Why a SMO is not a CRO, or is it?

Stan W. WoollenAssociate Director for Bioresearch Monitoring

Office for Good Clinical Practice,

Office of the Commissioner

FDA

Oct. 2001

A regulator’s perspective on CROs/SMOs

• Today’s Clinical Trial Environment– Environmental pressures driving evolutionary

changes – Identifying the different species and their place

in the new environment

• CRO vs. SMO - A new species– Similarities and differences– Regulatory issues

Today’s Clinical Trial EnvironmentPressures for change

• Increased competition for subjects and investigators

– Large trials widely dispersed geographically over many sites

– Influx of new Clinical investigators

– Principal investigators remote to sites

• Increased need for speed

– Remote data collection and electronic transmission

– Central IRBs and study monitoring

• Increased reliance on contractors (e.g. CROs/SMOs)

– greater fragmentation in dispersing study functions

Today’s Clinical Trial EnvironmentIdentifying the species

• Players identified by regulation:– Investigator/Subinvestigator– Sponsor– Sponsor-investigator

– Subject

– Contract Research Organization (CRO)– Applicant

– Institutional Review Board (IRB)– Institution

Today’s Clinical Trial EnvironmentIdentifying the species

• Players defined ad hoc

– Site Management Organization (SMO)– Monitors/Clinical Research Associate– Study Nurse/Coordinator– Data manager– Medical monitor– QA auditor

• Anyone who participates in a study activity

Today’s Clinical Trial EnvironmentAssigning Responsibilities

• Responsibilities assigned by regulation

– 21 CFR 312 Subpart D- Responsibilities of Sponsors and Investigators

– 21 CFR 56 Standards for composition, operation, and responsibility of an IRB

– 21 CFR 50 Responsibility for obtaining informed consent

• Sponsors, Investigators and IRBs by regulation

Today’s Clinical Trial EnvironmentAssigning Responsibility

• Responsibilities assigned by contract– 312.52 Transfer of obligations to a CRO

• Any or all sponsor obligations may be transferred• Transfer must be described in writing• If not all obligations are transferred each obligation

being assumed by the CRO must be described• If all are transferred a general statement is

acceptable• Any obligation not covered shall be deemed not to

have been transferred

Today’s Clinical Trial EnvironmentAssigning Responsibility

• Responsibilities assigned by contract– 312.52 Transfer of obligations to a CRO, legal

liability• A CRO that assumes any obligation of a sponsor shall

comply with the specific regulations applicable to the obligation

• A CRO is subject to the same regulatory action as a sponsor for failure to comply

• All reference to “sponsor” in the regs. apply to a CRO to the extent that it assumes one or more obligations of the sponsor

What is a Contract Research Organization?

• A CRO means a person that assumes, as an independent contractor with the sponsor, one or more of the obligations of a sponsor, e.g.., design of a protocol, selection or monitoring of investigations, evaluation of reports, and preparation of materials to be submitted to the FDA.

• To the extent that an SMO meets this definition it would be considered a CRO

Determining Responsibility by Function

• IF YOU HAVE CONTRACTED WITH THE SPONSOR TO

DO ANY OF THE FOLLOWING….– Select Qualified Investigators.*

– Provide investigators with information they need to conduct an investigation properly.

– Ensure proper monitoring of the investigation(s)

– Ensure study is conducted in accordance with study plan and protocol

– Control investigational product(s)

– Safety reporting

• YOU MAY BE LEGALLY LIABLE AS A SPONSOR

What is a Site Management Organization?(The world according to Stan)

• A SMO means a person that assumes, as an independent contractor with the clinical investigator, one or more of the regulatory obligations of a clinical investigator, e.g., preparation and maintenance of case histories, ensuring compliance with IRB review and informed consent requirements, AE reporting etc.

Determining Responsibility by Function

• IF YOU Sign a FDA Form 1572…… YOU ARE AN INVESTIGATOR FULLY COMMITTED TO:– Personally conduct or supervise the investigation

– Ensure that all associates, colleagues, and employees assisting in study conduct are informed about their obligations

– Conduct the study in accordance with the protocol

– Comply with all requirements regarding obligations of clinical investigators (including preparation and maintenance of records)

– Inform subjects drugs are being used for investigational purposes and ensure informed consent and IRB requirements are met

– Report Adverse Events to the sponsor

– Read and understand the investigator’s brochure

CRO vs. SMO Similarities and differences

• Both are contractors the principal differences are with whom they contract, services contracted for, and their legal liability– CROs contract with sponsors and are explicitly

regulated

– CROs are legally liable for the obligations they assume

– SMOs contract with clinical investigators and are not explicitly regulated

– SMOs are not legally liable for the CI obligations they assume

Regulatory Issues

• SMOs assume clinical investigator duties but the regulations make no provisions for transfer of CI responsibilities. CI remains responsible, though they may not know it.

• CROs subcontract sponsor obligations to SMOs

Regulatory Issues

• A CRO’s complaint– Forced to use SMO network for whom

compliance cannot be assured• one principal investigator at SMO HQ with

hundreds of subinvestigators geographically dispersed

• physical access to site denied to CROs/Sponsor monitors

• all monitoring to be done at central site only copies available for audit

• IRB selected by SMO remote to CI, unknown to CRO

Know Your Responsibilities

It’s better to have them written in a contract rather than in a letter from the FDA