Tightening regulations for clinical trials

The joint task force set up by the BioIndustry Association (BIA) and the Association of the British Pharmaceutical Industry (ABPI) has released recommendations to enhance and clarify the existing guidelines governing the testing of new medicines in humans following the notorious TGN1412 trial in the UK.

In this trial an immunomodulatory drug, TGN1412, intended to treat rheumatoid arthritis and B cell chronic lymphocytic leukaemia, resulted in the hospitalisation of six volunteers with at least four of them suffering major organ failure. The volunteers received about one five-hundredth of the dose which previous, non-human primate studies had indicated was the maximum safe dose but even so, within hours all participants who had received the TGN1412 were experiencing a syndrome called 'cytokine storm'. This is where an outpouring of immune molecules attack organs of the body. All participants required weeks of intensive care and suffered failure of their kidneys, lungs and circulatory system. The long-term health prospects of all of the men are reported to have been compromised with one participant expected to loose his toes and several fingers.

A final report, published by the Medicines and Healthcare products Regulatory Agency (MHRA) into the adverse incident, says: "In addition to the various inspections carried out by MHRA inspectors and the German Regulatory Authorities, further tests have been conducted on the drug product. The product testing focused on the batch used in the original toxicology studies as well as the batch used in the trial. Although there were some 'good clinical practice' discrepancies identified...an unexpected biological effect is the most likely cause of the severe reactions in the six trial volunteers."

The MHRA and Paul Erlich Institute investigations did not identify any deficiencies in relation to the standard of pre-clinical testing of TGN1412 by the drug developer, TeGenero Immuno Therapeutics, and have concluded that the adverse reactions experienced by the volunteers were completely unforeseeable.

"This is a very complex scientific issue, which will be reviewed by the independent expert scientific group appointed by the Secretary of State for Health. We are satisfied that the adverse incidents which occurred were not as a result of any errors made in the manufacture of TGN1412, its formulation, dilution or administration to trial participants," said Professor Kent Woods, MHRA chief executive.

The ABPI and BIA set up their joint taskforce to provide industry input into Professor Gordon Duff's expert working group established to learn from the TGN1412 clinical trial adverse events. Membership of the group comprised bioscience and pharmaceutical industry experts in fields such as immunology, biopharmaceutical development and clinical trials.

The taskforce has highlighted aspects of those guidelines that are particularly important for the very small proportion of clinical trials in which novel agents stimulating the immune system are given to humans for the first time. Within this arena, recommendations cover the whole range of the Phase 1 development sequence, from comments and advice on the compound's mechanism of action and biological activity through to the education and training of those involved in safety assessment.

The taskforce recommendations, which are based on existing best practice within industry, have been submitted to the scientific expert group chaired by Professor Gordon Duff reviewing early stage clinical trials. Specific recommendations include:

• Use of an alternative initial dose-setting assessment for certain novel agents.
• Giving only one subject the active medicine on the first day.
• Following this with 'staggered dosing' as doses are increased.
• Conducting such studies at a hospital with intensive care facilities.
• Providing all investigators with appropriate training in such studies.
• Giving particular emphasis to manufacturing controls to ensure safety, quality and efficacy of the finished product.

"As a responsible industry, we were shocked and want to ensure a similar event never occurs again, and that is why we have developed these 'points to consider' for first-in-human clinical studies,"said Dr David Chiswell, one of the co-chairmen of the taskforce.

"In order to safeguard patient safety, we want to make the guidelines available to the research-based industry and - if either the UK or the European regulatory bodies find this useful - to help develop them into a more formal set of points to consider."

The taskforce carefully examined existing regulatory guidance for biopharmaceuticals. Said co-chairman, Sir Colin Dollery: "On the one hand, it was clear that there are no major safety-related issues not addressed in the existing guidance - as demonstrated by the fact that there have been tens of thousands of such trials without any major incident.

"However, it was also clear that the specific wording of certain points could be clarified and that some may need greater emphasis, primarily in relation to novel biological agents or medicines based on a novel way of working. Decisions about the first administration to man of agents that stimulate the immune system need especially careful scrutiny."

Some groups have expressed concern that British regulators approved the TGN1412 trial in just 17 days, however in Australia that would be considered quite a long period of time. Using the Clinical Trial Notification scheme in Australia, companies can notify and receive acknowledgement from the Australian Therapeutic Goods Administration (TGA) and start clinical trials in a week. Currently, 99% of clinical trials in Australia use this scheme.

Either a week or 17 days, this time is significantly shorter than that required to have a paper published in a peer-reviewed journal. Also, publishing does not involve any risk to trial participants.

Australia is well regarded internationally as a site for clinical trials with around 700 trials being performed in more than 2000 sites around the country annually. These studies routinely meet international regulatory requirements, including those of the US Food and Drug Administration (FDA) and the International Conference on Harmonisation.

The FDA has just announced a series of policy and regulatory developments to strengthen the Agency's oversight and protection of patients in clinical trials and monitoring as part of the Critical Path Initiative. The Human Subject Protection and Bioresearch Monitoring (HSP/BIMO) Initiative will facilitate the modernisation and the regulation of clinical trials and bioresearch monitoring, specifically the protection of human subjects and the integrity of data in clinical trials, and encompasses human drugs, biological drug products, devices, foods and veterinary medicine.

TGN1412, developed by German biotech company TeGenero, was manufactured by Boehringer-Ingelheim. US company, Parexel International conducted the phase I trial at Northwick Park Hospital in London.

TeGenero filed for insolvency on 4 July.