Compliance with GCP provides assurance that the data and reported results of clinical investigations are credible and accurate and that the rights, safety, and confidentiality of participants in clinical research are respected and protected. Hence, to protect public health, only sufficiently and verifiably GCP-compliant studies are accepted by regulatory authorities. Oncology trials, with their inherent complexity, length and number of amendments have a higher risk of protocol non-compliance. Many of these challenges can be mitigated through study-specific risk-based measures including adaptive trial designs, risk-based monitoring, protocol-based GCP training, vigorous feasibility process (at programme, protocol, site and investigator level), correcting and preventing root causes, administrative tools and other measures.
Inherent GCP Compliance Challenges in Oncology Trials
Good Clinical Practice (GCP) provides an internationally accepted standard to ensure subject safety and data integrity in clinical trials incorporating ethical and scientific guidelines. GCP, which is incorporated into regulations, must be followed when generating clinical trial data that are intended to be submitted to regulatory authorities for marketing authorisation. Sufficiently and verifiably GCP-compliant studies can detect and mitigate against biases that may confound analysis of clinical trial outcomes. While each therapeutic area has its own unique intrinsic challenges when conducting clinical trials, oncology can be particularly testing with many inherent characteristics including:
- Trial Design:
Cancer therapies can have highly variable modes of action which sometimes necessitates:
• Complicated inclusion and exclusion criteria; while some exclusion criteria are fact-based, others might be with no clear delineation (e.g. theoretical, precautionary) in the respective protocols, as to which exclusion criterion has been drawn from known fact/data (which means that non-compliance could impact patient safety) and which is theoretical. While investigators must comply strictly with all exclusion criteria, this has often led to non-compliance by many investigators.
• Frequent dose modifications caused by toxic effects.
• Numerous prohibited concomitant medications: In Phase I oncology trials, for example, where patients’ cancers have proved refractory to standard therapies, and where patients’ prognoses at trial entry are very poor, many investigators (in agreement with or upon request from the patients) try or add another (protocol-prohibited) therapy if they do not perceive the trial therapy to be successful after a few doses. Again, while the default setting is for investigators to strictly comply with the protocol, the final decision on a patient’s therapy belongs to the patient and her/his physician in such difficult circumstances. Being a study investigator is not, in all its dimensions, above the fact that the investigator is the patient’s physician.
• Tight schedules of clinical assessments for patients who may already be enduring disease-related and drug-related fatigue.
The potential negative impact of this issue can sometimes be mitigated by aligning study schedules with those of the clinical site to minimise the burden on site staff and patients, and can improve compliance.
• Numerous laboratory tests; this can obviously have a negative impact on the compliance/willingness of patients but can also be a burden for the investigators who could miss the review and/or its documentation of some of the numerous laboratory reports which, in turn, can be considered as a serious GCP non-compliance as it could mean lack of safety monitoring in general or, in particular, for dose escalation purposes. This challenge can be mitigated by avoiding excessive tests that are not required to substantiate safety or efficacy endpoints.
• Long trial duration: The length of oncology trials (and/or follow-up) can have a negative impact on the patient’s compliance and drop-out rates. The long duration of trials can also result in the need to deal with potential changes in trial personnel (sponsors, monitoring staff, investigators, site coordinators, suppliers, service providers, etc.) with associated potential impact on continuity, experience, familiarity with procedures, knowledge, training needs, etc.
