Why a SMO is not a CRO,

or is it?
Stan W. Woollen
Associate 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 Environment
Pressures 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 Environment
Identifying 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 Environment
Identifying 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 Environment
Assigning 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 Environment
Assigning 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 Environment
Assigning 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 R esearch 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