[e-drug] Further lessons from the TGN1412 tragedy

["E-Drug" <e-drug@healthnet.org>]

E-DRUG: Further lessons from the TGN1412 tragedy 
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[Articles of BMJ and NY Times on the disastrous T-cell agonist trial; copied as fair use; WB]

http://bmj.bmjjournals.com/cgi/content/full/333/7562/270
BMJ  2006;333:270-271 (5 August), doi:10.1136/bmj.38929.647662.80 
Editorial
Further lessons from the TGN1412 tragedy 
New guidelines call for a change in the culture of research 

As eight young men assembled at a London hospital on 13 March this year, they had no idea that within an hour their lives would be changed irrevocably and they would have contributed to a fundamental rethinking of the development and testing of new drugs. The first trial of TeGenero's TGN1412 (a T cell agonist) in humans took place at Parexel's clinical pharmacology research unit at Northwick Park Hospital, London. The events that followed fuelled speculation not only into the conduct of the trial and the nature of the drug, but also into aspects of research as diverse as comparative molecular biology, bioethics, and health economics.1 

The Medicines and Healthcare Products Regulatory Agency initiated an investigation, but the BMJ and other journals called for a more far reaching inquiry independent of the regulatory agency that had approved the trial. On 5 April the agency released its interim report,2 and the government announced that an independent Expert Scientific Group, chaired by Professor Gordon Duff, would be appointed "to learn from the Parexel clinical trials incident." On 25 July this group released their interim report and recommendations.3 

Inevitably, the report has pleased some people and disappointed others.4 5 Although it shows common sense, thoughtful reflection, and even vision, it fails to answer all the questions asked by the BMJ. Part of the problem is that the expert group was given a narrow remit, which focused on the biology and mechanics of high risk "first in man trials." In contrast, the BMJ had asked that the events of 13 March be interpreted in the context of the broader social and economic forces that shape research, because things happen for reasons related to the systems that create these factors.6 

Critics of the trial highlighted many factors that should have indicated the potential for disaster. However, people who are disappointed with the report must understand that the expert group wisely avoided the appearances of a "judicial style inquiry." The group refrained from criticising the parties involved, but reading between the lines shows that many things could have been done better and that these factors were compounded. Another difficult task the group faced was creating a balance between improving safety without being accused of "stifling innovation." Many pieces of the puzzle are still missing (including the clinical data that were withheld from the report, pending publication), and in the end more questions are asked than answered. 

The recommendations fall into several broad categories: preclinical development that is both directed and consultative; evidence based transition to testing in humans; more open regulatory and ethical review, including independent scientific expertise; and most importantly, the need for more transparency.7 8 Although the report is carefully couched in the language of the terms of reference, the reader will realise that the findings have profound implications for all aspects of human research and drug development. There is a Buddhist story about seeking truth, in which disciples enter a darkened temple and on emerging compare their experiences of encountering an elephant. Although each witness to the inquiry described a part of the elephant, it is not clear that the expert group actually realised that there was an elephant in the temple.9 Specifically, they did not engage the many voices that have pointed to a collapse of integrity in research and the crisis in evidence based medicine that has been built on a corrupt database.10 11 

It would be easy just to concentrate on the technicalities. For instance, one thing that is clear is "that the preclinical development studies... did not predict a safe dose in humans." The group's recommendations on dosing are sensible and prudent-for instance, shifting the threshold from one at which adverse effects are observed to one at which biological effects are observed. The deeper issue is why are we asking these questions now? Should they not have been self evident? Another recurrent theme of the report is the need to retreat from a blind obsession with a regulatory "process" and "correct" procedures to the use of sound clinical judgment based on all relevant information and common sense, on a case by case basis. A good example is the regulatory clock, in which agencies guarantee to provide an approval within a timeframe embedded in regulations, and which has probably done more harm than good. The recommendation that "the clock should be stopped" is timely in an environment that pressurises regulators to bring drugs to market faster. 

Among the more far reaching recommendations are those that place more responsibility on sponsors and investigators to prove that it is necessary to perform a clinical trial in humans. Even more wide sweeping is the emphasis on openness in development and regulatory and ethical review, and a burial of the sacred cow of proprietary information. Even so, the expert group was reluctant to grasp some of the more prickly nettles. These include advocating a single integrated and publicly accessible database in conjunction with the World Health Organization and resisting the claims that more emphasis on safety threatens the swift delivery of lifesaving drugs to the bedside and forces research overseas. A closer look at the contributions of pharmaceutical research to improving global health might draw a different conclusion. Although witnesses emphasised the word "unprecedented," this does not mean that it won't happen again. 

The concerns and recommendations of the expert group about the rapidly changing environment of research are commendable. Concerns include the commercialisation of research and its loss from clinical and academic centres; the prevalence of inexperienced and small start-up biotechnology companies reliant on venture capital; lack of training and adequate facilities; and the failure to plan for and deal with adverse events. The new ethical guidelines from the royal colleges will lend a supporting voice to some of these aspects of the report.12 13 

Will the report of the expert group make a difference? That will depend on the quality of the public debate and the responses to the consultation, the deadline for which is 14 September. It will also depend on the degree of resoluteness that the group displays in recommending the need for a more fundamental inquiry and action, the extent to which the affected parties embrace their vision, and the willingness of those parties and the Department of Health to implement them fully. 

Michael D E Goodyear, assistant professor 
Division of Medical Oncology, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada B3H 2Y9 
(MGoodyear@dal.ca) 

References
1. Goodyear M. Learning from the TGN1412 trial. BMJ 2006;332: 677-8.
2. Medicines and Healthcare Products Regulatory Agency Press release: Latest findings on clinical trial suspension 2006 April 5. www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&useSecondary=true&ssDocName=CON2023515&ssTargetNodeId=389 (last accessed 27 July 2006). 
3. Department of Health. Expert Scientific Group on phase one clinical trials: a consultation, 25 July 2006. www.dh.gov.uk/Consultations/LiveConsultations/LiveConsultationsArticle/fs/en?CONTENT_ID=4137501&chk=x%2BoJ/%2B (last accessed 27 July 2006). 
4. Leigh Day and Company. Northwick Park drug trials update, 25 July 2006. www.leighday.co.uk/doc.asp?cat=844&doc=900 (last accessed 27 July 2006). 
5. Perks B. Clinical chaos under scrutiny. Chemistry World 25 July 2006. www.rsc.org/chemistryworld/News/2006/July/25070603.asp (last accessed 27 July 2006). 
6. Reason J. Human error: models and management. BMJ 2000;320: 768-70. 
7. Goodyear M. Closing the gaps: moving closer to a collaborative culture: comments on disclosure timing: balancing increased transparency and competitive advantage. World Health Organization Clinical Trials Registry Platform March 31st 2006. http://www.who.int/ictrp/007-Michael_Goodyear_31March06.pdf (last accessed 27 July 2006). 
8. Sim I, Chan AW, Gulmezoglu AM, Evans T, Pang T. Clinical trial registration: transparency is the watchword. Lancet 2006;367: 1631-3.
9. Downie J. The power of money: commercialization of research conducted in public institutions. Otago Law Rev 2006;11: 305-25. 
10. Ho MW, Cummins J. London drug trial catastrophe-collapse of science and ethics. Science in Society 2006;30:44-5. www.i-sis.org.uk/LDTC.php (last accessed 27 July 2006). 
11. Godlee F. Can we tame the monster? BMJ 2006;8: 333. 
12. Bickerstaffe R, Brock P, Husson JM, Rubin I, Bragman K, Paterson K, et al. Guiding principles for pharmaceutical physicians from the ethical issues committee of the Faculty of Pharmaceutical Medicine of the Royal Colleges of Physicians of the UK. Int J Clin Pract 2006;60: 238-41.
13. Bickerstaffe R, Brock P, Husson JM, Rubin I, Bragman K, Paterson K, et al. Ethics and pharmaceutical medicine-the full report of the ethical issues committee of the Faculty of Pharmaceutical Medicine of the Royal Colleges of Physicians of the UK. Int J Clin Pract 2006;60: 242-52.

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http://www.nytimes.com/2006/08/03/world/europe/03britain.html?_r=1&ref=health&oref=slogin
Inquiries in Britain Uncover Loopholes in Drug Trials 
By ELISABETH ROSENTHAL
Published: August 3, 2006

The trial of a new drug in a London hospital that nearly killed six men three months ago and left them in intensive care for weeks has prompted numerous reports and recommendations that will change the way drugs are tested.

But the six men, who were all young and healthy just months ago, now suffer from serious medical problems, and they have been unable to get any of the drug companies involved in the trial to cover their medical expenses, or provide compensation * other than a one-time payment of under $20,000 apiece. 

In recent weeks, lab tests and medical reports have shown that the men are suffering from severely damaged immune systems that will probably leave them vulnerable to disease for life. All have spent weeks in intensive care with organs failing, and they still suffer myriad symptoms. 

One of the men, Navneet Modi, 25, who recently received a master's degree in business, said that his damaged memory and blackouts made it impossible for him to work, and that he also suffered from fatigue and diarrhea.

"Everyone's turned their back, and I'm angry, really angry," Mr. Modi said. He noted that the British National Health Service has covered his medical costs so far, but that the company that performed the trial would not reimburse the cost of travel to the hospital. 

New tests and investigations into the incident have highlighted loopholes in a drug-testing system that in some instances seems better devised to bring drugs to market than to protect human safety, especially when it comes to medicines made possible by advanced biotechnology, specialists said. Already, regulators in the United States and Europe say they are taking a go-slow approach as they develop new procedures. 

The trial three months ago, conducted at London's Northwick Park Hospital, "highlighted an urgent need to review the safety of first-in-man trials of novel agents," concluded an interim British Health Department panel's report, which was released in late July. The report also urged an examination of "how risks in medicine development are currently assessed and minimized" by drug makers.

The drug in the Northwick Park trial, TGN1412, was a potent immune system stimulant that overrides the body's normal regulatory mechanisms. But it was tested according to much the same standards that govern more ordinary pharmaceuticals. British regulators approved the trial in just 17 days, and the testing company did not have an adequate response plan should disastrous adverse reactions occur, British investigators have concluded.

Since the trial, the British Health Department, the United States Food and Drug Administration and the Association of the British Pharmaceutical Industry have been reviewing the data and issuing recommendations for testing new medicines, particularly those aimed at essential biological pathways.

"The lesson learned is that now when we see a molecule like this * one with a novel mechanism * we need a very different approach," said Dr. John K. Jenkins, of the F.D.A. "Now that we've seen this episode, we will be very cautious going forward."

TeGenero, the small German biotechnology firm that developed the drug as a revolutionary treatment for cancer and arthritis, filed for bankruptcy-court protection on July 4. A lawyer for four of the six trial subjects, including Mr. Modi, said TeGenero's insurance coverage * which was $3.7 million * was not adequate to cover a calamitous outcome. 

The lawyer, Martyn Day, of Leigh Day & Company in London, said the insurance policy included a clause that no payments would be made to subjects who sued. The American-based testing firm that conducted the trial, Parexel International, of Waltham, Mass., has said that it carried out the trial according to "appropriate policies and procedures," and that it is not culpable. 

Parexel, which declined to comment for this article, does contract drug testing, with centers in the United States, Europe and Africa. It continues to operate research units at Northwick Park, and has removed all mention of the trial from its Web site. 

Recent investigations into the trial said all parties did their jobs according to formal regulatory and legal requirements. But, in retrospect, almost all scientists agree that these requirements were inadequate for TGN1412.

Mr. Day said that under British law, TeGenero was primarily responsible. The company has maintained that the reactions were unforeseeable. 

But he said that he would argue that Parexel should have made sure that TeGenero had adequate insurance. He also questioned the design and conduct of what it should have seen as a delicate trial.

The six research subjects were given infusions of the new and unknown drugs only 10 minutes apart. Virtually all reviews of the trial have concluded that such new drugs should be given to one patient at a time, with long intervals in between, so that monitors can screen for serious side effects.

Mr. Day said that the men should have immediately been given high doses of steroids to treat the serious reaction to the new drug. He said such a reaction was noted as a possibility in the study's official protocol.

He also said that he was shocked to discover that British regulators had approved the first trial of the new drug after 17 days, and had not called in specialists to guide them. In contrast, he said, "It would take three to four months, minimum, to get a paper about this drug published in a peer-reviewed journal."

Within hours of being injected with the new drug, the six men were all experiencing a syndrome called cytokine storm, where an outpouring of immune molecules attack organs of the body. All required weeks of intensive care, suffering failure of their kidneys, lungs and circulatory systems.

Lab work on their blood has been recently made public, and immunologists have been thunderstruck by the fury of the reaction.

"These numbers are over the top, far different than anything that would occur in nature," said Marc Gavin, an immunologist who studies immune regulation at the University of Washington in Seattle. "The drug went right to the very heart of immune activation." 

In recent tests on four of the subjects, all showed previously unheard-of severe depletion of a type of immune cell called "regulatory T-cells," according to reports from Prof. Richard Powell, an immunologist, provided by Mr. Day.

The cells modulate the body's reaction to foreign molecules, like those that produce allergies or even infections, and if they are lacking or dysfunctional, it can create overwhelming immune reactions against minor allergens or even the body itself.

At the milder end of the spectrum are diseases like lupus and colitis. Professor Powell wrote that Mr. Modi was "highly likely" to develop one of these disorders, at least, based on symptoms and lab tests.

For the past three months, regulators all over the world have been trying to piece together what went wrong, because the drug has not outwardly provoked such a response during animal testing. In the United States, the F.D.A. is trying to develope "better biomarkers for human toxicity" that can be used to screen new products for safety before they are introduced into humans for the first time, Dr. Jenkins said.

Mr. Modi had just finished business school in London when he signed up with Parexel to earn a bit of extra money, about $3,000. He had planned to return to India this summer to join his family's electronics business in Calcutta.

At 8:30 a.m. on March 13, he became the third human to be infused with TGN1412 at Northwick Park. Within 90 minutes, the pain in his head and back was unbearable, he recalled.

Soon, all six trial subjects were moaning or screaming and begging for pain pills. The doctor and half-dozen nurses from Parexel running the trial urged everyone to remain calm and administered paracetamol, a mild pain reliever.

Mr. Day said that after Mr. Modi had lapsed into semiconsciousness, the team administered a low dose of steroids. 

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 cytokine storm for hours.

Mr. Modi expressed anger at Parexel, saying that the night he was transferred to the intensive-care unit, the company "turned their back and drew up the drawbridge."