Guatemala’s Own Tuskegee

•October 1, 2010 • 1 Comment

Here’s another sad example to add to the annals of why-research-ethics-is-important.

Here’s the story, by Robert Bazell for MSNBC: U.S. to Apologize for STD Experiments in Guatemala

U.S. government medical researchers intentionally infected hundreds of people in Guatemala, including institutionalized mental patients, with gonorrhea and syphilis without their knowledge or permission more than 60 years ago.

Many of those infected were encouraged to pass the infection onto others as part of the study.

About one third of those who were infected never got adequate treatment.

On Friday, Secretary of State Hillary Clinton and Health and Human Services Secretary Kathleen Sebelius offered extensive apologies for actions taken by the U.S. Public Health Service.

For people familiar with the world of Human Subjects Research, this story will immediately bring one word to mind: Tuskegee. (For everyone else, see here: Tuskegee syphilis experiment.) Like Tuskegee, this was a government-funded study. And like Tuskegee, the topic was STDs. And, like Tuskegee, there were serious violations of what we now see as absolutely basic ethical standards for research on human beings. The similarities between the two cases is not incidental. The records of the Guatemala study were apparently unearthed by Susan Reverby, a Wellesley College professor who has written extensively about Tuskegee.
See an update here: Guatemala Update

A Tale of Two Cousins: Tragedy and the Clinical Trial

•October 1, 2010 • 7 Comments

Recently the New York Times published a story about two cousins in the US, both with a lethal form of melanoma, who were also both enrolled into a Phase III Clinical Trial to test a new, breakthrough cancer drug. The drug, PLX4032, has been shown to radically reduce the size of solid tumours in specific kinds of cancers, including intractable melanoma, in recent previous trials. Compared to the current standard drug for use in cancers like this, PLX4032 shrinks more tumours and does it much faster and more effectively than any other drug previously tested. But the drug, like many new breakthrough cancer drugs, is not yet available on the market until full clinical testing is complete. Until now, the drug used for what we refer to as the “standard of care” to treat these patients is dacarbazine, a drug that one oncologist in Massachusetts was quoted in the story as saying is “a drug we all hate and would rather never give a dose of again in our lives.”

An important point — while PLX4032 has been shown to drastically reduce the size of tumours for a limited time (compared to current drugs on the market), it is not known whether or not the drug can actually extend life, in comparison to treatments already used. The current Phase III clinical trial is being conducted to figure this out, and as the lead investigator for the trial, Dr. Paul Chapman (an oncologist at Memorial Sloan-Kettering) states, “I think we have to prove it. I think we have to show that we’re actually helping people in the long run.”

Both cousins had aggressive melanoma and both were enrolled into the Phase III clinical trial. While one cousin, Thomas, ended up randomized to the treatment arm of the trial and received the “wonder drug” PLX4032, his cousin Brandon was instead randomized to the control arm. Instead of getting the new medication (in the form of pills) Brandon received the “standard of care”, i.e. the traditional IV infusion of dacarbazine, shown to be, as the article states, “notoriously ineffective” in the treatment of melanoma. His oncologist informed Brandon and his mother that he was enrolled in the control arm with a heartfelt apology. Because each drug in this trial is delivered in a different way (one by mouth and one by IV infusions), both treating doctors and patients/participants would obviously know which arm they were enrolled in from the outset of the trial. This differs from most traditional randomized controlled trials which are “double-blinded” meaning that neither participants nor their doctors know which treatment they are receiving. Practically, that was impossible in this case so the cousins, their families and their doctors, all knew that Thomas was getting the newer, more promising drug while Brandon was getting the drug that, it seems, no one wanted.

Tragically, Brandon has since died from the cancer and Thomas is still on PLX4032. This compelling case has raised many questions and concerns from both the clinical and the research ethics communities about the rigidity of controlled trials for testing drugs for clinical use and whether or not we need to carefully examine or be more flexible with the standards in cases like this one. With the rapid development of new potentially breakthrough drugs and the proliferation of genetically-targeted cancer drugs, are controlled trials always the right way to go about getting these drugs to market safely and effectively?

Here’s a link to the article from the New York Times: New Drugs Stir Debate on Rules of Clinical Trials

…the new science behind the drugs has eclipsed the old rules — and ethics — of testing them. They say that in some cases, drugs under development, PLX4032 among them, may be so much more effective than their predecessors that putting half the potential beneficiaries into a control group, and delaying access to the drug to thousands of other patients, causes needless suffering.

“With chemotherapy, you’re subjecting patients to a toxic treatment, and the response rates are much lower, so it’s important to answer ‘Are you really helping the patient?’ ” said Dr. Charles L. Sawyers, chairman of human oncology at Sloan-Kettering. “But with these drugs that have minimal side effects and dramatic response rates, where we understand the biology, I wonder, why do we have to be so rigorous? This could be one of those defining cases that says, ‘Look, our system has to change.’ ”

Dr. Richard Pazdur, director of the cancer drug office at the Food and Drug Administration, said in a recent interview that the new wave of drugs in development — especially for intractable cancers like melanoma — might require individual evaluation. “This is an unprecedented situation that will, hopefully, be increasingly common, and it may require a regulatory flexibility and an open public discussion,” he said…

This lengthy (but well worth reading) article raises a number of serious issues and questions related to the kinds of ethical standards and regulatory practices that are in place surrounding clinical trials. I’m going to try to take apart some of these issues, one by one, in subsequent blog entries over the next week or so. But let me state them here first:

1. At this point, it’s clear that clinical equipoise, in this case, no longer exists, if it ever did. The standard of care is a drug no oncologist wants to give. It’s ineffective at both shrinking tumours in a significant way and prolonging life. So to compare (by experimental use in seriously ill patients) a clearly inferior agent to what has been proven to be a markedly better drug seems, at first glance, unethical.

2. The way that clinical trials are structured and regulated is something that is important, for many reasons. Putting new drugs on the market is not a process in which we necessarily want lots of possible shortcuts. Yet, in some cases, when a particular drug might be shown to be clearly superior in particular cases, should we be looking at different structures to support getting such a drug to market faster and being, perhaps, more flexible on a case-by-case basis?

3. This article demonstrates that the goals of care and the notion of what we might, for example, want cancer drugs to do may well differ from person to person. While some oncologists clearly support PLX4032 for use as an agent to shrink tumours, the fact that it is still unknown how much (if at all) the drug can prolong life is something others feel is just as, or even more important to demonstrate. If a drug allows a critically ill person to have significant (but perhaps temporary) relief through shrinking of their solid tumours without an additional guarantee of the prolongation of life, is that enough? Should that be a sufficient reason to push the drug to market faster?

4. Finally, the fact that this trial was never double blinded, as the article notes, “intensifies” certain tensions, specifically the tension experienced by physicians who are, at once, clinicians and researchers. Knowing your patient has been enrolled into a control arm with an inferior treatment means, to some, knowing that the patient is being provided with substandard care. While the control arm may well be the current “standard of care”, if that “standard of care” is an agent that many in the medical community agree is not beneficial relative to the newer drug, it may well feel like your patient is at risk of harm by receiving it and by not receiving the superior drug.

Each of these issues raises important questions that aren’t going to go away as newer, better drugs are developed faster. With a growing “consumerist” movement and limited access to expensive “wonder drugs”, the pressure on physicians, pharmaceutical companies and the medical and research communities to get these drugs on the market is only going to increase.

Cancer Research & Red Tape

•September 11, 2010 • 2 Comments

by Chris MacDonald

It’s always newsworthy when an eminent senior scientist comments on the current state of science policy. They’re not always right, of course, but always worth listening to — even if only to hear the sorts of messages and signals they are sending to those who are going to put stock in what they say.

James Watson (co-discoverer of the double-helix shape of the DNA molecule) has recently argued that ethics boards are hampering research — cancer research in particular. See this piece, posted by Eoin Lettice on The Guardian‘s Science Blog: James Watson: ‘cancer research is over regulated’. Here’s the key paragraph:

…Watson told journalists that he was in favour of less regulation for clinical trials as this could speed up the process of finding a cure for cancer: “We’re terribly held back on clinical tests by regulations which say that no one should die unnecessarily during trials; but they are going to die anyway unless we do something radical. I think the ethics committees are out of control and that it should be put back in the hands of the doctors. There is an extraordinary amount of red tape which is slowing us down. We could go five times faster without these committees….”

Now, all we have here is a fragment in a blog entry, so we should be careful about taking this as constituting Watson’s full, considered view on the role of ethics committees. But if, for the sake of argument, we take his view as presented, we can point out the following gaps:

  • It’s just not true that, in most cases anyway, “they’re going to die anyway.” For many cancers, there are effective treatments, and we need to be cautious about subjecting patients to treatments that might well be inferior.
  • The claim that “We could go five times faster without these committees” is entirely without support, and seems a gross exaggeration. I’d be surprised to find that ethics board ‘red tape’ made more than a few percentage points difference in the amount of time it takes to get a new idea translated into a new cancer drug.
  • Watson is only counting the costs (in delayed research), and not the benefits (e.g., patients’ rights protected, methodologically-suspect trials weeded out), of the involvement of ethics boards in the cancer research process.

Canadian Working Group Recommends Against Funding for Controversial MS Trial

•August 31, 2010 • 2 Comments

By Nancy Walton

On August 2nd, we blogged about the controversial treatment for MS, called the “liberation procedure”, created by Italian neurosurgeon Paolo Zamboni, who has theorized that MS is caused by a narrowing of the veins that drain blood from the brain, a condition known as chronic cerebrospinal venous insufficiency (CCSVI). His procedure, which is basically a venous angioplasty, opens up the veins allowing for better drainage and, according to his studies, helping to cure MS. The link that he has claimed exists between CCSVI and MS is highly controversial.

Across Canada, provincial governments are trying to decide if they will help fund clinical trials to further test the procedure for patients with MS. Saskatchewan (the province with the highest prevalence of MS) has confirmed that they will support fund clinical trials of the procedure but so far, there are no commitments from other provinces one way or the other.

But now, a working group from the Canadian Institutes of Health Research and The MS Society of Canada have unanimously recommended against supporting clinical trials of Zamboni’s procedure in Canada, according to a CBC news story this morning. They have recommended that a Canadian/US working group be formed to analyse outcomes from CCSVI studies elsewhere in the world and over time, make further recommendations about pursuing research on the link between CCSVI and MS before forming conclusions about the validity of the treatment.

Here’s a link to the story: Experts urge rejection of MS therapy trial

In a Globe and Mail report on this story, the president of CIHR is quoted as saying,“There was unanimous agreement from the scientific experts that it is premature to support pan-Canadian clinical trials on the proposed ‘liberation procedure’. There is an overwhelming lack of scientific evidence on the safety and efficacy of the procedure, or even that there is a link between blocked veins and MS.”

There have been no independent replications of Zamboni’s work (which has been criticized from a methodological standpoint). Claims about the success of the procedure are anecdotal and these claims, as the CBC story notes, are motivating patients to spend thousands of dollars seeking the procedure elsewhere. What is unknown is whether the procedure is being offered elsewhere as part of a trial or as a therapeutic/curative intervention for those who might be willing to pay for it and travel to get it.

This will be an interesting story to follow. Tomorrow the Health Minister Leona Aglukka will hold a press conference to comment on the recommendations of the working group.

Could Research be Done on Trapped Miners?

•August 29, 2010 • 3 Comments

By Chris MacDonald
This blog entry is all about questions, not answers.

As most of you will have heard, 33 miners have been trapped in a mine in Chile since the mine they were working in collapsed on August 5. (Here’s the latest news on the story: NASA called in to support 33 trapped Chilean miners) Last week, rescuers succeeded in boring a small hole — about 3 inches in diameter — through the 2,300 feet of rock that separates them from the surface. That tube has allowed rescuers to send down “food, water, clothing, video and radio equipment.” It is expected to be months — yes, months — before a hole can be drilled that is sufficiently large to let the trapped men escape.

Tyler Cowen, the economist who co-writes the Marginal Revolution blog, posted this:

At lunch today, one topic was how the Chilean miner experience, when it is over, might revise our understanding of social science. A related question was to estimate the probability that there will be a killing before the time underground is over. How much would that chance go up if one woman were in the group? An equal number of women?

Is it unethical for us to “watch” them, talk about them, or speculate about them?

It’s not idle speculation. Or is it? In theory, since communication is possible, it would be possible to conduct social science research (or even medical research) on the trapped men. Certainly the video feed allows for the possibility of observational studies. Doctors are already monitoring (remotely) the men’s health; why not go further and study the men, so that we can learn about the effects of prolonged isolation on the human body and mind? Consent forms could be sent down (and back up) the newly-drilled access tube. Would doing so be ethical? Informed consent is certainly possible, but would it be legit? Do trapped miners count as a “vulnerable population,” in the same sense as prisoners and children and people mental health institutions?

Children in Developing Nations as “Lab Rats”?

•August 24, 2010 • 8 Comments

By Chris MacDonald

Do children in poor countries participate in drug trials for drugs that will eventually help people in richer countries instead of them? Yes. Is that a problem? That’s debatable. One bit of information that can help form that debate is statistical information about the scope of such testing. In that regard, researchers at Duke have offered some insight.

Here’s the story, as reported in the Times of India: Lab rats? Drugs for US children tried on Indians. The story reports the findings of this paper, by Duke University’s Sara Pasquali and colleagues: Globalization of Pediatric Research: Analysis of Clinical Trials Completed for Pediatric Exclusivity. The basic factual finding of the Duke study is this:

The majority of published pediatric trials conducted under the Pediatric Exclusivity Provision included sites outside the United States, and more than one-third of trials enrolled patients in developing/transition countries.

The “Pediatric Exclusivity Provision” is a U.S. regulatory mechanism that gives drug companies financial incentives (by extending patents) to test their drugs for use in children. This is a response to a real problem: too few drugs — even drugs used regularly in children — are actually tested on children. Without rigorous testing, using drugs on kids can amount to guess work. So encouraging companies actually to test on kids is important. But not surprisingly, many of the trials prompted by the Pediatric Exclusivity Provision are being carried out, like many other clinical trials, in developing countries, like India.

So, is this a problem? Many people think it is. Many argue that it’s unfair to test drugs on individuals (or populations) that will never be able to afford the high-priced pharmaceuticals that result. For example, the story quotes Marcia Angell (former editor of the New England Journal of Medicine, and author of The Truth About the Drug Companies), as saying: “We are now using vulnerable people in vulnerable countries as drug laboratories….”

And of course, strictly speaking, Angell is right. We’re using the people of India (and China and other countries) as drug laboratories. We’re also using them as garment factories. And as places to assemble cheap electronics. And in all these cases, the people involved (or their guardians, in the case of children) choose to participate because they see doing so as being in their interests. And as long as they’re properly informed, voluntary participation is in their interest. Now, of course, sometimes that’s a sad fact. It’s sad when the only way you can feed your family is by working in a dingy garment factory. And it’s sad when the only way you can get basic healthcare for your child is by enrolling her in a drug trial.

Sad or not, the fact remains that the people who participate benefit from doing so. So the ethical question really is, do they benefit enough? And that’s a very hard question. Many of us will have an immediate instinctive reaction. When people are in dire straights, help almost never looks like enough.

For more on this topic, see:
Exploitation and Developing Countries: The Ethics of Clinical Research by Jennifer S. Hawkins and Ezekiel J. Emanuel

Research by popular demand

•August 2, 2010 • 1 Comment

This is a story quite specific to Canada, but it certainly has global implications. Recently, one provincial government made public the fact that they are approving clinical trials on the new, experimental “liberation procedure” for patients with multiple sclerosis (MS). The procedure itself isn’t innovative – it’s simply a venous angioplasty (or opening of the veins in the neck and spinal cord to, as claimed, improve blood flow by allowing greater venous blood drainage away from the brain) but as a “cure” for MS, it’s very new and the evidence is, well, simply anecdotal. Dr. Zamboni is an Italian neurosurgeon who has, through this procedure, claimed to cure MS through neurosurgical means even though a surgical solution has never been even vaguely hinted at in the past. He suggests that patients with MS have an underlying condition called “chronic cerebrospinal venous insufficiency” (CCSVI) and that this procedure can provide a cure. Some patients have had the procedure and claim an almost miraculous recovery and palliation of symptoms and the neurological community is modestly intrigued.

As of now, the province of Saskatchewan will fund trials on the procedure while Ontario’s premier, Dalton McGuinty has stated that he would rather see something more than “anecdotal evidence” for the claims of the procedure before allocating funding towards further formal testing of it on patients with MS.

Here is the story from the Globe and Mail: Wall sticks by MS plan, but other premiers skeptical

I don’t often agree with Margaret Wente of the Globe and Mail, but I do agree with her views in her article on the politics of MS. In this, she is critical of decision-making regarding funding for research based on political waverings, anecdotes or popular demand. Here’s her article: The explosive politics of MS

A few quick points:

I also don’t tend to agree much with Dalton McGuinty, however his point about wanting “more than anecdotal evidence” before making decisions about funding clinical trials is one that should be seriously considered. While there have been “stories” about the success of the procedure, in two independent replications of Zamboni’s procedure, the results were completely negative. Here is a posting from the Neurologica Blog about these two studies and the importance of replication: CCSVI – The Importance of Replication. Of course, some might argue that the only way to accrue evidence is, in fact, through conducting trials. That’s true, of course. But in this case — one which involves a catastrophic and debilitating disease with no apparent cure — it seems obvious that we should take particular care and demand strong reputable evidence while actively rejecting anecdotal evidence, i.e. evidence in its weakest form. Zamboni, as the writers of Neurologia state, may not have necessarily found the cure for MS, but he may well have found a piece of the puzzle. And in this posting I’m not, in any way, taking sides here with claims that his procedure either works or doesn’t: I’m simply saying that until we know more, we should demand more rigorous evidence from a variety of independent sources before we make these kinds of big decisions.

Second, I’m quite interested in the fact that the provincial premiers are the ones speaking out here. Research and funding for research is and always has been influenced by politics and by governmental decisions on allocation of resources and money. However, I find it interesting that the highest provincial politicians are speaking out on this issue at this time. They’re not talking about other kinds of decisions related to clinical trials. Why not? Because this one, as Margaret Wente notes, has “gone viral”.

Certainly there is, and should be, a place for the voice of the public in contributing to these sorts of decisions, but these voices must be well informed and clearly must state their stake in the matter up front. We shouldn’t make decisions about how to fund large clinical trials based on what’s “gone viral” or because something has gained in popularity through “word of mouth”. Sure, we can make decisions about what cute kitten video to watch on YouTube based on what’s gone viral, but clinical research decisions? Let’s keep popular demand and politics out of it.