Considerations for Topical Microbicide Phase 3 Trial Designs, an Investigator’s Perspective Andrew Nunn Medical Research Council Clinical Trials Unit London, UK

20 minutes In 20 minutes 100 women will have been infected with HIV How many of those infections could have been prevented by the use of an effective vaginal microbicide?

A common goal We need a microbicide which is: -effective -safe -acceptable -affordable

Safety and efficacy Local adverse events may be closely linked to infection and thus to reduced effectiveness. The experience gained through the COL1492 study has alerted us to the need for a new level of vigilance concerning possible adverse effects.

Priorities What is most urgent? –A highly effective product? –A licensed product? –Proof of efficacy?

Proof of efficacy The effectiveness of a microbicide will depend on the extent to which it is used. - Use will be dependant on acceptability - Acceptability is likely to vary considerably between populations - Heterogeneity of populations may provide the best chance of demonstrating proof of efficacy

Trial Design in an ideal world Ideally - We would have several promising products and test them in one trial - The products would be outwardly indistinguishable from each other and from placebo - The placebo would be completely ineffective - Behaviour would be unaffected by ‘being in a trial’

In reality 1.Products may not be indistinguishable - it maybe necessary to have a placebo for each product 2.Placebos may have some protective effect 3.Behaviour will change As a consequence of 2 & 3 any such trial would not mirror what happens if microbicides were to be introduced in a real life situation.

Would a second control arm help? Two controls arm have been proposed: -the conventional matched placebo arm -a condom only (‘no gel’) arm

The ‘no gel’ arm Advantages: It would eliminate the problems associated with a placebo which may have a protective effect. It would reflect ‘real life’ BUT ARE THESE ADVANTAGES REAL?

The disadvantages of a ‘no gel’ arm Disadvantages: -differential behaviour change - difficulty in achieving uniformly high follow-up

A ‘no gel’ arm: Behaviour changes issues In a randomised clinical trial participants usually behave differently to how they would outside the trial. Within the trial behaviour changes are not important when comparing indistinguishable treatments. A ‘no gel’ arm unblinds participants and almost certainly results in differences in behaviour change Women allocated to receive gel may choose to share gel with those allocated to ‘no gel’.

Could we allow for this in our analysis? Sexual behaviour data (e.g. partner change, frequency and type of sexual intercourse, use of condoms) are inherently very difficult to ascertain accurately. We could never be sure of the true differences between the distinguishable treatment arms. In consequence interpretation of differences would be impossible.

A ‘no gel’ arm: Follow-up issues However good our consent processes it is almost certain that many women will enrol into a trial in expectation of receiving gel. Women requested to attend for regular follow-up who receive no gel are likely to be less adherent to the study protocol than those who receive gel. Without coercive incentives women allocated ‘no gel’ are more likely to default from the study than those receiving gel.

‘No gel’ arm: conclusions A ‘no gel’ control arm would make the study impossible to interpret Results from a study including a no gel arm are likely to be at best ‘of interest’ but at worst will be ‘seriously misleading’

Collecting accurate sexual behaviour data Although difficult to collect it is very important to attempt to obtain accurate sexual behaviour data throughout the trial in order to be able to better understand the results. e.g. could no effect in one site be explained by condom migration?

Interpreting sexual behaviour data If a gel shows evidence of effectiveness in most but not all clinical sites this maybe due to differences in acceptability and adherence and/or to sensitive behavioural factors such as frequency of anal sex. We need to know why.

Heterogeneity of sites: good or bad? Heterogeneity of sites could be regarded as a bad thing, reducing the chances of demonstrating overall effectiveness. Alternatively, since a product may not be universally acceptable or effective, variation between sites could increase the chance of demonstrating an effect on the primary endpoint or of explaining reasons for lack of an overall effect.

How long should the Phase III be? Both adherence to gel use and regularity of follow-up are likely to be influenced by the duration of the trial design. Even in persons under treatment for active disease maintaining adherence is difficult, e.g. TB and HIV therapy trials. Maintaining good adherence with preventive therapy becomes increasingly difficult with time.

How short should the Phase III be? Short study designs of say, 6 or 9 months, are more likely to be able to demonstrate proof of efficacy than studies requiring that participants should be adherent for 24 months or more. Long term safety data can be obtained from such studies by following a subgroup for longer. Long term effectiveness, because it will be dependent on adherence, is likely to improve once proof of efficacy has been demonstrated

Population selection Proof of efficacy will be more difficult to achieve in certain circumstances, e.g. if we include participants who are unlikely to benefit, e.g. regular condom users or those frequently practising anal sex. Restrictive inclusion criteria prevents subsequent generalisation of findings. Site selection and to a lesser extent study personnel are likely to be important determinants of outcome

20 minutes If we are to reduce the number of new infections we need a flexible approach to study design which will maximise our chances of achieving proof of efficacy.