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"guerrilla science"

In his keynote address at the 2000 annual meeting of the Society for Neuroscience, paralyzed actor and activist Christopher Reeve pleaded with scientists to take bigger risks, including conducting more human trials, in the hope of finding new cures faster. "Please, take that leap," he begged, "Don't be scared. We're not scared. We'll meet you halfway. We'll succeed." Pressure like this from patients and their families is forcing the scientific community to find faster drug testing models, invent creative new technologies, streamline peer review and improve collaboration. But what are the practical and ethical implications of these demands? FRONTLINE asked some experts.

Participants

Arthur Caplan, Ph.D., Emanuel and Robert Hart Professor of Bioethics, Chair of the Department of Medical Ethics and Director of the Center for Bioethics at the University of Pennsylvania

Brent James, M.D., Executive Director of the Institute for Health Care Delivery Research and Vice President of Medical Research and Continuing Medical Education at Intermountain Health Care, a nonprofit health system based in Utah

Laurie Zoloth, Ph.D., Director of the Center for Bioethics, Science and Society and Professor of Medical Ethics and Humanities at Northwestern University's Feinberg School of Medicine

 

What are the pros and cons of adapting the traditional drug development process? Do you have any concerns about scientific research moving too fast? How should science ethically balance the desire to find cures as fast as possible with the need to do safe and comprehensive research?

Arthur Caplan, Ph.D.
Director, University of Pennsylvania Center for Bioethics

arthur caplan, ph. d

The desire to speed up the process is very real on the part of many Americans. But at the same time, any deaths -- such as occurred with the total artificial heart or gene therapy -- or hastening of death -- as occurred with fetal cell implants for parkinsonism -- leads to cries for more oversight, control, regulation and a slowing down of clinical research. We have an administration and until recently had a Congress inclined toward allowing free choice and the market to sort the issue of how fast research should proceed. This may now be changing with the Democrats in charge of Congress, who have a more cautious approach toward clinical research.

The balance that must be achieved is between the needs of individuals to have access to safe, effective and affordable drugs, devices and vaccines and society's need to insure that quackery, exploitation and rampant risk don't come to characterize medicine and the pharmaceutical industry.

I think the values can be balanced, but it requires a recognition that more is needed to decide to make a treatment available than an endorsement from someone who has a financial stake in the treatment and the desire of someone to take it. Independent verification of the safety and efficacy of treatments is required if we are not going to kill or hurt many people or promote treatments that turn out to lack efficacy or only have marginal efficacy. That balance must exist. We are not far from having it now. I would not cut back on animal, phase one or phase two [the first limited testing phases of clinical trials] regulations. I might ask for more oversight of phase three and four studies [where a treatment is given to a larger number of people]. I am not convinced that great benefits are being lost due to an overly onerous regulatory system, but I am convinced that great harm can still be done by the failure to have a system that can adequately police drugs and devices out in the community as recent experience with Vioxx, drug-eluting stents, the artificial heart, limb transplants, defibrillators and anti-depression drugs makes clear.

Laurie Zoloth, Ph.D.
Director, The Center for Bioethics, Science and Society, Northwestern University

Laurie Zoloth, Ph.D.

... Our system grew out of failures to regulate drugs safely, and a concern for how research subjects were treated. Like many systems, it is crafted to avoid your last mistake. Moving from that standard will involve a calculated risk. It is clearly in everyone's interest to move quickly from hypothesis to cure. But unless the cure is really proven, it is not scientific research at all -- it is another model, one sometimes used in medicine, of trying a clinical idea, one by one. Many interventions begin in that way too, for example, artificial reproduction. But many ideas that were never really proven turn out to be harmful or useless, or not much better than cheaper, earlier ideas.

In your ideal system, you would want an appeals process [to grant exceptions to the rules] -- not [for the purpose of proving] things, but for some compassionate use for dying patients for whom all else has failed. Their recovery would be a blessing, of course, but not clinical proof.

Many ethicists are worried that science may move "too fast," which is a legitimate and open question. I tend to be concerned that science may be overly restricted as well. I believe that a fine balance between these appeals is what keeps our system intact. It is the role of scientists to be eager about their work and to be passionate about their ideas -- and that is precisely why we do not want them to be the ones to test or evaluate their own hypothesis, and why we build a structure of others who evaluate results. But without a passionate push by scientists, medical research would simply not proceed. Without active involvement by patients, families and communities, science would not be supported. We need that passion for the system to work.

Brent James, M.D.
Executive Director, The Institute for Health Care Delivery Research, Intermountain Health Care

Brent James, M.D.

This year the United States will invest $28 billion in biomedical research through the National Institutes of Health. This was an initiative that Bill Clinton started to increase medical research dollars and that George Bush then carried through. It was a huge increase in funding. The hope is that we'll find things that enable us to do a much better job of treating a disease, of mitigating its impact, of changing people's futures.

The trick is that we know that it takes about 20 years from the point in time when a major new research finding that has direct application to patient treatment is first developed, first published in the scientific literature, to when it first becomes truly usable.

I've spent an awful lot of time in studying that lag in research making it from the bench to the patient. It turns out that we could probably achieve as much good for the American public as we will get from the next 10 years of investment in biomedical research if we could simply take what we know today and get it to the patient's bedside. ... We do not invest in moving [new discoveries] out of research into practice. Just to put it in perspective, the budget of the agency in the federal government tasked to do that, the Agency for Healthcare Research and Quality, is $318 million, compared to $28 billion [funding the initial research]. And so it's a mismatch of investment in making things happen. It's like you're developing this huge resource and sticking it somewhere where no one can use it. ...

Let's say that you have a disease, and there are five major treatments. And for every one of the five, I can show that they're better than nothing, because that's how the studies are structured. ... Not often does the evidence tell me which one of them is best. It turns out that when we look at it that way, the evidence base is extremely poor. I can identify best therapy for you for common things typically less than 20 percent of the time. ...

How do you fill this major chasm in the evidence base? It's not just about biomedical research, but about practice research -- about how I get the best thing for you to you every time. The one major idea that has evolved there, it's a brand new idea -- it happened here at Intermountain first -- we started to structure clinical care delivery with the purposes of making sure that you get the best therapy every time. We were trying to close the quality gap. And we used a particular method to do it that derived from the way that you design randomized controlled trials in medical research. When you're organizing care to get best results for every patient you're treating, it creates a little research engine where you can now measure the impact of treatment, and it massively advances your ability to learn from experience as you work. ... You get this overlap between how do I get performance out of the system to benefit you individually, ... and you get a secondary benefit that you can generate massive amounts of new evidence. ... It doesn't replace the traditional research methods; it just complements them. And it closes that gap between the [research] bench and getting things into active practice. ...

 

What are the success stories coming out of efforts to speed up scientific progress? What are the cautionary tales/failures?

Laurie Zoloth, Ph.D.
Director, The Center for Bioethics, Science and Society, Northwestern University

A clear success story is how the world community, when it was given funding and when it was pushed by activists, discovered the cause of AIDS and how to interfere with the virus's ability to destroy the human immune system. HIV infections can now be effectively controlled in most people, and that was unthinkable at the beginning of the epidemic. It would not have happened without efforts to speed up scientific progress. A second example is the treatments for childhood leukemia, and a third is how the computational rapidity of DNA sequencing allowed for a precise and quick discovery of the cause of SARS.

There will always be failures in clinical trials: Science is science after all, and the way scientists seek truth is to falsify theories. And science is always done by human scientists -- and human scientists are, well, human, with our fragility, our competitive sense, and our clumsiness as well as our genius. It would not be science if the project did not fail. What we should attend to are avoidable failures -- and here, the classic case is the tragic death of Jesse Gelsinger [during a gene therapy trial] at the University of Pennsylvania, where a second, slower look at the lab data could have prevented that great loss.

But let me add something very important: There are also opportunities to fail when we are too cautious, or too fearful. ... First, it is possible that we stopped research on nuclear energy instead of figuring out how to develop it safely. Our abandonment of that project and our turn to fossil fuels led to unforeseen and dreadful consequences. Second, the moratorium on human stem cell research is thought by many to have inappropriately hampered advancement in that science, and in possible cures. Third, a generalized fear or moral panic about science itself as a reasonable source of knowledge has lead to rejection of vaccination, allowing a resurgence of polio across Africa and now Indonesia.

Brent James, M.D.
Executive Director, The Institute for Health Care Delivery Research, Intermountain Health Care

We have a man named Bob Christensen [at Intermountain]. He's a researcher. He's also embedded in clinical practice. He's the head of perinatology, high-risk pregnancy. A specific part of his role is to do research that directly impacts our care delivery. One of the things that he did was he got looking at children who have something called hyperbilirubinanemia when they're born, [a condition in which babies have an excess of bilirubin, a blood by-product that causes jaundice and, at high levels, brain damage]. ...

Looking backwards, pediatricians had two things that were just plain wrong in practice. The first was that they believed that they could look at a baby and visually estimate what their blood bilirubin levels were and if they were at risk. [The skin and eyes of an infant with elevated bilirubin levels will appear yellow.] That turns out not to stand the test of data. The second thing is they had a very simple little rule that if a child's bilirubin levels were greater than 10 milligrams per deciliter, they needed to be worried, and less than 10 milligrams per deciliter, they didn't have to be worried.

What Dr. Christensen did was measure this across a large group of patients. That's one advantage of being at Intermountain -- we deliver 30,000 babies a year. He actually built the risk curves. As a result of that, we produced a policy and published it, showing how old the child is in hours of life and, if you measure blood bilirubin, what the long-term peak level is going to be. ... It was research directly designed to support regular practice. We had the system in place; we went to 100 percent bilirubin testing on all newborns. That was unpopular with some physicians, but we just punched it through. We went from about 25 cases of kids at significant risk per year to under three.

So what you had was embedded research that was leading directly to care changes. I could show you similar things with diabetes. I could show you similar things with heart disease.

As you start to integrate the research into the practice, one of the things that happens is you start to use a range of study designs, not just randomized controlled trials. You fit the study design to the problem, and it requires a much more sophisticated understanding of the philosophy of science design that underlies practice -- how do you match the science to your project? ...

One of the things I find I can do at Intermountain is I can do something called a quasi-experiment -- a non-randomized controlled trial. Now that's going to increase the probability that I'll make a spurious causal association -- maybe it increases it from 5 percent to 7 percent. ... I'm going to increase it a teeny bit, but if I design a quasi-experiment trial very carefully, I can come within a hair's breadth of full RCT (randomized controlled trial). The difference is that a quasi-experiment is literally a tenth of the cost to run. ...

You get this snooty randomized controlled trial crowd where the only thing that counts is randomized controlled trials. It's entirely impractical because there are classes of evidence where you can't get them. So what you learn, when you're in the real world, is your goal is to see how far up the evidence chain you can push.

 

Scientists are not only pushing to speed up traditional drug development, but also to develop controversial new treatment techniques. What is the ethical status of cutting-edge treatment options such as gene therapy and stem cells? Have these potentially promising new options been sufficiently vetted?

Laurie Zoloth, Ph.D.
Director, The Center for Bioethics, Science and Society, Northwestern University

This science is still largely basic research, far from clinical trials. Hence it is unclear as yet about how they will be vetted, but my assumption is that given how regulated even basic research is, by special committees (Embryonic Stem Cell Research Oversight Committees) in addition to Institutional Review Boards, such research will receive elaborate attention and be very well vetted indeed. What is not regulated is the plethora of "natural" or homeopathic or off-shore "therapies," which I am far more concerned about.

One other note: We need to think about the nature of the controversy itself. The assumption of some of the controversy is that scientists cannot be trusted to regard their work correctly, or with sufficient attention to moral issues, or that they are crossing impermissible borders of knowledge, and that ethicists might know better -- which is not clear. Here, some controversy is due to the fact that different religions view the embryo or the genome or nature itself very differently. Some controversy is a part of normal science in every early stages -- there are competing truth claims, or scientists themselves disagree, and in this case, we should welcome the controversy, for only in such debates are ideas really vetted. And that is precisely why a society should support basic research, allowing scientists the full range of possibilities of knowledge in the lab setting. Ethicists need to ask the full range of our questions as well -- for our goal, in part, is to allow scientists to be challenged by our questions of morality and the public's concern for basic safety.

Arthur Caplan, Ph.D.
Director, University of Pennsylvania Center for Bioethics

It is too soon to know. There has been relatively little research done on gene therapy in the past decade and nothing really worth talking about with respect to embryonic and fetal stem cells. There has been a lot of hype about these strategies partly to draw financial backing when the government will not provide it and partly due to the politics of pushing through controversial forms of research such as therapeutic cloning. I think these strategies may well deliver benefit, but it will take at least another 10 years to start the real research that will make this a possibility.

 

A pending suit by the Abigail Alliance for Better Access to Developmental Drugs, named for a teenager who died of cancer after being unable to enroll in clinical trials of a new drug, is challenging the FDA's ability to regulate drug trials. What are the current rules about human testing of new drugs? Should patients with terminal or often-fatal diseases like ALS be able to participate in drug trials with higher risk levels? Should family members of sick individuals be able to volunteer themselves as subjects in clinical trials? What should constitute informed consent in these cases?

Arthur Caplan, Ph.D.
Director, University of Pennsylvania Center for Bioethics

... Part of the problem in using the term "terminally ill" is that there is not societal consensus on what the criteria are for meriting that classification. Nor is there consensus as to who should have the authority to declare someone as fulfilling these criteria. Physicians are notoriously poor at predicting who has six months to live, much less a year.

The desire to hope for the best -- what is sometimes termed the "therapeutic misconception" -- is often present on the part of those facing death and sometimes on the part of the researchers experimenting upon them. If the only source of information about the promise of a new drug or device is the person who invented it or who seeks to become known as the pioneer in the field or who stands to make money by the sale of the treatment, then there are well-known problems when the inventor/promoter/cutting-edge researcher is the only real source of information for desperate patients, in terms of comprehension and understanding about what can be expected to happen.

Should society deem it ethically imperative to give more weight to the wishes of the dying and the desperate, it must undertake special efforts with respect to informed consent -- subject advocates, waiting periods, better assessments of comprehension, strict restrictions on conflicts of interest by information providers -- that would help ensure that a true choice -- and not misplaced hope or hype -- is the basis for choice. Recent experience with consent to the use of innovative drugs, devices and technologies such as the total artificial heart, limb transplants, and fetal cell implants into the brain should give pause about how well the terminally ill and those facing severe dysfunction are able to make truly informed choices in the face of death.

The fact is that a phase one study proves relatively little about safety. No one should think that completion of a phase one study shows much about what will happen when they take a vaccine or a drug. Moreover, most phase one treatments do not pan out. And some phase one treatments accelerate death and exacerbate suffering. That is the message that the desperately ill need to hear and society needs to keep in mind in thinking about the wisdom of granting access to drugs or devices at the end of phase one clinical trials.

Laurie Zoloth, Ph.D.
Director, The Center for Bioethics, Science and Society, Northwestern University

Like many ethicists, I am re-thinking these very questions. I would favor allowing compassionate use of drugs in a wider manner, with patients fully knowing the bleakness of their diagnosis and the untested and potentially dangerous drugs that they take -- drugs that may bear dreadful side effects. There are two classic problems that bioethicists have worried about: the lack of clinical equipoise and the fear of therapeutic misconception. Let's look critically at both.

Clinical equipoise means that you need to believe that your experimental intervention and the control are equally able to work, and that only a fair trial will prove the worth of any intervention. But, as I said before, basic researchers actually are arguing that they know the biochemistry of the intervention, and thus do not have equipoise at all -- they want to see if the drug's success in animals can be falsified, but they would not be doing the trial in the first place unless they thought it would succeed.

Clinical trials are not chemistry lab practice. That leads us to look at the second issue -- the fear that a patient might actually also believe that being in a trial might cure their condition. This, too, seems reasonable, especially since, clearly, what they are now doing is not working, and since they have a 50 percent chance of being in the treatment arm of a drug that someone clearly thinks will work or the trial would not have been funded.

Family members, eager to help, and willing to be in an actual clinical trial, should be allowed to do so. Some worry that they face undue pressure, or that they are only doing it out of love, not dispassionate interest. Of course; but what, exactly, is the ethical wrong when we act out of love, or duty, or yearning? Why is that a less noble motive than, say, wanting the money for participation?

 

There are some new Web sites and organizations that allow patients with certain diseases to share data and outcomes from treatments they're trying among themselves. What are your thoughts on this trend?

Brent James, M.D.
Executive Director, The Institute for Health Care Delivery Research, Intermountain Health Care

The information that [the people on these Web sites are] sharing is level four evidence -- personal anecdotes -- which is generally not considered of acceptable quality to inform any medical decision-making. Now, technically, when I'm building an evidence-based best practices guideline, I certainly prefer to have level one evidence, randomized controlled trial evidence. Level two evidence [such as a quasi-experiment] is also acceptable. ... Level three evidence is where I have expert consensus among a group of experts -- not solo individuals, but a group -- using formal methods, models, and techniques. And believe it or not, that's considered acceptable evidence within the profession right now for treatment. The layer below that is called personal anecdote, level four, and we exclude that. So on the one hand, I'm not going to treat that as evidence.

On the other hand, those anecdotes can be greatly informative in terms of how you think about or structure a program. As a researcher, if I'm going to generate evidence, that kind of background can be extremely useful.

Now, on the other side, imagine I'm a patient. The guy who did the research on this one is Al Mulley at Massachusetts General Hospital and Jack Wennberg, and now David Wennberg as well -- studying how patients make decisions. ... What they've demonstrated conclusively is that patients pay far more attention to stories than to statistics. ... [Anecdotal evidence] turns out to be immensely useful for patients facing similar decisions. It's extremely useful. It's because it hits at an emotional level.

So, for example, if you had breast cancer, and we treated it surgically -- so you probably have a complete cure -- but you're offered a choice of follow-up chemotherapy, which can be pretty obnoxious, ... I honestly do not believe that you can understand that from looking at the statistics. If you're not talking to other women who've been through that and experienced it, ... the mathematical description of it just falls completely short without hearing people talk about the impact of that in their lives and the compromises they had to make and the burden that they bore. ... That's what Wennberg and Mulley showed so clearly was essential to good decision-making. And so when I look at these databases and hear people describe [their treatments] back and forth, you look at it as a support group happening at that emotional level, but it goes beyond that too. It's helping people understand not just the physical results they will get, but how they'll experience it and how they'll feel about it. And it gives you a chance to test it in your head before you have to live it. It's just absolutely essential.

Laurie Zoloth, Ph.D.
Director, The Center for Bioethics, Science and Society, Northwestern University

These Web sites are wonderfully interesting for a scholar, but most important, they are wonderfully important for patients, who in this new way find community and support. One can feel entirely isolated, locked in one's own disease and befallenness, and the temptation to feel utterly singular in your fate adds to the idea that you must depend entirely on the information coming from your treatment team. Knowing other patients facing similar choices and discussing similar issues creates the possibility of learning about a range of answers, not only those in your state or region. Communities of patients and families can, and do, create interest in rare diseases, create new practical solutions to problems of daily care and create innovative ways to research and study disease.

In the case of Canavan's Disease [a degenerative, fatal brain disorder present from birth that primarily affects children of central or eastern European Jewish ancestry], it was the organization of parents who supported the first work in understanding the genetic basis of this disease. There are many other examples.

Yet, the Web is also a complex "place" that does not sort or vet what is told there. It can be a source of confusion or error, it can offer false hope, or it can offer terrifying and unverifiable stories. Unlike a face-to-face meeting, it is hard to judge the truth and worth of words, and mistakes are just as possible as they are in any part of medicine.

I like the idea of empowered, knowledgeable patients coming back to their doctors with information they have researched themselves -- it has changed the medical encounter for the better, for learning about one's own condition can be a valuable step in regaining control over one's life choices.

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posted apr. 3, 2007

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