Wednesday, January 13, 2016

The Problem with Clinical Trials


While the clinical trial I participated in probably saved my life, the truth remains that clinical trials are very poorly run often using drugs known to be ineffective as benchmarks, costly to PATIENTS (in time, treasure, and lives at risk), fail to focus on the individual, lack transparency, frequently apply results in a rigid, pseudo-scientific manner by drug companies and the FDA alike, and the role of the NIH produces more questions than answers.  Opdivo's latest approval is one more example of both the wonder and sad realities of FDA approvals and Big Pharma.

Clinical trials are designed to answer questions about the effectiveness and safety of drugs.  However, trials...set up by medical researchers, institutions, and pharma....utilize rigid old-school statistical methodology that fails to allow a comprehensive look at data from multiple trials and more often than not, pits older, clearly ineffective drugs against new, obviously superior ones.  Rarely are top shelf drugs placed one against the other.  In melanoma world, interferon and dacarbazine have been the benchmarks against which everything from ipi to anti-PD1 to BRAF inhibitors have been placed.  Why?  In very preliminary testing all three of those drugs/categories were superior by miles.  This approach wastes time.  Time in which real people suffer and die.  Meanwhile, the FDA takes clinical trial design as a literal reflection of the real world.  Obviously, it is not.  And all of this begs the question:  Who are these trials designed to help?  Patients?  Or Big Pharma?

For instance, in the latest Opdivo approval, only patients with BRAF wild type mutation can utilize the drug as a first line option.  Folks with BRAF positive lesions are still relegated to trying ipi and failing, then BRAF inhibitors and failing, before advancing to Opdivo.  Why?  Multiple studies clearly demonstrate equal effectiveness of the anti-PD1 drugs no matter BRAF status.  But, the FDA's commitment to basing approvals entirely upon the trial at hand dictates this "logic".  The trial upon which this approval was based used only BRAF wild type patients...so that is how Opdivo was approved.  All other concomitant trial results be damned.  So?  Does pharma set trials up this way so that older drugs must continue to be used?  So that coin for those treatments can continue to fill their coffers?  Now, will docs allow their patients to suffer through greater side effects and a decreased rate of success by prescribing ipi first, rather than trying one of the anti-PD1 products?  Will insurance companies prefer to pay for a drug that helps fewer patients and causes more complications that they will also have to put out money to take care of, only to have to pay for the NEXT drug as well?  Time will tell.

The FDA's tunnel vision and literal interpretation of singular trial data one by one is the equivalent of this scenario:  Say a trial for a new drug to treat fractures is set up so that it allocates patients with left arm fractures to the test drug and those with a right arm fracture to an old one.  Miraculously, the folks given the new drug for their left arms were healed within days while those with right arm fractures derived no benefit from their drug.   The FDA approval comes out as:  This amazing fracture drug is now available!!!  BUT....only for folks with fractures to their left arms!  Pretty silly, right?  Yet, that is the system we currently embrace.  Obviously, when only one type of trial or circumstance of use is available for a drug in question, that is the way it should be approved.  However, when other data exists and common sense dictates what is good for the left arm is also good for the right, that information should figure into FDA approvals.  To do otherwise makes trial development look as though it was designed for niche marketing rather than improved patient health.  An argument can easily be made that the primary focus of clinical trials and FDA approvals seems to be to produce proprietary treatments for big profits rather than a cooperative effort to help as many individuals as possible.

Then we have the poor little rich pharma companies, complaining of, yet endlessly touting, their exorbitant research and development costs.  First of all, the figures touted are much inflated.  Numerous studies, including one recently out from Doctors Without Borders, dispute and provide clear evidence against Big Pharma's numbers.  Secondly, ratties (and their insurance companies) pay for much of the research.  Clinical trials are not free!!!  I paid for everything from scans to needles to tubing to lab to doctor visits to transportation to institutional charges for bed space and nursing services.  BMS provided the drug and a few "research labs"....period. Thirdly, Big Pharma receives federal support in the form of research grants from NIH that provide the nidus of basic discoveries.  And guess who pays for that?  YOU!!!  The taxpayer.  And fourth, Big Pharma makes humongous profits...billions of dollars.  Do wall street reports talk about major pharmaceutical companies operating in the red?  NO!!!  They report financial gains and incredible mergers like the recent purchase of  Allergan by Pfizer for 160 BILLION dollars!!!  See what I'm saying?????

In order to be of real benefit and utilized by science for the good of all, it is essential that data and information gleaned from clinical trials be transparent at all levels.  Patients need, deserve and have a right to their OWN information.  All clinical trial information should be readily available to all trial participants.  However, this is not how it works.  Doctors withhold information to protect themselves and sometimes under the erroneous assumption that they are protecting the patient. Pharma withholds information because they think they OWN it.  I have never been told, nor have any of the other ratties in my trial, the results of our PD-L1 testing.  This is important stuff.  The rattie needs to know anything that is learned about them.  It may impact later treatment options or choices they make. The data needs to be readily available for other researchers, too - even if they work for different organizations.  A different set of eyes may find patterns and trends not apparent to the initial investigators, thereby elevating what is 'known' to a new level.  Even failed or negative study results need to be available.  People died for it.  Think of the data you have learned in your own life experience.  I know I certainly learned as much from my failures as I did from my successes!!!  Yet, almost 50% of cancer trial data goes unpublished!!!  Here's a link to that report:  Almost 50% of results are NOT published - 2013
 
So, why is everything a secret? Trial information is proprietary so that Big Pharma can protect their market share and inflate their bottom line or the drug price.  It is proprietary in order for researchers and their institutions to protect future patent rights, potential material gains, both financial and in PR.  It is proprietary to produce big profits, promote careers, and effectively block cooperative efforts that would ultimately help as many individuals as possible at the least cost....in dollars as well as suffering.

The monolithic system in which current clinical trials operate, under the banner of "safety and science" while more often seeming to advance proprietary products for profits, needs to give way to the humanitarian system of creative thought, mutual aid, transparency, and the commitment to the individuals affected - each and every one.  Many will still suffer.  Some will die.  But in an open system, where reasonable drugs are used as comparators, ALL data is available for ALL to see (the good, the bad and the ugly) all of us....researchers, institutions, Big Pharma, and Ratties... will be doing their best for each other.

Wishing you all my best, Les....Rattie, Mom, sister, friend, Pediatric Provider, researcher, and Melanoma survivor for almost 13 years with great help from my dearest love and coauthor - B....Daddy, care giver, friend, Pediatrician, linguist, researcher.....with a combined 71 years between us, spent in the care of children and their families.

5 comments:

  1. Absolutely editorial post regarding the current state of clinical trials...have felt similar sentiments, though not so eloquently, over the last few years. Have a few initial comments:
    a) how would a humanitarian update to current public policy being codified and executed? When dealing with often complex subjects related to health I think one of the challenges is to translate the intended outcome into rules and procedures that people administering the process (eg FDA largely) can follow. Hear I think there would be no substitute for a "human in the loop." E.g. a doctor and/or team of doctors that are not in the pocket of any vested interests but could, through given authority, exercise things like reason and common sense. I won't pretend to know the inner workings or key players in the current system. There may be rules that govern or call for just that, but are not being exercised. If that is the case, shame on them. There's a ton of money involved no doubt, but there are also a ton of lives at stake too. If I remember correctly, we are talking a yearly death toll just in American lives that is three time comparable numbers of the victims of 911.
    b) Talking about open systems, in which information is freely exchanged, one of the true heroes in the arena of melanoma advocacy and change died yesterday, Susan Steel. Susan founded Skin of Steel in an effort to establish tissue banks across the US in which researches could freely share and exchange information regarding their work with sample tissue. These same kinds of banks, started by patients and not the gov or big pharma, have resulted in tremendous advances in breast, colon and lung cancer. God bless you Susan and thank you. http://www.donnellanfuneral.com/memsol.cgi?user_id=1732263
    c. One thing I have thought for awhile is that, in particular with the burgeoning numbering of treatment options, is that somebody should be investing more in diagnostic or screening technologies and tests for the drugs available. E.g. before you make my a your guinea pig, tell me if this drug is even going to work or might possibly work. There are companies that offer avatar services now (eg grow my cancers in mice and test against available meds, look for potential weaknesses in my strain of cancer) for $10-20K. Why shouldn't or wouldn't all insurance companies want to invest or insist their patients do this. As an engineer, I can tell you we would lose our jobs if we ever sent out a fix to the field that was not properly tested first in a lab. Why not apply the same logic to this? Why not invest the money to develop better and better screening for PD1, PDL1, yervoy etc. There is some going on, but in my mind that would be a game changer.
    d) Finally, my advise (and hope I don't need to participate in any of these again) to anyone that draws the short stray for some old school chemo instead of the fancy new immune therapy or whatever is 'walk' or better 'run.' Until the gap in efficacy gets closes between options presented that's the right thing to do, science be damned (instead of 'you').

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    1. How do you know you've drawn the short straw?

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    2. Carolyn, I think Leland is referring to when, in a clinical trial, you are assigned the lesser drug, like dacarbazine or interferon or nothing, rather than the treatment drug. Today there are too many more effective drugs on the market to accept a drug that is known to be less effective than those. However, when poor ratties have already utilized the "better" drugs without the desired effect, then more experimental drugs and treatments become a necessary evil should you wish to continue to seek care! It can all become very difficult indeed. That is why the entire clinical trial system needs to be improved with greater transparency for all concerned.

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  2. Agree, and yes that is what I meant to say, typos and all...just re-read my comment...man I need an editor. 0-;

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  3. the problem is as you so eloquently put it - is that there so often is NO EQUIPOISE - we knew on both my husbands trials which arm we hoped to be on BEFORE starting - until patients vote straight away with their feet and leave a trial when it is not giving them what they need , we will continue to see poor trial design and fall victim to them : I like to quote Article 8 of the Helsinki Declaration "While the primary purpose of medical research is to generate new knowledge, this goal can never take precedence over the rights and interests of individual research subjects."
    Thanks as usual a great piece !

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