Clinical trials are a vital aspect of drug development and approval. Whether it be a single-site, Phase 1 study in healthy subjects to understand the safety and pharmacokinetics of a new compound or a multi-center, pivotal Phase 3 study to demonstrate efficacy in patients, there is no escaping the fact that clinical trials are necessary to get drugs approved. Clinical study protocols are the foundation of clinical trials. A clinical study protocol is a document that describes the study objectives, design, methods, assessment types, collection schedules, and statistical considerations for analyzing the data. The protocol also outlines steps for protecting subjects and obtaining quality data. In order to ensure compliance with subject protection standards and statutory requirements, protocols are submitted to both an Institutional Review Board (IRB) and to regulatory authorities (e.g., U.S. FDA) for rigorous review prior to a Sponsor being allowed to conduct a study. Poorly designed or poorly written protocols can have the following negative consequences (among others):
These consequences are costly and delay timelines. In the worst-case scenarios, poorly written protocols can jeopardize patient safety or result in data that do not support regulatory approval. To decrease these risks, the following best practices can help create clear, well-written protocols that are operationally feasible, generate quality data, and are compliant with regulatory guidelines.
One of the first questions that needs to be answered in designing a protocol is, “Where is the study going to be conducted?” All studies must be compliant with International Conference on Harmonisation (ICH) guidelines and have subject protection that is founded in the Declaration of Helsinki, but the laws and regulations of the country where the study site is located may place additional requirements on the protocol. For example, studies conducted in the US, under the purview of the FDA, must also be compliant with applicable sections of the Code of Federal Regulations (CFR); however, these requirements would not apply at an international site, like Australia. In another example, studies conducted in Europe would need to follow new GDPR (General Data Protection Regulation) mandates, while studies run in non-adopting countries would not. Because of the many country- and region-specific requirements that exist, it is crucial to identify where the study will be conducted before writing the protocol. This will ensure efficiency and prevent costly delays and rewrites later. Also, regulatory requirements can be complicated; if you have questions, do not hesitate to reach out to our regulatory experts for guidance.
Submitting a protocol that is missing critical details, or even entire sections, is not uncommon; however, it is completely avoidable. Collect a list of what needs to be in a clinical study protocol by referring to relevant ICH guidelines (ICH E6 [R2]) and FDA guidances. Templates may also be available online (e.g., the joint NIH/FDA protocol template); however, any template should be carefully validated against current regulatory requirements to ensure compliance.
The protocol synopsis is an overview/summary of the protocol. The schedule of events is a tabular description of all study-related events and assessments, including: subject screening and enrollment, safety assessments, efficacy evaluations, pharmacokinetics sampling, etc. These sections offer the perfect opportunity to solidify the study design with all stakeholders, including sampling/assessment timepoints, before the full protocol is drafted. Finalizing a synopsis and schedule of assessments prior to authoring the full body of the protocol can eliminate inconsistencies within the text and prevent confusion or deviations that might require a protocol amendment.
Since all drugs present some level of risk, all clinical studies should have clearly defined objectives that seek to answer important questions. In addition, every objective should have an endpoint or endpoints that will provide the necessary information without confounding or ambiguity. Writing clear, definitive objectives for the study will allow the Sponsor, regulatory authorities, and the IRB to critically evaluate if the proposed study design is likely to provide the intended information. It can also help the Sponsor as they begin to think about possible outcomes and how the study design will support not only the conclusions from this particular study, but the development program as a whole. It is highly recommended that scientific and medical experts evaluate the validity of the study design, considering the objectives, endpoints, and other elements as a complete package. This includes evaluating these in the context of the schedule of events in order to answer the question, “Do the planned assessments support the objectives and the endpoints?” Ambiguity is the enemy of a well-written protocol. Examples of vague objectives and endpoints for a Phase 1 pharmacokinetic study are given below, with suggestions for improvement:
| Objectives | Endpoints |
| Evaluate pharmacokinetics | PK profile of study drug |
| Evaluate safety | Tolerability of study drug |
| Objectives | Endpoints |
| Evaluate the single-dose pharmacokinetics (PK) of study drug | Plasma PK parameters including, but not limited to, Cmax, AUC0-last, AUCinf, Tmax, and t½. |
| Evaluate the safety and tolerability of study drug after single-dose administration | Incidence of treatment-emergent adverse events and serious adverse eventsChange from baseline in hematology parameters |
Clinical protocols often lack appropriate details in describing the who, what, when, where, and how of study conduct. When these critical details are missing, it reduces the chances that a protocol will be approved by the IRB and regulatory authority and increases the chances of missteps and inconsistencies during the study. Each study assessment description should contain enough detail for individuals to carry out the procedures without additional information and such that all procedures are done consistently, even if they are conducted by different individuals. During protocol authoring, anticipate common questions that could arise during the study. For example, for vital signs: should the subject be sitting or supine? What assessments are meant by “vital sign measurements”? Should adverse events be graded for severity with a numeric scale, such as the Common Terminology Criteria for Adverse Events (CTCAE), or using terms like mild, moderate, or life-threatening? Remembering to include sufficiently detailed procedures will help ensure a smooth clinical trial. While details are important, you do not want to be so detailed that the procedures become operationally infeasible. Some flexibility in the language may be necessary to allow the collection of important information without triggering a protocol deviation. A potential example is provided below:
An alternative to flexible wording is to place details that are not critical to study design into a study procedures manual (or SPM). Use of an SPM can allow slight modifications to be made during the study without the need for a protocol amendment. As the protocol is being drafted, consider whether flexible wording or an SPM is helpful to prevent deviations while still allowing for the collection of high quality data, or if more rigid language is required in the protocol (e.g., in cases where flexibility could affect data quality and, by extension, the validity of the conclusions that could be drawn from them).
While every Investigator and staff member involved in the study will be responsible for familiarizing themselves with the protocol, the organization of the protocol should make it so that details are simple to find quickly. Create informative sub-headers so that information can be quickly located using the Table of Contents. This will help the study staff find important information efficiently, and will also help IRB/regulatory officials during protocol review. Also, if the protocol is being submitted to the FDA, remember that the document needs to be compliant with all required document specifications, including eCTD requirements.
Clinical protocols often repeat information in multiple locations. Be careful when employing redundant text in the document, since changes to one section may be inadvertently missed in others, which introduces inconsistencies. Instead of copying text, consider cross-referencing to one appropriate location. If text is copied throughout the protocol, be sure that any changes are thoroughly reviewed and consistently reflected in all applicable sections.
Well-written protocols are essential for protecting subjects, allowing collection of quality data, and preventing delays in development timelines. Understanding regulatory requirements, clearly defining relevant study objectives and endpoints, providing sufficient detail within the protocol, and ensuring that the protocol document is user (and reviewer) friendly, will all help position the study for success. Allucent’s experts can help with protocol authoring, strategic advice for pharmacokinetic study design, and regulatory guidance. Reach out for support for your clinical development program!
