1. New Prevention Technologies Workshop Module 3: Overview of Prevention Research WWW.ICAD-CISD.COM

2. UNDERSTANDING THE RESEARCH PROCESS

3. Clinical Trials Process Preclinical Phase I Phase II Phase IIB “Test of Concept” Phase III Licensure, Manufacturing & Distribution For Vaccines For Microbicides Lasts 12 – 18 months Studies Safety Lasts up to 2 years Studies Safety & Immunogenicity Bigger than Phase II but smaller than Phase III Used to determine what products to move to Phase III Lasts 3 – 4 years Studies Safety & Efficacy Lasts 1 – 6 months Studies Safety Lasts up to 2 years Studies Safety & Acceptability Lasts 2 – 4 years Studies Safety & Efficacy Sometimes simultaneous studies (HIV+ and penile) Smallest group of volunteers Larger group of volunteers Largest group of volunteers

4. The product pipeline Early-stage concepts Preclinical testing More than 50 candidates 8 in early human safety trials 1 in large-scale efficacy trials Source: Alliance for Microbicide Development

6. None of this research would be possible without the willingness and dedication of the study volunteers!

7. Experience of a trial participant Screening Visit 1: Education about the trial, HIV and pregnancy test, sexually transmitted infection tests and treatment, baseline data collected Screening Visit 2: Results of tests, counselling, education about trial reinforced Randomisation: Participant assigned by chance to a group Family Planning Informed consent for screening Informed consent to enrol Condoms + placebo Condoms + experimental gel

8. UNDERSTANDING TRIAL RESULTS

9. What is a Successful Trial?

10. A Successful Trial A successful trial is not necessarily one that yields a positive result but one where the:  Research plan conducted as stated & sound methodology  Trial provides further information  Health of participants protected  Trial continuously monitored at defined intervals  Participants & community engaged with the research process in an ethical respectful, and efficient manner  Study results communicated to participants, community & stakeholders  Plan for access to study product developed in case of + result

11. Scenario #1: Benefit (It Works!)  Trial shows compelling evidence of benefit  Examples:  Male Circumcision (3 trials)

12. Scenario #2: Flat Result  The trial shows no benefit  The product caused no harm  Examples:  Carraguard©, MIRA diaphragm

13. Scenario #3: Evidence of Harm  Trial shows product has no protection  Product causes harm  Usually, these trials will be closed early…  Examples:  N-9, Cellulose Sulfate

14. Why might a trial end early?

15. 4 Reasons a Trial Ends Early Evidence of Harm: There is evidence that the test product may be causing harm. Overwhelming Effect: The product being tested is definitely effective and there is proof of efficacy. Futility: In other words, the trial can no longer answer the assigned question. Concerns: Concerns may come from regulatory bodies, community, or the trial sponsor.

16. Evidence of Harm: DSMB Stops Study DSMB stopped the CONRAD and FHI Cellulose Sulfate studies in 2007  CONRAD – Benin, India, South Africa, Uganda  1,333 enrolled  35 women seroconverted (23 in CS arm, 11 in placebo)  DSMB met, saw possible evidence of harm, stopped trial, alerted FHI  FHI – Nigeria  1,644 enrolled  21 women seroconverted (approx. same in each arm)  DSMB met, saw no evidence of harm, stopped trial to err on the side of caution

17. Overwhelming effect: Male circumcision  3 studies conducted: Orange Farm, Rakai, Kisumu  In 2006, DSMBs closed the studies early due to overwhelming effect (from 51 to 60%)  WHO published recommendation based on study results

18. Closed for Futility: DSMB Discontinues One Arm Data monitors can also stop part of a trial.  MDP 301 Trial of PRO 2000: 2% and 0.5%  DSMB closed 2% arm “as there is no more than a small chance of the high dose showing protection against HIV infection compared to placebo gel”  Remaining.05% and comparator gel arms continued

19. Concerns: Study Ends Over Controversy  Miscommunication between researchers and the community led to political controversy and halted PrEP trials in Cambodia and Cameroon in 2004. Political controversy can halt trials just as quickly as scientific findings.

20. All Clinical Trial Results Are Valuable  They can tell us which products are not worth pursuing  They can point to the kinds of modifications that could be made to improve trial design  They may yield beneficial information about behavioral and cultural practices that influence HIV transmission and clinical trial outcomes; and  They provide valuable information about how prevention trials can be better managed.

21. UNDERSTANDING PREVENTION TRIALS

22. HIV Prevention Trials Differ From Treatment Trials Treatment Trials:  Enroll those needing treatment – individual urgency.  May help prevent disease progression.  Only benefits those with the disease. HIV Prevention Trials:  Enrolling healthy people – no immediate benefit to individual  May help prevent disease transmission.  Benefits society; everyone at risk of HIV.

23. Special Challenges of HIV Prevention Trials  Complex clinical trial design: multi-site, multi-country, 2,000- 10,000 participants, transnational research collaborations  Healthy individuals -- yet at “high risk”: 3-5% annual incidence minimum  Often involved marginalised or stigmatised populations (sex workers, IDU, MSM); stigma associated with HIV, sexual activity, drug use  All new intervention likely to reduce, not eliminate risk = require large trials to detect partial efficacy  No clear surrogate endpoints (“correlates of protection”); only new infections tell us whether a product works or not  Results affected by user behaviour, in many cases

24. Why are most of the phase III trials taking place in Africa and Asia?  Microbicide trials require large numbers of women at risk of vaginally transmitted HIV  High incidence  Relatively stable (non-transient population)  Little or no injection drug use  Most populations of women in the US or Europe with high HIV incidence also use IV drugs

25. Sample Size Calculations Notes: Significance level =.05, power = 90%, test statistics and log rank test, two-tailed, equal size groups. Assumes 15 percent loss to follow-up. Figures prepared by Charlotte Ellertson and Kelly Blanchard using nQuery (version 1.0) survival analysis option. Effectiveness Annual HIV Sero-Incidence 1%2% 3%4%5% 20% 11026654638360942682421259 30% 46315229651518111289 8955 40% 2453912176 8056 5995 4760 50% 14736 7320 4847 3609 2868 60% 9560 4753 3612 2351 1868 70% 6529 3249 2158 1612 1282 80% 4621 2304 1532 1144 913 90% 3353 1673 1115 835 666

26. Exercise: Outcomes of past studies Signs of efficacyNo efficacy Safe Trend toward harm

27. What will NPTs mean for HIV prevention? The answer depends on us! “Science teaches us everything except what to think and what to do.” – Søren Kierkegaard