There is currently an increased enforcement focus by regulators on the oversight which sponsors of clinical studies exercise over Contract Research Organizations (CROs). Pharmaceutical companies that conduct clinical studies – both clinical trials and non-interventional studies – increasingly outsource work to CROs but are not clear about their responsibilities. Fulfilling the legal requirement to properly oversee the work of a CRO is often not straightforward, particularly when it comes to secondary data and Clinical Trial Master Files.
Contract Research Organizations: Ensuring That Sponsors of Clinical Studies Meet Their Oversight Obligation
The sponsor’s obligation to oversee a Contract Research Organisation
For some years, pharmaceutical companies have been outsourcing most of their clinical studies activities to Contract Research Organisations (CROs). As a result, Good Clinical Practice (GCP) inspectors from the regulatory authorities are now increasingly focusing their attention on whether sponsors have properly overseen the CROs to which they have delegated the conduct of clinical studies activities.
Pharmaceutical companies are, of course, well aware by now of their obligation to maintain proper oversight of CROs. However, many are still not entirely sure how they should apply these rules in practice, and are struggling to translate the oversight obligation into effective processes.
The rules state that a CRO to which the conduct of a clinical study has been delegated does not take over the role and the responsibilities of the sponsor. CROs simply take over tasks from the sponsor on the basis of a service provider agreement, while remaining under the sponsor’s control. The fact that a sponsor has delegated work in this way does not remove its ultimate responsibility toward patients and authorities for the work carried out by the CRO. It remains the responsibility of the sponsor to exercise proper supervision.
Clinical trials: handling the Clinical Trial Master File
Study managers employed by sponsors are frequently being asked by the regulators to demonstrate in detail how they go about supervising CROs. For example, GCP inspectors are paying a great deal of attention to how sponsors of clinical trials set up and maintain the Clinical Trial Master File (TMF), an area of work which can become particularly complex when a CRO is involved.
The European Union Clinical Trials Directive and Clinical Trials Regulation require both sponsors and investigators to keep a TMF containing all the essential documents needed to verify the conduct of a clinical trial, and the quality of the data collected. The TMF is a key tool used by auditors and inspectors to reconstruct the trial and check whether it meets legal and GCP standards.
However, a TMF is a big and very complex collection of clinical trial documents. As a result, sponsors have a tendency to lose oversight of the TMF, in particular over the parts of the TMF that they may have outsourced to CROs. It is often only when sponsors are actually faced with a GCP inspection that they realize, too late, that there are gaps in the TMF. Some may not even become aware of this whilst preparing for an audit or inspection, and it is only during the inspection itself that they realize that the inspectors find it hard to navigate their way through the TMF because its structure lacks clarity. Such a lack of clarity can have a major negative impact on the outcome of an audit or inspection.
The fact that this risk exists does not necessarily mean that sponsors need to put more resources into having their clinical operations staff review TMFs more frequently and more comprehensively. Paradoxically, such a move could lead to staff losing their grasp of a TMF because it is such a large and complex collection of documents. Trying to achieve frequent and thorough TMF reviews can cause staff to fall behind schedule, fail to resolve all issues in time and even to miss major or critical issues. This in turn leads to staff becoming discouraged and running into problems when their clinical trial or GCP processes are inspected.
Ultimately, maintaining proper oversight of a CRO does not mean that a sponsor’s internal staff needs to duplicate the work of the CRO. There would be no sense in engaging a CRO to take care of certain parts of the TMF if the sponsor had to carry out the same work in parallel in order to ensure compliance with GCP requirements. The best approach to correctly overseeing the work of a CRO in this particular area, is for a sponsor of a clinical trial to have a strategy for the review of its TMF that focuses on the areas of real concern. This means the sponsor setting out its strategy in a formal TMF review plan which identifies areas of risk, and focusing its controls on these areas.
Non-interventional studies: data challenges
The CRO oversight obligation has an effect not just on clinical trials but across clinical studies, which is a broad term that includes both clinical trials and non-interventional studies. Clinical trials test the efficacy and risks of a potential new drug (or, in a broader sense, a medical device, activity or procedure). In non-interventional studies, researchers observe and track the health outcomes of participants undergoing an established therapy, e.g., taking an existing medicinal product that is already prescribed in accordance with normal clinical practice.
There is a great deal of misunderstanding about non-interventional studies. Many pharmaceutical companies treat them simply as a “light” version of clinical trials. However, we are generally seeing an increase in the use of secondary data for the purposes of clinical studies, and non-interventional studies give rise to specific challenges in the field of data collection, data management and pharmacovigilance. Indeed, because of these challenges, non-interventional studies often give rise to concerns that are anything but “light” when the regulators scrutinize the results and the underlying data.
When authorizing non-interventional studies, regulators do not always examine thoroughly the delegation of tasks from the sponsor to a CRO in relation to such a study. However, it is also important for the sponsor to give a clear mandate to and oversee a CRO in a non-interventional environment, as the study results may become worthless if the CRO violates patient rights or puts data integrity in jeopardy.
In non-interventional studies as in clinical trials, the key to maintaining good and proper sponsor oversight is for sponsors and their clinical research teams to look beyond the pure legal requirements and consider how these requirements actually impact on the organization of their work. The best way to make a company’s processes more robust and effective from a GCP perspective is to consider operational practicalities in tandem with the rules.