The trials (and tribulations) of drug trials

While two of the participants in the disastrous drug trial that came close to killing six volunteers have now returned home, four remain in hospital, one still in a critical condition. The near-fatal consequences of these recent trials have sparked calls for a radical overhaul of drug trials and the safety procedures involved in human testing. It also raises questions about the risks and benefits of clinical trial participation, and places the spotlight on informed consent.

Professor George Zimmer, a cancer patient who participated in a number of Phase I clinical trials, provided an interesting perspective on drug trial participation:
“Human participants in a protocol differ in two ways from the rats and dogs that preceded them. First, because human participants are not distinguished by breed, they do not have identical or blanket reactions to an experiment…Second, human patients have differing mental and personality characteristics…but the trials cannot compensate for the thoughts and emotions of individual participants. These important facets of the whole person are largely ignored when trial programs are designed” (Daugherty, Siegler, Ratain & Zimmer, 1997, p.892).

“Although Professor Zimmer describes personal experiences encountered during his battle against cancer, his views on how some patients respond to incurable illnesses certainly apply to many other terminal diseases. Zimmer raises serious questions about basic aspects of clinical trials…” (Daugherty, Siegler, Ratain & Zimmer, 1997, p.893).

His essay also highlights the importance of considering the unique particularities that each individual trial participant brings to the trial site. In HIV vaccine trials, for instance, there are unique social consequences of HIV infection that must be considered in the ethical analysis of vaccine trials. “People infected with HIV have experienced stigma, marginalization, and discrimination in many forms. Volunteers participating in HIV vaccine trials may be falsely identified as HIV-positive simply through their association with the trial…Thus, the risk of social and psychological harm for human subjects participating in vaccine research is substantial” (Guenter, Esparza & Macklin, 2000, p.38). And this coupled with the physical risks of participating in drug trial research – risks that have been clearly demonstrated in what appeared to be a test for a simple anti-inflammatory drug.

The ethical complexities involved in clinical human subjects research may be one of the factors that have slow down progression to the final step of randomized, controlled large-scale Phase III efficacy trials, despite the fact that many candidate HIV vaccines have proceeded to the point of testing for safety in human subjects (Phase I and Phase II clinical trials). Other challenges facing these trials are scientific, logistical, political, and economic (Guenter, Esparza & Macklin, 2000).

Meanwhile, few drug trials in South Africa seem to get past Phase I research. Could these challenges be part of what is slowing the trial process down? Or is the red tape of regulatory procedures compromising the medical research industry in this country? Clinical trials are pulling in up to R2-billion a year in South Africa, according to a recent report, but researchers fear the industry may be compromised by the slowness of regulatory authorities to approve, or reject, potential trials.

It is not unknown for multinational drugs companies to test unproven drugs on vulnerable subjects in the developing world. Because of this, South African regulators have to balance competing in a competitive international market with ensuring that trials participants are not exploited. But researchers are concerned that lack of human resources is slowing down the clinical trials registration process, encouraging companies to look elsewhere.


Daugherty, C.K., Siegler, M., Ratain, M.J., & Zimmer, G. (1997). Learning from our patients: One participant’s impact on clinical trial research and informed consent. Annals of Internal Medicine, 126, 892-897.

Guenter, D., Esparza, J., & Macklin, R. (2000). Ethical considerations in international HIV vaccine trials: Summary of a consultative process conducted by the Joint United Nations Programme on HIV/AIDS (UNAIDS). Journal of Medical Ethics, 26, 37-43.

Turns out sex selection *is* illegal in India

According to this article from BBC News, a physician and his assistant were arrested following a government sting operation designed to catch physicians who would assist women in identifying, and then aborting, famale fetuses. Although the practice has been outlawed for 12 years, this is the first time the government has prosecuted offenders.

A Virus Could Be Making You Fat...

Researchers at the University of Wisconsin are finding that viruses — specifically certain human adenoviruses — may actually be causing some cases of obesity. Adenoviruses are usually associated with common infections like colds and pink eye. They can also cause enteritis and diarrhea. But as nutritional scientist Leah Whigham says, "Those are the acute responses. We're e finding that some of these viruses also cause a more chronic response that involves increased fatness.

It would be unethical to test the suspected viruses in humans, so for now all of the evidence for their effect on people comes from associative data. Previous work done shows that in a randomly tested population, 30 percent of obese people had been exposed to one of the suspected viruses as compared to only five percent of lean people.

The Next Small Thing...11 key essays

The Center for Responsible Nanotechnology (CRN) today announced its first series of new research papers in which industry experts predict profound impacts of nanotechnology on society. Eleven original essays by members of CRN's Global Task Force appear in the latest issue of the journal Nanotechnology Perceptions, published today, and are also being posted online at KurzweilAI.net, which will host discussions on these vital issues.

From military and security issues to human enhancement, artificial intelligence, and more, these papers give readers a peek under the lid of Pandora's box to see what the future might hold.

An online forum for women in science ... finally

I wouldn't normally heap kudos on a company like L'Oreal. The cosmetic giant's marketing schemes are partially responsible for the self-esteem and body-image problems of an entire generation of women ... well, that and my gender's unreasonable expectation that our wives and girlfriends resist aging and remain fresh-faced pumped-up supermodels even as we males slowly morph into pot-bellied pigs with comb-overs and the need for PDE-5 inhibitors.

Still, it's nice to see that L'Oreal, in conjunction with UNESCO, has launched an open, online forum designed to support and highlight the role in women in science. As reported on the wonderful yet underappreciated news resource SciDev.net, the AGORA forum "will focus on topics such as science education for girls and women, women of science and sustainable development, bioethics and diversity."

Hopefully, this forum will not languish in obscurity like so many UNESCO projects but will become a dynamic community that supports the role of women in science and academia, and that leads even more women to demand greater (and equal) access to education, particularly in developing countries.

Sorry ma'am, you're HIV-positive...just kidding, no you're not: HIV Hoaxes and AIDS Legends

A tele-recruiter of the South African National Blood Service (SANBS) was suspended this week after falsely telling a donor that she was HIV-positive - a joke, he said later, intended to test her reaction. The 19-year-old donor said she was “utterly shocked and burst into tears…(and) then he said it wasn’t really true, that he just wanted to see how I’d react if he said something like that.” Knowing that she had engaged in safe sex, this donor had good reason to express disbelief and incredulity at the news she was given after donating her blood. But, given that many people – including well-educated donors – believe they can contract HIV from donating blood, one can see how rumors and myths around HIV are fuelled and spread.

In a study of attitudes and beliefs about blood donation in Nigeria, even well-educated donors believed that they could contract HIV or hepatitis from blood donation. Others were afraid of what they believed to be side effects of blood donation, including weight loss, sexual failure, convulsion and sudden death. One study of HIV and blood donation in the KwaZulu-Natal province in South Africa found that “despite very sound knowledge about HIV and high risk factors, significant proportions of respondents apparently fail to make a link between high risk behaviour and lack of suitability for blood donation…A secondary but disturbing finding is repeated indications among a small minority of respondents of a desire to spread HIV if they find themselves to be HIV-positive…”

The power of beliefs – factual and fictitious - around HIV/AIDS is explored by Diane Goldstein, in her book, Once Upon a Virus: AIDS Legends and Vernacular Risk Perception. Goldstein traces “the rich tradition of AIDS legends in relation to current scholarship on belief…Since reports of the first cases of HIV/AIDS in the early 1980s, contemporary, or "urban," legends about origins of the virus, modes of transmission, deliberate infection, withheld treatment, and minority genocide have proliferated…Though fascinating, intriguing, and often frightening, these narratives more than merely entertain. They warn and inform, articulate notions of risk, provide political commentary on public health actions, and offer insight into the relationship between cultural and health truths. As parts of community discourse about the nature of disease, legends provide powerful information about cultural understandings of the virus.”

Gillian Bennett (of the Folklore Society, UK) has written an interesting review of the narratives and topics explored in Once Upon a Virus. The first chapter of the book, “Tag, you’ve got AIDS: HIV in folklore and legend” explores some popular jokes, myths and children’s games involving AIDS references. Some of the issues reviewed in the “Bad people and body fluids: Contemporary legend and AIDS discourse” chapter include vernacular concerns about health, emergent meanings, tainted food and contaminated space, and deliberately infecting the other. “Banishing all the spindles from the kingdom” describes the legends of deliberate infection – the dangers of infected needles in cinema seats or of mad dancers who inject others in nightclubs – that “assert that the danger is not in the bedroom at all but ‘out there’ where we are all vulnerable.”

One wonders whether this latest tele-recruiter’s inspired idea of jokingly telling a blood donor she is HIV-positive has the potential to become another narrative of yet another chapter in the AIDS myths and urban legends book.

Synergy between Advocates of Environmental Justice and Women's Reproductive Health

Chinué Richardson has recently authored an article highlighting the opportunity and potential of collaboration between environmental justice advocates and reproductive advocacy organizations. It is a milestone for the Alan Guttmacher Institute to bring together the common interests of environmental justice, reproductive health and reproductive advocacy. See: "Opportunities Arise in Common Ground Between Reproductive Health and Environmental Justice". I learned of this article from CHE, an online collaboration between researchers, advocates, and citizens concerned with health and the environment. CHE is a model of an online collaborative project.

Women's Voices on Abortion Absent from New York Times

This news is from Salon.com. Staff at the American Prospect surveyed "the gender of the authors of Times Op-Ed pieces that dealt with abortion over the past two years -- including staff columnists -- and found that a shocking 90 percent were male. They wrote 83 percent of the articles that even mentioned abortion. And get this -- more Op-Eds on the subject were by pro-life men than by women of any persuasion." The Prospect reporter, Garance Franke-Ruta, suggests it reflects an editorial stance by Op-Ed editors. Of 124 articles that mentioned the subject, only 21 were written by women.

What's the difference between human and chimps? Gene regulation

The vast differences between humans and chimpanzees are due more to changes in gene regulation than differences in individual genes themselves, researchers from Yale, the University of Chicago, and the Hall Institute in Parkville, Victoria, Australia, argue in the March 9, 2006, issue of the journal Nature.

The scientists provide powerful new evidence for a 30-year-old theory, proposed in a classic paper from Mary-Claire King and Allan Wilson of Berkeley. That 1975 paper documented the 99-percent similarity of genes from humans and chimps and suggested that altered gene regulation, rather than changes in coding, might explain how so few genetic changes could produce the wide anatomic and behavioral differences between the two.

Using novel gene-array technology to measure the extent of gene expression in thousands of genes simultaneously, this study shows that as humans diverged from their ape ancestors in the last five million years, genes for transcription factors--which control the expression of other genes--were four times as likely to have changed their own expression patterns as the genes they regulate.

Because they influence the activity of many "downstream" genetic targets, small changes in the expression of these regulatory genes can have an enormous impact.

"When we looked at gene expression, we found fairly small changes in 65 million years of the macaque, orangutan, and chimpanzee evolution," said study author Yoav Gilad, PhD, assistant professor of human genetics at the University of Chicago, "followed by rapid change, along the five million years of the human lineage, that was concentrated on these specific groups of genes. This rapid evolution in transcription factors occurred only in humans."

"For 30 years scientists have suspected that gene regulation has played a central role in human evolution," said Kevin White, PhD, associate professor of genetics and ecology and evolution at Yale and senior author of the study. "In addition to lending support to the idea that changes in gene regulation are a key part of our evolutionary history, these new results help to define exactly which regulatory factors may be important, at least in certain tissues. This helps open the door to a functional dissection of the role of gene regulation during the evolution of modern humans."

To measure changes in gene expression from different species, White and Gilad developed the first multi-species gene array. This allowed them to compare the level of expression of more than 1,000 genes between humans, chimps, orangutans and rhesus macaques--representing about 70 million years of evolution. To make the samples comparable, the researchers studied tissue from the liver--one of the most homogeneous sources--from five adult males from each of the four species.

They focused their search on expression levels of two sets of genes, those that remained largely unchanged across all four species, suggesting that there was little room--or need--for improvement, and those that changed most dramatically, usually in the human lineage--an indication of powerful incentives to adapt to a changing environment.

Of the 1,056 genes from all four species, 60 percent had fairly consistent expression levels across all four species. "The expression levels of these genes seem to have remained constant for about 70 million years," the authors wrote, "suggesting that their regulation is under evolutionary constraint."

Many of these genes are involved in basic cellular processes. The authors suggest that altering the regulation of these fundamental and ancient genes may be harmful. In fact, five of the 100 most stable genes have altered expression levels in liver cancer.

When they also looked for human genes with significantly higher or lower expression levels, they found 14 genes with increased expression and five with decreased expression. While only 10 percent of the genes in the total array were transcription factors, 42 percent of those with increased expression in humans were. None of those with lower expression were transcription factors. This pattern, the authors note, is consistent with "directional selection."

Previous studies have found that many of these same genes have also evolved rapidly in humans, accumulating changes in their coding sequence as well as in expression rates. "Together," they add, "these findings raise the possibility that the function and regulation of transcription factors have been substantially modified in the human lineage."

This is a very efficient way to make big changes with very little effort, according to Gilad. By altering transcription factors, the entire regulatory network can change with very few mutations, increasing the impact and minimizing the risk.

"The big question," he said, "is why are humans so different? What sort of changes in the environment or lifestyle would drive such a rapid shift in the expression of genes--in this case in the liver--in humans and in no other primate?"

Part of the answer, he suspects, is rapid alterations in diet, probably related to the acquisition of fire and the emerging preference for cooked food. "No other animal relies on cooked food," he said. "Perhaps something in the cooking process altered the biochemical requirements for maximal access to nutrients as well as the need to process the natural toxins found in plant and animal foods."

This is just the first of a series of similar studies, said Gilad, that will look at changes in gene expression over evolutionary time. The next steps are to look at larger arrays of genes and to focus on other tissue types.

Additional authors include Alicia Oshlack, Gordon Smyth and Terence Speed from the Hall Institute in Parkville, Victoria, Australia. The study was supported grants from the Keck Foundation, the Beckman Foundation and the National Human Genome Research Institute to Professor White.

Too Poor To Be Sick

As my inaugural attempt at writing a blog, I thought that I would have trouble picking an IMPORTANT topic. Not a worry. The pharmaceutical industry was happy to oblige. The new Medicare part D was not confusing enough and the benefits of the various offered plans were not elusive enough. Now Merck has sold its rights to two cancer drugs, Mustargen and Cosmegen, to other companies and the price of the drugs has escalated exponentially – in one instance from $77.50 for a 2 week supply to $548.01 for the same amount (The New York Times, 3/12/06.) Even without a sale, the same article points out that Genetech will double the cost of its colon cancer drug, Avastin, so that the price tag will be about $100,000.

At these rates only the super rich can afford to get sick. Should the rest of us then fold our tents and simply prepare to suffer and or die? As an attorney, I understand clearly that corporations are in the business of making money and that their loyalties lie with their shareholders. But patients are not consumers and life saving or life restoring drugs are not commodities like cars. While many of us require a car in order to get to and from work or even to do our work, the car, as long as it runs and is safe, can be second hand, old, dented, whatever. That does not apply to drugs, especially drugs that can make the difference between life and death, or working or not working, or comfort or pain. It seems to me patently unethical to put the profit motive ahead of the human purpose. But so long as we allow industry to change the language to “consumer” and “product,” then the argument for more patient friendly approaches will fall on dead ears.

Corporations may not have a heart and a soul but as ethicists we must begin to change the vocabulary and dialogue to bring about affordable drugs along with accessible health care.

[Crossposted at Health Advocacyslc.blogspot.com.]

-- Alice Herb

Human Trials to start soon in Nanomedicine

From Technology Review this morning: The treatment begins with an injection of an unremarkable-looking clear fluid. Invisible inside, however, are particles precisely engineered to slip past barriers such as blood vessel walls, latch onto cancer cells, and trick the cells into engulfing them as if they were food. These Trojan particles flag the cells with a fluorescent dye and simultaneously destroy them with a drug.

Developed by University of Michigan physician and researcher James Baker, these multipurpose nanoparticles -- which should be ready for patient trials later this year -- are at the leading edge of a nanotechnology-based medical revolution. Such methodically designed nanoparticles have the potential to transfigure the diagnosis and treatment of not only cancer but virtually any disease.

Pacemaker for Depression: But Does it Work?

Eight months ago the Food and Drug Administration (FDA) approved a pocket-watch-sized device billed as "a pacemaker for the brain," the newest cutting-edge treatment for as many as 4 million adults whose severe depression is not relieved by psychotherapy, drugs or even shock treatments.

Since then, more than 550 Americans have undergone surgery to have a vagus nerve stimulator (VNS) implanted in their chests to activate parts of their brains. However, the only rigorous clinical trial of the device -- which is approved to treat severe epilepsy -- failed to demonstrate effectiveness in alleviating depression.

What happened to evidence-based medicine?

Obsessing about Drugs

The notion that brain chemicals play a powerful -- but hidden -- role in human behavior is at odds with American convictions about free will and choice; but an article in the Washington Post this morning more than suggests that chemical changes, brought by certain prescribed drugs, can lead to impulsivity, and destructive obsessive compulsive behavior like pathological gambling.

New evidence unearthed by scientists at the Food and Drug Administration, Duke University and other centers are looking into the possibility that dopamine, which is associated with a host of addictive behaviors, may turn some patients into obsessive pleasure seekers.

In a related matter, AJOB guest bloggers Christina Persaud and Yang Liu, do an excellent post on the ethical issues relating to nootropic and brain enhancement drugs.

Male Gametes or Manolo Blahniks?

Interesting article in the NY Times today about how buying sperm over the Internet is not much different from buying shoes. Single Mothers by Choice hosts 11 Listservs, each addressing a different aspect of single motherhood. Women around the world pore over these lists, exchanging tips and information, selling one another leftover vials of sperm.

How do the children born of these lists fare? A continuing study of a group of children in England, who were conceived by single women using donor sperm concludes that so far they are healthy and well adjusted. But the long-term questions of how these children will fare or about the different experiences of girls and boys have yet to be answered.

In a related story on CBS' 60 Minutes, an estimated 30,000 children per year are born in this country to mothers who have been artificially inseminated with sperm from an anonymous donor. Most of these children grow up never knowing their biological father — but now, with the help of sperm bank records and the Internet, some of them are finding half-brothers and half-sisters they never knew they had, who were sired by the same anonymous donor, forging family ties they never knew existed and re-defining the family relationships.

Ban on Blood Donation Revisited

The Food and Drug Administration is considering revising its policy that bars as a blood donor any man who has had sex with another man since 1977, officials said yesterday.

The change in policy is being recommended by the American Red Cross, the American Association of Blood Banks and America's Blood Centers, which collect virtually all the blood used for transfusions nationwide.

FDA May Launch Safety Review of RU 486

On the occasion of the tragic deaths of two women after having taken the abortion pill Mifepristone (Mifeprex™), also known as RU486, some Republicans in Congress are demanding that the Federal Drug Administration launch a special safety review of the drug. Anti-choice advocates are demanding that the drug be banned. Seven deaths in North America have been attributed to RU486 although over one million women in the world have used the drug safely. In an announcement on their www site , Planned Parenthood points out that “at this time, none of those deaths have been directly attributed to mifepristone.” The deaths may be the result of a fast acting sepsis, a blood infection, clostridium sordelli, “a common soil bacterium that has shown up in a small number of obstetric and gynecological cases, including following childbirth and surgical abortion...it has been identified as a cause of pregnancy-associated toxic-shock syndrome.” (ref) According to a spokesperson for the FDA, “four cases were women who had received this treatment vaginally, who then ... reported back to their physician with very serious, rapidly spreading infection which led to sepsis and death.” As a precautionary measure, Planned Parenthood announced that it would change the protocol for the second dose: “Our health centers will no longer recommend the option of administering misoprostol vaginally (misoprostol is the second drug in the two-drug medication abortion regimen). Patients will now receive misoprostol orally or buccally (where the pill is placed between the cheek and gum and dissolves). This change in protocol is effective immediately.” For information on the RU 486 debate see: http://www.religioustolerance.org/aboru486f.htm

More on Plan B and the FDA

Rep. Henry A. Waxman is still making noise about FDA's treatment of the Plan B studies and recommendation, as you can see for yourself here: his letter to Andrew von Eschenbach, President Bush's new nominee for FDA chief. The letter includes a nice overview of what actually happened during and after the scientific review, for those who are interested in the play-by-play.

Rep. Waxman keeps the pressure on FDA

Rep. Henry A. Waxman is still making noise about FDA's treatment of the Plan B studies and recommendation, as you can see for yourself here: his letter to Andrew von Eschenbach, President Bush's new nominee for FDA chief. The letter includes a nice overview of what actually happened during and after the scientific review, for those who are interested in the play-by-play.

Drug Trials Gone Wrong

Six people are in hospital, two critical, after participating in a clinical trial for a new anti-inflammatory drug in London, according to the Sky News report today. Alongside this report, a Sky News poll asks: should drug trials be banned on humans? One wonders how those who vote in favor of such a ban (a mere 13,6%, with 86,4% voting against a ban) expect to ever have access to new medical drugs that have the potential to ease suffering and save lives if the developers were not permitted to test these drugs on humans.

Nonetheless, this report comes after calls for more transparency regarding drug trial results as it is evident that drug companies are neither legally required nor ethically compelled to make all the data publicly available. In fact, according to an article published in the New England Journal of Medicine last year, several major pharmaceutical companies do withhold important details about clinical drug trials. Although a clinical trial registration website exists to monitor and track clinical trial results, it by no means makes it mandatory for drug companies to make public all findings from such trials.

So what went wrong in this London trial? Was it just a fluke, a drug that may have been safe in animals but evoked a negative reaction in humans? Or were the correct procedures not followed, resulting in the human administration of a drug that had not yet been declared safe for testing in humans? Authorities are now looking into the testing procedures: watch this space.

Fetal Origin of Disease Hypothesis

According to an author writing in the London Times , Roger Dobson, the time spent in the womb may influence whether folks suffer, years later, from cancer, obesity or heart disease. A research program working under the “fetal origins of disease” hypothesis suggests that diseases may originate through fetal adaptations to under-nutrition, over-nutrition or unbalanced nutrition, or to other environmental changes. According to Dobson, the debate now is not so much about the validity of the theory, as to how strong its effects are, and how they can be changed. This does not seem to be accurate, however, because there are fatal statistcal problems with these kinds of analyses, say other scientists.

The theory, first put forward by researchers at Southampton University, is that the fetus responds to an adverse environment by re-setting its growth plans to prepare for a life in a deprived environment. But if that environment turns out not to be deprived it is not best equipped to survive. Fearing that life outside the womb is going to be as deprived as it is inside, the fetus may, for example, create a level of insulin resistance that allows survival in times of famine through efficient storage of fat in rare times of plenty. But in a postnatal world of constant plenty, that set-up would lead to a greater risk of obesity, diabetes and heart disease. Research shows that babies conceived during the Dutch famine (1944-1945) were more prone to heart disease and obesity.

Most human disease is the result of the interaction of genetic susceptibility and environmental factors. While most research has looked at environmental effects after birth, studies at Southampton University and elsewhere claim that the 266 or so days from conception to birth is the time when much of what will happen during the decades ahead is determined. The mother’s diet, hormonal changes, changes in the placenta, maternal exposure to disease and toxins and the general weight, fitness and lifestyle of the mother are all said to contribute.