Clinical Trials

Confidentiality Certificates: A False Sense of Security?

2008-11-17T21:35:00.006-05:00

First, for those who don't know what a Confidentiality Certificate is (and if you didn't, why would you be reading this?), let me just briefly explain. A Confidentiality Certificate is issued by the federal government to researchers who ask for it and who are conducting research involving information about participants which, if disclosed, could put the research participant at risk financially, socially, criminally, or otherwise. For example, just knowing someone was enrolled in a study of a sexually transmitted disease, such as syphilis, would potentially be harmful to a participant. For this reason, and to enable researchers to enroll otherwise unwilling participants, all information collected during the research covered by a Confidentiality Certificate is protected from disclosure. That means the investigators can withhold the information, even if a court orders its release.

For years, researchers in psychiatric disorders, substance and behavioral addiction, and other fields have relied on the protection afforded by Confidentiality Certificates to offer participants assurance that information collected about them would not be shared. Researchers at Duke University have just published a paper in Science suggesting that this reliance may be far from secure.

In the case described in the November 14 Science article, the authors describe how, when they objected and Duke appealed a judge's order that information about a research participant be released in a criminal case, it became apparent that the judge was not even aware of the protections afforded by Confidentiality Certificates. Further, even when he was made aware, he ultimately ordered the information be released, under seal, to those involved in the case over which he was presiding. The information never actually saw the light of day only because it was ultimately deemed irrelevant to the case.

Laura Beskow and her colleagues at Duke, Lauren Dame and E Jane Costello, have done the biomedical and social science community a great service by bringing their experience in this matter to the public's attention and by highlighting the need for research into the incidence of breaches of confidentiality. Meanwhile, researchers and clinical trial participants alike should be aware that information collected during a clinical trial, while maintained as confidential under normal circumstances, may be exposed in a court of law.

-Joe

Putting Alternative Medicine to the Test

2008-03-10T18:18:00.000-04:00

Alternative, or complementary, medicine encompasses all of the therapeutic and preventive strategies which enjoy a measure of success, despite not having been developed based on solid scientific principles. They include everything from herbal remedies to acupuncture, yoga and mindful thinking. Practitioners and patients alike swear by the effectiveness of particular healing methods, even where there may not be a scientific explanation of how they work or even empirical evidence that they do really work.

That alternative medicine has been taken seriously of late is evidenced by the establishment of one of the newest units of the National Institutes of Health - the National Center for Complementary and Alternative Medicine. The web site http://nccam.nih.gov/ lists a large number of clinical trials in this arena, involving the use of such interesting therapies as magnetic brain stimulation, broccoli sprout tea, moxibustion, polarity therapy, and expressive writing.

Criticism of research on alternative medicine arises on occasion, and when it does, is met with fierce opposition from advocates. The discussion customarily goes something like this:

"Alternative medicine is baloney."

"But many patients feel they've been helped by it."

"The science that is being done to prove whether or not these things work is pretty lame and, where it's been done properly, there's not much evidence of any real clinical effects."

"But many patients feel they've been helped by it."

"Patients aren't helped by the therapy at all - it's just the placebo effect at work."

"But many patients feel they've been helped by it."

I believe rigorously conducted clinical trials can make significant contributions to the conversation about alternative and complementary medicine.

First, clinical research on particular therapy or preventive measures could demonstrate their safety and weed out those that are actually harmful to patients.

Second, clinical research could demonstrate whether or not a particular therapy had a particular effect on patients, irrespective of whether or not the patient felt better. This would provide solid scientific information useful both inside and outside the alternative medicine debate.

Third, clinical research could quantify how much better patients felt as a result of a therapy, or by how much the incidence of a particular condition was lowered in a patient population as a result of a preventive measure.

I'm not sure there needs to be a determination, using clinical trials, of which alternative and complementary approaches should or should not be allowed, except in the case where significant health safety issues are raised. Rather, clinical trials can show whether or not a particular approach can be moved out of the "Alternative" realm and be accepted by the medical establishment and the communities it serves as a scientifically proven approach. And in the meantime, those approaches that have yet to be proven to have a measurable physiological explanation or effect can continue to benefit those patients who believe in them.

-Joe

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Who Owns Your Blood? (continued)

2008-03-05T09:13:00.001-05:00

Photo Credit: Shen Shi'an

The U.S. Supreme Court recently weighed in on a case involving a university researcher, Dr. William Catalona, who claimed that the tissue samples collected under clinical trials he conducted while at Washington University in St Louis belonged to him and he could therefore take the samples with him when he transferred to Northwestern University in Chicago. Not surprisingly, the university objected, and the case made its way up the through the courts. Ultimately, the Supreme Court in effect upheld an earlier ruling that the samples belonged to the university and not to the researcher.

Throughout the process, the researcher was supported by a number of the research participants. In their minds, they felt the researcher deserved ownership of the samples because he designed and conducted the research, collected the samples, and had plans for continued research involving the samples. To them, the university was simply the institution at which the research was conducted, an impersonal entity compared to the individual they knew and associated with the research.

California's Supreme Court ruled that John Moore did not own the cell line developed from his bone marrow. Mr. Moore was a leukemia patient and participant in clinical research at UCLA conducted by Dr. David Golde who was also Moore's physician. Dr. Golde and the university licensed the rights to the cell line and products derived from it to Genetics Institute and Sandoz for several hundred thousand dollars. Mr. Moore claimed rights to the cell line, but was denied those rights by the court.

Bottom Line: When you participate in clinical research, you are probably giving up any property rights you have in your blood, tissues, saliva, urine, organs, and everything else.

-Joe

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Who Owns Your Blood?

2008-02-07T08:44:00.000-05:00

As a participant in a clinical trial, it would not be unusual for your blood to be drawn as part of the research protocol. Once a sample has been taken, to whom does it belong? You? The researcher conducting the clinical trial? The university, hospital or research institution hosting the clinical trial? Who cares?

In most cases, the blood sample would belong to the institution, to be used by the researcher as described in the Informed Consent document you were given. And, in fact, you probably wouldn't think twice about who owned the sample from that point on. If you were donating blood or an organ, for example, your donation would ultimately belong to the individual into whom the blood was transfused or the organ transplanted.

Now for some what ifs...

What if questions arose about the ownership of the blood, or saliva, or tissue, or urine sample collected from you as part of a clinical trial? What if the researcher transferred from the original institution hosting the clinical trial to another and wanted to claim ownership of the sample, but the original institution wanted to retain ownership and didn't want to allow the sample (your sample) to be transferred? Would you care then?

Or what if the sample turned out to be valuable? Suppose your blood contained a hormone that had never been seen before. Maybe the hormone controls the spread of cancer or reduces pain. Certainly the researcher and her institution would be keenly interested in studying the new hormone. And if turned out to be safe and effective, then the institution would license the hormone's use to a pharmaceutical company which would manufacture and market it in large batches. The institution and researcher would receive royalties from the company for the discovery - which wouldn't have been made if you hadn't volunteered your blood for the clinical trial in the first place! Have you started caring yet?

Even if you accept the fact that you agreed to donate your blood to the study and gave up your ownership of it at that time, what about the hormone found in your blood? If it was unique to you, would you feel some rights of ownership then?

Next time... a couple of real life examples of these circumstances.

-Joe

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Don't Give Your Child Cold Medicine

2008-01-24T08:57:00.002-05:00

Update: This information has been updated by new FDA guidelines. Please see our WebMD article here.

Last week the Food and Drug Administration (FDA) issued a warning to parents: don't give infants and toddlers over-the-counter (OTC) medications for colds. Why not? Because those medications, many of which have been pulled off the shelves by their manufacturers over the past few months, may do more harm than good, overall.

Of course, it's a little more complicated than that.

First of all, we're talking about medications that have been marketed for infants and toddlers - 0 to 2 years of age.

Consider the possibility that an infant or toddler could be given more than the dose prescribed on the label. This might happen when they are given more than one medication (to treat more than one symptom, say a cough and sneezing), each of which contains the same active ingredient. It could also happen when they are unwittingly given multiple doses by multiple caregivers (say a day care staff member, dad, and grandma). Either way, the result is unintentional overdose.

While such overdoses and other adverse reactions may be the exception, they are not rare. Add to that the fact that many of these medications have not been demonstrated to be effective in infants and toddlers, and there is just no reason to expose these children to the risks for no proven benefit.

Let's take a step back and ask a couple of questions.

If the medications in question have not been shown to be effective in children, then why are they being marketed for children in the first place? It's not that they have been proven ineffective. Rather, it's that they have not actually been tested in clinical trials in children. Many have only been tested in adults - that's how they received FDA approval. In those tests, they were shown to be safe and effective at relieving symptoms - in adults. It was just assumed, then, that they would be safe and effective in children - in lower doses. But, in fact, they have never been shown to relieve symptoms in children.

How is it the medications were never tested in children? Probably because of the risk and expense of testing them in children. What if something goes wrong? As I described in a blog posted here two years ago this month, it is not uncommon for a new drug to be tested in adults, but not children (or pregnant women), for fear of harming the research participants.

As a result, we are now at a point where we'll need to await the results of clinical trials of cold medications in infants and toddlers before these products can reappear on the pharmacy shelves. That is, if the manufacturers believe the cost of conducting the clinical trials is worth the potential market.

Something to remember - cold medications do not "cure" a cold, anyway. They only treat the symptoms of a cold, making the person, child or adult, temporarily feel better.

-Joe

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Just Another Lab Rat

2008-01-16T06:57:00.000-05:00

Photo: Jean-Etienne Poirrier

www.jalr.org is a web site intended for individuals interested in volunteering as healthy subjects for clinical trials as a way of earning money. The site even suggests it is possible to make a modest living as a "professional" research participant.

While the site's host promotes the idea of volunteering for the money and to "make the world healthier," he also reports having taken over 700 pills and undergoing 1,200 blood draws during the past three years. The host appears to be an experienced participant, but (appropriately) does not provide medical advice.

The site is attempting to maintain a searchable database of clinics for healthy volunteers, but is still struggling a bit with the execution of that database. The site's strength is the candid, practical, often somewhat amusing tips it offers. For example, the site provides a suggestion on how to prepare yourself for being able to provide a urine sample when you arrive at a clinic, as well as where to sit on a bus to be the most comfortable when traveling long distances to a clinic (near the front so as to avoid exhaust fumes and the smell of the rest room). Once at the clinic, it suggests packing plenty of socks and underwear. "Some clinics strip search you down to your underwear. So be sure to wear underwear!"

There are message boards to which registered individuals can post questions, answers or their personal experiences at specific clinics, noting whether the food is good and the study staff are friendly. You don't need to register to view the messages. These boards don't seem to be heavily used yet, but they are available.

Overall, the site attempts to provide some useful information and links. It is obviously run pretty much on the energy, enthusiasm and effort of its host. And while it sometimes falters when navigating from page to page, it probably serves a useful purpose as an information node about clinical trials.

-Joe

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The Placebo Effect Strikes Again

2008-01-09T21:05:00.000-05:00

Every once in a while a clinical trial produces results that are difficult to accept. Such is the case with a study involving hotel maids published in the journal Psychological Science last year (February 2007, Vol 18, Issue 2). A recent segment of Morning Edition on National Public Radio brought the study to my attention.

The researchers began by measuring the maids’ weight, blood pressure, and body mass index, among other things. And they were all asked about their exercise habits. Interestingly, most reported that they exercised little or not at all on a daily basis. At this point, the maids were divided into two groups. One group was shown how the work they did daily as maids was, in fact, exercise and were told how many calories each of their daily routine cleaning activities burned. The other group (the “control” group) was not given this exercise and calorie information. But they were all observed for 4 weeks, at which time their weights, blood pressures and body mass indexes were measured again and they were again asked about their exercise habits.

What the researchers found was that the group given the exercise and calorie information actually lost weight and registered lowered blood pressure and body mass index, while the control group did not experience these changes. Because they were all observed, the researchers made sure that neither group was actually changing their daily routine.

What could possibly explain this observation?

In January of 2006, I blogged a couple of times on a phenomenon known popularly as "the placebo effect." The experiment with the hotel maids seems to provide evidence of a specific and rather amazing (to most people, at least) placebo effect. The fact that the one group of maids knew they were exercising somehow caused them to lose weight although they apparently did nothing extraordinary to change what they did or ate. The knowledge alone seems to have effected the change.

This study is not without its detractors. Even its authors agree more research is needed to answer lingering questions. But it does provide an example of how some clinical studies can lead to results that capture the imagination - of scientists and the rest of us.

By the way, the American Medical Association's policy on placebo use stipulates that their use by physicians is acceptable only when patients are informed of their use and agree to it.

It wouldn't be surprising to see further developments in this area of research and medicine over the next few years.

-Joe

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Research While Impaired?

2008-01-04T12:43:00.000-05:00

Have you (or a family member or friend) been involved as a research participant while your capacity to make decisions was impaired? If so, you have a unique opportunity to advise the federal government as it considers revising its regulations on research involving human subjects. There are 10 more days remaining for public comment - and yes, you are eligible to comment.

Normally, of course, potential research participants are provided with information about a clinical trial, in writing and usually also orally. If they decide they wish to be enrolled in the study, they are then required to read and sign an Informed Consent form. Some research necessarily involves participants who are decisionally-impaired. That is, due to long-term or temporarily low mental capacity, an individual is unable to adequately understand and weigh the risks and benefits of volunteering for the clinical trial. Examples of such research would include studies of behavior when someone is heavily under the influence of alcohol or drugs, studies of individuals with advanced Alzheimer's disease, and studies of the severely mentally disabled.

The Office for Human Research Protections is soliciting comments from the public through January 14. The original solicitation "Request for Information and Comments on Research That Involves Adult Individuals With Imparied Decision-making Capacity" may be found at http://www.hhs.gov/ohrp/documents/20070905.htm. This deadline represents an extension of the original December 4, 2007 deadline.

Many of the specific questions posted are directed at researchers themselves and at members of Institutional Review Boards (IRBs - the committees that review and approve clinical research at hospitals, universities and other research organizations). However, several of the questions solicit responses which should include those from actual research participants or their family or friends. I've listed some of those questions below, numbered as in the government posting:

1f. For research involving adult individuals with impaired decision-making capacity as subjects, how are subjects' potential or actual objections to enrollment or continued participation in research being addressed by investigators and IRBs?

1h. For studies that have included an assessment of potential subjects' capacity to consent, how has this assessment been used in the informed consent process? Are subjects notified when they have been found to lack capacity to consent? When informed consent is sought from such a subject's legally authorized representative, are potential subjects provided an opportunity to assent or object to their participation in the research?

1i. For research involving subjects who are able to provide informed consent, but are expected to have fluctuating, limited, or diminishing decision-making capacity during the course of the research study, what processes or procedures have investigators implemented, or have IRBs required, in order to ensure that the rights and welfare of such subjects remains adequately protected?

2. What problems or concerns have arisen for investigators, IRBs, or research subjects in the conduct or review of research involving decisionally impaired individuals as subjects?

2b. Please describe the process used when a legally authorized representative is asked to consent on behalf of a prospective research subject for research involving adult individuals with impaired decision-making capacity as subjects. Do the legally authorized representatives use substituted judgment (decisions that reflect the views of the individual expressed while decisionally capable) or the best interest standard? Which seems more ethically justified?

2c. How are advance directives for health care and for research used when a legally authorized representative is available?

2d. Have any problems or concerns arisen in regard to seeking consent from a legally authorized representative on behalf of a prospective research subject for research involving adult individuals with impaired decision-making capacity as subjects? If so, please describe the issues that have arisen.

4. How should the population of adults with impaired decision-making be defined for the purposes of guidance or regulation?

6a. If an adult with impaired decision-making capacity is capable of providing assent to participation in research, should the guidance or regulation indicate that the adult subject's assent should always be a condition for proceeding with the research? If there are circumstances when an adult subject's assent should not be necessary, what are those circumstances?

Your participation in this national dialogue may assist the federal government in hearing all sides of this issue. Your experience is at least as important as what researchers and IRBs will be telling the feds. And please, feel free to share your thoughts here as well.

-Joe

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Why Did She Do It?

2007-08-28T09:45:00.000-04:00

At first, I couldn't figure out why Jolee Mohr would take the advice of her rheumatologist, Dr Robert Trapp, and volunteer for a clinical trial of an experimental drug for inflammatory arthritis.

Jolee suffered from chronic inflammatory arthritis, a painful joint condition. Targeted Genetics Corporation, a molecular therapeutics company based in Seattle, was conducting a clinical trial of one of its pipeline gene therapy drugs - tgAAC94. The study was an early-phase study, primarily intended to test the safety of the drug. If it proved to be safe in humans, then further clinical trials would presumably be designed and conducted to demonstrate its effectiveness in relieving the symptoms of inflammatory arthritis.

The protocol called for participants to receive two injections, several months apart. The first treatment would be either the drug or a placebo, decided by chance according to the study design. The participant would not know which she had received. The second injection would be the drug for sure. Jolee received her first injection last February, with no significant side effects. Her second injection was administered by Dr. Trapp on July 2. On July 24 Jolee died of an unexplained massive infection.

The clinical trial has been suspended. The company and the Food and Drug Administration (FDA) are investigating. Jolee's husband and young daughter are left behind.

It is too early too tell for sure whether or not the tgAAC94 was the cause of Jolee's death, although the fact that she developed symptoms leading to her death very soon after receiving the second injection suggests a connection.

What I wondered, though, is why Jolee volunteered for the clinical trial in the first place? Why?
Because, even though there was a sentence in the 15-page consent form which stated that participants were not expected to receive any direct medical benefit from the drug, she believed there was a chance tgACC94 would help her. She believed this because scientists and physicians were developing this compound and had designed the study. Because the study was reviewed and approved by an Institutional Review Board and was being overseen by the FDA. And because her doctor, Robert Trapp, recommended it.

She didn't have a chance.

~Joe

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Is Someone In Your Inner Circle Making You Fat?

2007-08-24T21:11:00.000-04:00

One of the most highly-publicized clinical trials in recent history was published last month in The New England Journal of Medicine. The results of the study, conducted by Dr. Nicholas Christakis at Harvard Medical School and his colleague Dr. James Fowler at the University of California San Diego, suggest that obesity is spread among people having close relationships with one another.

Several thousand people in Massachusetts were studied over a 32-year period. Those who had a very close friend, a sibling or a spouse who became obese had a better chance of becoming obese than those who did not have a close relationship with someone who became obese. The risk increased by 30-60%, in fact!

This is not to suggest that obesity is spread in some kind of communicable way, although the authors did not totally dismiss that possibility. Rather, the research supports the idea that our social network - those people who are closest to us emotionally - influences whether or not we gain large amounts of weight.

The paper also gives several possible explanations for how this might occur. It's not that our obese friends, siblings or spouses "talk us into" gaining weight. The authors propose instead that we become more comfortable with the idea of obesity by having someone who becomes obese in our inner circle to observe closely. We may begin adopting some of the behaviors that may lead to obesity, such as overeating or not exercising. In this way, obesity "spreads" throughout a social network.

In addition to the subject of this clinical trial, the way it was conducted is interesting.

Did the researchers decide to start studying obesity in these people over 30 years ago and then collect data on them, including who their close friends, siblings and spouses were, as well as what those friends, siblings and spouses weighed? No. Instead, they used data available from an ongoing study that is decades old. Known as the Framingham Study because it began with individuals who lived in Framingham, Massachusetts, the original purpose was to study heart conditions in a large, connected population. That clinical trial generated a huge database of information on the medical status and progress of thousands of individuals including, of course, their weight. But how did Drs. Christakis and Fowler get the information on the individuals’ friends, siblings and spouses? The Framingham Study asked participants for information on family members as well as for a contact person who was not family. That contact person was considered to be a close friend.

I find it fascinating that this timely, topical piece of research was made possible entirely with existing information from people who volunteered for a completely different clinical trial, years ago.

~Joe

Risks and Benefits

2007-08-03T16:00:00.000-04:00

Institutional Review Boards (IRBs) are responsible for determining whether or not a clinical trial may be conducted and under what conditions. Hospitals, clinics, academic medical centers and the institutions that host clinical trials all rely on their IRBs to carefully consider what is being proposed, including who the research participants will be. One of the most important considerations involves comparing the risks and benefits of the proposed research - also known as the "risk:benefit ratio."

While this may sound very exact and quantitative, typically no calculations are involved. Rather, several aspects of the proposed clinical trial are examined to compare the benefits and risks of each.

First, is the science solid enough to reasonably lead to an advance in our understanding of the biomedical phenomenon being studied? Is the protocol (the way the clinical trial is designed) logically constructed? That is, are the costs or risks of doing the research justified by an expected yield of significant new information?

Second, are the discomforts and risks to the research participants reasonable when compared with the likely benefits to the participants and to society at large? Time spent, uncomfortable clinical tests and obnoxious side effects all contribute to the overall risk. Individual participants may benefit from closer health monitoring and potential improvement of their medical condition. Knowledge about curing or preventing the clinical condition being studied is a potential benefit to society.

The risk:benefit ratio cannot be reliably predicted for the individual research participant, however. (If it could, there would be no reason to do the research.) In fact, for an individual, the side effects of a medication being tested may be so severe that the individual perceives her participation to present a very unfavorable risk:benefit ratio.

The role of the IRB is to make sure the clinical trial is designed in such a way that the overall benefits are worth the overall risks. And if they are not, then the IRB must disapprove the clinical trial.

As for the individual - she must decide for herself whether the benefits are worth the risks. And she often doesn't have enough information to do that until her participation in the clinical trial has finished.

-Joe

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China's FDA Troubles

2007-07-24T20:08:00.000-04:00

Let's say a high-ranking US official, perhaps the commissioner of the US Food and Drug Administration (FDA), was found to have accepted bribes from pharmaceutical companies to give the FDA's stamp of approval on drugs that had not been sufficiently tested for safety and efficacy in humans. What's the worst that would happen to him (yes, it would probably be a him)? Perhaps he would be fired or asked to resign. He would likely be assessed fines. And he might even be sentenced to some prison time (although it's not inconceivable such a sentence would be commuted). Then he goes on the lecture circuit and eventually accepts a very highly compensated consulting position in industry. After all, he is an expert.

That is essentially the scenario that recently unfolded in China. Zheng Xiaoyu, the former head of China's State Food and Drug Administration, was convicted of taking bribes to give approval to market untested products, including drugs. As might be expected, problems were attributed to some of drugs, including a number of deaths.

Because China is concerned about establishing a global market position in the drug industry (as well as many, many other industries), it considers it critical to project an image as a reliable source of safe drugs. So what did it do?

It sentenced Zheng Xiaoyu to death. Zheng was executed on Tuesday, July 10.

~Joe

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New Rules for Publishing Clinical Trials

2007-06-19T18:27:00.000-04:00

Back in December of 2005 I mentioned the clinicaltrials.gov web site. This site, where many large multi-center clinical trials are registered online, was primarily intended to store information on research being sponsored by the National Institutes of Health.

That site, and several others like it, expanded considerably as a result of a 2005 policy implemented by the International Committee of Medical Journal Editors. The ICMJE, as it is known, is a very influential group of the world’s most prestigious journal editors. Much of the leading clinical research is published in these medical journals.

In 2005, the ICMJE established the policy that authors wishing to submit manuscripts for consideration in any of the ICMJE journals which described the results of clinical trials could only do so if the clinical trials were registered with one of the online clinical trial registries, such as clinicaltrials.gov. Since that policy was established, the number of clinical trials registered on clinicaltrials.gov more than tripled, to over 40,000 today.

The ICMJE was criticized for at least two major flaws in its policy. First, it did not cover the earliest kind of research, Phase I clinical trials, which are usually designed to test the safety of a new compound or device in a relatively small population of research participants. Second, because the policy required that results of the clinical trials also be published online, many manuscripts were turned down for publication because the results had, in effect, already been published (online).

Fast forward to June of 2007.

This month, the ICMJE updated its policy to include Phase I clinical trials. This means that, for any clinical trial in which participants are enrolled on or after July 1, 2008, even if they are only small trials designed to see how toxic a potential new drug is, they must have been registered online in order to be eligible for consideration as publications in any of the ICMJE journals.

Many physician-scientists who conduct clinical trials are interested in publishing their results in prestigious journals so they can progress in their academic fields. They will not be able to publish in ICMJE journals if the clinical trials they conduct have not been registered.

Why would they NOT want to register the trials in the first place? Such pressure usually comes from the drug company sponsoring a particular clinical trial. For strategic business reasons, companies do not want to give away any information on its research and development activities, especially so early in the process. Not only does it potentially tip the company's hand to competitors, investors may be scared away by published scientific reports of "failed" ideas.

The second perceived flaw in the ICMJE policy, the paradox created by requiring online publication of results, making those results less valuable for publication in journals, was also addressed. ICMJE journals will now treat results that are published in the same online registry in which the clinical trial itself was published as brief abstracts (brief being defined as less than 500 words) or as tables of data as though they had not been previously published at all. Therefore, the results, when submitted to the journals as fully developed scientific manuscripts, would be acceptable to the journals.

Yes, these represent baby steps. But they are baby steps forward and do represent movement toward greater transparency when it comes to testing compounds which will be used to treat people.

~Joe

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What the FDA Guidelines are Recommending

2007-06-05T16:30:00.000-04:00

This is the second of a two-part blog inspired by recent recommendations by the Food and Drug Administration (FDA).

The FDA's recommendations, published as guidelines on April 9 in the Federal Register for public comment, are intended to streamline the adverse event reporting process somewhat.

The idea is for adverse events to be reported to IRBs only when they are known to present unanticipated problems for the clinical trial. In other words, they must not have been anticipated when the clinical trial was developed and they must truly present a problem of some consequence to the clinical trial.

The guidelines further recommend that adverse events be reported in context and/or with some analysis that will enable IRBs to determine what implications, if any, the reports have on the continuation of the clinical trial and the safety of the research participants.

Administrative streamlining is generally a good thing, provided a critical step is not missed or information is not omitted. And providing context for data is also generally good.

The problem here arises with the FDA's suggestion that the entity providing reports to the IRBs is the clinical trial sponsor. It is true that if all of the reporting of adverse events that is currently required of investigators to the sponsor is done, then the sponsor is in the best position to identify a particular adverse event as an unanticipated problem. But what if a sponsor chooses not to do so, either intentionally or unintentionally, due to its overriding interest in bringing the product being tested to market?

Companies sponsoring clinical trials of products they own are already under tremendous pressure to see that the trials are finished as quickly as possible, as cheaply as possible and with as few adverse events reported as possible. Asking them to put individually-reported adverse events into context for the IRBs would seem to be asking for trouble.

At a minimum, in addition to submitting reports of adverse events (unanticipated problems) to IRBs, clinical trial sponsors should be required to post all adverse events received from investigators.

This posting could be done easily enough on the World Wide Web, and be made accessible only to those involved in conducting and regulating the clinical trial. The data should remain available for the duration of the clinical trial and throughout the FDA review process. Data would only be taken down if and when the sponsor withdraws its application for FDA approval.

Such open disclosure of all adverse event data would show how the sponsor interpreted the data of which it was aware, perhaps preventing some of the bias (recognized or not) resulting from the sponsor's financial interest.

~Joe

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FDA's New Adverse Event Guidelines

2007-05-30T14:50:00.000-04:00

Last month, the Food and Drug Administration (FDA) published a set of what it calls non-binding recommendations concerning when and how adverse events are reported.

In the world of clinical research the term "adverse events" refers to things that go wrong during a clinical trial. An adverse event may be caused by the drug or device being studied. It may be caused by the clinical trial itself, but not directly by the study drug. An adverse event may also be the result of a mistake made by the study team. In any case, researchers and those who regulate clinical trials are always on the lookout for adverse events - for lots of reasons. They may indicate that the drug or device being studied has side effects that may prove to be so significant that marketing, or even approval for marketing, becomes impossible. They may pose severe liability issues for the clinical trial sponsor. Most importantly, they are a sign that participants in the clinical trial are experiencing unwanted effects.

Existing federal regulations governing clinical research require all adverse events to be reported to IRBs - Institutional Review Boards that are responsible for reviewing, approving, and monitoring clinical trials at an institution such as a medical school or private clinic. As researchers and clinical trial sponsors have become more and more compliant with the reporting requirements due in some measure to enhanced FDA scrutiny, IRBs have become deluged with individual reports of adverse events. Such reports are often difficult, if not impossible to assess without analyzing the individual adverse event in the context of the entire clinical trial.

Even the existing definition of an adverse event as an "unanticipated problem" does not always help. While a severe headache may be considered an adverse event requiring reporting in a clinical trial of a drug for treating migraine, a single such report does not enable an IRB to determine whether or not there are global implications for the safety of research participants. Only if it became clear that severe headaches were being experienced by the research participants who received the study drug more often that those who received placebo and more often than the general population of migraine sufferers would it make sense for an IRB to consider taking some action regarding the study.

Next Time: What the FDA Guidelines are Recommending

~Joe

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Cost of IRBs

2007-05-22T07:45:00.000-04:00

Today, virtually all clinical trials are subject to oversight by Institutional Review Boards (IRBs). Members of the IRBs are experts in science, medicine and ethics and are responsible for reviewing the design of the clinical trials and for monitoring the way they are conducted as well as the results. While health care professionals and scientists employed by the institution served by the IRB usually make up the majority of the membership of that institution's IRB, there is also a requirement for participation by non-institutional members. Although most of the members are employees of the institution, they are frequently not paid extra for their service on an IRB. Rather, their service is considered a part of their duties as employees. Nevertheless, there are costs associated with maintaining IRBs.

A recent peer-reviewed study published in the journals IRB: Ethics & Human Research and Academic Medicine presents some idea of the costs of IRB oversight of clinical trials at US medical schools.

Half of the nation's 125 medical schools participated in the cost study, reporting their own costs. Of those, the authors of the study subsequently visited 10 of the responding schools to validate the accuracy of the self-reported costs.

The number of clinical trials conducted at the medical schools varied from a few to several thousand. The lowest reported total cast was $171,000 (per year). The highest was $4,700,000. Quite a difference. Much of that difference is due to the difference in size of the IRB operation at the institutions. When the costs were reported per clinical trial, the numbers varied from $300 to $500.

Probably the most significant question emerging from this study involves the difference in costs among institutions. Do some institutions spend more on reviewing clinical trials than others simply because they are less efficient in their review processes? Or does the quality of the reviews explain some of the differences? That is, do the institutions that spend more review the clinical trials more carefully? And, if so, does that greater attention to the research protocols translate into better safety records?

Those are questions for future research.

~Joe

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Professional Research Subjects: Issues to Consider

2007-05-03T14:25:00.000-04:00

Luca Volpi

The way our system of drug and medical device testing is set up requires the participation of human subjects. And early phase testing often calls for healthy participants, for at least two reasons. First, side effects are usually more easily observed and measured in healthy individuals because they are not masked or affected by other health problems. Second, healthy individuals are more likely to be able to tolerate obnoxious side effects.

While it may seem to be more efficient and effective to enroll in more than one clinical trial at the same time, it is almost never a good idea. Clinical trial protocols usually prohibit it because it confounds the science. It is nearly impossible to be certain which of two or more drugs are causing a particular reaction. Maybe they both are, but it is unclear how much each drug is contributing to the reaction.

More important than the science, however, is the safety issue for research participants. Many side effects or reactions would not occur at all, or are magnified, by a combination of drugs. We pay attention to this when we ask the pharmacist or doctor about taking more than one medication at the same time. But it's even more a concern for drugs that have not been extensively tested!

When the need or desire for income outweighs the volunteer's ability to fully appreciate the risk and dangers of participating, then clearly that individual is unable to give truly informed consent. Often, this causes the potential subject to lie about something, such as whether they drink alcohol, smoke, have headaches, or have a history of a particular medical condition in their family, in order to meet the criteria for enrollment in the protocol. For obvious reasons, this is dangerous for the individual. And it's another factor that negatively affects the science. Potential participants should be truthful when being interviewed for enrollment. And clinical researchers should develop protocols so that inaccurate responses by potential participants are detected.

Finally, participants should consult their personal physicians about volunteering for clinical trials - both before they enter the trial and for the entire duration of their participation. Being up front with your doctor will help her advise you in your decision to volunteer.

In summary, with adequate medical oversight, participating as a clinical research subject may be a viable way of earning money on an occasional basis. As a career, I'd say it's not only risky, but it promotes bad science.

~Joe

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Professional Research Subjects: Paid Guinea Pigs?

2007-05-01T07:55:00.000-04:00

The concept of earning something of a living by volunteering for clinical trials is not new. Clinical trials often pay volunteers to participate. Payment usually reflects to some degree the time required by the participant, as well as the discomfort and risk s/he will experience. A clinical trial requiring a 24-hour presence in a hospital setting to undergo safety monitoring for a drug which may have unpleasant side effects, for example, may pay several hundred dollars or more a day and may last a week or more.

This may be an appealing employment option for some, including the unemployed, those who are "between jobs," students, and others. Usually, the volunteers are healthy individuals, as required by the research protocols. Healthy, that is, until they subject themselves to potentially risky effects of the drug being tested. And that's the real challenge - balancing the desire of the subjects to enroll (for the money) and the desire of the researchers to enroll subjects against the risk (largely unknown both in nature and degree) to the subjects of enrolling in early phase testing.

That said, potential research participants and the clinical researchers who would enroll them should keep a few key issues in mind. Next time, I'll introduce those issues, which should also be of interest to health care providers of individuals considering volunteering for clinical trials.

~Joe

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FDA Denies Approval of Merck Arthritis Pain Medication

2007-04-27T12:38:00.000-04:00

On April 12, the Food and Drug Administration panel reviewing Merck & Co's application to market a new drug, Arcoxia (etoricoxib), recommended disapproving the application by a resounding 20-1 vote.

Does this result demonstrate that our system for testing the safety and efficacy of drugs is effective?

Arcoxia is in the same class of compounds as Vioxx. Remember Vioxx? Merck voluntarily removed Vioxx from the market in 2004 following publicity surrounding a number of deaths blamed on the drug. Merck is now defending itself against lawsuits brought by numerous affected individuals and their families.

In November 2006, Merck published the findings of a large clinical trial which it portrayed as demonstrating Arcoxia to be essentially equivalent to the most frequently prescribed drug for chronic arthritis pain, diclofenac, in effectiveness and in side effects. According to Merck, its drug had fewer gastrointestinal side effects, which it argued should make Arcoxia preferable and worth marketing.

The FDA panel, however, found that the reduced gastrointestinal side effects and its ability to relieve pain were overshadowed by cardiac side effects. Its findings, which are not binding on the FDA, will be considered as the FDA issues its final determination, expected soon.

If the vote were closer to even, rather than overwhelmingly against approval, the costs of the testing and analysis might be worthwhile. Such extensive review may not seem reasonable when it seemed so clear to the FDA's experts that the drug was just too risky to allow on the market.

And what about the thousands of participants in the clinical trials of Arcoxia? Have their contributions been for nothing? Maybe not, since patients will not be subjected to the drug's side effects.

As for Merck, its stock jumped 8% overnight, following the release of the FDA panel's recommendations on April 13. It seems that Merck's Friday the 13th announcement of good first quarter profits far overshadowed Arcoxia's apparent obituary in the minds of investors.

In the meantime, let's see what the FDA's final decision on Arcoxia turns out to be.

~Joe

Update: On April 27, Merck announced that the FDA has rejected Merck's application to market Arcoxia.

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Unapproved Drugs for the Terminally Ill?

2007-04-24T00:30:00.000-04:00

Marcelo Alves

If federal regulations change - and they are being reviewed by the FDA and the courts this spring - drugs that have not yet been approved for use will be made available to patients.

As the regulations currently stand, a physician can prescribe a drug that shows potential even though it has not received FDA approval if certain conditions are met.

The patient's condition must be "serious" or "immediately life-threatening."
Comparable approved and experimental treatment options must not be readily available to the patient for some reason.
The drug must have some potential to save the patient's life as shown in preliminary, ongoing clinical trials.
And (and this is the center of the current debate) the FDA must approve the use of the drug in the patient. This is done on a case-by-case basis - for what is known as "compassionate use" or "investigational new drug treatment" use.

It is the requirement for FDA approval that is being questioned.

Patient advocacy groups argue that the terminally ill should hold special status when it comes to experimental compounds that have not been fully tested in clinical trials. For those for whom all existing medications have failed, the opportunity for hope provided by drugs having the potential to prolong life should not be denied.

The pharmaceutical industry and the FDA raise several objections to this argument. First, the FDA approval process relies on sophisticated and relatively long-term science to assure that drugs that reach the market are both safe and effective. Second, the Big Pharma foresees numerous lawsuits against the manufacturers of compounds that prove to be unsafe, perhaps even dangerous. Finally, there are fears that patients will take this "easy route," making fewer individuals available for clinical trials.

Should the safeguards that are now in place to protect the market from drugs with significant life-threatening side effects be jettisoned for the terminally ill who may feel they have no choice but to gamble on a cure or improvement because their dire prognoses warrant the risk?

Perhaps this is not the real question. Perhaps the real question is exactly what value is the FDA's approval contributing to the existing decision-making process? If it is not adding significantly to the effort, then what is the harm in eliminating it?

Even if the FDA approval does not reflect a thorough case-by-case review of risks and benefits, the very fact that the requirements for approval are checked and documented, may be enough to keep the process honest and give terminal patients some legitimate hope.

-Joe

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Research vs Standard Medical Care: What's the Difference?

2006-05-09T21:31:00.000-04:00

Many clinical trial protocols involve a number of procedures. Some of the procedures are routine for the diagnosis, treatment or monitoring of the disease or condition involved. Those that are not routine, and those that are conducted in a way that is not routine, constitute the research-related (or experimental) procedures. Why are these distinctions between standard (routine) and experimental procedures important?

The first consideration is financial. If you are a patient who is a participant in a clinical trial, your medical insurance will usually cover those procedures that are routine for the disease or condition. Depending upon your insurance plan or the state in which you live, your insurance may or may not pay the expenses associated with the experimental procedures. It is important, then, to determine which procedures your insurance will cover and confirm that those not covered by your insurance will be paid by the clinical trial.

Second, and more importantly, the experimental procedures really represent the risk you will be assuming if you participate in the clinical trial. You will already have to undergo the standard procedures for your condition. By volunteering for the clinical trial, you will be signing up for some additional risks - those associated with the experimental aspects of the study.

Bottom line: If you're considering participating in a clinical trial because of a disease or condition you have, ask about which procedures are standard medical care for the condition and which are experimental.

-Joe

Related Links: Glossary of Terms Used in Clinical Trials, Benefits and Risks

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Why Your Doctor Wants You to Participate In a Clinical Trial

2006-05-01T21:34:00.000-04:00

You're in the doctor's office -- maybe it's the primary care physician you or your family sees all the time, maybe it's a specialist you've been referred to. Maybe you have a new condition you're concerned about, maybe you are just in for a routine physical. But, after examining you, the doctor says she thinks you would be a good candidate for a clinical trial and asks whether or not you would be interested.

You probably trust your doctor. To some degree, you have to -- whether you like her or not. She knows things you don't, so you put considerable trust in what she suggests.

So, before you register at the front desk for the guinea pig suite, you might wonder what's in it for your doctor? Why is she suggesting that you, her patient, be subjected to the risks and benefits of a clinical trial?

First of all, assuming she has your best medical interests in mind, she may have reason to believe that you will benefit medically by participating. If you're ill or have a particular condition the clinical trial is designed to treat, and if past and current therapies are not satisfactory or the side effects are bothering you, she may feel that the therapy being tested would offer you an opportunity to improve your health.

Second, her practice may be paid for every participant enrolled in the clinical trial. Such payment typically amounts to covering the expenses of administering the clinical trial. Bonuses or "finder's fees" are usually considered improper, although they are not unheard of. The principle most often followed is that any such incentive to the doctor or her practice not be so great as to cause her to pressure patients into participating.

Third, your doctor may feel that her practice would benefit generally from offering clinical trial opportunities to its patients. Perhaps the opportunities would attract new patients.

Finally, she may be interested in learning more about medicine and medical research by participating as an investigator in clinical trials. She will become familiar with the latest advances and will observe first-hand how such advances are translated into practice.

In different ways, all of the above reasons for your doctor's interest in clinical trials may well be to your advantage as a patient.

-Joe

Related Topics: Americans Want More Medical Research, Sorting Through the Latest Drug Studies

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The Business and Politics of PolyHeme

2006-04-16T17:05:00.000-04:00

Northfield Laboratories' web site says that the deaths observed in its elective surgery clinical trial were not due directly to PolyHeme. Apparently, Northfield also announced last month that one of the study's investigators, the principal investigator from Johns Hopkins, would be speaking at a conference on the data on PolyHeme. Northfield suggested that the Hopkins investigator would be commenting on the safety of PolyHeme and that the deaths observed in participants in the clinical trial were not caused by PolyHeme. The investigator and Johns Hopkins objected, saying on Hopkins' web site that the investigator would not be speaking on PolyHeme at the conference mentioned by Northfield.

Companies enlist experienced investigators at prestigious institutions such as Johns Hopkins for several reasons. They know how to conduct clinical trials and they have solid reputations for doing them. It is good for business to be able to say that the research data being used to back up a particular new compound were generated by researchers of the highest caliber.

Apparently, those participants enrolled by Johns Hopkins experienced no serious adverse events - like the deaths experienced at other of the clinical trial sites. How is it no one died at Hopkins? How does Northfield know that the deaths were not related to PolyHeme? And why does the Hopkins investigator not want to speak at the conference?

These are all important questions. But none of them can be answered without a thorough and transparent review of all data collected at all of the clinical trial sites. In the short term, even acknowledging the deaths will likely hurt business for PolyHeme and Northfield. But it will be difficult for Northfield to hold out for very long when well-respected investigators at premier research institutions are calling for release of the data.

-Joe

Related Topics: Clinical Trials: Take the Quiz, Newly-Approved Drugs (2006)

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What's the Deal with Northfield Laboratories?

2006-04-14T06:16:00.000-04:00

Apparently, Northfield sponsored a clinical trial of a technology it would like to market - a blood substitute called PolyHeme. The hope is that PolyHeme might be useful in situations where a supply of blood is needed, but is not readily available, such as where a traumatic injury has resulted in a significant loss of blood requiring an immediate, on-site, massive transfusion. The battlefield would be another likely site for this product.

Nineteen clinical trial sites were involved in testing the safety and efficacy of PolyHeme in patients who needed blood as a result of having elective surgery. It was reasonable to assume that such patients would be relatively healthy and able to withstand adverse reactions to the blood substitute, should there be any.

Some of the clinician-investigators at the nineteen sites have complained - to Northfield and publicly - that Northfield has not published the results of the clinical trial, which concluded in 2000. By failing to make all data from the study available to the scientific and medical communities, Northfield is depriving everyone of the knowledge generated by this research. The public good is not well-served when scientific information is generated but not shared.

Next time: The politics of business and science involved here.

-Joe

Related Topics: Rare Reactions Reported With Macugen, Cancer Vaccine Works Long-Term

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Clinical Trials In the Public Interest

2006-04-12T09:27:00.000-04:00

Who benefits from clinical research?

Obviously, individual participants stand to benefit from any particular clinical trial of a novel diagnosis or treatment. The new compound or method may be found to work safely and effectively on certain individuals. For those individuals, this may be the drug that cures them, or the one that makes their symptoms bearable, or that warns them they might be in the early stages of a condition that is curable if caught early on. Clearly, the most direct benefits are personal in such cases.

Groups of individuals with a condition or meeting certain criteria (such as the elderly or having a particular genetic background) may benefit from clinical research in less direct, but very significant ways. For them, the results of a clinical trial are necessary to improving the general approach to their condition.

In many cases, however, the benefits are even further removed and more abstract. Whether or not the primary hypothesis of the research is supported, solid information from the data generated by the clinical trial may be useful to the medical and scientific communities. It may not be obvious how such information would be of immediate use, but the availability of the information in the literature improves the chances that future research will be designed as intelligently as possible.

That's why it's incredibly important for the companies that sponsor clinical trials to display the utmost responsibility in collecting and analyzing data and in making it available.

Next time: Why a company called Northfield Laboratories is being criticized in this regard.

-Joe

Related Topics: Clinical Trials: Fact or Fiction Quiz, New Clinical Trial Matching Service for Breast Cancer

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