How tarnished is the crystal ball?

financial conflicts of interestBack in October of 2010 I published a review of FCR versus FC study published in the prestigious journal “Lancet”.  This was a multi-center and large scale Phase-III study where patients were randomized to either of two groups.  Such double arm studies are considered as good as it gets in terms of credible clinical results.  Indeed, in this study the two arms were very well balanced and one can hope the results are therefore a simple case of apples to apples comparison.  The author list on the Lancet article was top drawer.  The article was introduced in an editorial in the same issue of Lancet by no less than Dr. Peter Hillman.  There was very little to dispute in the article, FCR was definitely better than FC.  Phew.  Finally we had clinical results we could hang our hats on.

Not so fast..

Did I ever tell you that nothing about CLL is either simple or straight-forward?  Consider yourself reminded about this simple fact of life.

In recent days there has been a huge brouhaha about the very same Lancet article.  Three Australian physicians raised the question of conflict of interest possibly contaminating the study results.  Since our very lives depend on how we interpret and understand the value of clinical trial results, this is no small matter for us.  Were there conflicts of interest?  Were the results compromised? What is a poor CLL patient to do / believe?  Here is a link to the story unfolding in the popular press, so you can read all about it.  The quote below captures the essential point of their complaint:

Associate Professor Ian Haines, of Cabrini Hospital, Melbourne, and two colleagues said they were concerned that 27 of the 32 authors of the research, published last October, had potential conflicts of interest, given they had declared financial links to drug companies, including Roche, which funded the study. One of these 27 authors was a paid employee of the company.

”The editorial writer shared the same potential financial conflicts of interest as 27 of the 32 study authors and appeared too enthusiastic in his embrace of the study with terms like gold standard, ‘heralds fundamental changes in management of CLL‘ and ‘landmark.”

A close knit community

What makes this unusual is that there was such a complaint in the first place.  Physicians and researchers tend to be a close knit community, with strong professional ties to each other.  By the time a researcher is acknowledged to be world-class, he would have worked in several research and clinical institutions, done post doctoral work in a couple more, shared authorship credits with many of his colleagues working in the same area, applied for grants from the same funding agencies.  CLL researcher community is not all that large.  Everyone knows everyone else, almost incestuous, you might say.

Rocking the boat is not one of the survival traits of researchers who want to climb the professional success ladder.  Even when they disagree with each other in public, the sniping tends to be subliminal or couched in such heavy jargon that mere mortals have no idea they are disagreeing about anything.  Public solidarity of physicians and clinicians among themselves is quite impressive, even if they indulge in snarky back-biting more often than you think.  Whistle blowers tend to be few, and most often they come from outside of the professional ranks.  That is what makes this particular situation somewhat unusual.

Conflict of interest

Let us look at the disclosure statement the authors provided at the end of their article. This sort of statement is now mandatory and none of the major journals will accept an article for publication without it.

Conflicts of interest

  • MM is a paid employee of Roche. MHa (also from Mundipharma)
  • CMW, JM, JC, JFS, UJ, and SS declared consultancy or boardmembership for Roche.
  • GHo declared board membership for Mundipharma.
  • MHa, BFE, JM, GHo (also from Mundipharma), GHe,JC, JFS, UJ, MT, and SS received payment for educational presentations for Roche.
  • GFR, CMW (also from German Cancer Aid), BFE (also from Mundipharma), JM, GHe, MB (also from Celgene and Bayer) JC, JFS (also from Bayer Schering), UJ, BC, MT, PS, TZ, HD, SB, MK, and SS received honoraria or grants from Roche, partly forserving as investigators in Roche-funded research.
  • KF, GFR, AMF, AW,CMW, BFE, JM, MHe, GHe, MB, JC, JFS (also from Bayer Schering),UJ, BC, ABe, MT, PS, DW, TZ, SB, MR, and SS received travel grants from Roche.
  • RB, UvG, PLZ, FCC, and ABü declare that they have no conflicts of interest.

With the exception of the five individuals cited at the bottom of the list, each and every one of the authors had financial and professional connections with Roche and other drug companies associated with this trial.

How unusual is this level of coziness between researchers and drug companies?

Not at all unusual.  Large scale trials such as this are incredibly expensive to carry out.  No one has the money to do them, unless they are supported by deep pocket drug companies.  And since drug companies are in the game to make money, their funding support is usually based on hopes that they can use the clinical information coming out of the trials to further their own marketing or in this case, getting regulatory approval for their drug(s).  Here is the disclosure in the Lancet article about who paid for the trial and what role they played in how the study was done.

Role of the funding source

“This trial was planned and initiated in 2003 as an investigator-initiated trial by the German Chronic Lymphocytic Leukaemia Study Group. Since 2004, F Hoff mann-La Roche assumed the sponsorship for this trial, because it intended to use the trial for the approval of rituximab at regulatory agencies. The sponsor was subsequently involved in the first and second amendments of the study protocol. The sponsor of the study was responsible for data gathering, and shared responsibility for medical review of the data with the corresponding author. The corresponding author was responsible for data analysis, data interpretation, writing of the report, had full access to all the data in the study, and had the final responsibility for the decision to submit for publication”.

Does this sound like a bit too much control over the process by the very companies that stand to make a lot of money from the results of the trial?  You betcha. Is this out of the normal way of doing things in today’s marketplace?  Not at all.  Folks, this is how sausages are made, whether you like the process or not.

Editorial

The level of conflicts of interest in the Lancet article are not all that out of the ordinary, what is unusual is that it has been called into question.  Take away the profit motive, take away drug company money to do research and carry out expensive drug trials, and that will be the end of new drug discovery process.  That is the simple truth of the matter.  No money, no new drugs, no improvement in the lives of patients.

I submit to you that clinical researchers are human beings, like you and me. They are not monsters, nor do they wear shiny halos.  They put their pants on in the morning one leg at a time, just like you and me.  They have their pet peeves, their ambitions, their desire to do something worthwhile with their lives, be recognized for the work that they do.  In other words, a complex mix of altruism, selfishness, high minded desire to save lives and need for ego strokes – just like the rest of us.  One thing I can say in their favor: majority of them work awfully hard, putting in long hours each and every day over many decades of their lives.  Depression and thoughts of suicide are apparently quite high among physicians, especially so for oncologists.

I do not believe the authors of this Lancet article sold their souls to Roche in the process of doing this study. Were they influenced to be overly enthusiastic in their support, perhaps without even being aware they were doing it?  Possibly.  When was the last time you were guilty of similar behavior in your own life?

All of us love conspiracy theories, finding villains lurking in the background that are taking the whole world to hell in a hand-basket.   There are plenty of real life villains, some of them are even medical researchers.  But I do not believe that was the case in this study.  At most, they may have been guilty of a bit of cheer-leading for the home team.  By the way, the home team was winning.  FCR is a good therapy option to have for our guys.

Can we afford to be purists in this game?  I don’t think so. Not unless you are willing to stand down in your quest for better therapy options, make do with fludarabine and chlorambucil from now on.  Right.  I did not think so.

Who do you think is paying for CAL-101 and the new generation of kinase inhibitors?  The drug companies who stand to make zillions of dollars if their bets pan out, that’s who.  Can you reasonably expect them to tweak things just a bit behind the scenes, if they can possibly get away with it?  I would be surprised if they did not.  When “Genasense” failed to win FDA approval, I got several emails and even a couple of phone calls from the CEO of Genta – to see if I was willing to do a bit of rabble rousing in the patient community, help push the approval through.  Frankly, I happened to agree with the FDA on this call.  After the fact subset analysis does not meet the smell test and that is all that Genta could point to in favor of “Genasense”.

Will researchers who took the lead in these trials and have a lot of time and effort invested in them be tempted to overlook “minor” deficiencies in the drugs under study?  I expect so.  Does Cal-101 work only on lymph nodes and blood counts or does it also work on clearing out bone marrow infiltration?  This issue has been debated on this website as well as others.  Researchers have side-stepped this question as not really important.  I beg to differ. Bone marrow clearance is an important issue; perhaps a second drug in combination with CAL-101 will be needed to achieve it.  All this and more will be debated and tested in the months and years to come.

Some of our more hasty members want the FDA to approve all drugs as soon as they clear very preliminary early stage studies.  I can understand their need for haste, they feel they do not have the time to wait.  Their lives hang in the balance.

But sad as it may be, public policy cannot be made on the basis of single individual needs.  Compassionate use programs may be advanced to take care of special needs, but I would be strongly against taking away the power of regulatory authority and oversight when it comes to drug approvals.  There is too much money riding on these decisions, too much power and capitalistic greed.  We badly need a few protections watching out for us, make sure there is more truth and less hype in the drug approval process.  Brakes are needed even on the sexiest of cars.  Time for reflection, debate, looking things over by fresh pairs of eyes – all of this slows down the process.  But it also protects us from runaway disasters that have done so much harm in the past.  Just look up “thalidomide babies“, to see the harm that can be done when drugs are approved / prescribed too quickly. It is estimated that around 20,000 children were born with horrific abnormalities.

Maybe this is the reason why we need patient education and advocacy websites – someplace you can go to try and understand what is going on, where some of the jargon is translated into normal English.  Not every CLL patient has science education, not all of us have the time to sort through hundreds of professional journal articles each month.

Patients facing tough therapy decisions are not always the most objective of people.  Often they are too needy, too scared, too prone to post-purchase regret if things don’t work out the way they hoped.  Should you bet the farm based on a single anecdotal story of a patient who is unhappy with the remission he got?  Are heavy-handed attempts of “true believers” of herbal healing to proselytize others to their way of thinking any more dependable?  Beware of hidden agendas.  Conflict of interest does not always mean big $$ signs.

My potential conflicts of interest

Since we are discussing potential conflicts of interest, it is only fair that I disclose my personal conflicts of interest.  Here they are, every single last one of them.

  • Money received as honoraria from pharmaceutical industry: $ 0.00
  • Research grants from anyone: $ 0.00
  • Educational grants from anyone: $ 0.00
  • Board memberships: none.
  • Advertisement revenue: $0.00
  • Stock ownership:  200 shares in Genmab (original owner of ofatumumab).  I bought these shares in 2006 in a fit of solidarity because PC had responded so nicely to ofatumumab.  So far I have lost $3,946.18 on this lot (hey, never said I was a good stock picker!)  but I have not had the heart to sell these 200 shares.
  • There have been no expense account lunches, no golf trips, no all paid trips to attend conferences. The only exception was when I attended the CLL patient advocacy meeting in Canada in 2009.  The organizers paid for my tickets and hotel charges. There were no guest speaker fees.
  • Every dime we get comes from you – our generous members.

You may question my hard nosed attitude, my take on alternative medicines etc.  But monetary conflicts of interest is not one of the issues.  I read the full articles, try to sort out the methodology and results to the best of my ability.  Often I come away less than impressed (as in the case of a recent review of FC + Campath study for previously treated patients), pissing off a few people in the process.  Sometimes I am happy to be proven wrong.  I was not an early fan of FCR, I did not think this high impact combination had enough positives to off-set the admittedly high toxicity.  More recent work (including the work reported in this Lancet article) has convinced me otherwise.

How much of the hoopla do I buy?  I try not to get too sucked into it. But you would be foolish if you thought I was entirely unaffected by the verbiage I read in articles and editorials extolling them.  I too am guilty of using “gold standard” to describe FCR, more than a couple of times.  The best I can promise you is that I try to be as objective and fair as I can in my reading of the tea-leaves.

If you are looking for an honest reporter that does not benefit financially from the healthcare industry, you have found one. If you are looking for an all-knowing and eternally wise seer that has all the answers to what ails you, keep looking. I don’t fit the description.

pinocchio