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CRO contracts: Use caution! When formulating contracts with CROs it is important to ensure responsibilities are clearly assigned or you could be in breach of FDA regulations. Terry Winchell GCP Innovative Dynamics, Kansas City, KS, USA
Title 21 CFR 312.3 (b) essentially defines a CRO as an independent contractor that assumes one or more obligations of a sponsor, eg, design of a protocol, selection or monitoring of investigations, evaluation of reports, and preparation of materials to be submitted to FDA. This definition encompasses any facet of FDA regulations to which a sponsor is obligated, essentially defined in this same section as the initiator of a ‘clinical investigation’. The elusive part of the above definition is that a CRO is commonly thought of as a clinical trial monitoring organization. CROs have been common in the pharmaceutical and medical device industries for many years and CRO monitoring organizations have been a very - if not the most - common form of this segment of the industry, particularly when numerous CROs began to develop in the 1980s. © Brand X Pictures / Alamy
Contract research organizations have been supporting commercial clinical research for well over 20 years. Today, companies of all sizes use CROs to perform a wide variety of tasks that extend far beyond clinical trial monitoring, which was the focus of many CROs in past decades. FDA regulations 21 CFR 312.52 allow sponsoring drug firms to transfer any and all of their obligations to a CRO, but this transfer of responsibilities must be done in writing and sponsors should establish independent assurances that CROs are adequately performing contracted obligations. Contract clarity regarding the details of responsibility transfers and assurance of adequate CRO performance is essential, particularly when sponsoring drug firms employ multiple CROs for numerous functions over the course of a drug’s development. This not only will facilitate enhanced quality of contracted functions, but will avoid misunderstandings regarding regulatory responsibility.
Clear obligations
Today a CRO may take on many forms that encompass adverse event tracking and reporting, Drug approvals depend on clear contracts. Sponsors and CROs IND and NDA submission, “The agency does not contemplate taking administrative action selection of clinical investigators, study drug release, control, and against a sponsor based solely on the failure of a contract shipment, among others. Some sponsors may contract out all or research organization to perform obligations that have been nearly all of their 21 CFR required obligations to CROs thus transferred to it by the sponsor. Sponsors should, therefore, take becoming ‘virtual companies’. special care that transferred obligations are described clearly. Title 21 CFR also states that a sponsor may transfer any or Preamble to FDA IND regulations. all of its obligations to a CRO and that IND and NDA
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submissions are required to list all obligation. FDA regulations do allow for a sponsor obligations transferred. general statement regarding the Therefore, it is imperative that transfer of all obligations: “Any “Use caution with contracts, making them clear contracts clearly state what obligation not covered by the a n d e x p l i c i t w i t h n o q u e s t i o n o v e r w h i c h p a r t y i s has been transferred and in written description shall be some cases, what has not. This deemed not to have been responsible for each transferred obligation.” is certainly in the best interest of transferred”. sponsors, but can be in the best It is significantly disappointing for a interest of the CROs as well. It is certainly sponsor to have a marketing application possible for a CRO to perform sponsor obligations that are delayed or fail and even worse to subject the sponsor and its legitimate candidates for transfer, but where the sponsor has not officers to FDA enforcement actions. After paying considerable intended for this transfer to occur. Conversely, the sponsor may sums to a CRO, sponsors expect that specific obligations have have assumed that a transfer occurred but did not accomplish been trans-ferred effectively. This is often not the case. Increased this effectively via the written contract, form FDA 1571, and/or CRO con-tract clarity is needed which will benefit all parties and listing in the clinical data section of the NDA. In situations enable a clear under-standing of what each company’s specific where an unclear written transfer of obligations occurs, the functions are and the potential depth of the consequences for sponsor routinely remains the primary FDA enforcement target non-compliance. for non-compliance with applicable regulations.
Site management organizations Site management organizations have also been around for a number of years but are not as well established in the industry as CROs. There are many models for SMOs and the duties contracted may vary widely from simply providing lists of clinical investigators who are capable of conducting specific clinical research trials to contracting for the conduct of the trial to selection of specific clinical investigators, monitoring, reporting of adverse events, and so on. They are not yet mentioned in FDA regulations, but have recently appeared in FDA guidance regarding bioavailability & bioequivalence retention samples. Where an SMO contracts a sponsor obligation (eg, selection of investigators, monitoring, submission of materials to FDA) it is in effect a CRO and therefore subject to the same FDA 21 CFR requirements. Regulations specific to SMOs are very likely evolve in the near future. There is a warning in the IND preamble that states: “While a contract research organization may assume any or all of the sponsor’s responsibility for the conduct of the study, it should be emphasized that the transfer does not relieve the sponsor from responsibility for the quality and integrity of any data derived from the investigation that are submitted to FDA.” It is therefore in the interest of all sponsors to implement some quality assurance activities regarding any CRO transferred obligations. This is not yet a regulation, but is strongly recommended both in the above preamble as well as in the Good Clinical Practice guidelines produced by the International Conference on Harmonization.
Terry Winchell GCP Innovative Dynamics LLC 7400 Kansas Avenue Kansas City KS 66111-2639 USA Email:
[email protected]
FURTHER READING Preamble to IND regulations, Federal Register Volume 52, No 53, Thursday, March 18, 1987. 21 CFR 312.23 (a) (1) (viii), Form FDA 1571 and 21 CFR 314.50 (d) (5) (x). www.fda.gov Winchell T (2000) GCP compliance: A dynamic approach to auditing: www.drugdev123.com/editorial/archive/ EthicsAndRegulatory/articlelist2.shtml Woollen S (2001) Why a SMO is not a CRO, or is it? FDA Office of GCP October. Guidance for industry, handling and retention of BA and BE testing samples. (2004) Federal Register 69:(102) 2995929960.
Explicit responsibilities Use caution with contracts, making them clear and explicit with no question over which party is responsible for each transferred
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Guideline for good clinical practice. ICH Topic 6.
August 2002
