Respectful Insolence

Until recently, most of my research was laboratory-based. It included cell culture, biochemical assays, molecular biology, and experiments using mouse tumor models. However, one of the reasons that I got both an MD and a PhD was so that I could ultimately test ideas for new treatments on patients and, if I’m good enough and lucky enough, ultimately improve the care for cancer patients. If there’s one thing, though, that I’ve learned in my nearly nine years in academic surgery, it’s that far fewer patients end up enrolled on clinical trials than are eligible to participate in them. Every meeting regarding clinical trial accrual I’ve ever attended, or so it seems, concentrates on how disappointing accrual has been or how accrual has been flat or even declining. That was especially true at my first job post-training, although it is less true at my current job, mainly because the clinical trial office there is superior to that at my old job.

So it was with great interest that I saw this article in the Los Angeles Times that acknowledged a problem that those of us in academic medicine have known about for years:

A year ago, U.S. researchers launched what they deemed a high-priority study to determine if women with an often-fatal type of breast cancer could live longer by taking a specific combination of drugs. If the study found that to be true, the average rate of survival — four years — could be significantly extended.

A worthy question to address? It would seem so. But the answer may be a long time coming.

The U.S. arm of the international trial got underway nine months behind those in other countries. And researchers now expect to enroll only 350 U.S. patients of the original 3,500 sought.

Before drugs and therapies to save lives or reduce suffering can reach the market, they must be tested to ensure they’re safe and effective. But the reluctance of Americans to participate in clinical trials has been a serious drag on medical research.


The irony of this problem is that we are in an unprecedented era in which the fruits of science are producing potential therapies at a rate not seen before: biological therapies, gene therapies, new drugs, and even new genetic tests that can predict disease or response to therapy better than ever before:

“It’s sort of ironic that there are more compounds available to study than ever before, and most are based on some new scientific principles, yet we are still having trouble recruiting participants,” says Diane Colaizzi, executive advisor of the nonprofit Coalition of Cancer Cooperative Groups, founded by research groups to promote study participation.

Actually, it’s more than “sort of” ironic. Only about 5% of patients who are potentially eligible for clinical trials actually participate in them–and that’s just patients seen at academic medical centers, where the bulk of clinical trials are up and running. If you count patients being seen in the community by private doctors who don’t enroll patients on clinical trials, the actual percentage of patients who participate becomes very tiny indeed.

I can’t understate how much of a problem this is. Although from my position it’s tempting to blame increasingly onerous federal regulations, I rather suspect that that is a relatively small contributor to the difficulties. Moreover, although there is a fine balance between too little regulation such that patient safety is compromised and so much regulation that clinical trials become so expensive and onerous that more and more physicians don’t want to put themselves through the pain of doing them, patient safety must never be compromised. True, no system designed by humans is perfect and there will always be some degree of risk in a clinical trial. After all, if we knew how an experimental drug will work and what its risk profile would be it would no longer be an experimental drug. However, we must do what we can to minimize that risk; so whatever we do to try to increase clinical trial accrual, it must not involve doing anything that might jeopardize the human subjects protections built up over so many years. If we do, we risk more problems with clinical trials that result in patient harm, each of which does more damage to efforts improve clinical trial accrual than almost anything else.

One of the reasons for this problem, unfortunately, is that patients don’t understand what modern clinical trials are about. There seems to be a persistent belief that participants in clinical trials will be randomized to groups that receive a placebo. For most treatment trials that just isn’t true anymore. In cancer, for instance, most clinical trials test the standard of care versus the standard of care plus the new drug. Medical ethics for human subjects research, as set forth in the Helsinki Declaration and the Belmont Report, demand no less. Indeed, if I may digress a minute, this fundamental misunderstanding seems to be what leads the antivaccine movement to be so obtuse when it comes to their insistence on a “vaccinated versus unvaccinated” trial. Either they are too ignorant to understand that it is unethical to give anything less than the standard of care to persons participating in clinical trials, or they have a superficial understanding of how clinical trials are done that leads them to believe that only a double-blind, randomized placebo-controlled clinical trial is the way to answer a question. In a world of pure science, that might be true, but ethics limit how purely we can apply the scientific method to human subjects participating in clinical trials. Unfortunately, as similar misunderstanding seems to lead all too many potential subjects believing that by signing up for a clinical trial they might risk receiving placebo only.

Of course, that this is true is clearly a failing on our part as clinicians and scientists. It’s also a failing among us that, as the article points out, some centers are simply trying to treat patients more like human beings as a strategy to improve clinical trial enrollment rates.

We have a saying in oncology that clinical trials represent the best patient care. Although there is some risk in the experimental arm, overall the benefits of clinical trials outweigh it. Indeed, a well-respected oncologist and former cancer center director who used to be one of my bosses liked to say it all the time, and there is evidence to suggest it:

The one area of medicine in which clinical-trial enrollment is relatively common has positive results to show for it. In pediatric cancer centers, more than 60% of children receive experimental therapies. That decades-long practice, which began out of desperation to treat children who would otherwise die, is now credited with vastly improved rates of survival, such as the astonishingly high cure rate associated with childhood leukemia.

“I think the real issue here is that in adult medicine, the clinical trial process is not an integral component of the entire treatment paradigm,” Comis says. “What we’re trying to do is make it more mainstream.”

It may be difficult to translate the success in pediatric cancers to adult cancer and adult diseases, however. The reason is that pediatric cancers are relatively rare, and there are relatively few centers that have the expertise available to treat them. It’s therefore much easier, given the small number of patients and the horror of pediatric cancers, to entice parents to enroll their children in such trials.

However, one example doesn’t demonstrate that clinical trials provide in general the best care; so let me explain why we in academic medicine generally think that the participation in well-designed clinical trials represents the best possible care. One reason is, as has been explained, that no group gets only a placebo, except in the case of prevention trials or, far less commonly, in treatment trials for which no effective treatment exists. Medical ethics has evolved to the point where a placebo control is considered neither necessary nor ethical in most cases; new modalities must be tested against or with the standard of care. Another reason is that patients in clinical trials are followed far more closely by far more people than most patients undergoing standard therapy. The protocol must be followed, and there are people there who make sure that the doctors and nurses actually do follow the protocol or explain why they don’t think it’s appropriate for an individual patient. In other words, because of the weight of human subjects protections, arguably the chances of medical error tend to be lower.

Other strategies being tried are databases that patients have access to, including ClinicalTrials.gov, TrialCheck, and BreastCancerTrials.org. Future efforts will lead to linking up electronic medical records to such databases so that potential subjects can be identified:

The databases are only a first step. As electronic medical records become the norm, researchers hope to tie the records into an automated clinical trial matching system that will alert doctors and patients alike. One company, Impac Medical Systems of Sunnyvale, Calif., offers this service to oncology practices that use its health records software. After a patient’s health record has been entered into a computer, the software searches TrialCheck to see if that person may be eligible for clinical trials.

Comis describes the ultimate goal for patients: “They will have access to their own health records and they can say to their doctor, ‘It says here I’m eligible for three studies. Why didn’t you talk to me about that?’ “

However, perhaps the most important reform that could help boost the number of patients willing to sign up for clinical trials is the following:

Researchers and patient advocates in various states are also fighting for federal legislation that would require insurance companies to pay for the patient care involved in clinical trials, following 23 states — including California — that already have such laws. The federal bill was developed specifically to address enrollment in cancer trials, which make up a majority of clinical research. Called the Access to Cancer Clinical Trials Act, it was introduced by Sen. Sherrod Brown (D-Ohio) last year and is before a House committee.

Though the research sponsor, such as a drug company, usually provides the drug or therapy free of charge, some insurance policies don’t pay for care, such as blood tests, scans or examinations, linked to the treatment, says Dr. James Thomas, director of clinical trials at the Ohio State University Comprehensive Cancer Center.

This is not requiring insurance companies to pay for experimental treatments. Rather, it is requiring them to cover accepted medical expenses that flow from clinical trials. Given the potential benefits in terms of better treatments, in the long run this could end up saving insurance companies money, although it would admittedly cost more up front and any cost savings possible would be in the long term. It would greatly streamline the process of clinical trials by eliminating the need to try to parse what blood tests (for example) are being done for the trial and what tests would be done for routine medical care.

Clinical trials are, as I have said before, where the rubber hits the road for science- and evidence-based medicine. Without well-conducted clinical trials, all that elegant science, all that hard-won understanding culled from biochemistry, molecular biology, cell culture experiments, animal experiments, and early measurements in humans will be for naught. All that science has to be tested in humans to see if it actually works. If we don’t find a way to persuade more people that it is in their best interest to participate in clinical trials, we cede that ground to Europe, whose human subject protections are every bit the equal of ours, but whose academic medical centers appear better able to persuade patients to enroll in clinical trials, an advantage that might have something to do with nationalized health care systems and centralized databases. Worse, we encourage drug companies to look elsewhere for subjects, and they are doing exactly that–in China and Third World Countries, where the human subjects protections are–shall we say?–a bit more lax than they are here. If we cannot do the clinical trials, we risk being unable to capitalize on the promise of science- and evidence-based medicine. We’ll in essence, have all these neat new treatments, but no way to determine if they’re actually better than our old treatments.

Comments

  1. #1 Mu
    March 17, 2009

    Orac, even without the placebo involved, in many cases the “standard of care” is little better (pancreatic cancer seems to be a death sentence within a couple of years for example). So enrolling in a clinical trial with randomization means a 50/50 shot at being dead in 2 years anyway, just from the luck of the draw. Somehow it’s not a comforting feeling to know you were instrumental in beating a cancer by dying for the control group. People desperate enough to enroll in a clinical trail want at least the assurance that they actually are getting a chance of a cure.

  2. #2 D. C. Sessions
    March 17, 2009

    this fundamental misunderstanding seems to be what leads the antivaccine movement to be so obtuse when it comes to their insistence on a “vaccinated versus unvaccinated” trial.

    Cut them some slack on this one, Orac. From their perspective, the unethical part isn’t the “no vaccine” branch, it’s the active vaccine branch of the study. Admittedly it takes a powerful Reality Distortion Field to get there, but they manage it.

  3. #3 Scott
    March 17, 2009

    An important post on a topic that will influence our success in improving cancer treatment outcomes.

    In Ontario we use participation in clinical trials as a quality indicator for the cancer system. We compare different regional cancer programs against each other to promote recruitment and participation.

    The data suggests this approach may be having some success:

    http://www.cancercare.on.ca/english/csqi2008/csqievidence/csqi-clin-trials/

    My sense based on your post is that there is no overall strategy for enhancing participation. Granted this is much more difficult given the framework of cancer treatment in the U.S.

    It’s odd that insurers are reluctant to fund supportive care costs. They’re saving tens of thousands of dollars on the cancer drugs that they would otherwise have to fund.

  4. #4 David
    March 17, 2009

    an excellent post. as a physician at a pharmaceutical company, I am daily faced with challenges in recruiting patients into trials.

    Academic medical centers no longer have a monopoly on clinical research. Increasingly, there are private practices that either conduct sponsored clinical trials as a part of their practice, or as their sole focus. Almost always, these practices execute trials faster and cheaper than academic centers. Whether their quality is comparable is open to discussion. Academic centers have a lot of work to do in improving responsiveness, turnaround time at local IRBs, indirect cost structures, and (especially) slow recruitment. Without performance improvements from academic centers, clinical research will become a commodity, and ultimately will be outsourced to third world sites. This trend has already begun. See NEJM 2009, v360(8)p816.

  5. #5 Mandos
    March 17, 2009

    Orac, I’d like to follow up on the insurance point. To what extent might the exigencies of the American health care system (private insurance, relative uncoordination) be the reason for which private practice doctors don’t collectively strive as much as they could to enroll patients in clinical trials?

  6. #6 Ramakrishna
    March 17, 2009

    I have read this article in Los Angeles Times and my comment is that because of the reluctance not just in the US but other countries and the advantage of low costs clinical trials are being outsourced to poorer countries like India where legal and ethical standards are less rigid. Compensatory mechanisms if injury occurs are not in place. The population is economically weak and illiterate.

  7. #7 Dan Weber
    March 17, 2009

    I guess I didn’t know much about clinical trials. I assumed that the clinic would cover all of my health care costs related to the trial, especially the lab tests to find out what their stuff is doing to my body.

    I surely appreciate the desire to push the costs of the trial onto someone else. That will make the effort (look) cheaper and make it more likely to happen, which is good, as long as we pretend that the people we’ve pushed the costs onto don’t exist.

    For legislation, I’d like to see a safe-harbor provision for people enrolling in clinical studies. I should be able to leave my participation in a clinical study off of my life insurance or health insurance application. If this participation makes me more of a risk (or more costly, which will surely be the effect of Sherrod Brown’s bill), I should be able to keep that information from them.

  8. #8 David C. Brayton
    March 17, 2009

    @David. Excellent post. Having worked at a medical device company and having served on an IRB, I’ve seen exactly what you are talking about from both sides. Typically, the more prestigious the academic center, the more bureaucratic, slow and expensive it is.

    Back to Orac’s point. I agree that clinical trials are generally the best care available because discipline is enforced on both the patient and practitioner.

    But the decision to participate in a clinical trial is very complex. Certainly, the fear of getting a placebo (i.e. no treatment whatsoever) is a big factor. But patients are weird (i.e. they’re human). Their decision calculus is all over the place. But the bottom line is that they are scared and when people are scared, they are risk averse.

  9. #9 Lee
    March 17, 2009

    Maybe participation would be greater if participation weren’t so difficult or frightening. My mother, who had frontotemporal dementia, was asked if she would participate in a study at the University of Michigan (where she was diagnosed) on the very day she (and we) got the official diagnosis — telling my Mom she would be getting one free MRI per year. That alone scared the hell out of her and she refused (even though we would have done anything to facilitate her participation) because nobody at U-M before, during, and after her diagnosis ever explained to her or to us what was going on, what the tests meant, whether tests hurt or not, what the options were, what the study entailed, etc. U-M might be able to diagnose neuro ailments, but the clinicians are not doctors in the sense that we received a diagnosis but absolutely no care or help finding care from them — perhaps if we had, we would’ve had a reason to talk Mom into participating. But we had no evidence from U-M neuro that they would or could do us any good, or were concerned about the patient rather than just the data, so why bother? They don’t practice medicine, they run tests and give labels to the test subjects and then are disapproving when a patient (and her family) are so reeling from the diagnosis that they refuse to participate in something that’s “for the good of science.” (Oh, yes, I’m still bitter about the whole experience.)

    Then there was a study by the NIH, which involved a trip to Maryland and numerous tests. Getting Mom from her home in Oscoda to Ann Arbor was hard enough — we were supposed to drag her to Maryland, stay several days, and subject her to tests that terrified her? After our experience with the clinicians at the University of Michigan Medical Center, forget it. If they could’ve made arrangements for Mom to be tested closer to home, we would’ve made the effort — after all, she has six kids and we’re all at risk for developing FTD ourselves, so why wouldn’t we encourage her participation — as long as it wasn’t abusive to Mom.

    Then there’s a clinical trial for psoriasis that I might’ve participated in. But it was too difficult to get information and then it was too difficult to travel on THEIR schedule, which would’ve involved traveling two hours to get to a town 20 miles away (we have brutal rush hours here in Southeastern Connecticut) instead of scheduling my appointment for I time I could get there in 20 minutes. It was too inconvenient for them. It smacked more to me as if they were interested in conducting their study at the lowest cost possible so they could make the most money possible from whatever pharmaceutical company was funding it. That may have been wrong, but that’s how seemed to me at the time.

    If clinicians are so hard up for participants, maybe they should take a look at 1) how they treat potential candidates and 2) how easy they can make it for candidates to participate. Maybe they should be physicians first.

  10. #10 Karl Withakay
    March 17, 2009

    Mu,
    In your scenario, given S.O.C meaning near 100% chance of death in 2 years, enrolling in clinical trial is not a 50/50 shot at being dead in 2 years anyway, unless the experimental treatment is know to have a 100% chance of extending life beyond 2 years (which if already established, would require a post approval surveillance trail, not a double blinded trial.)

    In the trial, you have a 50/50 shot of receiving the experimental therapy, which may or may not make a difference, that’s it. The purpose of the trial is to determine if the exp treatment is effective, and if so, how effective.

  11. #11 Karl Withakay
    March 17, 2009

    Is it not also acceptable to use a true placebo group where non-treatment is acceptable, that is where there is no unacceptable/adverse outcome for withholding treatment, such as in mild headaches, non life threading allergies, etc? Otherwise how would one justify a trial of acupuncture vs sham acupuncture for something like treatment of mild headache without also including an analgesic like aspirin in both groups?

    Also, would I be correct in assuming that if a treatment’s viability is confirmed, there may be the possibility of studies to explore whether the treatment is sufficient on its own w/o the standard of care?

  12. #12 Mu
    March 17, 2009

    Karl, we’re talking about why so few people participate in the trials, and the question is – what’s in it for me, the patient? I only have one shot (unless I go the woo approach of shotgun cures) at beating whatever the trial is trying to cure. My motivation is – a chance for survival, which is why I sign up for all the problems mentioned in Lee’s post. Sure, it’s a chance only that the new stuff does what it’s supposed to be doing. But it’s better than nothing, what’s the SOC.
    As a chemist, it looks to me I’m better off getting my hand at an experimental drug then assisting in the randomized trial. At least I tried something. And in case I’d survive, I’d really annoy the hell out of Orac as “anecdotal evidence”:)

  13. #13 Grep Agni
    March 17, 2009

    I assumed that the clinic would cover all of my health care costs related to the trial, especially the lab tests to find out what their stuff is doing to my body.

    In the one trial I was involved in, a placebo-controlled test of lovastatin in patients less than 18 years old, all the blood tests, office visits, and parking were covered, and there was a small travel/lunch stipend as well. Apparently things are different in cancer studies.

  14. #14 Mark Hochhauser
    March 17, 2009

    As an IRB member for 14 years, there are a couple of omissions from this discussion. One is the possible role of “therapeutic misconception” in clinical trials by subjects who view a clinical trial as treatment–which it is not. Paul Applebaum and his colleagues have written extensively about this issue.

    Second, while oncology consent forms tell prospective subjects that medical care will be provided if they are injured in a clinical trial, many note that the subject’s insurance company–or the subject–will be billed for the cost of that treatment. Given deductibles and copays, subjects in clinical trials can be hit with pretty large bills if they’re injured in the trial. I suspect that as long as research-related injury costs aren’t covered by some sponsors that they’ll have a hard time recruiting subjects.

  15. #15 Karl Withakay
    March 17, 2009

    In your example, we are dealing with the rarer scenario where the S.O.C/Standard of Care offers no hope of improvement. In such a hopeless situation, participating in the trial offers the chance of receiving the experimental treatment (with the possibility of benefit), while opting out of the trial does not.

    I’m not sure whether you’re describing a scenario where one obtains the experimental drug used in the trial on their own outside of the trial, to avoid being in the control group, or a scenario where one goes out and obtains some other experimental drug outside of any clinical trial to guarantee access to a treatment beyond the SOC that may or may not have any benefit.

    Either way, it’s not a can’t loose proposition. You have to consider that, especially with an alternative drug, there is the possibility that by experimenting on yourself, you may be shortening an already short life even further.

    Let’s say hypothetically you are unaware that in addition to your terminal condition, you have impaired liver function. Let’s also say, that your experimental drug can affect liver function and is contra-indicated for someone who already has liver issues, and that the clinical trial would have eliminated you from the trial in the screening process. Let’s also say that you, being unaware of your liver issues, obtained the drug on your own, used it regularly, and died in 6 months due to liver failure instead of 2 years due to the cancer. Would it have been worth it to you and your loved ones?

    If you did survive beyond the expected 2 years, we would only know that you were not dead, and had exceeded all projections for your survival. We’d have no idea if your self treatment made any difference at all. Your anecdote would have next to no value for anyone.

  16. #16 Karl Withakay
    March 17, 2009

    Forgot to put that my previous post was a response to Mu’s last comment.

  17. #17 Rogue Medic
    March 17, 2009

    A few things that are a problem with research in some areas.

    If the standard of care is not something that has been demonstrated to improve outcomes (meaningful outcomes, such as leaving the hospital alive with a functioning brain), then there is a good reason to include a true placebo control. One example of this is resuscitation. There is no evidence that epinephrine, lidocaine, amiodarone, or the other resuscitation drugs that have become standards of care are as good as, or better than, not giving any medication. The drugs are better at producing a short-term pulse, but that is just treating the vital signs, not treating the patient. they are able to get a pulse back, for a short time, but they do nothing to improve survival. Yet it is only recently that we have begun to decrease the emphasis on the drugs and the tubes and the oxygen.

    For victims of witnessed VF arrest, prompt bystander CPR and early defibrillation can significantly increase the chance for survival to hospital discharge. In comparison, typical ACLS therapies, such as insertion of advanced airways and pharmacologic support of the circulation, have not been shown to increase rate of survival to hospital discharge.
    (Circulation. 2005;112:IV-58 – IV-66.)
    © 2005 American Heart Association, Inc.
    2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
    Part 7.2: Management of Cardiac Arrest
    Introduction

    Essentially, all of the patients receiving treatment that is the standard of care, unless resuscitated prior to receiving drugs, are receiving treatments with no evidence of benefit. It is considered unethical to deprive these patients of the standard of care, even though it is really just a huge uncontrolled experiment. These treatments are based on expert recommendations from 3 decades ago. Our understanding of pathophysiology has progressed, but our treatments remain stuck in the 70′s and 80′s.

    Recently, there has been a greater focus on continuous chest compression CPR. The acronym MICR (Minimally Interrupted Cardiac Resuscitation) is used for this de-emphasis on pharmacology and re-emphasis on compressions. Real resuscitation rates have tripled.

    Conclusions – Survival-to-hospital discharge of patients with out-of-hospital cardiac arrest increased after implementation of MICR as an alternate EMS protocol. These results need to be confirmed in a randomized trial.
    Minimally Interrupted Cardiac Resuscitation by Emergency Medical Services for Out-of-Hospital Cardiac Arrest
    Bentley J. Bobrow; Lani L. Clark; Gordon A. Ewy; Vatsal Chikani; Arthur B. Sanders; Robert A. Berg; Peter B. Richman; Karl B. Kern
    JAMA, March 12, 2008; 299: 1158 – 1165.
    Free (I think it is free) Full Text

    We need for the ethics committees to be looking out for what is best for the patient. In resuscitation research, they appear to have been the enemy of the patient, and the enemy of progress.

    Another consideration that has been brought up. How do you approach patients about participation? If the patients have misconception about the treatment they will be randomized to, that sounds as if they are not having the research explained by someone capable of explaining research to those unfamiliar with research. A friend of mine was an organ procurement coordinator. He stated that his biggest problem in approaching families was the hospital staff having prepared the family for the person from the donor center. The staff were trying to do the right thing, but due to a lack of understanding of the way to approach patients, the staff would often create misunderstandings that he would have to spend a lot of time correcting. We need people who are experts at explaining to patients the way the research works. Several people commenting have pointed out that at least some of the people doing the recruiting do not make it easy for the patient to say Yes. After determining that the patient is right for the study and the study is right for the patient, does the recruiter have any more important job, than to get the patient to say Yes?

  18. #18 antipodean
    March 17, 2009

    Lee

    I’m very sorry to hear of your experience with clinical trials.

    I design clinical trials with exactly this sort of problem in mind. Too often I’ve seen protocols that are overly onerous on patients. These studies tend to run forever because nobody will volunteer and the physicians will steer their patients into something less difficult. i try very hard to imagine what the protocol will be like for the patient going through it.

    The other problem I’ve noticed working in an academic medical centre is what I call freeloaders. These are physicians who like evidence-based medicine but who never enrol patients in trials.

  19. #19 AnnR
    March 17, 2009

    We’ve been in a couple of trials and they haven’t been so bad.

    As one poster noted, sometimes the requirements are onerous. Showing up for blood work every day for months might not be so bad if you’re retired and not to ill, but showing up every day when you’re working is a problem.

    Our state requires that insurers pay for legitimate NIH-registered trials. I’m sure it doesn’t do a thing to reduce health costs, but it can work to your advantage.

    We had HMO coverage with no out-of-network benefit and ended up being seen by 2-3 different experts as a part of considering various trials.

    I think if you have something your Oncologist isn’t quite sure what the next best step for is is that he/she is more likely to encourage trial participation. Overall the ones we’ve been in have been good experiences.

  20. #20 Karl Schwartz
    March 17, 2009

    Today, ClinicalTrials.gov provides essential functions for patients and researchers, but the task of finding clinical setting-appropriate studies remains daunting, due in part to the success of ClinicalTrials.gov: the overwhelming number of studies one must review

    One challenge is the difficulty that patients and physicians have in finding studies (among the thousand + for lymphomas in clinicaltrials.gov) that are appropriate to the patient’s clinical circumstances and treatment objective

    Patient circumstances require translation into database structure:

    o I have lymphoma but have never had treatment. I want to consider studies that have curative potential, because standard therapies are not yet curative.

    o I’m elderly and in poor health. I require a therapy that has lower expected toxicities than standard treatments.

    o I have indolent lymphoma and do not require therapy, but I’d like to consider study protocols of a type that are low risk, that may slow progression and are also unlikely
    to preclude benefiting from standard therapies later on.

    o I have disease that is refractory to standard protocols. I have an urgent need to locate study protocols of new agents with unique mechanisms of action.

    See for our proposal to PDQ:
    http://www.lymphomation.org/settingsrch.pdf

  21. #21 Phoenix Woman
    March 18, 2009

    I tried getting into early clinical trials for the ExAblate fibroid removal treatment, but my clinic dawdled so damned much getting my records to the trial site that I lost my shot at it — and now my ‘roids are so damned big I’m ineligible for any clinical trial to deal with them.

  22. #22 MartinB
    March 18, 2009

    @Karl Withakay

    Mathematically, you are correct. But emotionally, I think it would be very hard, if diagnosed with terminal illness, to enter a study, hoping for experimental treatment and never knowing whether you actually get it. This additional emotional strain may well keep you away from the study. Just imagine the cure was found to be incredibly effective, but you were in the control. Of course, objectively, you have not lost anything, but would you not feel cheated?

  23. #23 Dianne
    March 18, 2009

    Do you have any clinical trials you are planning to start soon or have recently started? Any interest in expanding them to a nearby institution…

  24. #24 Jud
    March 18, 2009

    Nearly all the folks I’ve known with illnesses for which the outlook with conventional treatment isn’t great would *love* (or would have loved) to get into clinical trials. So I’m not sure patient reluctance is to blame. (Though I agree informed consent, after being massaged by regulators and lawyers to try to cover all possible negative contingencies can sound, especially in the hands of an unskilled presenter, a lot like “Are you really sure you want to die horribly for the sake of science?”)

    I’m also not aware of tremendous insurer reluctance to cover the conventional medical costs associated with clinical trials, and the posts from participants in this thread seem to bear that out. As recited in your post, about half the states mandate such coverage already, and I’d be willing to wager there hasn’t been a wave of increased clinical trial participation in those states.

    There are 3 factors I’m anecdotally aware of that could play a part (this isn’t meant to be an exclusive list):

    First, it isn’t easy to qualify for many trials. My best friend at work, who passed away last year from colon cancer, could not get into any of the relevant clinical trials in the area. The problem in each case was that he had been in remission from prostate cancer at the time the colon cancer arose, and this excluded him from the trial criteria. In general, sick folks can have many things wrong with them, while researchers are trying to minimize potentially confounding factors.

    Second, if one finds a trial for which one meets the criteria, it may not be located within practical traveling distance. This means family members potentially having to find new jobs, and terminating current employment might mean losing the income and insurance that would pay for the trial. (I wonder if more work might be done on spreading the geographic availability of trials to qualified candidates through local hospitals, outpatient clinics, or doctors’ offices?)

    Finally, I just don’t think people are sufficiently aware of the availability of clinical trials. There are web sites, but the majority of people still don’t get their information that way. It’s very seldom that I see the availability of even specific trials, let alone reference sources for the availability of clinical trials in general, advertised on radio or TV. Public service announcements on radio and TV about the relevant web sites would be a good idea, ISTM.

  25. #25 martin
    March 18, 2009

    “After determining that the patient is right for the study and the study is right for the patient, does the recruiter have any more important job, than to get the patient to say Yes?”

    While I strongly agree that the recruitment for trials should be done by a person understanding the way how to approach patients/families (and having enough time for each patient), it would be terribly wrong to manipulate the patients to join the trial. It should be their decision, as it is they who take the risk. I would suggest that the recruiter’s job is rather to explain fully the trial, all pros and cons, to the patients, so they can make informed decision than just make sure they say ´Yes´.

  26. #26 Karl Schwartz
    March 18, 2009

    Jud, I agree with the points you make.

    Trial participation is not any easy decision to make, even for the well-informed patients.

    A marker of an unethical study is slow enrollment …. the study does not match up well with other options for one reason or another … or the control seems inferior to the study arm, or vice versa. … or you’re not eligible…

    So far, in our survey (very early), Locating studies appropriate to my patients, and travel challenges have been cited most by oncologists (non-specialists) as obstacles to referring patients to trials.

    http://www.lymphomation.org/ds-report.pdf

  27. #27 Don
    March 18, 2009

    But there appears to be another dimension here that we don’t have all the necessary information on. I personally found out about a clinical trial that seemed to apply to a medical problem I was having, sent my contact info and some case background to the contact given, and never heard anything at all back. Perhaps that particular trial got all the participants they needed, but the request for participants remained on the web site for months afterward (perhaps it’s still there — after awhile I stopped checking). Are some researchers just disorganized about lining up participants?

  28. #28 Rogue Medic
    March 18, 2009

    martin,

    By, the study is right for the patient, I mean that the study is in the best interest of the patient. I am not trying to encourage high pressure sales techniques, but a presentation by someone who is good with people. Someone who is able to address their questions and concerns rather than someone who has a stock answer that they think should answer whatever questions people have. Integrity is something that means a lot to someone potentially facing death. They aren’t looking for someone trying to fake it.

  29. #29 trog69
    March 18, 2009

    Living near a university medical center, I’ve seen many ads for trials dealing with much less serious medical problems than those talked about here, but I am astounded to learn that, in some cases, patients are responsible for some of the test’s costs, as described above. I admit that due to my complete ignorance of anything involving these trials I just assumed that, since the pharmas that would manufacture the drugs stand to reap massive profits, they would gladly pay for any tests/procedures required for the trial’s success.

    I would also think that a generic mistrust of pharmaceuticals, unfair as it may be, would have something to do with my reluctance to accede to trials, though of course, staring death in the face would undoubtedly alter my thoughts on this.

    Anyway, just a probably unhelpful post from the peanut gallery.

  30. #30 Amy
    March 18, 2009

    There are social costs.. psychological costs.. in addition to whatever financial ones the trial might not cover. I’m fairly familiar with MS, having it and all.. I’ve read that of married couples with one party having MS, divorce rate is about the same as for other couples, but significantly higher (like half again as high) if there’s involvement in clinical trials. Stressful, I guess. Maybe some of the reason is that these are generally done against placebo and while MS has a very low mortality rate, being on a trial is literally betting your brain. Scary prospect, that.

    I took part in a study.. not a clinical trial, the drug was already on the market, but a study of how the drug might effect.. other things (I’m not sure how much I can say). The study paid for the.. drugs, what have you, involved in the study.. but not the facilities needed for this to be. If the hospital hadn’t been willing to eat the cost, it would have been my responsibility though I didn’t have the funds.

    There’s also the issue of whether people with significant cognitive problems can properly give informed consent.. I’m thinking of getting involved in a “study” about that. The big question, I guess, is whether I can give informed consent there.. and if their results show I can’t.. did I?

    I’m very glad of the people who participated in trials so that I can have the drug I have.. but if I could have tolerated anything else, there’s no way I would have risked my brain by possibly not taking anything at all for a couple of years.

  31. #31 Karl Withakay
    March 18, 2009

    MartinB,
    I might feel cheated in that scenario, but if I opted out of the trial and the treatment turned out to be incredibly effective, I’d feel pretty stupid for not taking a chance on the trial. I’d rather run the rick of feeling cheated than feeling stupid.

    I don’t have any practical experience with trials, but if the treatment was “incredibly effective”, wouldn’t that show during the study, even if it was double blinded? If so, isn’t there a chance they’d end the trial early on the basis that withholding treatment from the control group was no longer ethical? (Question for Orac)

  32. #32 martin
    March 18, 2009

    Medic,

    I apparently misunderstood your post – thanks for explanation. I understand that your main concern was that patients are lost for trials because of poor communication with the patient/family. Still, I think that the person who decides what are “the patients best interests” – should ultimately be the patient himself/herself, not the recruiter. I see a lot of similarity to genetic counseling, where neutral, non-directive and respect for patients autonomy has become a mantra (although a mildly directive approach has come to be acceptable in recent years).

  33. #33 Rogue Medic
    March 20, 2009

    martin,

    I did not mean to suggest that others would decide for the patient, unless the patient does not have the capacity to make decisions for himself/herself. Patient autonomy is important.

    I reread what I wrote, After determining that the patient is right for the study and the study is right for the patient, does the recruiter have any more important job, than to get the patient to say Yes?

    I did not word it as well as I should have. I do not think that it is the recruiters job to decide what is best for the patient, but to present the information to the patient so that the patient can make a fully informed decision about what is right for himself/herself.

    My other point, the bulk of my original comment, was that we have so many emergency treatments that have no experimental basis. They are treatments that are based on expert opinion from decades ago, when there was little good research on emergency treatments. These have essentially been grandfathered in as the standards of care. The current approach to these treatments is to avoid finding out if they provide any benefit, or if they are harmful. since the treatments are standards of care, the argument is that it would be unethical to deprive the patient of the standard of care. A standard of care based on nothing more than a hunch. Essentially, the emergency treatments have no more scientific basis than alternative medicine.

    When the treatment is not supported by good research, but it is considered unethical to deprive patients of this treatment, as in to perform real research, there is no scientific basis for the treatment. This is bad medicine.

    Maybe there is a benefit to the treatment. If there is we need to know, not just blindly keep following tradition.

    Maybe there is significant harm, as the research seems to have demonstrated. When the goal is no longer to get a tube and an IV and give some medication, but to focus on excellent chest compressions, the resuscitation rate tripled. That is no small improvement. The drugs are still being given, just not as quickly. This is the biggest improvement in resuscitation since defibrillation. This improvement was not a drug, but a decrease in the emphasis on drugs.

    In the resuscitation setting, we should admit that all patients are being experimented on with no possibility to opt out other than a DNR (Do Not Resuscitate) order. And there is no oversight. That is unethical.

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