Trial Catastrophe Lends Impetus to Reform

The pharmaceutical industry initially seemed to have escaped more lightly than might have been expected from the catastrophic Phase I clinical trial with TGN 1412 in London nearly a year ago.

Peter O'Donnell

At the time, the acute and life-threatening damage to the trial subjects, and the massive media coverage it generated, looked likely to severely impact the continuation of clinical trials in the United Kingdom and in Europe. This was, after all, the very worst type of publicity for a sector that already tends to attract more than its fair share of criticism, and which is all too often seen as a menace to health rather than as a weapon against disease.

But the immediate storm blew over surprisingly quickly. Now the UK government–sponsored report on lessons to be learned has been released, and it is clear that there are going to be big changes for clinical trials—not just in the United Kingdom but in Europe too. "It is important that agreement is sought at EU and international level, to ensure that equal protection is afforded to clinical trial participants worldwide," the report insists.

Balanced investigating

The report, published at the end of 2006, isn't a witch hunt. The expert group's remit was to make recommendations for the future. It is not a whitewash, either. It makes some trenchant criticisms of the failings observed. But it broadly exonerates the manufacture and administration of the agent, putting the incident down to inadequate prediction.

The report stops short of suggesting that there are systematic deficiencies in the conduct or control of clinical trials in general, but it is uncompromising in its view that trials, particularly for first use in man of novel agents, need a more careful approach than at present. "Pre-clinical development studies that were performed with TGN 1412 did not predict a safe dose for use in humans, even though current regulatory requirements were met," it said.

In the end it made 22 separate recommendations, which, it said, are "expected to have far-reaching implications for those involved in the conduct and safety of first-in-man clinical trials."

Change is certain

Change is in the air. Even if, as the report acknowledges, "the alarming outcome of the TGN 1412 trial was unprecedented in the history of clinical trials," the pressure is on to tighten up controls, and the industry knows it must comply. "Medical science moves on, and it is important that our guidelines covering studies in nonpatient volunteers are up-to-date," said Dr. Richard Barker, director general of the Association of the British Pharmaceutical Industry (ABPI), promising "a full analysis of the inquiry's recommendations."

The report was welcomed by the British BioIndustry Association. Aisling Burnand, its chief executive, said the findings "will now enable us to learn from these tragic events and enhance the protection of patients and volunteers in the future."

Background to the Expert Report

So at the beginning of 2007, the clinical trials community in Europe is facing new demands for tighter regulation. And while the duty to protect trial subjects is uncontested as the principal priority, there are concerns that imperfectly designed or inappropriately managed moves to assure that protection could deliver another blow to clinical trials in particular and to drug development in general.

As the BioIndustry Association said when the report was released, "the manner and timing of implementation of these recommendations will now be key"—adding that "adequate resourcing and funding for the regulator will be required to ensure that there is no delay to the development of new medicines for patients."

Burnand spelled out the bottom line: "It is vital that innovative biomedical research is not unnecessarily delayed or moved overseas. By working with regulators and ensuring the widespread dissemination of best practice guidance, we must ensure that patients are protected and can continue to benefit from the continued safe development of new medicines that enhance and save lives."

The recommendations

The brief for the expert group was to examine trials involving new types of drugs, following the adverse reactions experienced with TGN 1412. Its recommendations are intended to apply to first-in-man clinical trials, and not to Phase I trials in general. "However," the report notes, "added caution should also be taken when administering a medicine with the potential for high risk to a distinct new population, be they healthy volunteers or patients."

Key elements from the recommendations relate to:

• the need for scientific advice from independent experts before trials of high-risk substances are approved

• information about unpublished clinical trials and adverse reactions occurring in trials

• the conduct and environment of clinical trials

• the clinical trial application process

• the skills and future specialist training needs of staff conducting trials

• the location of trial units and adequate medical back-up.

The good news, if such a term can be used in this circumstance, is that the report clearly acknowledges the merits of drug investigation. "There is certainly a need to develop new medicines for conditions where current treatment is inadequate," said the group's chairman, Professor Gordon Duff of the Division of Genomic Medicine at Sheffield University. "But," he went on to say when presenting the report, "in clinical trials, the well-being of volunteers must always come first."

The report itself straddles both positions: "The need for better and safer medicines is clear, as is the fact that the first human exposure to a new medicine will always carry some risk, even if extremely small. Our aim has been to optimize the safety of future first-in-man trials of the types of medicines within our remit without stifling innovation or raising unnecessary barriers to the development of useful new medicines," it says.

But the report offers no prospect of certainty or regulatory stability. "The regulatory process for first-in-man trials of higher risk agents and advanced medicinal products based on innovative technologies should be subject to regular review," it urges.

Next steps needed

Now that the report has been completed and published, one element of uncertainty is lifted from the clinical trials world. But the next step is to evaluate it and to reach agreement on which of its recommendations to put into effect—and exactly how. In consequence, a new form of uncertainty is generated. Some of the recommendations, such as greater sharing of information about trials and adverse reactions, have far-reaching implications, and—as the report acknowledges—these will have to be more widely discussed with the pharmaceutical industry and academia.

The UK Government immediately welcomed the report's recommendations, and said it would study them carefully. In fact, the UK's regulatory authorities have already introduced interim precautionary measures in the approval and conduct of trials in the United Kingdom, and these will remain in place until they are replaced by the envisaged European guidance. They have put in place procedures for accessing independent scientific advice, and an expert advisory group that will review applications for trials of high-risk substances is to be established early this year.

Industry is now reviewing the recommendations in detail too. The ABPI says it had already started work, before the TGN 1412 trial, on new guidelines, covering all aspects of clinical trials, "including those relevant to the very small number of compounds that act in a similar way to TGN 1412." The new document will cover justification for volunteer studies and the assessment of risk; recruitment of volunteers; safeguards and the suitability of facilities; and study design and protocols.

Meanwhile, scientific tests have also been conducted by the UK's National Institute for Biological Standards and Control, in a bid to provide answers to the scientific questions surrounding the adverse reactions to TGN 1412. And the expert group's report made clear that there are many other questions that require examination, although they were outside the group's remit.

So 2007 is going to see uncertainty not only in Phase I, but right across the clinical trials community.

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.