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Point of Care Research. Engineering a Learning Healthcare System Mary T. Brophy, MD MPH mary.brophy@va.gov. The State of Clinical Evidence Generation. Randomized Controlled Trials Gold standard Resource intense Relatively few in number Observational studies Affordable Bigger n’s

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point of care research

Point of Care Research

Engineering a Learning Healthcare System

Mary T. Brophy, MD MPH


the state of clinical evidence generation
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
medical evidence where is it
Medical Evidence: Where Is It?
  • Lots of guidelines – not much evidence
  • Guidelines not implemented
  • How can we develop more and better evidence?
are guidelines based on evidence
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

do practitioners follow guidelines
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

traditional clinical trials are too expensive
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
health r d as a percentage of health costs
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

problem statement
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
a solution
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’.

point of care research pocr

Point of Care Research(POCR)

A powerful tool of the learning healthcare system

pocr clinical trial example
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

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
pocr schema
POCR Schema

Care providers using EMR




& Consent



Data Capture


Decision Support


Study DB

Study team using traditional scientific tools

pocr requirements
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
pocr pilot study goals
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
pocr use case
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

pocr insulin protocol
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


Primary - LOS

Secondary - inpatient glycemic control and readmission within 30 days for glycemic control

pocr insulin protocol1
POCR – Insulin Protocol


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

pocr in the va
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


View of theEndocrine Medication Menu in VistA:

  • Consider Patient for Study Enrollment

Select Option 1


Study Information Page

Study Information and


(select Yes or No)


Enrollment Note Entry

Dialog template for note

(decision to enroll)

consent process for the study
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

closing the implementation gap
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

point of care research pocr1

Point of Care Research(POCR)

From the Specific to the General


Future Direction

optimal study attributes for pocr
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
requirements for poc adoption
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

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

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
from the present to the future state
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
ethical and regulatory issues in pocr
Ethical and Regulatory Issues in POCR
  • Informed consent
  • Engaged in research
  • Serious adverse event reporting
individual vs collaborative experiment
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

ethical benefits of pocr
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
ethical risk of pocr
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
informed consent debate
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

informed consent debate1
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

cluster randomization
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

waiver of informed consent
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

criteria for hipaa waiver
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.
ohrp guidance on engagement in research
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
sae reporting
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
pocr irb decision
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.


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.


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.


The Boston VA Healthcare System Pharmacy Department

  • 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
point of care research team
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
point of care research1
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