UK regulator's suitability to investigate Parexel questioned
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 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, 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.
