LATE PHASE CLINICAL OPERATIONS

David Selkirk 9 yrs working for large pharma 10 yrs working for mid-size CRO Core skills • executive leadership • operational excellence - late phase focus • business development • international perspective

ABOUT THE PRESENTER

AGENDA

Landscape

Regulations

HTAs

Operations

Vendors

The Future

LANDSCAPE

PATENTSHuge number of blockbusters coming off patent

Lower cost generic alternatives will flood the market

Pressure to demonstrate

Small Molecules Biologics

Source: IMS Sales Data as well as Jeffries & Company estimates

REAL WORLD

“The conditions under which products are examined for regulatory approval, are generally not the conditions under which they are actually used...” (ISPOR 2010)

Evaluate how the real world impacts the safety and efficacy of a therapy

Value of the therapy in terms of economics and outcomes that matter to patients

STAKEHOLDERSSponsor Groups • Health economics &

outcomes research (HEOR) • Epidemiology • Medical Affairs • Safety /

Pharmacovigilance • Clinical Operations • Marketing / Product

Management

Physicians

Patients

Payers

COMPARATIVE EFFECTIVENESS RESEARCH (CER)

No standard definition, but general consensus

Comparison of one treatment to one or more other treatment

Comparison of treatments is not limited to medications, i.e. outcomes, healthcare utilization, QoL, etc.

Inclusive of both risks & benefits

REGULATIONS

INTERNATIONAL REQUIREMENTS

FDA Amendment Act (FDAAA) enacted in 2007, giving significant new powers to the FDA for inspection & follow-up

Volume 9A of The Rules Governing Medicincal Products in the European Union - Guidelines on Pharmacovigilance for Medical Products for Human use

MIHARI Project in Japan is collected post-marketing surveillance data from multiple sources, eg. claims databases, clinical trials, ADRs, etc.

RISK EVALUATION & MITIGATION STRATEGIES (REMS)

Medication guides are almost always in place

Communication plans are required in roughly ⅓ of cases

ETASU are unlikely, as are distribution system restrictions

Source: Tabulation made from the FDA website of approved REMS

NEED FOR POST-MARKETING SURVEILLANCE

# of patients described in a NDA (eg. 2,000) can increase 1000-fold after introduction to the market (eg. 2,000,000)

This ‘tip of the iceberg’ is not representative of the broad demographics across the population

Demonstrative of need for post-marketing surveillance, eg. Vioxx, Avandia

HEALTH TECHNOLOGY ASSESSMENT

VALUE FOR COST

Treatment A or B?

Treatment A

Treatment A Cost

Treatment B Cost Outcome B

Outcome A

∆Cost ∆Outcome

Does the benefit (outcome differential) justify the cost?

PATIENT REPORTED OUTCOMES

A measurement based on a report that comes directly from the patient (i.e. study subject) about the status of a patient’s health condition without amendment or interpretation of the patient’s response by a clinician or anyone else. A PRO can be measured by self-report or by interview provided that the interviewer records only the patient’s response.

Source: Guidance for Industry Patient Outcome Measures: Use in Medical Product Development to Support Labeling Claims. US FDA December 2009

OUTCOMESLife expectancy / survival

Relief of symptoms

Improved patient functionality (eg. independence, ability to work, social activity, exercise, cognition, etc.)

Better side-effect profile

Convenience / mode of delivery

Health-related quality of life

HTA GLOBAL FOOTPRINT

Source: http://www.inahta.org/Members/ (International Network of Agencies for Health Technology Assessment)

NICE

National Institute for Clinical Excellence (UK)

Produces guidance on public health, health technologies (i.e. pharmaceuticals, interventional procedures, devices & diagnostics) and clinical practice

Makes recommendations based on clinical efficacy relative to the cost involved

All activities underpinned by the need for transparency, collaboration & involvement of stakeholders

http://www.nice.org.uk/

CLINICAL TRIAL OPERATIONS

OVERVIEW

Post & peri-approval studies can be very large with 100s - 1,000s of sites often recruiting 1,000s - 10,000s of patients

Often involve multiple international countries and have a duration of several years

Ratio of ‘prescribers’ to ‘researchers’ is weighted toward the former • may not have study coordinators • may not have GCP training • office logistics focused on patients, not documentation

DESIGN: WHAT DO YOU WANT TO DO WITH THE DATA?

Epidemiology • burden of disease • health care system • incidence rates, survival, etc.

Retrospective data abstraction • review of claims database,

national registries such as those from Nordic countries, or into patient medical charts

• ensure no clinical interpretation needed by abstractors

Observational study

Expanded access program

REMS

Disease/product/pregnancy registry

Comparative effectiveness vs. efficacy

Safety surveillance and/or risk management

CLINICAL TRIAL PROCESS

6/2/2010

2

Challenges

Non!operational

• Expectations

– Lack"of"clarity"on"goal

• Perception"/"misconceptions

– Need"for"precise"communication

• Marketplace"evolution"/"

Operational

• Purity"of"observational"design– Acknowledging"biases

• Accommodating"multiple"measures

• Site"selection

• Site"training"and"start!upp

uncertainty

– Regulatory"understanding

• Multiple"internal"perspectives

• Site"“interaction”"(monitoring)– Site"motivation

– Protocol"“adherence”• Inclusion

• Procedures

– Data"collection• EDC"issues

– Data"quality• SDV

• Analysis

• What"are"the"strategic"goals"

underlying"the"study?

– Direct"impact"on"how"the"

project/study"should"be"

‘operationalized’

Observational"Studies:"Building!an!Operational!Plan!from!the!Bottom!Up

REPORTS

PATIENT ENROLLMENT,

OUTCOMES TRACKING,

DATA COLLECTION

SITE

SUPPORT

ANALYSES

PUBLICATIONS ABSTRACTS, PRESENTATIONS

MEETINGS

p

• Direct"impact"on"budget"and"ROI

• What"are"the"research"goals?

• How"will"you"know"if"you’ve"

achieved"success?

– Performance"metrics"(impacted"

by"strategic"goals)

LEGAL, REGULATORY, IRB REVIEW

MATERIALS PRODUCTION AND DISTRIBUTION SITE RECRUITMENT AND TRAINING

NEWSLETTERS

STRATEGY

ANALYSIS PLAN COMMUNICATIONS PLAN

DATA COLLECTION FORMS,

PROCESSES, AND LOGISTICSSCIENTIFIC ADVISORY PANEL

SITE IDENTIFICATION (FIELD

INVOLVEMENT)

Source: Jeff Trotter’s Presentation on Observational Research at the 2010 ISPOR Annual Meeting

THE CONTINUUM

Randomized Controlled Trials

Efficacy Data

randomized

protocol driven

high internal validity

extensive inclusion/exclusion criteria

high cost

Observational Studies

Effectiveness data

non-interventional

adapted to usual care

higher generalizability

few exclusions (allows comorbidities)

lower cost

Experiment Real World

STREAMLINED DATA COLLECTION & CLEANING

Tight focus on collecting only the endpoints specified in the protocol • avoid the ‘nice to know’ trap

High utilization of drop-down menus and check boxes, with little to no free text

Pre-programmed disease and concomitant medication choices

Data management plan specifying authority to make simple revisions to data • edit checks must be simple and few in number • must be able to deal with missing or incongruous data that is commonplace with PRO

RISK-BASED SDVNot necessary to verify 100% of all source data

• Select the data points most important for the study’s conclusions to be drawn - fit for purpose

• Review the areas where inconsistencies most commonly occur, i.e. concomitant medications & adverse events

Ensure patient safety is monitored carefully regardless of efficacy measurements

Include ‘remote’ management through call centers and an EDC system

Important to establish lines of communication and escalation of issues with site staff upon site initiation

• what issues can be addressed via e-mail, phone, in-person

Establish a plan of how to scale up SDV if there are data integrity concerns

MOTIVATION

Consider motivation for both the Investigator and for the patients to become involved • there may be no medical benefit for patients to participate, so focus on removing the

barriers to enrollment, i.e. reimburse mileage & parking, hotels for out-of-town patients, etc.

• collect names of relatives who consent to be contacted if patient is unresponsive • compensation offered to PIs is generally low so the data collection process must be in

alignment with their clinical practice

Publication can be an attractive possibility for some site staff

Sponsorship of industry symposia and/or memberships

Retention is important in multiple year trials • vouchers have been used for on-line redemption of various products

CONSENTDepending on the applicable regulations, the need for patient consent can be waived if certain criteria are met; some of which are: • patient is deceased • no way to reach patient due to long duration between data

collection and current study • data collection in generalities instead of specifics, eg. age

range rather than specific birth date • typical example is a retrospective chart review

Always need an ethics committee’s approval to waive the need for patient consent

If consent is required, always train site staff on how to administer it, and how to document it

VENDORS

CONTRACT RESEARCH ORGANIZATIONS

Very large multinational clinical trial operation corporations that are growing with preferred provider relationships in place with large multinational sponsor organizations

Mid-sized CROs are specializing in niche markets, i.e. late phase, device, early phase, etc.

Others include central labs, electronic database providers, call centers, IVRS, packaging/labelling/distribution,

ELECTRONIC DATA CAPTURE

Validated, 21CFR11-compliant system

Rapid & cost-effective set-up

Library of forms available to minimize design time & cost

Multi-language capabilities - Asian characters

eLearning capabilities built-in and available on demand

Allow for mid-study changes in CRF for protocol amendments

Real-time report generation, ideally allowing customized data searches

Connection with EHR (electronic health records)

THE FUTURE

ACCOUNTABILITY

Data collection, analysis, interpretation and publication to be done independently of the sponsor • Clinical trial management • Statistical analysis • DSMB • Clinical study report

Who takes responsibility; NIH, regulator, HTAs, AHRQ, IQWiG, others?

Make data available for academia/regulators to perform meta-analysis

EVOLUTIONMuch larger trials incorporating a much broader base of patients, necessary for market approval?

Sponsors will still fund the research but decision-making to be done independently?

Full transparency of all exchanges with the sponsor?

Media scrutiny and perhaps sensationalization of results?

PUBLICATION

Is it feasible to publish all clinical trial results funded by commercial sponsors? • Not all results are scientifically interesting • Not all submissions are accepted for publication • Submissions are expensive and consume sponsor staff time

Establish a standard that commercial sponsors submit clinical trial results at least xx times?

Post protocols & study data on medical journal websites

THANK YOUEmail: davidselkirk2000@yahoo.com

LinkedIn: http://ca.linkedin.com/in/davidselkirk