Table 1 MRC CTU at UCL criteria for considering addition of new research comparisons

1.

Sound scientific rationale, including a robust biological hypothesis that supports the need to assess in the disease setting

2.

Preliminary evidence to support mechanisms of action or activity or, for combinations, synergy in the disease setting being investigated

3.

Therapy is as different as possible from other therapies in the trial (past, present and future)

4.

Clear path for the trial results to translate into improved clinical care or impact on public health

5.

Investigator enthusiasm for the new research arm and ability to recruit patient population

6.

Sufficient number of sites could be reasonably expected to meet the requirements to participate

7.

Successful independent peer review as for a new study

8.

If appropriate, relevant industry partners willing to collaborate and contribute to the trial, if the research comparison involves a pharmaceutical agent

9.

Financial sustainability: funding identified and secured to ensure central TMT support in place to support new comparison

10.

Future relevance: The results must still be relevant when the trial matures. Other trials are not already under way for this treatment or will not report sooner unless duplication, replication and/or more data are strongly required

11.

Recruitment to new comparison must not jeopardise completion of the ongoing research comparisons

12.

No implications for ongoing and future planned comparisons (e.g. overlapping populations of interest, impact on accrual)

13.

Preliminary evidence to support the claim that a particular class of drug or specific agent has mechanisms of action or clinical activity that identifies it as a candidate within the biomarker defined subgroup. Acceptable data include:

• evidence that targeting the driver pathway in the biomarker defined subgroup results in preclinical and or clinical evidence of activity;

• strong epidemiological evidence of a link between an agent and a biomarker defined subgroup;

• preclinical data to support a synthetic lethal interaction between a biomarker defined subgroup and an agent;

• clinical data from a different disease setting for drug activity in a defined biomarker subgroup

14.

Biomarker assay characteristics: Technical ability to test for the biomarker, reproducibly with establishment of an SOP for assessment of the biomarker, with clear positive and negative controls and a quality assurance programme established between the biomarker laboratories

15.

Biomarker operating characteristics: Prevalence of biomarker likely to be sufficient to define an achievable population

16.

Prognostic and predictive effects are sufficiently well understood