Parexel Misled Subjects Sickened in London Study, Ethicists Say
By David Evans
April 10 (Bloomberg) -- Parexel International Corp. hid risks from healthy volunteers enlisted into a clinical drug test in London that left six men fighting for their lives, say medical ethicists who reviewed confidential study documents.
The test subjects were the first humans to receive a laboratory-produced antibody drug in an experiment last month. TeGenero AG, a closely held biotechnology company that made the drug, and Parexel, which was hired to run the trial, are the focus of several British government probes.
The study also has attracted worldwide attention. Articles in medical journals like the Lancet and the British Medical Journal, and news stories, including one in the front page of the New York Times on April 8, say the mishap raises concerns about the safety of clinical trials run for pharmaceutical companies.
Ethicists shown the consent form, the document describing the experiment and its risks, say the document didn't sufficiently inform participants of the therapy's possible dangers or properly depict the treatment as a novel drug that can disrupt the body's immune system. The 13-page form also exploited the subjects' need for money, threatening to withhold the 2,000 pound ($3,500) payment if the men left the test early, the ethicists say.
``They failed to adequately disclose the degree of uncertainty around a first-in-man trial,'' said Michael Goodyear, a Canadian cancer physician and research ethicist. ``The risks were well known. They're not disclosed in the consent form.''
Goodyear, 59, and two other medical ethicists assessed the study's risk-disclosure form obtained by Bloomberg News. Parexel, a Waltham, Massachusetts-based company that conducts clinical trials for drugmakers, has declined requests to release the document. TeGenero, of Wurzburg, Germany, says it doesn't have a copy to provide.
Outsourcing Human Studies
``They hid the most serious risks with bland language,'' says Arthur Caplan, who directs the Center for Bioethics at the University of Pennsylvania in Philadelphia.
The study, which has left one man still hospitalized four weeks later, is drawing attention to a growing practice by drug companies to outsource to private contractors human studies that carry risks. Britain is conducting an investigation into the study. It also is assembling a panel of experts to review how drugs are first tried out in healthy people recruited with the promise of cash and other incentives.
Parexel says the company's own investigation found no wrongdoing. It says the British Medicines and Healthcare Products Regulatory Agency, or MHRA, ``has done an exhaustive inquiry of Parexel and confirmed that the trial was run according to the approved protocol.''
For-Profit Test Companies
The agency says its investigation didn't include a review of the consent form, which is used by researchers to explain details of the study's design or protocol to test subjects. Parexel and TeGenero declined to respond to other written questions for this story. Both companies declined to make their executives available for interviews.
Seventy-five percent of drugmakers' trials are conducted by for-profit companies like Parexel, according to CenterWatch, a Boston-based research firm. Fifteen years ago, 80 percent of drug-industry sponsored studies were run by academic centers, according to a May, 18, 2000 report in New England Journal of Medicine. Contract research organizations expect revenue of $14.4 billion in 2007, according to the Association of Contract Research Organizations, an industry trade group.
A Bloomberg News investigation last year found conflicts of interest and lax oversight in the U.S. for-profit drug-testing industry. The U.S. Senate's Finance Committee, citing Bloomberg, is now investigating the treatment of subjects in drug research.
When volunteers asked questions about the TeGenero study's consent form, the staff at Parexel's drug-testing facility in London's Northwick Park Hospital were dismissive, says Raste Khan, one of the participants. The 23-year-old university student was one of two people given a placebo, or dummy drug.
``The guy said, `We're in a bit of a push. Can you sign it now, and I'll explain it all to you,''' says Khan, who was interviewed in his London house on April 6. ``He didn't say anything whether the drug was going to be harmful or what it's been tested on.
``He was saying if you're ever late, you could lose 10 percent of your pay,'' Khan said. ``If you consume something or eat something or drink when you shouldn't, you could lose 10 percent of your pay. Most people do it because you need the money. It's a bit daunting.''
The 2,000 pounds, which Khan says he hasn't received, is about half of the amount of his student loan. The consent form says violations of Parexel's rules are ``misdemeanors'' subject to fines. The form also says participants will get the drug or a placebo. It doesn't say that 75 percent of the subjects would get the drug.
``They didn't tell us how many placebos there were, so I just thought it was 50/50,'' says Khan.
Parexel spokeswoman Jennifer Baird says these matters were handled properly. ``Best practices and policies and procedures were correctly followed,'' Baird said.
Ethicist Caplan, 56, says he considers it a ``major'' ethical violation to withhold the actual chance of receiving the drug. ``The subjects needs to be able to say these aren't odds I want,'' Caplan says.
The consent form describes the treatment as ``a `monoclonal antibody,' which means that it is an antibody (a naturally produced protein) that has been designed by scientists to target a particular type of cell -- in this case, a type of white blood cell called T-cells.''
``I've read a lot of consent forms and I don't understand this,'' says Caplan, noting that the description of the treatment was too confusing to expect volunteers to assess the dangers they were facing.
Parexel's consent form says the drug, called TGN 1412, was designed to treat arthritis, other inflammatory illnesses and leukemia. The form says that ``no significant side effects had been seen in the animal studies.''
``I think it was misleading not to tell participants that that this drug was genetically engineered from hamster cells and that it was designed to alter their immune system,'' Goodyear says. ``Reasonable people would think twice before allowing an experimental drug to change their immune system.''
Wyeth, a Madison, New Jersey-based drugmaker, in 2005 sold more than $1 billion of an antibody drug called Enbrel. It works against rheumatoid arthritis by moderating an overactive immune response that causes inflammation and damages joints. TeGenero says TGN 1412, was designed to act in an opposite manner by ``stimulating'' patients immune systems. There currently is no monoclonal antibody drug on the market that boosts the immune system, researchers in the field say.
``You don't put something in people's bodies' to turn something on until you know how to turn it off,'' says Goodyear, who wrote an editorial on the study published in the March 25 issue of the British Medical Journal.
Given to the healthy men, the experimental drug caused organ failure, according to a statement March 16 by Northwick Park Hospital spokesman Don Neame. The six were stricken within minutes of being given the drug at Parexel's trial site in London. Their bodies swelled as specialists tried to find ways to counter the drug's effect, according to a March 15 statement by Ganesh Suntharalingham, clinical director of intensive care at the hospital.
The volunteers knew the test had gone wrong within 20 minutes, Khan says. The men started to undress, even though the ward was cold, he says. They were grabbing their heads, and their breathing became erratic. Khan was sent to the canteen as nurses and doctors tried to relieve the men's pain. Khan says the man in the next bed pleaded for assistance.
``It was a horrible scream,'' Khan says. ``He was begging for help, saying `Doc, my head is killing me. My back is killing me.' He was moving around like a snake, arching his back.''
Two seriously ill volunteers spent two weeks in the hospital. All remain under doctors' care.
The participants in the Parexel trial were chosen because they were healthy. The study, a so-called phase I trial, looks at the safety and tolerability of the product, allowing scientists to find side effects in a small group of patients. Regulators require larger studies of people who have an illness to determine a drug's dosing level, efficacy and safety.
The consent document for a clinical trial should tell subjects precisely what the drug does and describe in detail its possible side effects, ethicists say. Volunteers should be free to quit at any time. The document shouldn't coerce them into staying in the experiment against their will.
Goodyear said the TeGenero drug's consent document omitted information for participants about what Parexel expected the treatment to do to their bodies.
``It doesn't actually say what it does,'' he says. ``This drug stimulates the immune system. I think `treatment of inflammatory diseases' is misleading,'' noting that aspirin and ibuprofen also treat some of these conditions.
On April 5, the British MHRA released the 58-page trial protocol, or formal trial plan, for the experiment and said the test was properly conducted. The MHRA didn't release the consent form for public review.
Parexel told MHRA investigators that the six subjects ``experienced a life-threatening incident of Cytokine Release Syndrome.'' Cytokines are human proteins that, when released by the immune system in large quantities, cause severe swelling.
Parexel's protocol document warns medical personnel that a ``cytokine burst'' could theoretically occur within the first few hours after infusion. Neither Cytokine Release Syndrome nor a cytokine burst was included as a possible side effect in the study consent form. It simply says a ``cytokine release'' is a ``theoretical'' side effect, ``causing a hives-like allergic reaction.''
``Since monoclonal antibodies are known to cause Cytokine Release Syndrome, which can be fatal, and Parexel was even planning for this, the subjects should have been warned,'' Goodyear says. ``They might have decided the risk wasn't worth 2,000 pounds.''
Parexel says the company did nothing wrong. ``The MHRA found no deficiencies during its inspection of Parexel's Phase I unit at Northwick Park Hospital that would have contributed to the adverse reactions experienced by the study volunteers,'' says spokeswoman Baird.
Need For Cash
Ethicists say the consent document exploited the participants' need for cash.
The first page of the consent document says participants can leave the trial at ``any time without giving a reason and my rights will not be affected.'' On page 9, the document says, ``If you leave the study and exercise your right not to give a reason or are required to leave the study for non-compliance, no payment need be made to you.''
``That's very coercive language,'' says Greg Koski, 56, a physician and former head of the U.S. Office for Human Subject Protection, interviewed by phone April 5. ``It's a bait and switch.''
Khan, who was studying to be a teacher at Roehampton University in London, grew up in small town in south Wales, and has lived in London for four years. He was attracted by the offer of quick and easy income, he says.
``It's such good money for a student,'' Khan said. ``It goes a long way.''
The rights of human subjects in clinical trials are protected by independent ethics committees, which can also reject experiments or halt them if they become too risky. They make sure risks are properly disclosed, and respond to inquiries from participants with concerns about the conduct of the trial -- when participants know where to call.
Parexel's TGN 1412 consent form omitted the name and contact information for the Brent Medical Ethics Committee, which approved the consent form and supervised the trial. It's an 11- member group under the auspices of the British National Health Service that meets monthly to approve clinical trials and review human experiments.
``The participant needs to know who to contact,'' says Caplan of the University of Pennsylvania. ``There has to be a source of independent advice. They are defeating the entire purpose of having an ethics committee if you can't find it.''
MHRA spokeswoman Silke Thomson, in an e-mail response to questions, said, ``There hasn't been and there won't be an investigation of the ethics committee or its work,'' including the informed consent document and the consent process.
Parexel's consent form advised subjects to read a pamphlet published by Consumers for Ethical Research, a London-based advocacy group. Naomi Pfeffer, chair of the organization, says the booklet shouldn't be used for healthy volunteers as it was written as advice to sick people considering treatment through a clinical trial.
``It's quite curious how we're being used as a way of making everything seem kosher,'' says Pfeffer, who is also a medical historian at London Metropolitan University. ``It's quite troubling. If they'd have contacted us, we'd have explained it wasn't about first-in-human trials.''
Ethicists say advertising used to recruit subjects is an extension of the consent document, subject to the same standards that require adequate risk disclosure. Parexel's London subject recruitment website, www.drugtrial.co.uk, discusses the benefits of participating in its clinical trials.
Under the heading, ``What's in it For You'' the site says: ``You'll have plenty of time to read or study or just relax -- with digital TV, pool table, videogames, DVD player and now FREE Internet access! You can even just catch up on some sleep!'' The site says the study will provide ``modern medical and monitoring equipment to ensure your safety whilst on trial.'' The company used this language to recruit for the TGN 1412 trial.
Goodyear says the language is deceptive, equating participation in a clinical trial to vacationing. ``I was blown away,'' he says. ``It's all about enticing people in.''
Parexel's recruiting Web site also promises payment, a free medical exam, and more. ``Free food for the duration of your stay
-- and NO shopping or washing up!,''' the site says.
``I'm outraged by that cavalier language,'' Caplan says. ``That would be fine if you want to recruit someone for a summer abroad, but not for a clinical trial with uncertain risks.''
Khan, who volunteered for a different clinic trial in December and was paid 1,600 pounds, says he wouldn't do another. A friend from college alerted him to the Parexel trial, and the advertising drew him in, he says.
``If you read the advertisements, they make it look like a holiday home,'' he said. ``It makes it sound fun and relaxing. I would never do a trial again.''