Pharma Industry on Trial
The recent disastrous clinical drug trials in Britain may result in serious side effects for researchers.
The recent disastrous clinical drug trials in Britain may result in serious side effects for researchers. The trials have prompted an international rethink of the development and testing of new drugs. In this country, more than 200 clinical trials are taking place, according to the Irish Pharmaceutical Healthcare Association (IPHA).
Since the trial of a drug at a London hospital that left six men seriously ill, the British Department of Health, the US Food and Drug Administration (FDA) and the Association of the British Pharmaceutical Industry have been reviewing data and issuing recommendations for testing new drugs - particularly early stage trials, which are often referred to as first-in-man trials.
The expert scientific group convened by British health secretary Patricia Hewitt released its report late last month and made a number of recommendations that have highlighted loopholes in the existing drug testing system.
The expert group said the trial of the drug TGN 1412 had exposed 'an urgent need to review the safety of first-in-man trials of novel agents'.
The report also urged an examination of "how risks in medicine development are currently assessed and minimised" by pharmaceutical companies.
Six of the eight men involved in the trial of TGN 1412 - which was designed to treat rheumatoid arthritis, leukaemia and multiple sclerosis - reported catastrophic multi-system failure.
The men, including 21-year-old Irishman Ryan Wilson, suffered adverse immune reaction causing swellings and multiple organ failure. One man is likely to lose all his toes and some of his fingers. Another now suffers from irregular bowels, kidney mal function, a skin condition and other symptoms that suggest malignant lymphoma.
The men, who were all healthy just months ago, 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-off payment of under €20,000 a head.
The trial drug was created by German company TeGenero, which has since filed for insolvency.
The trial was carried out by Parexel, a contract drug testing company.
The expert group has recommended that drugs such as TGN1412, which affect the immune system, should not be administered to healthy volunteers.
Instead, it argued the test should be conducted on patients with conditions that the drug is supposed to cure. It also said the initial drug dose should be given to just one person, which was not the case in the London trial.
The group's report also called for more dialogue between the drug developer and regulator when dealing with high-risk drugs, and better international sharing of data on serious adverse reactions.
Recommendations also include ensuring that such clinical trials are conducted at hospitals with intensive care facilities.
In the London trial, the men were initially given paracetamol after suffering serious adverse reactions.
The Irish Medicines Board (IMB) regulates clinical trials in this country. Dr Rebecca Cramp, scientific and regulatory affairs manager at the IPHA, said that, following a safety review by the IMB, companies must secure ethics committee approval before proceeding with a trial.
"The regulations are quite similar across Europe, in that there are overarching requirements under European directives," she said. Trials are then carried out by the pharmaceutical companies, contract research organisations or through industry collaboration with hospitals and medical consultants.
"The pharmaceutical industry invests considerable funding in clinical trials in this country, ranging from under €100,000 by smaller companies to over €1.5 million for larger companies," Cramp said.
The expert group in Britain has called for information regarding early "phase one" drug trials on humans to be made public. Media reports claimed the suggestion was partly inspired by calls from a retired medicine professor, who said he stopped his own trial involving the testing of a compound similar to TGN1412 on a patient more than a decade ago after identifying adverse side effects.
A growing number of medical specialists have also advocated greater public disclosure of the results of all clinical trials carried out on humans, in spite of opposition from the pharmaceutical industry. At issue are the benefits of improved patient safety and more effective research, weighed largely against corporate worries over commercial confidentiality.
Cramp claimed the IPHA's "clinical trials search portal gives details on all clinical trials that are ongoing and that have been completed. That was an industry-agreed and industry-led initiative. There is absolute transparency".
But Dr Michael Goodyear, a Canadian cancer physician, believes the portal does not go far enough. He was part of a working group from the World Health Organisation (WHO) which called for researchers to be more transparent. "The WHO is asking companies to register details before they put patients into trials," he said.
He believes the company that conducted the London trial "failed to adequately disclose the degree of uncertainty around a first-in-man trial.
"The risks were well known.
"They're not disclosed in the consent form," he said. Goodyear voiced a number of concerns about the clinical trials process.
He said it was vital for the WHO to "resist claims that more emphasis on safety threatens the swift delivery of lifesaving drugs to the bedside and will force research oversees to countries such as India, China and South America where the legislation is more lax".
Goodyear said part of the problem stemmed from the fact that more complex, targeted drugs were being tested.
"The type of drug being used 20 years ago was one where you could predict what would happen in man based on what happened in monkeys, rats and rabbits," he said.
"Now we are producing very sophisticated molecules that are targeting particular molecules in humans. There may not be animal models that will accurately predict what will happen in humans.
"If we're going to use the drugs in man, we have to test them on man. We will have to start with lower doses and treat one patient at a time. Doing it safely unfortunately means the process may take longer and cost more," he said.
By Susan Mitchell
August 13, 2006
