Ominous Clouds Over Outsourcing

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A large and growing number of sponsor companies engage contract research organizations (CROs) in functional and alliance-based relationships. Indeed, many companies are now using this approach in order to address capacity and competency needs and achieve higher levels of operating efficiency. But while drug developers have continued to progress and evolve in their outsourcing practices, regulatory agencies have lagged far behind in their understanding and awareness of these practices.

Due to several recent incidents, FDA and EMA appear to have abruptly discovered an outsourcing environment characterized by entire development functions being handled by autonomous, globally-disbursed parties, and by ambiguous oversight. In response, these regulatory agencies are considering issuing new guidance to regulate sponsor-CRO relationship governance and responsibilities.

The possibility of looming new guidance has many sponsors and CROs scrambling. Several have expressed growing concerns publicly; others have begun implementing preemptive and proscriptive measures in anticipation of regulatory reform. These responses affirm FDA and EMA concerns about shoddy oversight but fail to proactively educate these agencies about why outsourcing relationships have reached this point in their evolution and the array of oversight mechanisms that are already utilized typically to ensure protocol adherence and the safe and ethical treatment of study volunteers. Perhaps it is prudent to take a step back and look at the context of agency concerns and at what is already in place to address them.

Context

Arguably, agency interest in data integrity issues and CRO oversight increased dramatically in response to misconduct in the Aventis-PPD collaboration on clinical trials for the antibiotic drug telithromycin (Ketek). Aventis ultimately received a warning letter in 2007 for study misconduct. The incident led to a series of hearings, which were highly critical of the FDA's handling of the case.

Since the Ketek investigation, the FDA's Division of Scientific Investigations (DSI) has issued GCP-related warning letters to two additional major pharmaceutical companies—J&J and Pfizer. And for the first time in history, the FDA issued a warning letter to ICON, a CRO, for misconduct of clinical trial responsibilities delegated from a drug sponsor. All three companies were cited for failure to properly monitor their clinical trials. In the J&J letter, which was issued in August 2009, DSI charged that monitors failed to identify that drug infusions were given at the identical time to multiple subjects. That same month, Pfizer received a warning letter charging that study monitors failed to recognize or report that 13 children with bipolar disorder and schizophrenia received overdoses of the antipsychotic drug Geodon during clinical trials.

ICON's warning letter marks a significant shift in the agency's oversight of clinical investigations. Until now, it has always been assumed that the drug sponsor would be held ultimately responsible for ensuring that a study was conducted according to Good Clinical Practice (GCP) guidelines and for verifying the quality of data submitted in support of a drug approval. The warning letter issued to ICON, sent just three months after J&J received a similar letter, suggests that once the FDA detects problems in a clinical trial, it now wants to know what role both the drug sponsor and the CRO played in ensuring oversight and management of the study.

Management mechanisms

These incidents are critical events that have opened agencies' eyes to the growing involvement of third parties in clinical trial management. But it's important to note that both FDA and ICH regulations allow a sponsor to transfer any or all of its trial-related duties and functions to the CRO. All duties and functions that are transferred to the CRO should be specified in writing. The sponsor must provide adequate oversight and must report on project status and on acts of noncompliance. Under both FDA and ICH regulations the CRO assumes the obligations of the sponsor for all those responsibilities which have been transferred (21 CFR 312.52, ICH-E6 5.1). FDA regulations also state that a CRO that has assumed any obligation of a sponsor "shall be subject to the same regulatory action as a sponsor for failure to comply with any obligation assumed under these regulations" (21 CFR 312.52(b)). ICH guidelines further specify that the CRO should implement quality assurance and quality control systems with written standard operating procedures (SOPs) to ensure that trials are conducted in accordance with GCP (ICH-E6 5.1).

These regulations have spurred sponsors and CROs to implement numerous oversight practices and mechanisms over the years. And agencies have overseen thousands of programs involving sponsor-CRO collaborations during the past decade; hundreds that were managed under functional relationships specifically. Additionally, sponsor-CRO relationships have generally performed as well, if not better, than when the sponsor managed projects on its own. According to studies conducted by Tufts CSDD, high levels of CRO use are associated with faster cycle time at comparable quality (e.g., the number of errors per case report form, the number of FDA Forms 483 issued to investigative sites).

To make a point, consider the following long but partial list of typical measures used by pharmaceutical and biotechnology companies to ensure that they are fulfilling their ICH-GCP obligations under a transfer of responsibility arrangement:

Work order/responsibility/resourcing. Delineation and assignment of CRO and sponsor responsibilities; Organization and allocation charts of resources by country and investigative site

Training. Kick-off meetings to solidify the team and begin building team chemistry; Group training sessions often combined with other meetings; Special training programs with select personnel or teams

Operating procedures and systems. A detailed plan describing the process for functional representatives through senior management to communicate study status and updates; A detailed plan describing communication and escalation of issues affecting study schedules, quality, and cost; A detailed plan describing the process of issue resolution; A detailed plan describing the issue resolution communication process; SOPs of the sponsor, some of which will need to be followed by CRO personnel; SOPs of the CRO; Study Specific Procedures (SSPs), agreed upon by the sponsor and the CRO, which will be in place for the study and must be followed by all personnel involved; Budget management systems typically maintained by finance or procurement functions; Project management systems tracking schedules, study and patient recruitment progress

Routine meetings. Joint (CRO and sponsor) senior management governance meetings; Project management oversight meetings; Ad hoc management meetings; Informal meetings; One-on-one study manager meetings; Weekly project update meetings with functional representatives; Medical Monitor Meetings

Written and circulated reports. Directories of key sponsor and CRO team members and their contact information; Site monitoring visit reports (prepared from monitoring visits); Meeting minutes from all routine meetings; Management reports summarizing study status and issue resolution status; Summary site audit reports from both CRO and sponsor, if applicable

Site audits. CRO routine audits of investigative sites; CRO solicited audits of investigative sites (when major problems identified); Sponsor routine audits of investigative sites; Sponsor solicited audits of investigative sites (when major problems identified); Regulatory agency audits when serious violations of ICH-GCP identified

Pending reform?

Are reforms needed to further regulate sponsor-CRO relationships? Are oversight mechanisms and governance structures already adopted enough to ensure protocol compliance and the safe and ethical treatment of study volunteers? What is an adequate level of oversight and governance when the possibility always exists that any party involved in a clinical trial can be non-compliant?

Regulatory agencies are concerned about how responsibilities should be delegated to ensure effective oversight of outsourced studies in the future. At a recent conference, FDA articulated its concern that sponsors are transferring responsibilities to CROs and then forgetting about them instead of staying actively involved, ensuring that the CRO is doing an effective job, and addressing problems when they are escalated.

Drug sponsors can expect FDA and EMA scrutiny of their clinical trial oversight to intensify in the near term. Increased scrutiny will ultimately lead to higher drug development costs as sponsor and CRO companies will need to manage more proscriptive and restrictive behaviors. During a time when drug sponsors are eager to reduce their operating costs through outsourcing, new regulations will cause drug sponsors to rethink their outsourcing strategies and how they use CROs.

As the volume of global clinical trial activity has increased dramatically, pharmaceutical and biotechnology company headcount has not grown. Outsourcing has become an essential and integral strategy to securing capacity, expertise, infrastructure, efficiency, and quality. Functional relationships and sponsor-CRO alliances offer unique benefits that are only beginning to be realized: sponsors and CROs are sharing expertise and efficiencies while reducing the internal management resources that sponsors must dedicate to shadow and micromanage their CRO partners.

As ominous clouds gather over the outsourcing landscape, it is clear that new regulation could hinder, and even negate, the effective utilization and integration of CRO partner capabilities. Could sponsors ensure data quality and patient safety by other means? Perhaps—by choosing a well-qualified CRO, delegating responsibilities clearly at the outset, coordinating and integrating sponsor and CRO personnel and activities, and communicating effectively.

Kenneth A. Getz MBA, is a Senior Research Fellow at the Tufts CSDD and Chairman of CISCRP, both in Boston, MA, email: [email protected]