the IgVH gene mutations status as prognostic indicator? Recognizing the importance of this subtle but very important difference in the B-cell receptors of aggressive versus indolent CLL was the starting point for modern understanding of CLL. Terry Hamblin received the Rai-Binet Award for that important bit of research.
But Dr. Terry plays another and even more important role. He is one of the few CLL experts who tells it like it is.He has no axe to grind, no bosses to please, no professional ladders left to climb, no need for more money, no kudos left to garner from his peers. When he speaks his mind on the subject of CLL, savvy CLL patients drop what they are doing and listen carefully. Here is what he has to say on the subject of bendamustine’s pivotal clinical trial, the basis on which the drug was granted FDA approval for commercial marketing. I have reviewed this trial before, with the somewhat snarky title “Facelift for bendamustine”. The title alone should give you a hint about my feelings on the subject.
Here are quotes from Terry’s blog, reproduced here with his permission. (The highlighting is my contribution). Please read the last paragraph carefully, if you are considering this drug in the near future.
“A paper has appeared in the J Clin Oncol comparing Bendamustine with Chlorambucil in untreated patients with CLL. It shows Bendamustine to be much better than Chlorambucil, but can we believe it?
The trial was conducted by a group of hospitals in Austria, Bulgaria, France, Germany, Italy, Spain, Sweden and the United Kingdom, though the names of the authors do not spring out as CLL experts apart from Marco Montillo from Milan. Very few if any of the patients came from the UK. The trial was funded by the manufactureres and marketers of Bendamustine. The statistics were designed by an outfit in Germany (DSH statistical services) with a record of designing trials in Homeopathy and the data were handled by Cephalon who market Bendamustine as Treanda in the US. In other words this was an industry trial. It is usual with industry trials for the drug manufacturer to pay the hospital participating a fairly large sum of money (perhaps 5000 Euros) for every patient recruited. Of course, I have no access to what financial arrangements were in place for this trial.
319 patients were randomly assigned to receive either Bendamustine or Chlorambucil (162 B, 157 C). The overall response rate was 68% for B and 31% for C. CRs were 31% for B and 2% for C. Median progression-free survival was 21.6 months for B and 8.3 months for C. As I said Bendamustine seems astonishingly better than Chlorambucil, though this does seem a very poor result with Chlorambucil, compared with say the LRF CLL4 trial.
Toxicity was worse with Bendamustine. Grade 3 or 4 adverse events occurred in 40% for B and 19% for C. This level of toxicity was regarded as acceptable. (Editor’s note: Please read about the FDA’s toxicity warning regarding bendamustine, based on post marketing reports.)
This paper is published in JCO which probably means it was turned down by Blood. The criticism which any reviewer would have made would have been that the dose of chlorambucil was too low. (Editor’s comment: Please read Terry’s blog for detailed analysis of the dosing issue)
So my original criticism stands – they seriously underdosed the Chlorambucil compared to what is optimum – just as the fludarabine and alemtuzumab trials did.Moreover they offer no description of modern prognostic markers – something I would regard as essential in a clinical trial in CLL. It may be that mutated and unmutated cases and del 11q and 17p cases were equally distributed among the two groups, but it may be that they weren’t. This might be another explanation of why the Chlorambucil patients did so badly.
The introduction to this paper perpetuates the story that Bendamustine has both alkylating agent and purine analog activities. It is true that it bears superficial structural resemblances to a purine analog, but I have yet to see convincing evidence that it acts as one. I still believe that Bendamustine is just a way of getting adequate doses of an alkylating agent into a patient.”
All too often, reports of clinical trial results have become a tool for “data management” (“lying” is such an impolite word, don’t you think? People can get sued for saying things like that!) by powerful and wealthy drug companies. Truth is a rare commodity, statistics are twisted out of kilter to make the drug under study look better than it is. A wag once described after the fact sub-set analysis as shooting an arrow at a dart board, then drawing a bulls eye around it. Drug companies are sore losers, as we have seen all too many times.
We have written before about straw-man comparisons. Bendamustine is not alone in getting FDA approval based on comparison to deliberately low ball dosage of chlorambucil, in poorly defined patient cohorts (no modern prognostic indicators reported). Campath as front-line therapy won FDA approval by using similar tactics, please read our article “Jumping the gun“. If ofatumumab had done the same thing, compared itself to low dose chlorambucil, I think it would have gotten FDA approval by now and not still hanging around waiting for a decision from that self-important body.
Money corrupts. And lots of money corrupts in lots of ways. Terry talks about recruitment fees paid to doctors for each patient they recruit into clinical trials. Let me tell you a story that will make you hesitate before you take everything your doctor tells you as gospel truth, sign up for any clinical trial he recommends without doing your own due diligence. Surely you do that much before you buy a new car, or do you just take the salesman’s word for it? How much more valuable is your life?
Let us take as an example of how corruption spreads. Consider a patient advocacy site on the Internet that has wide following, a ‘hypothetical’ patient advocate that interacts with thousands of patients and has a loyal audience in the CLL patient community. She may even have reviewed a clinical trial or two on her site(s), and by the process of her positive (or negative) reviews she may have actually influenced the rate at which patients were recruited (or not) into the clinical trials she reviewed. What is the market place price for her good reviews? How much money for a patient advocate that sings the tune her masters tell her to sing?
Here is how the calculation was done, quite recently. Let us say she does 5 clinical trial reviews per year, a low ball estimate. And by the power of her influence in the patient community, she is able to help recruit an additional 100 patients into each clinical trial. That is a total of 500 patients recruited, a huge underestimation based on what we saw happen after one of her recent reviews, perhaps of the NIH clinical trial.
Head hunters charge anywhere between $3,000 to $5,000 per patient recruited, that is the going rate these days in the USA. Yes Dorothy, there are shadowy companies that do nothing more than act as go-betweens, hard working “yentl” that negotiate with strip-mall oncology practices, recruiting their patients for large scale clinical trials funded by powerful drug companies that don’t want to have their name directly involved in the recruitment process. And yes, if you have enough money and influence, you can click your heels three times and recruit as many patients as you want, for any number of clinical trials.
Based on these numbers, our ‘hypothetical’ patient advocate can reasonably charge to the tune of two million dollars for each year of her service. She was recently offered 5 million dollars – but the contract required that she not disclose the outright sale of her websites (and her soul too, of course), that she continues to write under her own name (but of course, she will be writing what her masters tell her to write), and she will use “secretarial help” provided by the clinical trial recruitment company in answering hundreds of individual patient emails she gets each week. Sweet deal! She had no idea her soul was worth quite that much. If one is going to be a whore, I guess it is satisfying to be considered an expensive whore. I will leave it up to you to imagine what she told the recruitment company negotiators to do with their business offer – after all, we do insist on polite language on this website.
All too often, clinical trials are a necessary evil as far as drug manufacturers are concerned. Without positive results demonstrated in clinical trials they do not get permission to sell their products in the market place, no way to recover the huge costs of drug development, let alone make a profit. Does this tempt companies to bend the truth just a teensy bit? After all, they have costs to cover, profits to make for their share holders. There are documented cases of companies that fund 10 or so clinical trials; if nine of the trials show nothing positive for their drug (perhaps an anti-depressant), but one trial shows an advantage, the nine negative trials are deep-sixed, the single trial that showed positive results is given huge publicity. No harm done, not unless a bunch of depressed teenagers on their new miracle anti-depression drug commit suicide. “Guest” authors with status as international experts are often recruited to give gravitas and credibility to the industry controlled papers. Peer review process is subtly influenced by well chosen awards of grant money. I say again, money corrupts and large amount of money corrupts even more.
(Me, I am a cheap date. I am pleased that we were able to shut down donations for Updates back in June, six months from when we launched this site. We met our target for revenues for the year and I saw no reason to keep collecting money from you, merely for the sake of collecting more of it. We will re-install the donations button January of next year).
Do we need clinical trials? Yes, if we are to have any progress in treating this and other life threatening diseases, we absolutely positively must have clinical trials with well informed patients participating in them. Ahh. There is the rub. Informed consent is such a hard thing to come by. Trials are getting more and more complex, the science is mind boggling for the innocent layperson patient without a head for medical jargon. Even well meaning researchers find it is next to impossible to teach each and every patient they try to recruit, given the constraints on their own time. In any case, they are trained as scientists and physicians, not teachers trying to teach complex medical jargon to a bewildered and frightened patient audience. Patient information packages are put together by lawyers trying to protect their institutions against potential lawsuits down the road. What is the solution? How do we refrain from throwing out the baby along with the very dirty bathwater?
This is the role that is just right for honest patient advocacy groups, organizations that have no allegiance other than to their patient-members. At their best, advocacy groups can bridge the gap, be the truly honest brokers between the drug / healthcare industry and patient-consumers of their products. With the advent of the Internet and easy to use software, sites like this one can reach thousands of patients with each article. We can take the time to teach, we have terrific leverage, we are not too busy, we don’t have to worry about financial or professional repercussions, we can afford to be honest. Is it easy to do? No. Teaching complex ideas to a lay audience is never easy. But it can be done, if the teacher and the student are both honest in their efforts.
I have a real problem with groups that call themselves advocacy groups with undisclosed financial ties to the drug industry or “educational grants” that they receive. Perhaps their grants are truly unrestricted, no strings attached, no obedience expected. But at a minimum such grants and such ties should be clearly disclosed and highlighted for all to see. Please read the “About Us” section of this website and our “Mission” statement. My only allegiance is to you – no one else. The only money we get is from your voluntary donations. We do not accept a single dime, not a single free gift or boondoggle, no free dinners in expensive restaurants, nothing, nada, zilch from anyone remotely connected with the pharmaceutical or health-care industry.
I cannot guarantee you wisdom in my articles; my educational background, perspective and biases are clearly spelled out for your evaluation. You be the judge of my credentials. I can do no more than the best I can in reading the tea-leaves for you. But this much I can and do promise: I will never sell out, I will never break my promise to you on that front. When I switch off my laptop for good, CLL Topics and Updates will be mothballed; never sold to the highest bidder. As I said, I am a cheap date, and proud of it.