Sunday, January 2, 2011

Drug Companies at Work: Subprime Clinical Trials

The term “subprime” has become a familiar adjective used to describe an enterprise with the following characteristics. The participant with ultimate responsibility for quality disburses that responsibility to a for-profit entity with no long-term interest in the endeavor. To be completely analogous to the subprime mortgage debacle one must also be preying on the poor and unfortunate, and making a few people fabulously wealthy. It is disturbing to learn that this sort of pattern has established itself in the medical industry where pharmaceutical companies are using similar methods to get drugs approved for use.

A recent article by Carl Elliott in the London Review of Books, The Torture Economy, discusses this activity. Elliott’s presentation is motivated by the appearance of three books addressing various aspects of clinical testing and the associated implications. The titles describe the relevant focus.
Medical Research for Hire: The Political Economy of Pharmaceutical Clinical Trials by Jill Fisher
Rutgers, 257 pp, £23.50, January 2009, ISBN 978 0 8135 4410 6

When Experiments Travel: Clinical Trials and the Global Search for Human Subjects by Adriana Petryna
Princeton, 258 pp, £18.95, June 2009, ISBN 978 0 691 12657 9

The Professional Guinea Pig: Big Pharma and the Risky World of Human Subjects by Roberto Abadie
Duke, 184 pp, £15.99, October 2010, ISBN 978 0 8223 4823 8
Elliott points out that the public knows little about how clinical trials are actually performed, and that any preconceptions are likely to be wrong because the process has changed dramatically in recent years.
“Over the past 20 years or so, without much fanfare, clinical research has undergone a remarkable free-market conversion. Until the early 1990s, most pharmaceutical research on human subjects was conducted by physicians in universities and teaching hospitals. (The FDA, which must approve drugs before they can be marketed, doesn’t conduct clinical trials itself.) However, pharmaceutical companies have been in search of cheaper, more efficient venues and today about 70 per cent of clinical trials take place in the private sector, often in the offices of private physicians or at dedicated sites. Clinical research has become a multibillion-dollar global industry, spawning spin-off businesses that barely existed 25 years ago, from patient recruitment firms and medical communication agencies to for-profit research ethics boards. The most important new players are contract research organisations (CROs) such as Parexel, Quintiles, PPD and Covance, which have built themselves into corporate giants by taking up the management of clinical trials. The research that many of us used to imagine as a humanitarian enterprise, carried out by selfless scientists and funded by Pink Ribbon campaigns and ‘Race for the Cure’ marathons, is actually a thoroughly Taylorised corporate system, outsourced and streamlined for maximum efficiency.”
There are plenty of indications that this is an area where things can go wrong.
“In Miami, investigative reporters for Bloomberg Markets magazine discovered that a contract research organisation called SFBC International was testing drugs on undocumented immigrants in a rundown motel; since that report, the motel has been demolished for fire and safety violations. Several pharmaceutical companies have been caught up in controversial cases of suicide, such as that of Dan Markingson, a young man who stabbed himself to death while taking Seroquel in an AstraZeneca trial at the University of Minnesota, and Traci Johnson, who hanged herself in a study of Cymbalta at the Eli Lilly trial site in Indianapolis. Britain had its own disaster at Northwick Park Hospital in north-west London, where six healthy subjects nearly died in a ‘first in man’ study of a monoclonal antibody. And Pfizer has spent longer than a decade dealing with the fallout of a study in Kano, Nigeria, in which 11 children died during a meningitis trial allegedly rigged to show that the antibiotic Trovan was superior to a competitor’s drug. The Trovan case has wound its way through various courts for years, generating millions of dollars in damages and a stubborn public relations problem for Pfizer.”
A system in which multiple participants can make large amounts of money while burdened with little responsibility is begging to be abused.
“What interests Jill Fisher, Adriana Petryna and Roberto Abadie is not so much the occasional outrage uncovered by investigative reporters, or even the formal regulation of clinical trials. They are more concerned with the everyday pressures and moral choices facing the workers who man the production line: the private-sector physicians who conduct the trials, the study monitors and trial co-ordinators who oversee them, and the research subjects who take experimental drugs, often in exchange for free medical care or a wage. What does clinical research look like when everyone is in it for the money?”
Elliott steps us through all the opportunities for abuse. Let’s start with the for-profit contractors.
“Contract researchers may find that their sponsors do not welcome bad news about the trials, especially if the drug appears unsafe. Reporting that subjects have experienced a ‘serious adverse event’ (industry-speak for the worst side effects) may mean losing the contract. One physician told Petryna she had done a clinical trial on a drug that appeared dangerous, but when she documented her concerns and recommended redesigning the trial, the sponsor ignored her and successfully submitted the drug for approval. The drug was later withdrawn from the market. ‘We never got a contract from that manufacturer again,’ she adds.”

“Institutional review boards, the quasi-regulatory bodies charged with overseeing the ethics of clinical trials, are often for-profit companies paid by the sponsors of the research they are evaluating. If one review board says a study is unethical, the sponsor can simply take it to another one.”
Is there anyone who does not see the similarity between these review boards and the rating agencies that were paid by financial institutions to label garbage as high quality investments?

Now consider the participation of the doctors.
“A contract researcher does not come up with original ideas, or design research protocols, or analyse research results, or write them up for scientific publications. All of this is done by the pharmaceutical company or its hired specialists. What a contract researcher does is recruit subjects, monitor their clinical care and sign off on the paperwork. Not a lot of original work is done, and in some cases, not much work at all (a running joke has it that physicians do clinical trials in order to improve their golf games). The industry term for these near absent physicians is ‘phantom investigators’. Usually they will ‘come in on a daily basis, on most days, and they’ll sign off on all the things they need to sign off on, see any patients they need to see, and they’re gone,’ a study monitor says to Fisher. The researchers are usually on-site for no more than an hour or two a day.”

“Contract researchers may not do much intellectual work, but this doesn’t mean they are not well paid. A part-time contract researcher conducting four or five clinical trials a year can earn an average of $300,000 in extra income. In 2000, a full-time clinical trial site earned an average of $1.6 million. According to Fisher, any given service will generate between two and five times as much money for a physician when a pharmaceutical company is paying the bill as when a health insurance company or a government agency is paying. Even an ordinary office visit will be paid at twice the usual rate if the visit is part of a research study. Some physicians sign up as contract researchers for the same reasons they might peddle nutraceuticals or dispense cosmetic Botox injections. It is a way to make extra money.”
At what point does paying people more than they are worth reach the ethical status of bribery? If we continue the mortgage analogy, doctors would seem to play the dual role of mortgage salespersons and packagers of financial instruments. In either role, there is not necessarily much personal responsibility involved.

There are plenty of companies who will contract to perform services for the drug industry, and plenty of doctors willing to be purchased. As in the mortgage case, profit ultimately depends on recruiting subjects for testing. This is the area in which the for-profit approach becomes most ethically challenged. What is a sick person with no means of affording standard treatments to do when a doctor, who is paid to recruit subjects, suggests “free” treatment, or even treatment for which they can earn a little money? And with such a large demand for subjects, how much pressure is there to needlessly draw in participants.
“However, the most valuable commodity in the contract research business is not the physician. It is the patient: ideally, the sort of patient that the industry calls ‘ready to recruit’. Ready to recruit patients are sick people who can easily be persuaded to enrol in clinical trials, often because they are so poor that they have no better alternative. If a patient can be persuaded to enrol in a study quickly, so much the better: drug patents last only 20 years, and the patent clock ticks down while the drug is being tested. Four out of every five clinical trials are forced to extend their timelines because of recruiting delays.”

“For years the demand for research subjects has been growing, driven not least by the sheer number of clinical trials being conducted in the desperate search for new blockbuster drugs. Nobody really knows how many trials the industry is currently conducting, but a WHO official estimates that 20,000 are initiated each year. They are getting larger and more complex, partly to satisfy safety regulations, but also because many of the drugs being tested are so similar to drugs already on the market: if a new drug is only incrementally better than a control drug or placebo, demonstrating a statistical difference requires many more research subjects. The pool of potential subjects is gradually becoming depleted, in part because so many subjects in North America and Western Europe are taking other medications, which will often exclude them from enrolling in trials. Drug companies need ‘treatment-naive’ subjects, who, like the ‘ready to recruit’, are easier to find in the developing world. In 1991, only 10 per cent of clinical trials were conducted in emerging markets; by 2005, that figure had increased to 40 per cent.”
So those performing the clinical trials are motivated to move to regions in the world where the people are poorer, have even less medical care, and the doctors who recruit them are even more interested in the money they can make from this process. Not surprisingly, these contractors eventually face increased public awareness and move on to ever poorer areas.

Elliott provides a succinct summary of why we should be concerned.
“By turning clinical research over to the market we have created a system in which private physician-investigators can make far more money persuading their patients to enrol in research studies than by simply treating their illnesses; in which patients sign up to test new drugs, either because they need the money or because they have no way to pay for ordinary healthcare; in which investigators are financially punished for telling companies that their drugs are risky or dangerous; and in which even ethical oversight has become a revenue-generating mechanism. Lost in this business model are the human research subjects themselves. As a CRO manager in Eastern Europe tells Petryna, apparently without irony: ‘We don’t see patients, we see data.’”
There were some participants in the mortgage industry who performed their tasks in a dedicated and ethical fashion, but not enough of them to prevent a disaster from occurring. I fear we face a similar situation here where there is sufficient reckless behavior that eventually we will face not massive financial losses, but rather, a massive health care problem.

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