Report calls for first-in-man drug trial reforms

The proposals for reform have been set by the UK's Royal Statistical Society (RSS) and are aimed at minimising drug trial risk, maximising design efficiency and improving protocol review.

They are the result of a working party set up by the RSS in order to prevent a repeat of last year's tragedy.

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.

"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 confirmed this view," said Professor Stephen Senn, chairman of the working group.

In addition, a Freedom of Information request lodged by the working party highlighted deficiencies in the linkage of the databases held by the UK Medicines and Healthcare products Regulatory Agency (MHRA) on first-in-man trials and associated serious adverse events.

"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," said Senn.

"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."

As a result, 21 recommendations for improvement are made in the report surrounding three key areas: risk assessment and communication; preparatory pre-clinical work; and experimental design, with particular attention to dosing.

"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," said Senn.

"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."

Sparking the scrutiny are the events that surrounded a first-in-man trial of TGN1412, a monoclonal antibody (mAb) that was being developed to treat conditions including multiple sclerosis, rheumatoid arthritis and leukaemia.

Six out of eight men involved in the trial experienced a severe and systemic adverse reaction and were admitted to intensive care with hours of taking the experimental drug.

Those that were unaffected had been given placebo.

Two firms were at the eye of the storm that followed - TeGenero, a small German biotech firm who developed the drug, and Parexel, an international contract research organisation (CRO) who carried out the Phase I trial on behalf of TeGenero.

Both companies were cleared of any blame in a subsequent MHRA investigation, however, there are lessons to be learned from the events of that day and the issue has continued to be tossed around by those in the scientific community and those in the relevant industry and government organisations.

Meanwhile, TeGenero has since gone bust and Parexel has been left to weather the ensuing storm.

Legal action could begin today against Parexel if the firm does not come up with "an adequate proposal" to compensate the victims, according to lawyers acting on their behalf.