Company Knew of the Catastrophic Risk–so did the British Medicines Authority

 Anaphylaxis could occur any time you encounter any new drug, cosmetic or even foodstuff in a restaurant (peanuts and shellfish are famous for causing it)."
 
That statement appears on the TGN1412 Informed Consent document (a copy of the single page "possible side effects" was received by AHRP).
 
In the "possible side effects" section, the consent document begins by assuring volunteers: "no significant side effects have been seen in animal studies…Expert advice from immunologists has been sought in designing the protocol to minimize risks."
 
The document goes on to disclose the "very unlikely" possibility of "immunosuppression" "autoimmunity" and "cytokine release" which is described as "(causing hive-like allergic reaction)."
 
As TGN1412  documents are made public, it is apparent that UK government officials of the Medicines and Healthcare Products Regulatory Agency (MHRA) did not tell the truth when they declared (in their interim report) that the catastrophic recation by all six previously healthy volunteers who suffered a "cytokine storm" (or massive autoimmune reaction) almost the instant they were exposed to this monoclonal antibody was “unpredicted biological action of the drug in humans is the most likely cause of the adverse reactions.”
 
The UK Observer reveals:  "It emerged this weekend that the Medicines and Healthcare Products Regulatory Agency (MHRA) which authorised the trial was notified beforehand that there was this risk of cytokine release. TeGenero did tell the agency of a previous incident involving a similar drug which had provoked a serious adverse reaction in human volunteers."
 
Approval of the experiment violated  the principles of the Nuremberg Code that stipulated that an experiment such as TGN1412 could ONLY be performed if the human subjects were investigators themselves:   
"No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects." Nuremberg Code, principle #5
 
 Britons are calling for "a fully impartial investigation not only of the MHRA but of the Research Ethics Council for allowing six (previously perfectly healthy) volunteers to enter into a potentially lethal clinical trial."
 
Indeed, the MHRA handling of the catastrophic experiment validates the conclusion of a major parliament report exactly one year ago in April 2005: House of Commons Health Committee The Influence of the Pharmaceutical Industry Fourth Report of Session 2004–05.

The committee expressed concerns about the MHRA evaluation of clinical trials, identifying the overly cozy relationship  between the regulator and the pharmaceutical industry, recommending that the MHRA needs to play a greater role during the early stages of drug development.   

“The organisation, process and techniques of the MHRA are focused on bringing drugs to market fast,” parliamentarians found.

“The organisation has been too close to the industry, a closeness underpinned by common policy objectives, agreed processes, frequent contact, consultation and interchange of staff.

“We recommend that more research be undertaken into the adverse effects of drugs, both during drug development and medicines licensing.”

See: http://www.publications.parliament.uk/pa/cm200405/cmselect/cmhealth/42/42.pdf
 
An investigation by the MHRA of itself makes a mockery of independent checks and balances–and will have no credibility with the public.

 Contact: Vera Hassner Sharav
veracare@ahrp.org <mailto:veracare@ahrp.org>  
 

http://observer.guardian.co.uk/uk_news/story/0,,1750055,00.html
The Observer  
Drug trial firm knew of risk
The consent form for test that left six men critically ill listed a side effect which can seriously harm the immune system
Jo Revill, health editor
Sunday April 9, 2006

The drugs company behind the clinical trial that left six volunteers fighting for their lives was well aware that the previously untested drug might seriously damage the immune system.

The consent form the men were asked to sign, which has been obtained by The Observer, warned that a possible effect of the drug was ‘cytokine release’ – a massive immune reaction to a chemical as it triggers a uncontrollable response from antibodies. Cytokine release or cytokine storm, as it is also known, can be life-threatening, although the form does not spell that out.

It is not known whether the doctor heading the trial at Northwick Park Hospital in north London verbally highlighted the specific nature of the cytokine risk to the participants. The form simply says it could cause a ‘hives-like’ allergic reaction. The volunteers were struck down with symptoms within minutes of being injected with the drug.

A string of possible side effects are listed on the form, revealed for the first time in this newspaper. Volunteers must sign such a document before they are allowed to participate in a trial, to show they understand the potential risks and so that the company is legally protected.

In the 12-page document prepared by Parexel, which carried out the trial on behalf of German biotech firm TeGenero, the potential side effects are listed. It states: ‘As this is only the first time this drug will be given to man, this study may involve risks currently unforeseen.’

It adds: ‘It is possible that you will not experience any side effects at allas the doses used in early human studies are always very small, and increased only … but the following unintended effects may theoretically be encountered during any trial with a monoclonal antibody drug, though they did not occur even at the highest tested doses in animals.’

It lists the possible side effects as ‘immunosuppression [increasing susceptibility to infection], autoimmunity [antibodies made by your own body against the drug], cytokine release [causing a hives-like allergic reaction] or anaphylaxis [a generalised allergic reaction that can be life-threatening].’

It emerged this weekend that the Medicines and Healthcare Products Regulatory Agency (MHRA) which authorised the trial was notified beforehand that there was this risk of cytokine release. TeGenero did tell the agency of a previous incident involving a similar drug which had provoked a serious adverse reaction in human volunteers.

One of the six men, Ryan Wilson, is still in hospital.

TeGenero said: ‘The preliminary findings of the investigation of the UK authorities confirmed the highest standards were observed in developing TGN1412. There was no sign of risk from the extensive preclinical testing and we could not predict the serious reactions. The study obtained approval from German and UK authorities.’

~~~~~~~~~~~~~

http://www.drugresearcher.com/news/ng.asp?n=66928-parexel-tgn-tegenero-mhra-clinical-trials
UK regulator’s suitability to investigate Parexel questioned
By Gregory Roumeliotis
 
06/04/2006 – The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) has said it has so far found no evidence of wrongdoing in the human trials of the monoclonal antibody TGN1412, which US contract research firm Parexel carried out for German TeGenero, yet the agency’s authority to carry out this investigation is undermined by a British parliamentary select committee report, published last year, which highlights flaws in the regulator that may have contributed to the disaster.

In its interim report the MHRA <javascript:KeywordSearch(‘KEYWORDS=MHRA&period=all&inner=1’);>  concludes that the adverse incidents, which left six men seriously ill in a north London hospital last month, did not involve errors in the manufacture of TGN1412   or in its formulation, dilution or administration to trial participants.

Instead, since the pre-clinical testing at high doses in monkeys and rabbits was also deemed adequate, according to the MHRA an “unpredicted biological action of the drug in humans is the most likely cause of the adverse reactions.”

But a parliamentary health select committee report <http://www.publications.parliament.uk/pa/cm200405/cmselect/cmhealth/42/42.pdf> , published exactly a year ago, casts doubts on whether the MHRA should be investigating itself in the TGN1412 case, with the lawyer representing the two most seriously affected volunteers calling for an independent inquiry.

The committee in April 2005 expressed concerns about the evaluation of clinical trials and identified a lack of communication between the regulator and the pharma industry, recommending that the MHRA plays a greater role during the early stages of drug development.

“The organisation, process and techniques of the MHRA are focused on bringing drugs to market fast,” parliamentarians found.

“The organisation has been too close to the industry, a closeness underpinned by common policy objectives, agreed processes, frequent contact, consultation and interchange of staff.

“We recommend that more research be undertaken into the adverse effects of drugs, both during drug development and medicines licensing.”

The report also criticises the agency’s lack of transparency, pointing out that there is no public access to the data presented by the pharmaceutical companies nor to the assessments undertaken by the MHRA.

“In view of the failings of the MHRA, we recommend a fundamental review of the organisation in order to ensure that safe and effective medicines, with necessary prescribing constraints, are licensed,” the select committee report concluded.

Raymond MacAllister, senior lecturer at the Centre for Clinical Pharmacology and Therapeutics at University College London, expressed his surprise to DrugResearcher.com about the way the TGN1412 trial was carried out.

“This was a phase I trial where assessing safety is the top priority, so if they had given it to one person first, and not all six at once, what would they have lost, a couple of days?

“Having serious adverse effects is of course always possible in a human trial, but six people becoming hugely unwell immediately is extremely rare.”

Five volunteers have since left hospital and the one remaining is said to be making a good recovery.

Also provoking criticism are clinical trial results, available since last May, about another monoclonal antibody, for metastatic renal cancer, claiming to go through the same immune response pathway.

Toxicities from that drug, which included enteritis, hypophysitis and meningitis, were observed in 12 of 20 volunteers, of whom one patient underwent a colectomy for perforation.

TGN1412 binds to a molecule called CD28 that is present on the cell surface of T lymphocytes, cells which the renal cancer drug also targets, albeit at a different receptor – CTLA4.

“The trial referred to in the US involved the use of a different drug acting on a different receptor at a different stage in the drug’s development,” MHRA spokeswoman Sara Coakley told DrugResearcher.com.

“It is not clear why this trial would be predictive for outcomes with a first in-man trial with TGN 1412.”

The issue has attracted international attention and damaged public confidence in clinical trials, so the British Health Secretary Patricia Hewitt has established a group of international experts in the field to review the evidence from the TGN1412 case and consider what necessary changes to clinical trials may be required.

However, the remit of the group’s enquiry is wide, as it will look into trials not just of monoclonal antibodies like TGN1412, but also of biological molecules with novel mechanisms of action, new agents with highly species-specific action and new drugs directed towards immune system targets.

Until the group has completed its work, the MHRA said it will take a precautionary approach for all further clinical trial applications involving first in-man trials of any monoclonal antibody, regardless of intended target, or other novel molecules targeting the immune system, acting via a novel mechanism.

These trials will be not be authorised without having had “additional expert opinion on whether the effects seen in the TGN1412 case may be repeated in relation to those substances,” the agency said.

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