Randomized Clinical Trials: A Multiple Myeloma Patient’s Viewpoint
Adults with cancer enter clinical trials at a dismal rate of 3 percent or less, with even lower participation among minority populations. To improve this absurdly low number it is time that we look at this life-and-death decision from a patient’s perspective, a viewpoint that is rarely considered in trial design.
Cancer patients know they have a potentially terminal illness, have often failed first and second therapies, and are desperate for better treatment of their disease. Why wouldn’t they be clamoring to join trials in large numbers? Assuming they meet inclusion criteria, why wouldn’t the vast majority be anxious to participate?
Without answering those basic questions and making the process more focused on the needs of patients, clinical trials will continue to get inadequate accrual numbers.
One would think that the immediate intent of clinical trials is to help patients, but that is not correct. Trials are performed to answer specific scientific questions. It is wonderful if patients are helped, but the purpose of any given trial is to obtain a statistically valid answer to the question raised.
By the time cancer patients have failed their first or second courses of therapy, most have a good understanding of their cancer. They have searched the Internet, sought second opinions, and have definite ideas about their next potential treatment. These educated patients should be prime candidates for clinical trials.
Suppose a patient truly researched a potential new treatment and has found a trial utilizing the new agent. In discussing it with the principle investigator, imagine their profound disappointment when he tells them they have a 50/50 chance of getting the experimental treatment or the standard treatment for their second or third relapse. The principle investigator patiently explains that no one knows which arm of the trial will do better. In his heart of hearts, however, he has his opinion, and so does the patient.
Whether it is right or not, the patient has an opinion and that opinion should have standing! Give patients all known information to date regarding the experimental treatment, and let them decide which arm they want to be part of. Accrual numbers will increase dramatically with patients who finally feel empowered with some degree of control over the cancer inside them.
Yes, I know that is statistical blasphemy. Anything less than the gold standard, the randomized clinical trial, would not count as a proper trial. Bias would make the whole trial suspect or worthless. The trial would not have statistical validity. I have heard this answer dozens of times.
I have also watched dozens of good trials close early because they did not attract patients. At the 2010 American Society of Hematology meeting, there were at least 10 promising new agents for myeloma, but there are not enough patients attracted to the clinical trial process to even test these treatments.
As it is now, patients are left with the feeling that their clinician is offering them a choice of treatments based on no more than a coin flip—which is exactly what he or she is doing. When patients have strong feelings about what they want for their next course of therapy, it is no wonder that they are completely turned off by such an approach.
Cancer patients are more than experimental “subjects.” They are not lab animals who have no reasoning ability, but are humans who should be allowed to make their own value decisions—right or wrong.
Some patients will be willing to accept side effects and potential unknowns of the new experimental treatment. Others, however, will be quite content to be in the control arm and ‘stay with what is known.’
The decisions of both groups should be accepted, and their numbers should be added to the corresponding trial arms. After their choice of arm, they should be treated and followed just as if they had been randomized by computer.
Statisticians will cringe and say the whole trial is worthless, despite the fact that accrual numbers would soar.
Consider, however, the woeful ineffectiveness of our current clinical trial system. What good is a statistically perfect, well-designed trial if nobody shows up? Our current system is broken and needs new approaches to randomize patients based on their informed right to choose their own treatment. This profound decision affects their life and their cancer. Treatment should be their choice.
Having personally known myeloma for 13 years, I have definite opinions regarding what my treatment course number 5 will be when it is time to make that decision. Like so many of my fellow patients (97 percent), I would refuse to be randomized and leave this life-and-death decision to the flip of a coin.
To all who denounce such an unscientific approach, please outline an improved system based on a patient’s absolute right to choose his treatment. We can ‘think outside the box’ and use a different approach, or we can keep the same system and get the same results—3 percent participation with many drop-outs. Without a change, we will continue to observe that only a tiny minority of clinical trials open, accrue, close, and are reported in a timely manner with useful information for clinicians and cancer patients.
Statisticians can take nearly any set of numbers, apply their formulas, and make pronouncements regarding those numbers. I contend that they can also devise statistical systems that provide relevant answers to outcomes of trials that are based on the right of cancer patients to choose their own treatments.
Jim Omel MD is a retired family physician and 13+ year myeloma survivor who is active in many areas of cancer patient advocacy.
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Dr Jim Thanks for clearly explaining why patients do not enlist in clinical trials.
There is an alternative to the classical randomized clinical trials currently demanded by the FDA. Incidentally, getting a drug accepted depends on FDA approval and they want randomized clinical trials. The alternative is adaptive clinical trials. Here we are not trying to disprove a silly null hypothesis but rather we are looking for a change in the response or toxicity of the patient which then immediately triggers a change in dosing in the treatment arm. In other words we "adapt" the dosing and thereby the therapy to the patient. The pharma companies are trying desperately to get this approach accepted by the FDA since it dramatically reduces the costs and time to get new drugs on the market. The biostatisticans in the FDA are conflicted between their classical "unbiased" approach and the biased bayesian approach which is the foundation for adaptive trials. Let's hope the FDA consider the concerns of patients and starets running patient friendly,shorter and cheaper clinical trials. Then they will see the enrollment skyrocket.
Its all designed around managing the "placebo effect". For a patient who responds positively to a treatment or the thought of a treatment, they could care less.
When it comes to myeloma, the placebo effect question seems like a moot point.
I had to laugh along with Berenson's reply about placebo effect in conjunction with pain relief from kyphoplasty - he said he doubted it, but if there is one, MM pain patients would be quite happy with the placebo effect.
When it comes to chronic back pain from MM and compression fractures, I don't think the placebo effect is worth a second thought. Nothing makes much of a dent in that pain, thinking happy thoughts is NOT effective.
If it works against cancer, sign us up for that placebo right now!!!
I am recently diagnosed and just starting this fight, so filter my comments accordingly:
Is it not so that, regardless of whether one gets the "tested" or "control" protocol, one is nonetheless getting valid medical (I mean, surely the control group isn't getting sugar water)? Is it not also the case that, since one is in fact in a trial, one is likely to be getting somewhat more attentive care?
Hello John, Sorry you are now part of the "myeloma community". Your point is an excellent one and needs to be emphasized. There are no placebo trials in cancer treatment UNLESSS the standard of care, the current accepted method of treatment, is NO treatment. If you are in a phase II or III trial, you will either get the absolute best current accepted treatment, or you will get that same treatment PLUS the experimental drug or treatment. You will NOT get sugar water. My point is simply that if you CHOOSE to get the experimental treatment with possible benefit and possible added risks, you should be allowed to do so. By all means join a clinical trial, and yes you will enjoy the very best of attentive care.
I am thankful for the clinical trials. I have exhausted all other treatments and the trials are my next therapy. After two failed autos, multiple other failed chemo drugs and one recently failed allo with a matched sibling. Currently I am on Rev/Dex and it seems to be lowering my numbers for now. My doctor showed me the next few trials once the Rev becomes ineffective and they all seem to have limited space available, so timing will be crucial for me to get into one. Of course we could all defect to Europe where most of these drugs are already approved.
I don't care what side effects occur with the trials. I know I will not be given zippo treatment, it may be just the current treatment I am on and I know I will never receive just a placebo. Until then I still have hope that somehow my sister's cells will kick in and blast this nasty disease out of my body. Anything can happen. Never stay die! There is always something on the forefront or in someone's back pocket.
Side note, amongst all of this constant research and such, OMGosh is anyone as sick of TV and the royal wedding as I am!!!!
Something along the way has done something to my eye sight so I cannot see very well anymore, reading is very difficult, especially small print. I have seen an ophthalmologist at MD Anderson, who rushed in and out, for the first time I don't feel like I received the proper care, may have to re-visit my eyes.
Thanks all and may we all find some sort of remission, Tricia Rainier in Houston Texas.
So sorry to hear of all that you've endured with this awful disease, Tricia. I sincerely hope you and your doctor find an effective new treatment in one of the clinical trials for myeloma, and that you GET the new treatment (instead of the standard arm). You are right in saying that you'll never receive a placebo; that just isn't done in treatment trials. Good luck to you and thanks for writing.
Good point about approvals. All the work of the ICH with the point of having mutual acceptance of data yet that doesn't seem to happen very often.
Good thinking Dr Jim.My lovely Doc has fought Hodgkins Lymphoma for many years as has my Dr next door neighbour.These horrible blood cancers know no boundaries.I have a new Haematologist to look after me as Dr Margot is semi retiring.I had a good partial response to Velcade/Cyclophosphamide and Dexamethasone for very aggressive Stage III MM.This regime ceased after 12 months last October.Complicated by a double mitral valve replacement ,prior to chemo starting in September 2009,I was unable to produce sufficient stem cells to proceed with an autologous SCT.Being on regular warfarin coumadin my risk factor of blood clots was such that I opted out of the SCT.Early lumbar radiation treatment would not have helped the stem cell position and we decided that another stimulating factor may not have produced a better collection outcome.My best option then seemed to be a clinical trial which I had in my mind for some time.My M cells have doubled over the past three months so hopefully I meet all the parameters for my proposed trial to start very soon.The trial suggested and settled on is that with Velcade/Dex.and Panobinostat with a placebo.As you say,I hope to get the Panobinostat because I have had a good partial response to the other two drugs.At worst case I at least get my Velcade (which the Australian Government now has on the free list for both initial and follow up treatment). Australia's populationt is only a mere 22 million so it is the US Trial I'll be joining.Seeing the 3% figure you state makes me feel even better about joining a trial.I could request Government supply of Velcade and have my Health Fund and Government pay for treatment but I would like the opportunity at least of possibly receiving Panobinostat to help other MM patients and prolong my life beyond the two years I have had thus far.A fifty percent chance of receiving Panobinostat is better than nil,but if I could choose,I would elect for one hundred percent.Forget all the statistical 'hoo haa' about random samples and just have a 'plain old sample' that all people understand.Get some more patients into trials and hit this MM out of the ground for 6.
JB A 65yo from DOWNUNDER
Hello John, Myeloma knows no boundaries or socioeconomic limits. Glad you are getting Velcade "down under" and I hope you will be on the Panobinostat arm of the trial. I think you SHOULD be on that arm if that is your wish, but having the right to choose your arm is an uphill battle against statistical requirements. It is YOUR cancer and the decision for treatment should be YOURS, not a chance randomization. If you are willing to accept whatever treatment risks come with Panobinostat, I contend that you should be allowed to be on that arm. I think you would agree. Good luck to you.
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