Point of Care Research

1. Point of Care Research Engineering a Learning Healthcare System Mary T. Brophy, MD MPH mary.brophy@va.gov

2. The State of Clinical Evidence Generation • Randomized Controlled Trials • Gold standard • Resource intense • Relatively few in number • Observational studies • Affordable • Bigger n’s • Contend with bias

3. Medical Evidence: Where Is It? • Lots of guidelines – not much evidence • Guidelines not implemented • How can we develop more and better evidence?

4. Are Guidelines Based on Evidence? • ACC/AHA Guidelines 1984-2008 • Number of recommendations increased from 1330 to 1973 (+48%) • Only 314 of 2711 recommendations were evidence level A (11%) • 1246 were level C (48%) • Only 245 of 1305 class I recommendations were level of evidence A (19%) • Too complex • Barriers in process of care Tricoci P et al. JAMA 2009;301:831-841

5. Do Practitioners Follow Guidelines? • Multiple studies show that practitioners’ adherence to guidelines is often poor • Reasons • Not based on level A evidence • Do not apply to individual patients Calvin JE et al. Congest Heart Fail 2012;18:73-78; Westergaard B et al. Clin Toxicol 2012;50:129-135; Burns SM Clin Nurse Spec 2012;26:22-28

6. Traditional clinical trials are too expensive • Require site and coordinating center study staff • Informatics infrastructure • Regulatory oversight • Informed consent , safety reporting and engagement in research • Financing • not aligned with needs of healthcare system • Result: Not scalable for Clinical Effectiveness Research

7. Health R&D as a Percentage of Health Costs Sources: NIH Data Book; Research!America, Investment in U.S. Health Research 2001, 2002, 2004-2009

8. Problem Statement • Healthcare system’s research needs are not fully met by the current research enterprise • Designed for basic science inquiry and drug discovery • There is no scalable model for: • Clinical Effectiveness Research • research comparing known treatments • Biomarker validation (Personalized Medicine) • For diagnostics, prognostic or therapeutic indications

9. A Solution Creation of a Learning Healthcare System that creates locally applicable knowledge Identifies its’ own needs Uses its’ own infrastructure Adapts available research methodology Directly implements research results The knowledge gained is thus not generalizable (thus not ‘research’) but rather is ‘locally selfish’.

10. Point of Care Research(POCR) A powerful tool of the learning healthcare system

11. POCR- Clinical Trial Example • A clinical trial with a substantial portion of its operations conducted by clinical staff in the course of providing patient/subject’s routine clinical care and where the choice of treatment is between two “equivalent” options

12. POCR Clinical Trials - Approach • Clinical research performed with minimal perturbation of the clinical care “ecosystem” • Subject identification and randomization occurs at usual health care encounter • Minimal study-defined procedures or visits (mostly directed via EMR) • Outcome data captured passively • Convert to decision support and implementation

13. POCR Schema Care providers using EMR Cohort Identification Enroll & Consent Randomize Intervention Data Capture Clinical Decision Support Analysis Study DB Study team using traditional scientific tools

14. POCR Requirements • Next-generation EMR • Incorporate study logic and workflows • Data and knowledgebase connectivity • Decision support sophistication • Culture change for patients and providers • Change in regulatory requirements • Informed consent • Engagement in research • Adverse event reporting

15. POCR - Pilot Study Goals A pilot study was adapted to assess the following: • Ability to modify the of EMR (VistA) to conduct the research • Physician and patient acceptance • IRB and regulatory acceptance of approach • Identification of logistical obstacles

16. POCR – Use Case Initiated as a Boston VA initiative Insulin protocol Sliding scale insulin regimen Weight based insulin regimen Both regimens are approved and in use at VA Boston No published data comparing outcomes

17. POCR – Insulin Protocol Open label RCT comparing the regimens Inclusion: inpatients who require an insulin regimen and are not in the ICU Exclusion: inability to give informed consent Endpoints: Primary - LOS Secondary - inpatient glycemic control and readmission within 30 days for glycemic control

18. POCR – Insulin Protocol Methods No modification of the current sliding scale or weight based regimens as they exist in the VA Boston VistA system Interface with clinicians entirely through the VistA packages Data collection and follow-up is done passively through the VistA system

19. POCR in the VA VistA - VA EMR Use existing features within EMR Alert System Order sets Consult System Customize features Identify, enroll and randomize patients Embed processes in dialogue boxes

20. Recruitment Workflow

21. View of theEndocrine Medication Menu in VistA: • Consider Patient for Study Enrollment Select Option 1

22. Study Information Page Study Information and Instructions (select Yes or No)

23. Enrollment Note Entry Dialog template for note (decision to enroll)

24. Consent Process for the Study Randomization for insulin treatment introduced by clinician; patient willing to talk with study nurse Study nurse explains study and seeks consent Signed Informed Consent – short, three-paged ICF with three options: 1) randomization and chart surveillance, 2) no randomization and permit chart surveillance, 3) decline participation Signed HIPAA authorization

25. Closing the Implementation Gap Hybrid Bayesian/frequentist approach “adaptive learning” Use of Bayesian posterior probability to reset the randomization (adaptive randomization) Use of conventional (frequentist) error rate calculations to evaluate the evidence “Learning” promotes automated implementation of the winning strategy

26. POCR Recruitment Summary

27. Point of Care Research(POCR) From the Specific to the General And Future Direction

28. Optimal Study Attributes for POCR • Limited to questions of the type: which “approved” treatment works better? • Interventions with well described toxicity • Broad inclusion criteria; limited exclusion criteria • Objectively identifiable endpoints • Minimal need for study specific visits

29. Requirements For POC Adoption • Rethink relationship between clinical care and research • Revisit engagement in research, consent, adverse event reporting • Educate to create a cultural change in ‘responsibilities’ of patients • Reengineer the EMR infrastructure • To allow questions to be asked and answered • To facilitate decision-support adoption • Develop novel analytical approaches • New ideas for supporting research • Alternative to the investigator-initiated approach • Support of research by clinical care dollars

30. POCR - Advantages • Pragmatic qualities address issues of Clinical Effectiveness • Results directly relevant to healthcare system (‘locally selfish research’) • Ability to assess long-term clinically relevant outcomes (lower cost) • Faster (immediate) Integration of results into practice thereby lowering the T2 translation barrier • Enhanced acceptance by providers • Adaptive randomization • Conversion to a decision support node • Improved logistics: • Facilitation of economic analysis • Accommodates device and strategy studies

31. POCR Trials Will Not: • Explain how biological, etiologic, or behavioral mechanisms interact to produce the observed clinical outcomes • Test new therapies where side effects are not well established

32. From the Present to the Future State • Early introduction of Point of Care Research to regulatory/oversight thought leaders to plan the way forward • Consider implementation requirements - from single site with highly engaged research personnel using in-person informed consent to national rollout • Conduct focus groups of providers and patients to better understand acceptability

33. Ethical and Regulatory Issues in POCR • Informed consent • Engaged in research • Serious adverse event reporting

34. Individual vs Collaborative Experiment “…physicians make therapeutic experiments daily on their patients….medicine by its nature is an experimental science but it must apply the experimental method systematically.” Claude Bernard, 1865 “This is what I regard as the University spirit, not simply diagnosing a patient and deciding what to do for him in order to earn our fee, but what we can get out of this case in order to do better next time.” Obituary of Sir FrancisFrasier, BMJ 1964 in Baum, Lancet, 1986 “Little progress has been made resolving the paradox of informed consent being unnecessary for the uncontrolled experimentation of normal practice but required for clinical research.” Hutton, 2001

35. Ethical “Benefits” of POCR • Individualized clinical care linked with systematic research • Honest admission of uncertainty in medical decisions • Wider clinician and patient participation – thus, wider applicability of results • Option for adaptive randomization – favoring more participants receiving the beneficial intervention • Potentially shorter implementation times – thus, potentially earlier results and benefits to healthcare system

36. Ethical “Risk” of POCR • Harm to doctor–patient relationship and respect for doctor’s knowledge and authority • Patient-centered care compromised • Inadequate informed consent process • time-pressured • patient vulnerable to coercion • waiver of documentation • Clinical care setting may impede providing patient with ongoing information relating to study participation

37. Informed Consent Debate • All trial protocols must be reviewed by award-granting bodies and local ethics committees (IRBs) – that said…. • For Informed Consent: patients’ rights to self determination – study information improves patient understanding of nature of disease and treatment – signed consent provides physician and institutional protection • Against Informed Consent: difficulty for patient to comprehend nature of disease, uncertainty of treatment and need for randomization – undermines confidence in doctor – bias created by refusals – delays inherent in consent process from Baum “Do we need informed consent” The Lancet, 1986

38. Informed Consent Debate • Fully informed consent is unobtainable ideal, concepts too abstract and details too technical; hence, all trials might be considered as unethical. • One approach - abandon requirement of informed consent, relying on safeguards such as ethics committees (IRBs). • Another approach - retain spirit of informed consent; take measures to maximize patient understanding; rely on ethics committees as a further level of protection. • Authors favor last approach – allowing patients to bring values and knowledge into play, to understand concept of equipoise and to make expectations of intervention more realistic. British Health Technology Assessment, 1998

39. Cluster Randomization • Intact units are allocated different interventions. • Consent for intervention from a “guardian” – e.g. head of a group practice or firm – best having several guardians to minimize conflicts of interest. • Must always guard against “authority” submitting persons to unwarranted and/or unsafe experimentation. • Must also consider validity of design and analysis, freedom to leave a trial, implications of early stopping of a trial. Hutton, in “Statistics in Medicine” 2001; Sabin et al., Hastings Center Report 2008

40. Waiver of Informed Consent • The research involves no more than minimal risk to the subjects • The waiver or alteration will not adversely affect the rights and welfare of the subjects • The research could not practicably be carried out without the waiver or alteration • Whenever appropriate, the subjects will be provided with additional pertinent information McCrae AD et al, Trials 2011;12:202; Weijer C et al, Trials 2011;12:100

41. Criteria for HIPAA Waiver • Use or disclosure involves no more than minimal risk • Research could not be practically done without waiver • Privacy risks are reasonable vis. a vis. benefits to individuals or importance of research • Plan to destroy identifiers exists • Assurance that data will not be reused or disclosed to others except for research that would also qualify for a waiver.

42. OHRP Guidance on Engagement in Research • Not engaged in research if: • Provide services that would typically be performed as part of routine clinical monitoring and/or follow-up of subjects • Do not administer the study interventions being tested or evaluated under the protocol • Do not obtain informed consent

43. SAE Reporting • FDA is encouraging risk based monitoring • Require reporting AEs only if unexpected, serious and would have implications for conduct of study • What is unexpected? • Single occurrence of serious event that is uncommon and strongly associated with drug exposure or uncommon in study population • More frequent than expected • More severe than expected

44. POCR – IRB Decision? At what point in the spectrum of medical knowledge discovery are assumptions like these reasonable? 1) POC research comparing two approved interventions introduces no risks beyond those normally encountered by patients receiving such treatments, and thus, having provided patients with appropriate information and choices, informed consent can be waived.

45. ……and 2) It is impractical to obtain HIPAA authorization in that informed consent was not required and since well-proven procedures were in place to ensure the confidentiality and security of any identifiers and protected health information obtained from medical records. 3) The treating clinicians, within their scope of practice, are simply offering patients either treatment A, treatment B or a roughly 50:50 chance of treatment A or B. Thus, they need not be identified or credentialed as members of the research team.

46. Example June 2011 Dear Veteran, We would like to inform you of a change in your prescription for mesalamine tablets or capsules. We will be changing your medication to mesalamine SA CAPSULES (APRISO®). Both products contain the same drug and work in a similar way. Both medications are safe and effective for your condition. Mesalamine is used for the treatment of ulcerative colitis and other conditions as determined by your provider. • Mesalamine SA CAPSULES (APRISO®) have the advantage of using one common dose and are only taken once a day. • Please finish all of your remaining supply of mesalamine EC TABLETS (ASACOL®) before starting your new mesalamine SA CAPSULES (APRISO®) prescription. Do NOT use both mesalamine products at the same time. • Read your prescription label carefully as the number of tablets and how often you take mesalamine may be different. The doctors and pharmacists at your VA clinic have authorized this change. If you have any questions regarding this letter please call the pharmacy. Sincerely, The Boston VA Healthcare System Pharmacy Department

47. Discussion • What level of patient and provider implicit or explicit “consent” is needed? • Notification +/- opt out • General enrollment into a program (non-study specific) • Consent • verbal +/- witness • written

48. Point of Care Research Team • Principal Investigators: Louis Fiore and Philip Lavori • Co-Investigators: Mary Brophy, James Kaufman, Mike Gazianoand Matt Liang and Ryan Ferguson • Informatics: Leonard D’Avolio and Chester Conrad • CPRS Engineers: Gus O’Neil and Tom Sabin • Ethics and Informed Consent: John Hermos • Pilot Content Expert: Stephen Swartz • Data Management: Lauren Weil • Statisticians: Philip Lavori, Robert Lew, Gheorghe Doros and Sarah Leatherman

49. Point of Care Research Sponsored by the VA Cooperative Studies ProgramOffice of Research & DevelopmentDepartment of Veteran’s Affairs Additional NIH support to Stanford University is gratefully acknowledged CTSA UL1 RR025744 CCSG P30 CA124435