The new arrangements put in place by the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) for first-in-man (FIM) studies of higher-risk compounds are “comprehensive and working effectively”, says early-phase specialist Simbec Research Limited.

The conclusion was based on the contract research organisation’s (CRO) experience in piloting the UK’s first immunomodulating monoclonal antibody (Mab) through the new system, introduced in response to the notorious Phase I study with TeGenero’s Mab TGN1412 at Northwick Park hospital in London.

Simbec, a long-established CRO with headquarters in Merthyr Tydfil, South Wales, did find the regulatory process raised a number of issues around justification of the design, population and site selection for the FIM trial, stretching the overall approval time from acknowledgment of the initial clinic trial authorisation (CTA) application to final notice of acceptance to 27 weeks.

This included parallel assessment by the South Wales Research Ethics Committee (REC), with repeated submissions to incorporate the amendments required by the MHRA and its advisory groups.

Despite these extended timelines, Simbec has described its initiation into the revised FIM procedure as an “invaluable” experience that will position the CRO well to advise companies whose products call for preliminary review by the MHRA’s dedicated Expert Advisory Group (EAG) for FIM trials.

Commenting on the procedure in a recent issue of NextGen Pharmaceutical, Simbec’s scientific director, Dr Trevor Tanner, noted that the UK “has a tremendous track record for early-phase research and the leading role they have adopted in introducing the new regulatory process, with easily accessible expert advice on protocol design at a very early stage, can only enhance the UK reputation as the region of choice for early-phase research”.

This view is in marked contrast to concerns expressed by the BioIndustry Association (BIA) when the new procedures were formalised with the first meeting of the EAG in April 2007.

At that time, there were rumblings about companies delaying their trials or taking them overseas in the face of lengthy and burdensome procedures for FIM trials – although the BIA admitted some of these responses related to the interim arrangements for higher-risk compounds that came into play shortly after the Northwick Park incident in March 2006.

In fact, Simbec’s CTA application, which was filed for initial review in December 2006, fell within this timeframe: the submission passed immediately to the interim Expert Scientific Group (ESG) at the MHRA’s Committee on Safety of Medicines that was the precursor to the EAG. It was then further reviewed by the Commission on Human Medicines (CHM), as now occurs under the formal system set up in line with the recommendations of the government-appointed expert working group on Phase I trials chaired by Sir Gordon Duff.

The BIA’s concerns were perhaps understandable, in that its members were most liable to feel the pinch from a tougher regime focused on novel compounds. But they were not shared by the Association of the British Pharmaceutical Industry (ABPI), which was confident about the EAG procedure and saw it as a likely template for revisions in other markets.

Simtec’s experience in taking a ‘higher-risk’ monoclonal antibody through the new procedure was outlined in a poster presentation at the Institute of Clinical Research’s (ICR) annual spring conference and exhibition in Birmingham last week.

Particular issues

Not surprisingly, the CRO’s correspondence with the ESG/EAG, the CHM and the MHRA reflected some of the particular issues raised by the TeGenero study, such as dosing intervals and the potential of monoclonal antibodies to trigger cytokine release syndrome (effectively a massive overstimulation of the immune system).

For example, the MHRA’s advisors wanted a justification for the trial site, further information on the pharmacology of the experimental compound and transfer times from the trial site to an intensive therapy unit (ITU), as well as an algorithm for cytokine release treatment.

The study protocol was amended to include a 24-hour gap between dose leaders and at least three hours between subsequent dosing of volunteers. Each subject was to participate in one dosing period only, while doses were administered by slow intravenous infusion over a two-hour period.

Moreover, the MHRA insisted on an ITU doctor being at the site during dosing and on two Advanced Life Support (ALS)-trained doctors being present for at least six hours after every dose.

The UK is “the leading regulatory agency to provide a thorough review and commentary on design and application for the development of new immunomodulatory agents”, the Simbec poster concluded. In order to “progress future applications in a timely manner”, though, “attention must be focused on justification of the studied population, trial design and appropriate site selection”, it added.

According to the latest data from the MHRA, the agency received a total of 11 CTA applications for studies in healthy volunteers or patients requiring EAG/CHM review between April 2007 and February 2008. Month by month, there were three such applications in April 2007, two in June, none in September (August was not recorded), two in October, three in December and one in February 2008 (January not recorded).

These submissions included FIM trials for higher-risk compounds. The average time from the latest filing date to a decision was, respectively, 34 days (April 2007), 28 days, 0 days (September 2007), 24 days, 35 days and 46 days.