Press Release

Working party on statistical issues in first-in-man studies

March 2007

Reforms necessary in first trials of experimental drugs, says Royal Statistical Society
 
Proposals for reforms in first trials of experimental drugs are set out in a report by the Royal Statistical Society published on Monday, 12 March 2007. The recommendations are aimed at minimising drug trial risk, maximising design efficiency and improving protocol review.
 
The Royal Statistical Society established a working party to investigate statistical issues in such first-in-man trials following last year's TGN1412 drug trial incident in which six healthy volunteers suffered a severe immune reaction (cytokine release storm).
 
The report concludes that the design of the TGN1412 trial was not well suited to its objectives of testing safety and tolerability of the drug. In addition, a Freedom of Information request lodged by the working party highlighted deficiencies in the linkage of the databases held by the Medicines and Healthcare products Regulatory Agency (MHRA) on first-in-man trials and associated serious adverse events.
 
The working party's report makes 21 recommendations for improvement, in three key areas:

    * risk assessment and communication;
    * preparatory pre-clinical work; and
    * experimental design, with particular attention to dosing

Professor Stephen Senn, chairman of the working group, says:
 
"Statistics is the science of information and information is what clinical trials are designed to produce. In practice, many issues of trial design are statistical. The fact that so many volunteers simultaneously suffered  severe reactions clearly signalled that the design of the TGN1412 trial might have been deficient.
 
"Our investigation has not only confirmed this view, but highlighted many areas for improvement in the general conduct of first-in-man studies.
 
"First-in-man studies are vital in the development of new drugs. It is, therefore, crucial that there is a high level of confidence in the safety of such trials.
 
"Collection of data on risk, including their relation to study design, type of experimental medicine, and whether volunteers are patients or healthy subjects, should be a routine matter. Drug regulatory bodies must take a leading role in analysing, sharing and communicating data on risk to all parties. Such analyses must pay heed to the trial design, in particular numbers being randomised to new drug versus placebo at each dose level, and whether adverse events occur at initial dose, during dose escalation, or at the highest pre-planned dose.  Risk communication itself would benefit from a numerically based description.
 
"Preparatory pre-clinical studies must have as their purpose the production of a document producing a specific risk assessment for the medicine being trialed, together with a statement of uncertainty. The document must be made available to regulators, ethical committees, subjects, trialing physicians and insurers.
 
 "First-in-man studies need to be designed and described much better than currently is the case. Particular attention must be paid to starting doses, dose intervals, dose steps and plans for allocating subjects to these. Studies should have the same clarity, care and detail regarding purpose, design and analysis as are currently required for studies supporting drug licensing. This means that assessment of the suitablity of the trial, trial management and intended analyses will need to be provided in much greater detail than is currently the case."