Lawyers for Victims of TGN 1412 Trial Criticize Parexel Chief's Bonus

We have previously posted, most recently here, here, and here, about the disastrous trial, implemented by Parexel International , of a new monoclonal antibody designated TGN 1412, manufactured by TeGenero AG, which is now bankrupt. After the bankruptcy, the focus has shifted to the role played by Parexel International. Here we noted additional concerns about how well the company protected its research subjects in this trial and whether a company with a"commitment to providing solutions that expedite time-to-market and peak market penetration" for pharmaceutical and biotechnology companies has the right set of priorities to be conducting clinical research on real human subjects.

The British Broadcasting Corporation (BBC) just reported that a lawyer for the victims of the TGN 1412 trial said "the cash and share bonus package awarded to Parexel chief executive Josef von Rickenbach had 'incensed and outraged' his clients. [Attorney Gene] ... Matthews said: 'The timing of this really couldn't have been worse.' According to accounts released by Parexel, Mr von Rickenbach - who founded the clinical research organisation and is also its chairman - got a cash bonus of $286,157 and share options worth $1,469,490 this year."

Also, "Mr Matthews said his clients were 'bitterly disappointed' at the payment made to Mr von Rickenbach. He said: 'This payout comes at a time that's very close to what happened to these men, in the same year. They haven't received any compensation apart from the £10,000 payment for immediate medical expenses. They are struggling with their finances and their health and that's made even more difficult when executives are getting bonuses of that size. It's very much insensitive.'"

Another of the lawyers for the trial victims, Martyn Day, said "It is astonishing that they are prepared to pay the chief executive this sort of money, at a time when they are refusing to sit round the table with the guys who have been injured."

In the US, where "pay for performance" plans for business executives have often been criticized as actually unrelated to their recipients financial peformance, and hence amount to "pay for pulse," it is not very surprising that a contract research organization failed to adjust its CEO's pay for the quality of the research trials it was carrying out.

However, this continuation of the tragic case of the TGN 1412 trial illustrates how misplaced are some of the incentives built into the US (and other developed nations') health care system. From a business standpoint, the long-term health of a company might be improved if its leaders were paid not only acording to the company's financial performance, but also according to the quality of the goods and services it provides, and its reputation in the marketplace. The long-term health of the people might be improved if leaders of health care organizations were paid not only according to their organizations' financial performance, but according to how well they treated the patients entrusted to them.

Were the "Elephant Men" Given TGN 1412 Infusions Too Fast?

We have posted frequently, here, here, here, and here, about the disastrous trial, now colloquially known as the "elephant men" trial after the bizarre clinical effects it produced, implemented by Parexel International , of a new monoclonal antibody designated TGN 1412, manufactured by TeGenero AG, which is now bankrupt. Last week, the Times (UK) found new information suggesting another hypothesis about what went wrong.

A "reckless” mistake apparently overlooked by government regulators lay behind the drug trial disaster that saw six young volunteers badly injured by an experimental medicine.

Confidential documents obtained by The Sunday Times and Channel 4’s Dispatches programme reveal the drug was administered on average 15 times more quickly to the volunteers than to monkeys in earlier safety studies. The possibility that such a crude error led to the disaster is likely to raise questions over whether the government’s Medicines and Healthcare products Regulatory Agency (MHRA) scrutinises trials adequately and protects the public from the risks of new medicines.

Experts say the drug, TGN1412 — one of a new generation of “magic bullet” treatments targeting the immune system — was infused so quickly into the volunteers that the potential for life-threatening problems was foreseeable.

'When you give an antibody . . . the quicker you put it in, the more likely you are to get an infusion reaction,' said Professor Terry Hamblin of Southampton University, a leading authority on monoclonal antibodies, the family of drugs to which the trial medicine belonged.

The volunteers were given TGN1412 in only three to six minutes. 'To quickly infuse it over three to six minutes in six individuals I think is . . . reckless,' said Hamblin.

Hamblin’s judgment is backed by other experts, including Dr David Glover, formerly chief medical officer of Cambridge Antibody Technology. He concludes: 'The drug was given too quickly.'

The speed at which the monkeys received TGN1412 was set out in the application to the MHRA for permission to carry out the trial. This was submitted by Parexel International, a contract research company, on behalf of TeGenero, a tiny German drug developer. But the paperwork did not explicitly detail how quickly the volunteers would be given the drug, although this could be calculated from the information given.

Parexel declined to comment.

And TeGenero is now bankrupt.

Obviously, whether an excessively rapid infusion of TGN 1412 lead to the terrible results of this trial is unproven. Hopefully, some sort of more detailed official inquiry might come to more definitive conclusions. Yet, as we said in a previous posting, "clearly, this article raises concerns about whether Parexel could have done a better job protecting its research subjects. Minimizing the risks to human research subjects should be the highest priority for those who do clinical research."

Parexel's web-site page on clinical research services states,

Your success depends on your ability to move your product concept from early research through clinical trials and regulatory review to the market in the shortest possible time. The bottlenecks and hurdles in your path, both known and unknown, must be identified and eliminated. Over the past two decades, PAREXEL has helped nearly a thousand clients find success.

Maybe the company's focus on speed hindered its ability to protect its research subjects.

In my humble opinion, it is time to re-think whether clinical trials of drugs and devices should be designed by the companies that make the products, implemented by for-profit contract research organizations, and supervised by for-profit "institutional review boards," as they are called in the US. If we continue these practices, we clearly need to think how to regulate them. Better yet would be to have these trials done by independent organizations who are not beholden to the manufacturers and whose missions include a priority on protecting their human research subjects, and then who are supervised by reviewers with similar independence and similar commitment to patient welfare.

WHAT YOU CAN DO: In the US, write your Representative or Senator, in the UK, contact your MP, and ask for a legislative review of how clinical trials of drugs and devices are designed, implemented, and supervised, with emphasis on scrutinizing the influence of the manufacturer (who want their products t0 look good), and the contract research organizations and for-profit review boards that serve the manufacturers.

The Parexel Blues Again

A number of concerning reports have appeared about the international contract research organization Parexel International.

We have previously posted, most recently here, here, and here, about the disastrous trial, implemented by Parexel International , of a new monoclonal antibody designated TGN 1412, manufactured by TeGenero AG, which is now bankrupt.

The International Herald Tribune summarized some new information about how the trial was conducted, focussed on the Parexel's conduct.

In recent weeks, experts said, new medical tests and investigations into the incident have highlighted loopholes in a drug testing system that in some instances is better designed to bring drugs to market than to protect humans, particularly when it comes to some of the newest medicines.

[An interim report on the trial by Professor Gordon Duff] called for reviews 'to examine how risks in medicine development are currently assessed and minimized' by drug makers.

Indeed, although the innovative drug being tested, TGN1412, was a potent immune system stimulant that overrode the body's normal regulatory mechanisms, it was tested according to much the same standards that govern far more ordinary pharmaceuticals.

British regulators approved the TGN1412 trial in just 17 days and the testing company did not have an adequate response plan for adverse reactions, regulators have said.

The American-based testing company that conducted the trial, Parexel International, of Waltham, Massachusetts, has said repeatedly that it carried out the trial according to "appropriate policies and procedures."

Parexel, a world leader in contract drug testing, with centers in the United States, Europe and Africa, said it could not provide further information.

The British drug regulators who reviewed the trial performed those duties according to accepted standards and to the best of their ability and so have no liability, lawyers said.

All parties did their jobs according to formal regulatory and legal requirements, narrowly defined.

But, in retrospect, almost all scientists agree that those requirements were inadequate for TGN1412 and that common sense would dictate different testing practices.

Day [the lawyer for four of the TGN 1412 trial subjects] said he would argue that Parexel, which contracts with drug makers to test new medicines, should have made sure that its client had adequate insurance. He also questioned the design and conduct of what it should have seen as a delicate trial, he said.

They gave the six research subjects infusions of new and unknown drugs only 10 minutes apart, so that there was no time to screen for serious side effects.

In addition, Day said, the men should have immediately been given high doses of steroids for the disastrous reaction that TGN1412 precipitated. He said that such a reaction was noted as a possibility in the study's official protocol.

The six [TGN 1412 subjects] were not moved from the Parexel Research wing to Northwick Park's intensive care unit for up to 16 hours, despite severe symptoms.

In testimony before the British expert review panel, the intensive care doctors said that while they were aware that the patients seemed to be having an inflammatory reaction, the Parexel team did not inform them of the possibility of a cytokine 'storm' until hours after the patients reached the intensive care unit.

Clearly, this article raises concerns about whether Parexel could have done a better job protecting its research subjects. Minimizing the risks to human research subjects should be the highest priority for those who do clinical research.

Parexel International, meanwhile, is also involved in a countroversy about another trial in the UK. The BBC just reported

Leading scientists have raised serious concerns about a major government study into the effectiveness of drugs used by thousands of people with MS.

The study was originally being conducted by an established team at Sheffield University.

But it has been switched to Parexel - a company with commercial links to three of the four pharmaceutical companies involved in the study.

The original contract to evaluate the progress of the thousands of MS patients on the scheme was given to the Sheffield team.

However, sources have told the BBC that the contract was re-tendered last year following a dispute over the university's right to publish independently on their findings. [Editor's note - it is unclear whether this has anything to do with the controversy about Sheffield's firing of Dr Aubrey Blumsohn after he went public about his difficulties getting access to data from his own research study, see most recent post here.]

Sir Iain Chalmers, editor of the James Lind Library, which reviews scientific research, is uneasy about the decision.

He said: 'I think it's a totally unreasonable expectation, that information which may be important to patients and prescribers should potentially be suppressed because a company does not find it in its interests to see it made public.'

One of the pharmaceutical companies involved in the scheme has denied that any of the research will be suppressed, even though each company in the risk sharing scheme has the right to decide if any research involving their own drugs should be published.

Pete Smith, managing director of Biogen Idec in the UK and Ireland, said: 'It may look like a veto but it really isn't a veto. 'We are very confident that our drug is going to demonstrate its value here in the UK and to those patients who are in need of care and we are quite frankly looking forward to those results being published at the completion of this study.'

The scheme was being overseen by a project management group that included the MS Trust charity, four pharmaceutical companies, the Department of Health and several others including scientists and academics.

However, the BBC understands that the group as a whole was not consulted about the decision to appoint Parexel, which was taken instead by the drugs companies, the Department of Health and the MS Trust.

This article raises concerns whether results from a trial to be run by Parexel International could be selectively suppressed were such results to threaten the interests of any of the commercial sponsors of the trial. Selective suppression of undesired research results would violate the integrity of the clinical research data base, and insult the altruism of the people who volunteered as research subjects thinking by doing so they would be contributing to science and the advancement of health.

It is more disturbing that while this was all going on, a recent announcement by Parexel International emphasized its "commitment to providing solutions that expedite time-to-market and peak market penetration."

Did this need for speed account for the (in retrospect) badly taken decisions about the design of the TGN 1412 trial? Will haste lead to waste, or worst, in the new multiple sclerosis trial?

More broadly, what are the real goals of contract research organizations? Should they be entrusted to protect their study subjects, and to ensure that their voluntarism is honored by he complete and honest dissemination of the results they helped to generate?

A FINAL IRONY: the announcement noted above was of the newest member of the Parexel board of directors. She is Ellen M. Zane, " President and Chief Executive Officer of Tufts-New England Medical Center (Tufts-NEMC) and Floating Hospital for Children, located in Boston, Massachusetts." She also "serves on the Board of Overseers at the Tufts University School of Medicine." Since Tufts University School of Medicine and Tufts-New England Medical Center are major sites for clinical research, the potential for conflict of interest here is obvious.

Updates on Commercially Sponsored Drug Research: "A Morally Flimsy Foundation to Advance Medical Knowledge"

There are new developments in several stories we have been following about commercially sponsored drug research done on human subjects.

Studies on Ketek (Telithromycin) Done by Pharmaceutical Product Development for Sanofi-Aventis

We recently discussed how results of study of Ketek (Telithromycin) done by Pharmaceutical Product Development for Sanofi-Aventis may have been affected by misconduct, including one conviction for fraud, by some of the physicians paid to enroll patients. Although the results of this trial were never published, they have been cited in the clinical literature.

Now Reuters has reported that Sanofi-Aventis is in talks with the US Food and Drug Administration (FDA) about strengthening the warning label on the drug. A report from PharmaLive said that US Senator Charles Grassley (R-Iowa), chair of the Senate Finance Committee, is pressing the FDA for more information on how it handled the approval of Ketek. The letter said,

the Committee continues to investigate the extremely troubling allegations related to , among other things, the approval and post-market [sic] surveillance of telithromycin (Ketek) by the Food and Drug Administartion. One of the most troubling allegations is that the FDA approved Ketek with full knowledge that some of the clinical safety data supporting its approval was beset by systemic data integrity problems. While the FDA takes its time negotiating with Sanofi-Aventis to decide what drug risk information the public should know, it is completely mystifying why a fraudulant clinical trial is reference in safety information on the FDA's web-site.

The Disastrous Trial of TGN 1412 Done by Parexel for TeGenero

We have previously posted, most recently here and here, about the disastrous trial, implemented by Parexel International , of a new monoclonal antibody designated TGN 1412, manufactured by TeGenero AG. All six healthy volunteers who got the antibody soon became critically ill. We had previously noted allegations that there was reason to think prior to this trial that TGN 1412 would pose risks to human subjects.

The BBC interviewed several experts who also felt that TGN 1412 should have been regarded as a risky drug from the outset. For example, it quoted Dr David Glover, "it may be that it [the adverse effect] was unpredicted by the tests that were done. I believe from the basic science it was predictable." Professor David Winter, of the Laboratory of Molecular Biology in Cambridge said that "those testing TGN 1412 may have been lulled into a false sense of security by the fact that it did not seem to harm monkeys - but it was wrong to make too many assumptions based on animal experiments." In response, TeGenero "said it was an 'oversimplification' to suggest that the side effects could have been predicted in advance."

Multiple Clinical Trials Done by SFBC International

We have posted before about the troubles of contract research firm SFBC International We started by posting about allegations that private, for-profit clinical research firms, including SFBC International, supervised by for-profit institutional review boards (IRBs), were doing sloppy and shoddy work. We then noted allegations that SFBC International had tried to threaten or intimidate research subjects who talked to reporters about such poor research practices. Furthermore, we discussed how a review commissioned by the company found that a top executive, Jerry Seifer, SFBC International's Vice President for Legal Affairs, threatened participants in clinical studies who had talked to the press with deportation. Seifer, it turns out, had been the subject of past regulatory sanctions by federal regulators. In addition, study participants in a trial of an immunosuppressant drug carried out by the firm's Canadian subsidiary, SFBC Anapharm, acquired tuberculosis after exposure to another participant with active disease, despite their complaints to Anapharm staff. More recently, we noted that Seifer had resigned, and the company's stock price had fallen. Finally, we noted allegations that 20 people, including trial participants and staff at SFBC International's Montreal facility acquired latent tuberculosis after exposure during trials.

Per Bloomberg News, SFBC International just announced it will shut down its facility in Florida that was the location of allegedly sloppy and shoddy research practices noted above. In fact, the Miami-Dade County Unsafe Structures Board gave the company 60 days to "file a permit to demolish its Miami facility.... The company said it would appeal the ruling and may file [for] an injunction." Bloomberg quoted Kenneth Goodman, Director of the University of Miami's bioethics program, who had toured the Miami area facility,

This is going to send a signal through the entire drug industry that human-subject protection is not a nicety or a courtesy, but a bold-faced moral and legal requirement.
What I saw was a research mill where vulnerable poor and uneducated people were being enticed into taking medical risks to make a living. That's a morally flimsy foundation to advance medical knowledge.

Summary

The cases of the Ketek trial, the TGN 1412 trial, and various trials done by SFBC International have rarely been juxtaposed, except on Health Care Renewal. However, their juxtaposition suggests

• Physicians and patients should be extremely skeptical of the results of drug research carried out by contract research organizations sponsored by pharmaceutical companies, since the design and implementation of such studies may not be what they seem. Other evidence that commercial research sponsors may manipulate the design of studies, the analysis of their data, and the dissemination of their results should only add to this skepticism (see most recent post here).
• People should be extremely wary about signing up as subjects for such trials, since their risks may be worse than they realize
• We ought to rethink the social desirability of the current relatively unregulated system of having human clinical research sponsored by commercial firms with interests in their results.

We are clearly on a "morally flimsy foundation to advance medial knowledge."

The New England Journal of Medicine Weighs in on the TGN 1412 Trial Debacle, But With a Twist

The New England Journal of Medicine published a commentary on May 4, 2006, on the ill-fated trial of TGN 1412. (Wood AJJ, Derbyshire J. Injury to research volunteers - the clinical-research nightmare. N Engl J Med 2006; 354: 1869-1871.) The first author of the study, Dr Alastair JJ Wood, will be joining Symphony Capital as a managing director in August, according to a New York Times article published May 2, 2006. Per the Times, "Dr Wood has been working as a consultant to Symphony since the fund's inception in 2002.... Symphony, which has $315 million under management, invests in particular drugs. It buys the rights to a drug from a biotechnology company and then works with the company to conduct clinical trials. The biotech company has the right to buy back the drug later at a specified price."

We have previously posted, most recently here, about the disastrous trial, implemented by Parexel International , of a new monoclonal antibody designated TGN 1412, manufactured by TeGenero AG. All six healthy volunteers who got the antibody soon became critically ill.

Unlike some other cases discussed on Health Care Renewal, this one had already received attention in prominent UK medical and scientific journals, including the British Medical Journal, the Lancet, and Nature. It's good to see that the most prominent US medical journal has weighed in.

The article by Wood and Derbyshire focused on the following points, in the article's own words (with emphasis added):

At some point in the development of every drug, the drug must be given for the first time to humans in a phase 1 trial. Until now, such trials have had a remarkably good safety record....
It is standard practice to begin with very small doses, often orders of magnitude below those determined to be nontoxic in animals and those expected to produce any effect in humans. Doses are then increased slowly, as the experience at lower doses is continually evaluated.
System or human failures — such as errors in dosage, manufacturing, or administration — are usually prevented by rigorous procedures for drug preparation and administration.
Toxic effects such as acute liver injury, leukopenia, cardiac arrhythmia, or rash may be related to the new drug molecule itself but unrelated to its intended mechanism of action. Considerable efforts are made to identify these types of toxicity in vitro and through studies in animals. However, our incomplete understanding of the mechanisms underlying such toxicity and the limitations of animal models inevitably mean that some potentially serious toxic effects go undetected in preclinical screening....
The second type of toxic effect results from the action of the drug on its intended biologic target. Such effects are always unknown when a target is 'drugged' for the first time — and there must always be a first time.
When a compound addressing a new biologic target is tested for the first time in humans, much greater caution must be exercised. Such caution should include avoidance of treating multiple volunteers simultaneously or without a reasonably long interval between them.
In some cases, a phase 1 trial does not, in fact, represent the first attempt to manipulate a particular biologic target — though the researchers may be unaware of previous efforts. Clearly, we should not be exposing people to such manipulation if it has been shown, in studies in either humans or animals, to carry serious risks outweighing any potential benefits.
Unfortunately, the companies that generate early safety data consider them proprietary — a concern that must somehow be reconciled with patients' safety. Volunteers rightly expect that we put their safety before competitive advantage, and researchers have an ethical obligation to prevent the exposure of additional volunteers to previously identified risks.
How can we improve the knowledge base for designing trials of new drugs directed at novel targets and make it available to developers and regulators when they are considering the safety of such trials? One approach would be to ensure that all data from preclinical drug research are held in a secure database, indexed by biologic target, and accessible only by major regulatory authorities, which are used to handling confidential data.
There are fundamental questions about which, if any, details of a clinical trial involving volunteers should ever be confidential or whether safety and ethics principles can be ensured only by an open, transparent process in which such trials and protocols are registered in a public database.

The commentary presented a reasonble summary, but it seemed to tread lightly in certain areas.

In particular, it side-stepped the question of whether that there was particular information available before the TGN 1412 trial that would have suggested that affecting the CD28 receptor targeted by TGN 1412 might be dangerous. There is at least a question about this. An article in the (UK) Times quoted Angus Dalgleish, "the previous studies which caused similar side effects were in patients already suffering from cancer, but [the researchers] should have known they would get a meltdown because the drug was hitting exactly the same target." An article in Nature (Hopkin M. Can super-antibody drugs be tamed?) stated, "with hindsight, it might be no surprise that the compound, dubbed a 'superagonist' antibody by its creators, could run amok in the immune system." Furthermore, research on drugs that target the CD3 receptors in mice, which have a similar function to the CD28 receptors, showed, "uncontrolled cytokine release was a problem - albeit not a large one because the mice were already immunodepleted...."

Furthermore, the New England Journal commentary did not address questions about whether the research subjects in this trial really gave informed consent. This question was raised in, among other places, a commentary in the British Medical Journal (Goodyear M. Learning from the TGN 1412 trial: this experience should foster an open culture in medical research. Brit Med J 2006; 332: 677-678.) See also our posts here and here.

Finally, it did not challenge the notion that safety data about particular drugs should be kept confidential during drug development. In constrast, Goodyear (see above), wrote, "this tragedy creates one more imperative for an open culture in medical research, a culture that many fear is increasingly losing its way."

Given that Dr Wood, the first author of this article, already consults for and will soon become a top leader in an organization that buys rights for particular drugs from biotechnology companies and then helps to run clinical trials on them, his choice of emphasis is understandable. Perhaps someone from a different background would have placed emphasis elsewhere.

But it is time for the final twist. The New England Journal only identified Dr Wood as "a professor of medicine and pharmacology at Vanderbilt University School of Medicine." It did not mention Dr Wood's current or future positions with Symphony Capital. Yet Dr Wood's new position at Symphony Capital had been made public by the New York Times two days before the article was published.

It seems that prominent medical journals still have difficulties disclosing financial and other interests of authors that might meaningfully affect their opinions, and might be relevant to readers who want to understand where these authors are coming from.

What Did Parexel Tell the Participants in the TGN 1412 Trial?

We previously posted about the disastrous trial, implemented by Parexel International , of a new monoclonal antibody designated TGN 1412, manufactured by TeGenero AG. All six healthy volunteers who got the antibody soon became critically ill. We recently reported an account of an interview with one of the participants which serious questions about whether research subjects were adequately informed about the nature of the trial and its possible risks, and why the investigators continued to administer the drug after the first subjects had begun to experience adverse effects (see post here).

Bloomberg news just reported on the consent form used in the trial, raising even more issue about what the participants were told or understood about what could happen to them. These issues are summarized below.

Risks Not Revealed - Bloomberg showed the form to several medical ethicists. Michael Goodyear stated, "they [the trial investigators] failed to to adequately disclose the degree of uncertainty around a first-in-man trial. The risks were well known. They were not disclosed in the consent form." Arthur Caplan, of the Center for Bioethics at the University of Pennsylvania, said, "they hid the most serious threats with bland language." Parexel countered only by saying that the UK Medicines and Healthcare Products Regulatory Agency (MHRA) "has done an exhaustive inquiry of Parexel and confirmed that the trial was run according to the approved protocol." However, Bloomberg noted "the agency says its investigation didn't include a review of the consent form."

Participants Questions Deflected - Bloomberg reported that study participant Raste Khan claimed that Parexel staff deflected questions, saying "we're in a bit of a push. Can you sign now, and I'll explain it all to you."

Proportion of Patients to Receive Placebo Not Explained - Khan also said, "They didn't tell us how many placebos there were, so I just thought it was 50/50." Caplan called this a "'major' ethical violation to withhold the actual chance of receiving the drug."

Drug Not Described Clearly in Lay Terms - The drug was described 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.'' Caplan retorted, "I've read a lot of consent forms and I don't understand this." Goodyear noted that the consent form never clearly said what the drug would do, specifically never stating that the drug would stimulate the immune system, and suggested that comparing the drug to aspirin and ibuprofen was also misleading.

Adverse Effects Minimized - "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,"' commented Goodyear. "Reasonable people would think twice before allowing an experimental drug to change their immune system.''
Furthermore, the form described a cytokine burst as akin to hives. Goodyear responded, "Since monoclonal antibodies are know to cause Cytokine Release syndrome, which can be fatal, and Parexel was not even planning for this, the subjects should have been warned." Parexel's response, again was "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.''

Possible Coercion - "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.'"

Failure to Identify Ethics Committee Which Approved the Trial - " 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." Caplan noted, "The participant needs to know who to contact. 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.'' The MHRA investigation did not cover the role of the ethics committee.

Referral to an Irrelevant Pamphlet - " 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."

Revelations about how Parexel failed to inform, or misinformed subjects in the calamitous TGN 1412 trial, coupled with previous reports about how SFBC International, another contract research organization, treated its trial subjects (most recent post here), suggest that commercial contract research organizations need to be much more closely regulated and supervised than they are now. And it may be time to question the whole notion of commercial firms doing clinical trials of drugs and devices.

Addendum (14 April, 2006): The Lancet just published a lead editorial that summarized the TNG 1412 trial, and concluded, "the TGN 1412 events indicate that urgest change is needed in the approval processes and regulation of phase I trials of biologic agents." [Anonymous. Urgent changes needed for authorisation of phase I trials. Lancet 2006; 367: 1214.]

The TGN 1412 Trial "Raises a Number of Big Red Flags"

We previously posted about the disastrous trial, implemented by Parexel International , of a new monoclonal antibody designated TGN 1412, manufactured by TeGenero AG. All six healthy volunteers who got the antibody soon became critically ill (see our most recently here). The International Herald Tribune has done some investigative reporting on this trial.

First, the Tribune confirmed that TeGenero, the manufacturer of TGN 1412, was aware prior to the trial of the possibility that subjects might undergo "cytokine release syndrome" after taking the drug. This syndrome had apparently been observed in some animal testing, although the species of primates tested did not manifest the syndrome. TeGenero, however, felt that this reaction was "not expected," in the human trial.

The Tribune interviewed a survivor of the trial, who stated:

• He believed "he was participating in a fairly standard trial of a painkiller like ibuprofen, for arthritis."
• He said that "the novelty of TGN 1412 never came up in upbeat pre-trial briefing, adding: "I had no idea it altered the immune system.'"
• "At Parexel's orientation meeting there was little time to read the study's 11-page consent form before signing, Rob O. said. Headaches and bruising were listed as potential side effects, as well as the possibility of a severe allergy. But that risk was downplayed."
• Once the trial was underway, the investigators continued to dose subjects even after the first subjects had started to experience adverse effects. "About the time Rob. O's infusion started, at 9:10 am, the first patient had actually passed out in the adjacent room...." charged one of the subjects' attorneys.
• Since the trial, "the companies [TeGenero and Parexel] have been unwilling to meet with the trial subjects or provide more data...."

The Tribune quoted Dr Michael Ehrenstein of University College London, who said that human research on TGN 1412 was "a high risk strategy." Michael Goodyear, described as an oncologist and medical ethicist at Dalhousie University, Halifax, Nova Scotia, Canada, said that the conduct of the trial "raises a number of big red flags."
Nonetheless, Dr Ezekiel Emanuel, Chief of Clinical Bioethics at the US National Institutes of Health (NIH) , said "This is a terrible tragic event but so far I don't see any clear ethical problems." (Note that Emanuel formerly expressed indignation when the NIH made conflict of interest rules more stringent, so that his secretary would no longer be allowed to keep stock holdings in health care companies worth more than US $15,000, as noted in this post.)
In my humble opinion, this newspaper article raises further serious questions about whether research subjects were adequately informed about the nature of the trial and its possible risks, and why the investigators continued to administer the drug after the first subjects had begun to experience adverse effects.
Hopefully, further investigations will afford more transparency, and will lead to improved conduct of trials that put the interests of patients ahead of the imperative to "speed your product through clinical development." (The latter phrase is currently a promise made by Parexel on its web-site.)

A Report Leaves Many Questions About TGN 1412 Unanswered

We previously posted about the disastrous trial, implemented by Parexel International , of a new monoclonal antibody designated TGN 1412, manufactured by TeGenero AG,. All six healthy volunteers who got the antibody soon became critically ill.

Our first post noted that little was known about how the trial was designed, and about who had reviewed the ethical aspects of its protocol. A later post summarized questions posed in a BMJ editorial, including how were research subjects recruited and motivated, what were they told about possible risks, why were healthy volunteers rather than patients recruited, and why were all patients given the drug simultaneously? The BMJ editorial, a Lancet editorial, and our first post all called for more openness and transparency in drug research.

Now the UK Medicines and Healthcare Products Regulatory Agency has issued an interim report. (See news articles in the Times [UK], Nature, and the Boston Globe.) Basically, the MHRA "ruled out contamination, overdose, and procedural problems," as per the Globe. But it revealed nothing more about the trial protocol, nor how it was reviewed. For example, the Globe stated that "Parexel spokeswoman Jill Baker said that she couldn't comment on the design of the trial, but it had been approved by health authories and reviewed by an ethics committee in Britain." None of the other news accounts provided any other answers to the questions above.

The main conclusion of the report was that "the drug TGN 1412 caused an unprecedented and unexpected reaction that did not occur in tests on animals," per the Times. This seems to be stating the obvious. The questions remain whether this unprecedented and severe adverse drug reaction could somehow have been anticipated by perusal of animal testing data or understanding of the science behind development of the drug; or whether the adverse drug reaction could have been reduced by a differently designed or implemented trial?

The Telegraph reported that a lawyer for two of the trial participants is not happy. Ms Ann Alexander said "the MHRA's report gives no detailed information about the pre-clinical trials, about which there has been conflicting information since the trial was suspended."

So there is still little transparency to this trial. We still do not know the results of testing the antibody in animals, the design of the trial protocol, the justification for aspects of the trial design, or who reviewed the ethical aspects of the protocol.

This sad case still illustrates how commercially sponsored pharmaceutical research often remains hidden behind the veils of trade secrecy and business confidentiality. If pharmaceutical companies really want patients and physicians to trust them more, they should start making their human research more transparent.

More Questions, Few Answers About TGN 1412

The disastrous results of the phase I trial of TGN 1412 (see our most recent post here) has lead to a news article in the British Medical Journal, and opinion pieces in the BMJ and the Lancet.

None of these has important new answers. The Lancet editorial noted that the journal's request for the protocol of the trail was rebuffed by TeGenero, the manufacturer of the TGN 1412, and by the UK Medicines and Healthcare Regulatory Agency (MHRA) as "commercially sensitive."

The BMJ editorial listed the questions raised by this incident, which somewhat parallel the list of thing we did not know about the trial at the time of our first post on TGN 1412. The questions were:

• How were the volunteers recruited and motivated?
• How much accurate information, based on full risk analysis, do volunteers receive?
• How much money is too much, and when does money cloud the judgment needed to evaluate risks realistically?
• Why was the drug tested on healthy volunteers rather than patients?
• Why were all eight volunteers given the drug at the same time? [Actually, only six were given the drug, while two others got a placebo - Ed]
• What information did the ethical and regulatory bodies have before the trial?
• How much do regulatory and ethical bodies have to rely on information from investigators and sponsors, which may be subject to publication bias, rather than truly independent reviews?
• Finally, what does this trial tell us about the degree of transparency througout the process of developing new drugs?

The conclusion to the BMJ article,

This tragedy creates one more imperative for an open culture in medical research, a culture that many fear is increasingly losing its way.

and the conclusion of the Lancet article,

the fact that [dreadful events] ... have occured should lead to maximum transparency to reaffirm trust in clinical trials and their regulation.

mirror the conclusion of our first post about TGN 1412, "research subjects and future patients deserve complete transparency about the drug or device to be tested, and how the testing will be performed and supervised."
Maybe if enough people repeat this sentiment, it will actually have an effect on the increasingly opaque world of drug development and evaluation.

An Update on the Tragic TGN 1412 Trial

Our most recent post on the lack of transparency in the trial run by Parexel of TGN 1412, a drug developed by TeGenero, which left all six participants in intensive care with multi-organ system failure, was here.

This trial has generated tremendous media attention. Thus, we now know a bit more about it, but still not much.

According to TeGenero's website, the drug TGN 1412 is a monoclonal antibody that targeted the CD28 receptor on T-lymphocytes. The drug is not meant to destroy T-lymphocytes, but rather to activate the CD28 receptor. According to TeGenero, the TGN 1412 leads to "pronounced T-cell activation and expansion." Thus, unlike some other monoclonal antibodies used to treat cancer, this drug was meant to change the settings, as it were, of the patient's immune system. This was thus a novel therapy, and hence one whose results might have been unpredictable.

Furthermore, the Times (UK) reported that before the trial was carried out, there may have been reasons to be concerned that this drug might have had adverse effects. The Times article quoted Angus Dalgleish, (who holds the Foundation Chair of Oncology at St. George's Medical School in London, but is also the Research Director for Onyvax, a company that also is developing cancer treatments based on immunology), "I would have told the people doing this trial [on TGN 1412] not to do it because the dangers were so great." He cited studies of a "similar drug," "They should have known they would get a meltdown because this drug was hitting exactly the same immune response pathways." (I have not yet been able to figure out precisely which studies he meant.) Furthermore, the Times quoted Jorg Schaaber, "a member of the German drug industry monitoring group Buko Pharma" (whose web-site is here, but appears to only be in German), that monoclonal antibodies like TGN 1412 carry "considerable risks." Finally, it quoted Michael Seed, a Senior Research Fellow at the William Harvey Institute at Barts and the London Hospital and the Queen Mary's School of Medicine and Dentistry, "The danger is that they are messing around with T regulator cells and we don't know what all the T regulator subsets do. Some will switch things on and some will switch things off."

Furthermore, newspaper reports hint at irregularities in how the trial was conducted. The Times (UK) article suggested that the fees paid volunteers were sufficient to be inducements, rather than just payments for time and expenses. It also alleged that in other trials, Parexel, the contract research organization conducting the TGN 1412 trial, used consent forms so long as to be unreadable, and "pressured" volunteers to sign the form with reading it, "because I felt like I was slowing everyone down." Also, it noted that some trial participants may have been professional research subjects, e.g., one, referred to as a "serial human guinea pig," had reportedly made 60,000 pounds sterling in four previous years from participating in drug trials.

An article in the Telegraph (UK) cited a review article on the effects of monoclonal antibodies to CD28 (Hunig T, Dennehy K. CD28 superagonists: Mode of action and therapeutic potential. Immunol Letters 2005; 100: 21-28 )which noted "massive expansion and functional activation of regulatory T-cells by in vivo treatment with CD28 superagonists," but also revealed gaps in current knowledge about what CD28 activation does, and then asked "does it even make sense to talk of informed consent when the experts themselves admit to sugh gaps in their knowledge?"

Thus, there are reasons to suspect that this trial had not been fully thought through, and that it it was not optimally implemented.

Once again, while hoping that six participants in this trial get better, I also hope this tragedy prompts a re-evaluation of our drug testing procedures, and particularly more transparency in all phases of the process.

A Window on Human Research Done by Contract Research Organizations

The recent tragic and unprecedented results of a Phase I clinical trial of a monoclonal antibody known only as TGN 1412 provide a new window into the issues surrounding the now heavily commercialized world of drug testing.

The outcome of the TGN 1412 tests have received global attention. Briefly, TGN 1412 is a monoclonal antibody developed by the German company TeGenero AG. An initial test on six volunteers was arranged by Parexel International at their facility at Northwick Park Hospital in London, UK. Six volunteers received apparently the same initial dose of the drug, while two others received placebo. Within hours of receiving the drug, all six complained of fever, and severe pain in their heads. They apparently developed severe swelling of their heads and upper bodies, and then developed multi-organ system failure. All were rapidly admitted to the hospital's intensive care unit.

The particular symptom complex these patients suffered seems to be unprecedented. Previous instances in which everybody who received a new drug rapidly developed life-threatening illnesses are apparently unheard of.

The media have been doing their best to investigate what happened, while the UK Medical and Healthcare Products Regulatory Agency (MHPRA) suspended the trial and is also investigating. Based on newspaper reports available so far, though it is striking what is not known about this drug trial.

We know the company designation for the drug, and its general type (a monoclonal antibody, or protein developed to bind to a specific molecule), but nothing more specific. We do not know what the target molecule was for the antibody, the rationale for its potential therapeutic usefulness, or the results of its in vitro (test-tube) or animal testing. Some of the news reports suggested conflicting results of animal studies. For example, one report in the Times (UK) quoted the girl-friend of one of the trial subjects , "They [the drug company] said there was an oversensitivity in monkeys...." Furthermore, "a dog and some animals had died." But the Times also reported that the Chief Scientific Officer of TeGenero, Thomas Hanke, "refused at a press conference to say whether animals had died during earlier tests. 'There has been no issue on the safety of the drug oanimalsls. This is not relevant.'" In addition, Bloomberg News reported that the CEO of TeGenero, Benedikte Hatz, said "these events were completely unexpected and do not reflect the results we obtained from initial laboratory studies...." Finally, the Independent reported a claim by a lawyer for one of the research subjects that "there is confusion about whether the drug had been testsuccessfullylly and safely on animals before the tests on these volunteers."

We know very little about how the trial was designed. The Times reported "the trial protocol had been agreed with the MHPRA and was carried out 'according to strict ethical and regulatory requirements,' per Parexel. The MHPRA yesterday refused to give precise details, citing commercial confidentiality, and questions to Parexel went unanswered." Some reports suggested that all six volunteers got doses of the drug simultaneously. The Times noted that this practice was not condoned by a textbook it consulted, which instead suggested sequential dosing.

We do not know what sort of oversight or review this trial had received. The Bloomberg report quoted Parexel's claim that it uses "standardized procedures for testing a drug in humans for the first time, based on a protocol approved by ethics committees and regulatory authorities." What ethics committee approved this protocol is unclear.

We have previously posted about how clinical research on human subjects has become more and more an enterprise done by for-profit commercial contract research organizations, (like Parexel), and supervised (in the US, at least) by commercial institutional review boards (IRBs). We posted (go here and see links) about various questionable practices by US based commercial contract research organization SFBC International, which is now under investigation by a US Senate Committee and the US Security and Exchange Commission (SEC). Furthermore, a trial immunosuppressantresant drug carried out by SFBC International's Canadian subsidiary resulted in 20 patients and staff members contracting latent tuberculosis.

Current regulations of clinical research on humans in the US were developed in the days when most research was carried out and directed by faculty members at academic institutions. Now most research is funded by commercial firms, mainly drug and device companies. When such research is carried out in academic institutions, it is performed often under contracts that give considerable control to the commercial research sponsors, rather than to the faculty ostensibly principal investigators. Furthermore, most such research is now carried out by contract research organizations, under contract to the drug or device company, and supervised by commercial IRBs also paid by the commercial sponsor.

Human clinical research has profound health and safety implications both for its subjects, and for any patients who eventually take the drug or use the device under study. Given that, research subjects and future patients deserve complete transparency about the drug or device to be tested, and how the testing will be performed and supervised. Such transparency was obviously not in evidence in the trial of TGN 1412. We need to revise regulation of drug and device testing on human subjects to make it sufficient to protect research subjects and patients in the current era of globalized commercial research.