By Catherine Stewart, clinical sciences group lead, Pfizer, and Laura Galuchie, TransCelerate program lead, Merck
Currently, clinical study protocols must be conducted according to the International Council for Harmonization (ICH) guidance on good clinical practice (GCP), which, among other things, helps safeguard the rights, safety, and well-being of study participants. If conducted as designed, the associated data should be reliable and reproducible and support clear interpretation of the results, while maintaining the participants’ protection. In light of this, one might reasonably assume that deviations from this protocol could be harmful to the participant or the accuracy of the data and should therefore be avoided.
The reality is that within clinical trials, protocol deviations do happen, despite best efforts. However, not all have the same level of impact on study results or patient well-being. At present, the ICH E3 Q&A R1 defines a protocol deviation (PD) as “any change, divergence, or departure from the study design or procedures defined in the protocol.” The ICH guidelines also introduce a definition for “important” protocol deviations, defining them as “a subset of protocol deviations that may significantly impact the completeness, accuracy, and/or reliability of the study data or that may significantly affect a subject’s rights, safety, or well-being.”
Within the biopharmaceutical industry, the topic of protocol deviations is met with a near universal groan. This is because clinical research sponsors struggle to interpret certain elements of ICH E3 and other associated guidelines related to PD. In fact, in response to a TransCelerate BioPharma member company survey, sites, institutional review boards (IRBs), and sponsors indicated that there is considerable variability regarding the interpretation and classification of what an important protocol deviation is, which creates challenges in the identification, collection, and reporting of deviations. For example, over-reporting PDs could potentially delay the identification of important patient safety information by increasing the noise in the system. On the other hand, under-reporting could influence the reliability of the study results and patient safety signals.
Investigational sites have echoed similar frustrations with the varied interpretation of what is considered an important deviation. Disparate, and at times conflicting, instruction hinders their ability to effectively identify protocol deviations and administer preventive actions, which can directly impact the participants. This variation may also delay reporting of obscure interpretations of PDs by IRBs or ethics committees.
An additional challenge is that sponsor interpretation may differ from that of health authorities. Agency inspectors have disagreed with sponsors’ classification of important and non-important protocol deviations. Unfortunately, this is not known until the time of inspection for a specific application, and that is well beyond a time point when any contemporaneous adjustment can be made.
Ultimately, these discrepancies in definition of PDs have created roadblocks to the effective delivery of new medicines. This ambiguity has led to an opportunity to share ideas and experiences about how to make improvements in this area. That’s why TransCelerate’s Protocol Deviations Initiative, with feedback from the FDA, has proposed a revised definition of important protocol deviations and developed three tools to help clarify the multiple processes of PD management — from identification through reporting, including several feedback loops.
More specifically, the Protocol Deviations Toolkit consists of a Protocol Deviations Process Guide, which is a proposed framework describing flexible PD management approaches, elements for consideration based upon proposed interpretation of the ICH E3 definition for important protocol deviations, and other associated PD guidance. It also contains a Protocol Deviations Map of the proposed PD management process for both important and non-important deviations and feedback loops. Additionally, the toolkit includes a Protocol Deviations Assessment Plan, which serves as a template to assist in the identification and documentation of protocol-specific important deviations.
This toolkit and the revised protocol deviations definition can better enable sites to support clinical trial participants by reducing uncertainties and inefficiencies where possible. Indeed, all stakeholders such as patients, regulators, sponsor companies, and sites will benefit from a better understanding of what important protocol deviations exactly are.
Patients will gain an improved identification of important protocol deviations, improved level of safety and human subjects’ protection, and a reduction in site burden that may potentially enhance a study participant’s clinical research experience. A main benefit for sites is reduced burden in protocol deviation definitions and associated site processes for management, which lowers confusion and increases the speed of identifying important violations. In turn, this may allow for an increase in time with study participants.
Sponsors may also feel a reduced burden through increased consistency in protocol deviation planning, processing, analysis, and reporting mechanisms. Applying ICH E3 R2 concepts of risk-based approaches to protocol deviation management processes may support more rapid identification of situations that could directly impact patient safety, reliability of study data, human subjects’ protections, and/or data quality.
Last, regulatory authorities could experience decreased protocol deviations reporting “noise” and deviation reporting with an increased focus on what really matters (i.e., deviations associated with patient safety, reliability of study data, protections for human subjects, and data quality).
Overall, the Protocol Deviations Initiative is dedicated to creating a sustainable framework that helps support a holistic approach to the management of PDs. To do so, we have been focused on identifying what impacts the safety of the subjects in studies, what influences the integrity of the data that’s collected, and what is important to regulators when they look at studies and try to evaluate the data. Further understanding these different situations will provide added clarity and support the core and pragmatic purpose of rapidly identifying situations that would directly impact interpretability of study data or patients’ rights, safety, or well-being.
By using a risk-based and issues management approach, this work will streamline and clarify the currently varied and complex protocol deviation processes. This should ultimately help support a central goal for the biopharmaceutical industry at large: expediting the delivery of life-transforming medicines to patients in need.
About the Authors:
Catherine Stewart is a Ph.D. and PMP-accredited drug development professional, with 25 years of broad-ranging Big Pharma experience. In her current role, she is responsible for the line management of clinical scientists and associated clinical process improvements at Pfizer. She is currently the Business Process Owner for Protocol Deviations and is proud to be co-lead of the TransCelerate PD Initiative. She has previously worked as a clinical project director (10 years) and as a study clinician (10 years) and has participated in two successful regulatory submissions.
Laura Galuchie is Merck & Co, Inc’s assigned leadership to the Oversight Committee of TransCelerate BioPharma Inc. The Oversight Committee is the primary governing body for decisions related to the operational direction of TransCelerate, including project direction and expected outcomes. Within Merck, she has responsibility for driving internal engagement with key stakeholders. She facilitates adoption and internalization of TransCelerate solutions in alignment with Merck’s objectives. Finally, she watches for opportunities to match innovative approaches to potential process improvement initiatives or other areas of focus.