1. TF_DEL_Oct07/1 Microbicide Trials – Role of Data and Safety Monitoring Boards Tim Farley Department of Reproductive Health and Research World Health Organization Geneva

2. TF_DEL_Oct07/2 The Balance of Benefits and Harms in Clinical Research All clinical research requires careful balance of potential risks and harms to individuals with potential benefits to society Usually risks are borne by volunteers while benefits accrue to others Hence need for well-defined protocol and rationale, scientific review, ethical review (local, national, international), informed consent, monitoring that procedures followed correctly Genuine equipoise and uncertainty about the effects of the test product essential for a study to be ethical and implementable

3. TF_DEL_Oct07/3 The DSMB’s Responsibility and Dilemma All trials need independent body to review progress, ensure equipoise still holds and it is ethical to continue trial DSMB reviews data from trial, data from other sources, external context, … At each review four options: – Recommend stopping for evidence of benefit – Recommend stopping for evidence of harm – Recommend changing procedures to minimise risks – Recommend trial to continue Every time any recommendation made >0 chance it is wrong Type I and Type II error rates carefully controlled in design of trial and monitoring plan

4. TF_DEL_Oct07/4 Purpose of Data and Safety Monitoring Boards To ensure regular and systematic interim monitoring To provide an objective assessment of the interim data To protect confidentiality of interim treatment comparisons

5. TF_DEL_Oct07/5 Example 1: Prevention of Mother-to-Child transmission of HIV (PMTCT) AZT able to slow progression of HIV in adults with advanced disease ACTG076 /ANRS 024 trial designed to assess safety and efficacy of AZT in PMTCT Target 636 mother-infant pairs Enrolment began April 1991

6. TF_DEL_Oct07/6 Interim Reviews by DSMB DSMB met twice a year to monitor safety Efficacy reviews planned after each 1/3 of projected infant infections First efficacy review in February 1994, based on mothers enrolled up to December 1993 and their babies

7. TF_DEL_Oct07/7 First Interim Efficacy Review

8. TF_DEL_Oct07/8 Confidentiality of Interim Results Interim comparative data considered highly confidential, because knowledge of interim data could affect – patient entry and patient care – patient assessment – sponsor action Each of these factors may influence trial conduct and muddy interpretation of results DOD/BRB/NIAID

9. TF_DEL_Oct07/9 Example 2: Nonoxynol-9 Early in HIV epidemic intense efforts made to identify products that might protect against HIV infection Nonoxynol-9, active ingredient of several widely- used spermicides, shown to kill HIV in addition to sperm, and to prevent HIV infection in macaques Several studies of N-9 in different formulations and doses showed conflicting results – protection suggested in some, no protection in other, excess of lesions suggested in other studies (?due to 1000 mg dose of N-9?)

10. TF_DEL_Oct07/10 Intense Interest in Trial of N-9 Since N9-spermicides registered in almost all countries, potential existed for rapid scale-up and wide availability of product once shown to be safe and effective Desperate demand for woman-controlled method that could protect against HIV infection Certain groups already promoting N9-spermicides for women at high risk of infection Considerable criticism of WHO-Global Programme on AIDS to require definitive trial before widely promoting the product – “Delays in waiting for study results would result in millions of additional unnecessary infections” – Opinion remained widely divided even in run-up to release of study results

11. TF_DEL_Oct07/11 DSMB Monitoring Plan Planned masked interim review after 25, 50 and 75 HIV infections If result significant at P < 0.001 level then DSMB would unmask Clear difference between study arms began to emerge at 2 nd and 3 rd interim reviews, but well clear of stopping boundary Long discussions in DSMB on implications of study results under scenarios that emerging difference – in favour of N-9 – against N-9 Conclusion of discussions were that trial should not be stopped prematurely under either scenario  No need to unmask

12. TF_DEL_Oct07/12 N-9 Trial Conclusion Final result – Group A: 59 infections – Group B: 45 infections – Risk ratio: 1.5 (1.0 – 2.2), P = 0.047 Many commentators assumed that any differences must be in favour of product and that DSMB would have stopped trial if direction adverse In response to criticism of DSMB: – “At this point I do not know the final result of the trial, but I presume from your reaction that it is not in the direction you expected (whichever that was). Rather than criticising the DSMB for not doing its duty, you should congratulate the DSMB for nurturing the trial to a clear result”

13. TF_DEL_Oct07/13 Example 3: Cellulose Sulfate New product, not yet on market Different stopping boundaries to stop early for evidence of benefit or for evidence of harm – The type I error rate for testing whether CS has a protective effect will be controlled … at the one-sided 0.025 level…. The Lan-DeMets spending function with O'Brien-Fleming type boundaries will be used to account for the planned interim analysis. … it is anticipated that the interim significance level for the one-sided log rank test of effectiveness will be approximately 0.0025 at the study half-way point.” – “A liberal significance level of 0.10 will be used to test for a potentially harmful effect of CS at the interim analysis” Planned interim analysis after 33 HIV infections (half the expected final number)

14. TF_DEL_Oct07/14 Cellulose Sulfate DSMBs in Action Study sites – Benin, India (2 sites), South Africa, Uganda Planned sample size: 2574 women Started July 2005, 1333 enrolled at interim review Interim review on 26-Jan-07 – Total 35 HIV infections, clearly in the harmful direction (P < 0.10), consistent in all sites – Recommended immediate suspension of trial because of potential harm to volunteers – Director CONRAD communicated with Director FHI, responsible for parallel trial in Nigeria

15. TF_DEL_Oct07/15 Characteristic of CS Stopping Rule for Harm

16. TF_DEL_Oct07/16 Cellulose Sulfate DSMBs in Action FHI study of identical products – Two sites in Nigeria – Planned sample size: 2160 women Interim review 29-Jan-07 – Started December 2004, 1644 enrolled, 614 completed – Earlier review at 16 infections, did not unmask – Next review planned at 33 infections – 21 HIV infections, marginally in protective direction when unmasked Recommended trial be halted – Potential harm suggested by multi-country CS trial – Even if product not harmful, unlikely CS will ever be registered as safe and effective product –  unethical to continue

17. TF_DEL_Oct07/17 Final Results Cellulose Sulfate Trials CONRAD Study – CS arm: 25 infections (5.29 per 100 w-y) – Placebo: 16 infections (3.33 per 100 w-y) – Incidence ratio: 1.61 (0.86 – 3.01), P = 0.134 FHI study – CS arm: 10 infections – Placebo: 13 infections – Incidence ratio: 0.8 (0.3 – 1.9), P = 0.56

18. TF_DEL_Oct07/18 Lessons for Other Microbicide Trials In absence of surrogate endpoint for HIV infection, no alternative but to proceed rapidly, but cautiously to an HIV prevention study Must ensure early safety review (= HIV endpoint review) Reasonable scheme: – Planned safety and effectiveness analyses after 25%, 50% and 75% of expected total infections, or of expected person-years of exposure Need carefully to consider stopping boundaries – Balance risks of wrong decision – P < 0.10 at each review in CONRAD CS trial possibly too liberal – Must be considered for each trial

19. TF_DEL_Oct07/19 Links between DSMB, Local Ethics Committees and National Regulatory Authorities DSMB has access to data from all study sites and can more easily detect trends Impact of interim reviews on Types I and II errors carefully controlled LECs and NRAs – Perform regular (annual?) reviews of study implementation – Need to rely on DSMBs for interim monitoring of safety and outcome data Conclusions of DSMB reviews must be provided to LECs and NRAs on regular basis Promote better dialogue between DSMBs and local and national review mechanisms to respond rapidly to emerging concerns