post-approval clinical epidemiological studies (paces) · post-approval clinical epidemiological...

Post-Approval Clinical

Epidemiological Studies

(PACES)

• John Sampalis, BSc, BA (Hon.), MSc, PhD, F.A.C.E.

• Associate Professor Faculty of Medicine

• McGill University

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Definitions

Controlled Clinical Trials Routine Clinical Practice

OUTCOMES

EFFICACYIDEAL/CONTROLLED CONDITIONS

• Selected patient population:

• Narrow spectrum of target population

• Controlled treatment administration

• Defined patient follow up &

assessments

• University / Research setting

EFFECTIVENESSREAL LIFE CONDITIONS

• No or minimal selection of patients:

• Broad spectrum of target population.

• Minimal or No Control of Treatment &

Follow Up

• Treatment as per routine care

• Access to care as per existing policies

Risk of Serious Adverse Events

• Potentially Life Threatening

• Increase Morbidity

• High Detection Threshold

Risk of Non Serious Adverse Events

• High Detection Threshold

Risk of Serious Adverse Events

• Potentially Life Threatening

• Increase Morbidity

• Comorbidity & Concomitant Medication

Related

• Lower Detection Threshold

Risk of Non Serious Adverse Events

• Comorbidity and Concomitant Medication

Related

• Low Detection Threshold

SAFETY

TOLERABILITY

Risk of Nuisance Adverse Events

• Comorbidity and Concomitant Medication

Related

• High & Low Likelihood

JSS Medical Research ® 2013

Post-Approval Clinical & Epidemiological Studies close

the safety & efficacy gaps

CONTROLLED CLINICAL TRIAL• Highly Selective Patient Population

• Structured Treatment Administration

• Protocol Based Follow Up and Assessment

• High Safety Signal Detection Threshold

• No Impact of Access to Care

EXPECTED

EFFICACY

from RCT

EXPECTED

RISK

from RCT

REAL-LIFE• Minimum Selection of Patient Population

• Routine Care Treatment Administration

• Non Structured Safety Assessment

• Physician Discretion

• Impact of Access to Care

OBSERVED

EFFICACY

OBSERVED

RISK

PROBLEMS

• Increased Cost to Society

• Compromised Return on Investment

• High Burden of Illness and Societal Impact

• Safety: Iatrogenic Adverse Effects

SOLUTIONS

• Describe Treatment and

Safety Gaps

• Identify and Segregate

Determinants & Contributing

Factors to the GAPS

• Design & Implement

Interventions to Alter

Modifiable Determinants and

Factors

• Assess Impact of Interventions

& Repeat until Effectiveness &

Safety are Optimized and

Gaps are Minimized

• Evolution to Optimal Disease

Management through ongoing

Evaluation

Treatment

Gap

Safety

Gap


PACES should be an integral and essential phase of the drug

development life cycle with implications comparable to that of

Phase II-III studies.

D r u g d e v e l o p m e n t

Pre-clinical Clinical I-III Post-Approval

• Basic science


• Safety PK/PD,

• Proof of Concept & Optimal Regimen

• Efficacy & Safety

• Effectiveness & Safety

Hig

h

R

ea

l-L

ife

Ge

ne

raliz

atio

n

Hig

hest

Pre & Post Approval Epidemiological Surveys(Disease Epidemiology, Burden of Illness, Treatment Patterns, Treatment Gap, Knowledge Gap)

PMOS & Registries(real life conditions)

Target Populations

Community MDs

Phase IV(Emulate real life

non-ideal conditions)

Target Populations

Patient Subgroups

Community MDs

Chart Review

Database data mining

Epidemiological Survey (pre & post-approval)

OBJECTIVE

To conduct a true observational study:

Assessment / Description of

• Disease Epidemiology

• Burden of Illness: Morbidity, Mortality, Quality

of Life, Economics

• Variance in Epidemiological Profile: Temporal,

Regional

• Practice Patterns: Medical Decision Making,

Physician / Patient Preferences

• Treatment Gap: Determinants and

Contributing Factors:

Adherence

Patients - treatment

Physicians - practice guidelines

Demographics

Comorbidity

Access to Care

Safety & Tolerability

Hypothesis Generating

Assess existing Interventions aimed at

improving effectiveness

DESIGN

• Prospective Cohort: Single & Multiple Cohorts

• Retrospective Cohort: Single & Multiple

• Cross Sectional Survey

+ −• Prevent Selection bias:

Ensure generalization to

target population

• Avoid Halo effect:

Responses must be valid

Large sample size: Ensure

adequate response rates and

unbiased responder sample

Relatively easy to conduct

• Short time to execute

Large sample size

• Random selection to ensure

representation of the target

population (External validity)

• Allows sub group analyses


Phase IV (post-approval)

OBJECTIVE

To Assess Real - Life / Routine Care• Effectiveness & Safety

• Patient and Physician Satisfaction

• Health Care Utilization

• Health Economics

• Patient Outcomes: Quality of Life, Utility, Satisfaction

with Treatment, Productivity, Health Care Costs

To expand physician and patient experience and

comfort with treatment

Treatment Gap• To identify profile of patients responding / not

responding to treatment (Responder analyses in real

life setting)

• Assess New Interventions aimed at reducing

treatment gap & optimizing effectiveness

Assess effectiveness and other outcomes in

patient subgroups• Patient Characteristics: Comorbidity & Concomitant

Medication Use

• Disease Severity or Phenotype

DESIGN

• Single prospective cohort treated with study intervention

• 2 or more prospective cohorts to compare treatments

Open label or Blinded

Random or Non-Random Treatment Allocation

• Sample Size & Follow Up:

Determined by Objectives and Hypotheses

Limited to provide valid answers to scientific questions

• All costs for patient care covered by the study

+ −Time to set up and execute

• Typically 1 -3 years

Attention

• Not to Confuse / Conduct a

Seeding Trial

• Prevent Selection Bias:

Physicians and Patients

• Select Outcomes that are

Relevant to Real-Life,

Routine Care

Emulates Real – Life Setting

• Effectiveness not affected by

access to care and adherence

to treatment

• Patient Outcomes can be

assessed

Physician / Patient Education

• Familiarity with the treatment


Post-Marketing Observational Study (PMOS)

OBJECTIVE

To conduct an observational study on the treatment and

outcomes of patients

• Usually asses the effect of specific treatment or

interventions observed in routine care

Typically follow all patients with a disease or

condition or could restrict to specific treatments(s)

Patient treatment and management is NOT

affected by the study

All assessments including follow up is as per

routine care

Decision to treat patient with study

intervention MUST be independent of

enrolment in the study

• Specific Hypotheses and Objectives are ESSENTIAL

Assess / Describe

• Real - Life / Routine Care:

Effectiveness & Safety

Compliance / Adherence

Patient and Physician Satisfaction

Health Care Utilization

Health Economics

Patient Outcomes: Quality of Life, Utility, Satisfaction

with Treatment, Productivity, Health Care Costs

Treatment Gap

• Determinants of response / non response to treatment

• Assess Existing Interventions aimed at reducing treatment gap

& optimizing effectiveness

DESIGN

• Single prospective cohort treated with study intervention

• 2 or more prospective cohorts having different treatments

• Sample Size & Follow Up:

Determined by Objectives and Hypotheses

Limited to provide valid answers to scientific questions

• All costs for patient care NOT provided by study;

• Payment is as per existing Insurance or by the patient.

+ −Relatively high cost to maintain

Complicated Design and Statistical

Analysis to adjust for potential bias

(Selection, Indication,

Confounding) and Observational –

Non – Structured Treatment

Schedules

Attention:

• Avoid Seeding Trials

Valid scientific questions,

study objectives

Regulatory requirements

with Ethics Review & Patient

Consent

Longitudinal follow up of patients

in real – life setting

Patient outcomes can be

assessed

Validity of Results

• Low risk for selection bias

• Hard outcome data collected


Patient Registry (post-approval)

OBJECTIVE

Similar to PMOS

Exception

• Specific Hypotheses and Objectives are not

required: General Purpose must be specified

(e.g. Effectiveness or Safety)

• Larger Sample Size (Indefinite)

Not determined / limited by specific

Hypotheses and Objectives.

In theory: Could include 100% of target

population

• Longer / Indefinite Follow Up

Not determined by specific Hypotheses

and Objectives

In theory: Could be as long as patient is

undergoing treatment and qualifies for

the registry

DESIGN

• Single prospective cohort with disease or treated with

specific intervention

• 2 or more prospective cohorts to compare treatments

• All costs for patient care NOT provided by study;

• Payment is as per existing Insurance or by the patient.

+ −Relatively high maintenance

cost

Complicated Design and Statistical

Analysis to adjust for potential bias

(Selection, Indication,

Confounding) and Observational –

Non – Structured Treatment

Schedules

Attention:

• Avoid Seeding Trials

Valid scientific overall

purpose

Regulatory requirements

with Ethics Review &

Patient Consent

Low cost to implement

Create a longitudinal & unbiased

database

• No limit or restrictions on

questions to be addressed

• Foundation for PMOS studies

Patient outcomes can be

assessed

Validity of Results

• Low risk for selection bias

• Hard outcome data collected


Chart Review (pre & post-approval)

OBJECTIVE

To conduct an observational study on the

treatment and outcomes of patients

• Effectiveness

• Safety

• Health care utilization

DESIGN

• Typical case-control (referent)

• Retrospective cohort (trohoc) design based on treatments

+ −Possible bias

• Indication

• Confounding

• Information

Data Quality

• Validation

• Missing data

Short duration

Lower cost than prospective

studies


Administrative Database

OBJECTIVE

To conduct an observational study on the

treatment and outcomes of patients

• Usually asses the effect of specific treatment

or interventions observed in routine care

Typically follow patients with a disease

or condition or could restrict to specific

treatment

• Specific Hypotheses and Objectives are

recommended to avoid unfocused data mining

Assess / Describe

• Effectiveness & Safety

• Compliance / Adherence

• Health Economics

• Health Care Utilization

• Treatment Gap

Determinants of response / non

response to treatment

Patient Subgroups

Treatment Patterns

Access to Care

DESIGN

• Prospective Cohort: Single & Multiple Cohorts

• Retrospective Cohort: Single & Multiple

• Case – Control Studies: Retrospective

Sample size and f/u: limited to target population in database

+ −Validity and Accuracy of the

data limited to quality of

administrative databases

Outcomes limited to those

recorded in databases:

• Mortality

• Morbidity

• Health care utilization

• Costs

No lab / clinical

assessment results

No patient subjective

outcomes

Short time to completion: 6-9

months

Less costly than chart review and

prospective studies

Unrestricted scope: Address

several questions and objectives

Generalization to Target

Population: Study based on almost

100% of local target populations


Epidemiological

survey

Phase IVPMOS &

Registry

Chart ReviewAdministrative

Database

Using PACES to assess different outcomes

Treatment Patterns

Disease Epidemiology

Clinical Outcomes

Safety / Tolerability

Effectiveness

Medical Decision

Knowledge Gap

Patient OutcomesPatient.

Outcomes

Health Economics Health Economics


Interventional or Observational

Interventional

Patient management is affected by study

participation:

Treatment(s) used are determined by the

study protocol.

Schedule of assessments is according to

the study protocol.

Decision making on management is

affected by study procedures or tests that

are not part of routine care .

Observational (Non Interventional)


Patient management is NOT affected by study

participation:

Treatment(s) used are determined

independently of the study.

Schedule of assessments is according to

routine care.

Recommendations regarding

assessment schedule are possible.

Decision making on management is NOT

affected by study procedures or tests that

are not part of routine care .

PACES: The challenges and the red flags

CHALLENGES

RED FLAGS Poorly Written Protocol: Rationale, Research Questions, Design

Patient incentives: Payment, Support programs, call in numbers, access to services, lottery

Study Execution: Poor Protocol Adherence, Consent Form

Physician Selection: Marketing and prescription driven

Reimbursement: Per prescription or Patient Enrolled

Who will do the study? Marketing Companies, Limited or No Scientific Support, No KOL Endorsement.

Avoid Seeding or Marketing Trials

Ensure Scientific Credibility and Valid Research Questions

Random representative physician and patient samples

No interference with routine care

Academic Participation

Sponsor - Arm’s length for execution

Dissemination of Results: Publications / Presentations

Core REQUIRED Expertise:

Clinical Epidemiology, Biostatistics, Health Economics, Patient Outcomes, Clinical Knowledge

Highest Quality in Project Management

Adherence to Regulatory Requirements (PATIENT CONSENT)


Necessary ingredients Things to look for

PACES: The necessary ingredients;

things to look for

Not a

market

research

Publication

of results

Scientific

rationale

Scientific

sound

protocol

Statistical

analysis

High

quality

study

execution

• Credibility

• Relationship with KOLs

• Transparency

• Independence: Arm’s length from Sponsor

• Clinical Epidemiologist

• Biostatisticians

• Clinicians

• Medical Writing team

• KOLs collaboration

• Good Clinical Operations Team

• Data Management System

• Quality Assurance

• GCP / Physician Qualification

• Independent Ethics Review Board

• Patient Consent


Regulatory

Compliance

PACES: The Target Optimization of Effectiveness

& Safety Through Ongoing Evaluation

OptimalEffectiveness

& Safety

Hypotheses regarding the causes of the treatment gap

Testing of Hypotheses

Design and Implementation of

Interventions

Initial Realization of treatment gap

&

Follow up Assessments

Description of the treatment

gap


PACES: Why do we need them?

Benefits: Integral Part of the Drug Development Program

Similar importance as Phase III studies

Only source of Real – Life Assessment of:

Effectiveness and Safety

Benefit Risk Ratio

Health Economics

Utilization and Practice Patterns

Medical Decision Making

Continuous Evaluation of:

Treatment Gap

Safety Signals

Measurements of Impact of Treatments:

Burden of Illness

Health Care Costs

Detection of Barriers to Treatment and Safety Optimization:

Patient

Health Care Provider

Health Care System

Access to Care

Evaluation of Interventions aimed at improving:

Benefit – Risk

Cost - Effectiveness


Disadvantages: Cost

Follow us


John Sampalis B.Sc., B.A. (hon.), M.Sc., Ph.D., F.A.C.E.

Professor of Surgery and Medicine McGill University, University of Montreal & University of Laval Director, Surgical Research Jewish General Hospital.

Head Surgical Epidemiology, Division of Surgical Research McGill University

CEO and Chief Scientific Officer JSS Medical Research Inc.

[email protected]

(514) 934-6116 ext. 232

THANK YOU

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