Author: Aarti Urs
Once your team receives the long-awaited approval to conduct a clinical study on your favorite compound or device, it is time to turn the wheels full speed. But before you begin with your study, you will need to write a detailed clinical study protocol (CSP). A CSP is the single most vital document outlining these questions: Why is the trial being conducted? How should it be executed? And what are the contingency plans? It is a crucial communication document between the investigators conducting the study, IRB, and federal regulatory agencies. According to International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) E3 , CSP is a document that describes the objective(s), design, methodology, statistical considerations, and organization of the trial. In order to write a solid, error proof protocol here are a few tips:
While writing the CSP it is crucial to keep the “audience” in mind. You will be communicating with physicians, nurses, IRB members, and scientific reviewers. Before you begin writing, read ICH E3 guidelines for the topics which are necessary to include in a fully integrated protocol. Consolidate the list of documents provided in ICH appendix 1 needed for your protocol so that you do not accidentally omit any item. These guidelines are meant to be as a guidance document which can be modified or adapted to better communicate the information if necessary.
To avoid any ambiguity and present a complete, well organized and easy to read report, many NIH programs encourage or require the use of protocol templates. There are many different templates available on the internet. Most of these templates include a detailed list of items that should be incorporated into the protocol.
The rule of thumb is to include the right amount of details to effectively communicate the study requirements to the reader of each section.
Thus, the protocol must inform the study staff about how the study treatments will be assigned, how the subjects are to be treated, and what assessments are to be performed when, with what equipment, and by whom.
It should inform pharmacy staff about how the study medication will be packed and when to dispense, return and track. It will also specify whether special storage facilities are required. There should be enough detail for the lab staff on how to obtain biological samples together with the allocation of responsibilities for their analysis.
Even at the protocol writing stage, there should be a clear idea of the data to be collected and the analysis to be performed.
ICH E3 Guideline provides guidance on the amount of detail expected from the data reporting: “The report with its appendices should also provide enough individual patient data, including the demographic and baseline data, and details of analytical methods, to allow replication of the critical analyses when authorities wish to do so. It is also particularly important that all analyses, tables, and figures carry, in text or as part of the table, clear identification of the set of patients from which they were generated.”
The guidelines also including the detailed discussion of adverse events: “The full integrated report of the individual study should include the most detailed discussion of individual adverse events or laboratory abnormalities, but these should usually be reexamined as part of an overall safety analysis of all available data in any application.”
An excellent way to simplify protocol writing is to create a concept-protocol by laying out the study schedule. This concept-protocol is an initial map showing the visit timings, study phases (e.g. screening, run-in, dose titration, wash-out, treatment, follow-on etc), inclusion/exclusion criteria and assessments, including relevant notes on how specific assessments are to be performed and what time points should be used for analysis. Mapping out the study timeline upfront reduces the likelihood of any changes during protocol writing, which in turn streamlines the production of the protocol. This is not a regulatory document so there is no standard format. It can be in a tabular form, a flow diagram or just bullet points. This is a condensed version of a protocol which can outline the “big picture” in a small, succinct format.
All protocols require a section detailing the scientific rationale for a protocol, and the justification in medical and scientific literature for the hypothesis being proposed.
The Introductory section should be as succinct as possible and should be organized in a logical, sequential manner. Background and rationale should not be more than 3-5 pages and can be referenced back to the investigator’s brochure, full grant or key literature references, if necessary.
Instead of trying to answer too many questions at the same time, it is necessary to get one primary objective right. However tempting it maybe to try to answer multiple questions at the same time, it will unnecessarily complicate the study by adding potentially confounding variables that may impede the interpretation of data. The objective should be (SMART objective): Specific, Measurable, Achievable, Relevant and Time based.The primary objective must be well-defined with a well-founded rationale that is logically explained in the introduction of the protocol. This will also help to convince ethics committees that the question needs to be answered, and that it is being addressed by the trial in an ethical way with the best interest and safety of subjects in mind.
The primary objective of the CSR dictates the primary endpoint. Primary endpoint is sometimes called primary outcome measure or primary variable. Primary endpoint also requires clarity of thought in order to justify the choice of endpoint, which needs to align with the expectations in your field. Try to keep your endpoints quantitative/ objective (e.g. Blood pressure, laboratory values etc), as opposed to qualitative/ subjective (Pain, discomfort etc). In case of subjective endpoints, try to back up these measurements with surrogate markers (e.g. laboratory value) that correlates with disease or symptoms. Alternatively, a validated scoring system can be considered.
Primary endpoints will also determine sample size. If the subject numbers run to be too large and impractical with respect to funds, it is important to consult statisticians.
Since the protocol has to be approved by both IRB and FDA, it is important to consider their complementary but distinct perspectives. IRB protects participants of the study by ensuring that risks to the participants is minimal and reasonable in relation to the anticipated benefits of the study. IRB also ensures that no specific gender, race, ethnicity or socioeconomic status of participants is disproportionately bearing burden or reaping benefits of the study.
FDA on the other hand, focuses on how the safety and efficacy of the drug or device affects the overall population. Hence the study results must provide rigorous evidence that the drug or device is for the welfare of people. Most investigators are well aware of FDA requirements but are less familiar with IRB requirements. Less invasive study designs and optimal use of all data points is the key to protect subjects and achieve IRB approval. Robust study design with validated safety and efficacy endpoints is the key for FDA approval. If a study protocol requires more than minimal risks, include a compelling rationale for the need of these procedures.
It is crucial to critically analyze yours’ and your organization’s strengths and weaknesses that would reflect in the protocol. Once you identify any weaknesses, fill those gaps by seeking outside expertise or by investing in training internal staff. Early investments to strengthen your study design will reap long term benefits.
Do not hesitate to take outside help on reviewing your protocol. Ask an outside member of the scientific community or a colleague to review your protocol. This will provide you invaluable feedback on the clarity of your writing, and whether your protocol has enough details for an outside member to understand your study and rationale behind the study.
If you lack the necessary writing expertise to generate a robust CSP, it would be prudent to seek professional writing help.
We are a team of full service medical writers with expertise in regulatory know-how and focus on flawless execution, thereby maximizing your chances of success. Contact Criterion Edge to learn more about our writing services and follow us on Twitter and LinkedIn.
As Antoine de Saint said “A goal without a plan is just a wish.” Writing down a robust plan, investing in proper resources and seeking outside expertise to bridge any internal gaps in knowledge is the key to successful execution of clinical study. Good luck with your CSP!