1. It Worked in the Trial but No One Will Take It Improving Methods for Moving from Clinical Trials into the Real World
Manya Magnus, PhD, MPH
Professor | Associate Chair
Department of Epidemiology
Milken Institute School of Public Health
George Washington University
I would like to extend my thanks to the organizers for including me in this exciting panel. In the next 10 minutes I would like to identify a key challenge in moving effective treatments to scale and offer a potential methodologic solution.

2. Dr. Magnus has no conflicts to disclose.
Conflicts of Interest
Dr. Magnus has no conflicts to disclose.

3. Pre-clinical drug development Phase I, II, III clinical trials
FDA review
Success!
The Drug WORKS and
is approved for use
-Policy and program changes
-Demonstration projects
-Implementation science
Identification of challenges and innovation surrounding removal of barriers
Eventually successful implementation and
realized outcomes
(But many years post-approval)
Purpose of this talk is to identify common barriers to moving from discovery to scale up, and to suggest reorganizing our conceptualization about where implementation science methods belong in the drug development process. First let’s talk about how this usually works: Note this is for US drug development but similar for EMA. After 9-14 years of drug development, plus additional ~2 for review, we waiting for a drug that we know works – and this can apply to prevention, treatment, eventually cure. How can we reduce the time from approval to successful implementation and scale up of a medication?
Approximately 9 to 15 years1

4. PrEP in US as an example Since 2012: Pre-2012
Studies to examine populations inadequately included in iPrEX2,3,4
Implementation science studies to decrease barriers and increase adherence (e.g., technology)
Continued poor PrEP delivery to those at highest risk of HIV and payor structures slow to resolve
Mistrust, stigma, provider barriers, structural barriers to PrEP and other prevention services care3,4,6,7
Success! 2012
TDF/FTC to prevent HIV and is approved for use by FDA
Eventually successful implementation and
realized outcomes

5. There Remains Disproportionate PrEP Use
Men and 25- to 44-year olds were more likely to be PrEP users 8
93% of all PrEP users in 2016 were male
Geographic differences 8
Nearly 50% of PrEP users in 2016 were located in five states: New York, California, Florida, Texas, and Illinois
The South has the highest number of new HIV diagnoses in the U.S. but disproportionately fewer people using PrEP
MSM at greatest risk are Black and Latinx yet least likely to receive PrEP 3,4,5,8
With 2017 guidelines, 1.23 million adults at risk for HIV acquisition for whom PrEP and other prevention methods are indicated from 25% in 2015 to 45%9,10

6. What are the challenges and barriers?
Generalizability
Clinical trials population does not reflect real world
Structural barriers
Cost and accessibility
Stigma
Political will
Providers
Adherence
Real world issues in adherence
Physical challenges (e.g., side effects)
Fatigue
Knowledge of importance
Acceptability of regimen
What are the challenges and barriers?
As I am both a clinical trials person and a structural barriers person, this gives me the opportunity to consider how and why this considerable delay is occurring. In order to shrink this timeline from drug approval to effective scale up we need to move more rapidly from studies of efficacy in ideal situations to effectiveness in the real world situations.
Similar for all HIV medications

7. What Can We Do?

8. Shortening the Timeline from Discovery to Implementation
The barriers are not a mystery
All treatment, prevention, cure strategies are likely to have the same challenges
We know what the issues are
Generalizability in trial samples
Identification of and proactive removal of expected structural barriers simultaneous with implementation
Including studies to elucidate these and identify solutions
Adherence

9. Solution: We need to move from sequential to simultaneous
Implementation science concomitant with clinical trials
Collaboration of multi-disciplinary investigators – remove siloes
Increasing examples of this (e.g., CAB LA development program), but we can do more
Address cost and access issues in studies (policies and barriers)
Improve understanding of challenges with adherence
Learn what they are from both clinical trial and community-based samples simultaneously
Develop, deploy, and measure adherence strategies at the same time as study drug rollout - not after
Make innovations that focus on the root causes and not just the app/vendor/etc. methods for identifying what will be successful
Positive changes: 083 composition of sample, in trial + community studies on acceptability of injectables,

10. How Methods Can Be Improved
Challenges
How Methods Can Be Improved
Generalizability
Lack of racial diversity in clinical trials sample
Cost and accessibility
Prohibitive cost and barriers to access of TDF/FTC
Stigma
Stigmas in field use and methods to overcome stigma not examined
Political will
Lack of interest in rapid deployment of life-saving medication
Providers
Knowledge of ARVs absent in primary care settings; stigma; stereotypes
Adherence barriers
Real-world challenges different from clinical trials

11. How Methods Can Be Improved
Challenges
How Methods Can Be Improved
Generalizability
Lack of racial diversity in clinical trials sample
Require a priori sample composition
Cost and accessibility
Prohibitive cost and barriers to access of TDF/FTC
Stigma
Stigmas in field use and methods to overcome stigma not examined
Political will
Lack of interest in rapid deployment of life-saving medication
Providers
Knowledge of ARVs absent in primary care settings; stigma; stereotypes
Adherence barriers
Real-world challenges different from clinical trials

12. How Methods Can Be Improved
Challenges
How Methods Can Be Improved
Generalizability
Lack of racial diversity in clinical trials sample
Require a priori sample composition
Cost and accessibility
Prohibitive cost and barriers to access of TDF/FTC
Examine barriers during clinical trials rollout in participants and community-based samples; advocate for payors to cover and reasonable cost
Stigma
Stigmas in field use and methods to overcome stigma not examined
Political will
Lack of interest in rapid deployment of life-saving medication
Providers
Knowledge of ARVs absent in primary care settings; stigma; stereotypes
Adherence barriers
Real-world challenges different from clinical trials

13. How Methods Can Be Improved
Challenges
How Methods Can Be Improved
Generalizability
Lack of racial diversity in clinical trials sample
Require a priori sample composition
Cost and accessibility
Prohibitive cost and barriers to access of TDF/FTC
Examine barriers during clinical trials rollout in participants and community-based samples; advocate for payors to cover and reasonable cost
Stigma
Stigmas in field use and methods to overcome stigma not examined
Issues in behavior disclosure challenging; packaging of medication
Political will
Lack of interest in rapid deployment of life-saving medication
Providers
Knowledge of ARVs absent in primary care settings; stigma; stereotypes
Adherence barriers
Real-world challenges different from clinical trials

14. How Methods Can Be Improved
Challenges
How Methods Can Be Improved
Generalizability
Lack of racial diversity in clinical trials sample
Require a priori sample composition
Cost and accessibility
Prohibitive cost and barriers to access of TDF/FTC
Examine barriers during clinical trials rollout in participants and community-based samples; advocate for payors to cover and reasonable cost
Stigma
Stigmas in field use and methods to overcome stigma not examined
Issues in behavior disclosure challenging; packaging of medication
Political will
Lack of interest in rapid deployment of life-saving medication
Garner stakeholders simultaneous with drug development program
Providers
Knowledge of ARVs absent in primary care settings; stigma; stereotypes
Adherence barriers
Real-world challenges different from clinical trials

15. How Methods Can Be Improved
Challenges
How Methods Can Be Improved
Generalizability
Lack of racial diversity in clinical trials sample
Require a priori sample composition
Cost and accessibility
Prohibitive cost and barriers to access of TDF/FTC
Examine barriers during clinical trials rollout in participants and community-based samples; advocate for payors to cover and reasonable cost
Stigma
Stigmas in field use and methods to overcome stigma not examined
Issues in behavior disclosure challenging; packaging of medication
Political will
Lack of interest in rapid deployment of life-saving medication
Garner stakeholders simultaneous with drug development program
Providers
Knowledge of ARVs absent in primary care settings; stigma; stereotypes
Rollout in desired settings from start; medical education as a part of planning
Adherence barriers
Real-world challenges different from clinical trials

16. How Methods Can Be Improved
Challenges
How Methods Can Be Improved
Generalizability
Lack of racial diversity in clinical trials sample
Require a priori sample composition
Cost and accessibility
Prohibitive cost and barriers to access of TDF/FTC
Examine barriers during clinical trials rollout in participants and community-based samples; advocate for payors to cover and reasonable cost
Stigma
Stigmas in field use and methods to overcome stigma not examined
Issues in behavior disclosure challenging; packaging of medication
Political will
Lack of interest in rapid deployment of life-saving medication
Garner stakeholders simultaneous with drug development program
Providers
Knowledge of ARVs absent in primary care settings; stigma; stereotypes
Rollout in desired settings from start; medical education as a part of planning
Adherence barriers
Real-world challenges different from clinical trials
Prevention fatigue; side effects; seasons of risk; knowledge

17. What might implementation look like with this approach?

18. The Drug WORKS and is approved for use, and methods
Pre-clinical drug development
Phase I, II, III clinical trials
FDA review
-Policy and program changes
-Demonstration projects
-Implementation science
Identification of challenges and innovation surrounding removal of barriers
Success!
The Drug WORKS and is approved for use, and methods
to overcome barriers deployed at same time as initial drug launch
Subsequent implementation science approaches to refine rather
than create ways to scale up to communities
Successful implementation and
realized outcomes
(Nearly simultaneous with approval)

19. Conclusions
Urgent need to develop methods that decrease time from drug discovery to scale-up and implementation
Improvement of methods and integration of implementation science concerns into clinical trials
Especially critical for populations at greatest risk of not accessing medication
While barriers to effective scale up may vary by location or sub-population, what we need to examine does not, making it possible to be proactive
Simultaneous rather than sequential application of methods is critical
Generalizability of sample
Addressing structural barriers
Overcoming eventual barriers to adherence
For HIV especially, the issues are unlikely to differ by drug allowing us to start earlier in the process

20. Literature Cited 1https://www.fda.gov/media/97229/download
2 Grant R et al. Pre-exposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men. NEJM 2010;363:
3 Wheeler D et al. Pre-Exposure Prophylaxis Initiation and Adherence among Black Men Who Have Sex With Men (MSM) in Three U.S. Cities: Results from the HPTN 073 Study. Journal of the International AIDS Society. 2019;22:e doi: /jia
4 Wheeler D et al. Building effective multilevel HIV prevention partnerships with Black men who have
sex with men: experience from HPTN 073, a pre-exposure prophylaxis study in three
US cities. J Int AIDS Soc Oct;21 Suppl 7:e doi: /jia
5 Levy et al. Understanding Structural Barriers to Accessing HIV Testing and Prevention Services Among Black Men Who Have Sex with Men (BMSM) in the United States. AIDS Behav 2014;18: 972–996, DOI: /s x.
6 Millett Ga et al. Comparisons of disparities and risks of HIV infection in black and other men who have sex with men in Canada, UK, and USA: a meta-analysis. Lancet Jul 28;380(9839): doi: /S (12)60899-X. Epub 2012 Jul 20. Review. PubMed PMID: 10
11 Centers for Disease Control and Prevention: US Public Health Service: Preexposure prophylaxis for the
prevention of HIV infection in the United States—2017 Update: a clinical practice guideline.
Published March 2018.
12 Weiss KM et al. Estimated PrEP eligibility in a national sexual network study of MSM. Conference on Retroviruses and Opportunistic Infections (CROI). March 4-7, 2019 Seattle. Abstract 971.

21. Acknowledgements Thanks to
Study participants over the years
GW HIV Community Advisory Board
DC Center for AIDS Research
HIV Prevention Trials Network Colleagues
Dr. Irene Kuo
This presentation was facilitated by the services and resources provided by the District of Columbia Center for AIDS Research, an NIH funded program (AI117970), which is supported by the following NIH Co-Funding and Participating Institutes and Centers: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, FIC, NIGMS, NIDDK, and OAR
The content is solely the responsibility of the authors and does not necessarily represent the views of the NIH

22. Manya Magnus, PhD, MPH 202 994 3024 manyadm@gwu.edu
Thank You
Manya Magnus, PhD, MPH

23. Interactive Example HIV cure

24. How Methods Can Be Improved
Generalizability
Cost and accessibility
Stigma
Political will
Providers
Adherence barriers