What is the Clinical Trial Protocol?
Introduction to clinical Trial Protocol
The clinical trial protocol is an essential document for the successful conduct of a clinical trial. As per the US FDA, “Clinical Protocol should be submitted for each planned clinical study or trial. An original IND application submission lacking a clinical protocol is considered incomplete.”1 Therefore, a clinical trial protocol must be prepared to conduct any trial under the US FDA. Though it is mandatory, however, what is more important is what this clinical trial protocol contains. Other than the sponsor, only an experienced medical writer could assess the real value of a well-written clinical trial protocol that could generate quality data. This blog will discuss the importance of a clinical trial protocol in drug development, the challenges related to clinical trial protocol development, and the importance of hiring an experienced medical writer.
Components of a Clinical Trial Protocol
As the clinical trial protocol lays down the plan for a clinical study, it provides detailed information about multiple downstream activities during the conduct of a clinical trial. Therefore, it should be enriched with valuable information, which can lead to as few amendments as possible. The major components of a clinical trial protocol include:2
- Background information (findings from previous nonclinical and/or clinical studies)
- Trial objectives and purpose
- Trial endpoints
- Trial design (including a schedule of activities/assessments)
- Selection and withdrawal of subjects
- Treatment of subjects
- Quality control and quality assurance
Importance of Clinical Trial Protocols
The clinical trial protocol is the basis for trial registration,3 and it guides those responsible for conducting the study. Its importance is reflected in the below points collected from the regulatory guidelines:
- US FDA1: As stated at the beginning of this article, the US FDA needs a clinical trial protocol to be submitted for each planned clinical study or trial.
- 21 CFR 3124: During an IND submission, as per 21 CFR 312.22(c), the general investigational plan and the protocols for specific human studies also need to be submitted. Far more detail about protocols is provided in 21 CFR 312.23(a)(6). Briefly, it states that the IND submission content should contain a protocol for each planned study. The clinical trial protocol is of such high importance that 21 CFR 312.23(a)(6) provides the details and elements to be included in the Phase 1-3 study protocols. Additionally, as per 21 CFR 312.30, any protocol amendments (as defined in 21 CFR 312.30) that lead to changes in the submitted protocol should be submitted as well.
- 21 CFR 3145: During an NDA submission, as per 21 CFR 314.50(d)(5), the technical sections should contain a section describing the clinical investigations of the drug. This includes providing a protocol along with other information. Additionally, if not included in the approved NDA, one or more protocols may be submitted as supplements to the approved NDA, which may provide more information related to the safety or effectiveness of the drug product.
- Besides these, many other Title 21 CFR guidelines state the use of protocols for drug product submissions.6, 7, 8
How do you write a Clinical Trial Protocol?
A protocol should be specific, uncomplicated, sensible, and understandable in terms of the study design and its implementation in the real world.
Clinical trial protocol writing begins while considering the sponsor’s viewpoints of their study. The primary error in writing an effective protocol can begin here only. Understanding the sponsor’s viewpoints and implementing these (considering the practicality of the protocol) is essential. Firstly, a sponsor should consider achieving a few precise objectives during the study instead of doing it all. Secondly, these objectives must be technically sound and clear to the writer. This way, the study design in a protocol will focus on answering these precise objectives only. This will make the protocol writing and implementation effective in the real world.
A lot of protocols lead to amendments because the documented activities in these seem impractical when the clinical trial is being conducted. Therefore, a sensible protocol is crucial for the timely completion of a clinical trial.
In many scenarios, the documented procedures in the protocol turn out to be unclear to the clinical study site personnel, and they misunderstand what they are intended to do and when. This further leads to protocol violations and errors in collecting data from enrolled patients. Therefore, a protocol should be written in simple and clear language that can be understandable by the personnel involved in its implementation.
Challenges in Developing a Clinical Trial Protocol
The most common challenge in developing a clinical trial protocol is deciding what to include in it and what not. Many protocols fail to provide clear information about important study elements (as described in the section above), which affects understanding and implementation of the protocol. The importance of protocol is often not truly recognized by the sponsors and writers, which delays the study and increases the cost to the sponsor.9
As per 21 CFR 312.42(b)(2)4, the FDA may place a proposed or ongoing Phase 2 or 3 investigation on clinical hold if it finds that the plan or protocol for the investigation is deficient in design to meet its stated objectives. Therefore, this challenge can be overcome by the medical writer in consultation with the sponsor team to include all required study elements in the protocol in a complete, clear, and easy manner.
An experienced medical writer will know these challenges and the importance of an effective clinical trial protocol. Writing protocols for multiple indications can be useful in providing suggestions about the study designs. Specifically, medical writers who are involved in writing all downstream documents related to a clinical study protocol (for example, an informed consent form or a clinical study report and its publishing activities) will know how the data collected with their written protocol can impact the clinical study report and its publishing.
The clinical trial protocol is a significant document in the journey of clinical drug development from the beginning to its marketing approval. Developing too complex a protocol can affect all the downstream activities involved with its implementation in the real world. Effectively written protocols can increase the value of a clinical trial by only collecting quality data. This can further make the work of the regulatory reviewers effortless, ultimately benefiting the sponsor. Therefore, choosing an experienced medical writer to develop an effective protocol is the key to this whole process, which should not be compromised at any level.
- IND Applications for Clinical Investigations: Clinical Protocols. US Food and Drug Administration. Updated September, 2015. Accessed July 25, 2023.
- E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1). International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). 2018. Updated March, 2018. Accessed July 25, 2023.
- Entering a New Registration: PRS Guided Tutorials. ClinicalTrials.gov. Updated September, 2020. Accessed July 25, 2023.
- 21 CFR Part 312. Investigational new drug application. Code of Federal Regulations. Updated March, 2004. Accessed July 25, 2023.
- 21 CFR Part 314. Applications for FDA approval to market a new drug. Code of Federal Regulations. Updated October 2016. Accessed July 25, 2023.
- 21 CFR Part 316. Orphan drugs. Code of Federal Regulations. Updated March, 2004. Accessed July 25, 2023.
- 21 CFR Part 320. Bioavailability and bioequivalence requirements. Code of Federal Regulations. Updated October 2016. Accessed July 25, 2023.
- 21 CFR Part 361. Prescription drugs for human use generally recognized as safe and effective and not misbranded: Drugs used in research. Code of Federal Regulations. Updated March 2017. Accessed July 25, 2023.
- Fogel DB. Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: a review. Contemporary clinical trials communications. 2018;11:156-64.