How do you write the perfect protocol for your clinical investigation? First, it’s important to understand what exactly a protocol is, along with its components.
You might be familiar with the term “protocol,” while “Clinical Investigation Plan” or “CIP” might be a bit more foreign. The two terms are referring to the same document. However, many industry Sponsors and academic medical centers refer to one over the other, or even both interchangeably. The Good Clinical Practice ISO 14155 standard also refers to both terms throughout the regulation document. This blog will refer to the Clinical Investigation Plan as the “protocol” to reduce confusion.
The protocol for a clinical investigation states the rationale, objectives, design and pre-specified analysis, methodology, organization, monitoring, conduct, and record-keeping for the clinical investigation. It is arguably the most essential document in your clinical investigation. Therefore, you must collaborate with numerous professionals with expertise in clinical investigations, monitoring, statistics, data and query management, regulatory requirements, medical terminology, and others.
Senior Clinical Research Associate,
ACRP CCRA, CRP
Many organizations offer expertise in regulatory affairs to write or review your protocol before submitting it to a major entity, such as the FDA or an EU member state. It is imperative to have a professional who is familiar with reviewing and submitting protocols to the regulatory body you must submit to.
Regulatory experts can advise on various topics, including Ethics Committee/Institutional Review Board (EC/IRB) review time and cost expectations for each submission. They should also be able to provide you with the pros and cons of choosing a particular region for your clinical investigation based on their regulatory affairs experience with that country or, more specifically, the investigational site.
As a Sponsor or device manufacturer, you should ask yourself, “What does the regulatory body want to see in my protocol for this type of submission, and how long will this take to be approved”? A regulatory affairs expert can answer these questions and lead you to a quick and seamless regulatory approval for your clinical investigation.
Using correct terminology is essential for your protocol. Using an incorrect term can lead to additional requirements for your investigation by the regulatory body reviewing your document.
The clinical research world can be seen to have its own language and can easily be confusing for someone with little to no experience writing protocols. It is critical for clinical investigation experts (such as Contract Research Organization [CRO] and regulatory affairs professionals) to review your protocol because they will likely catch significant terminology errors, thus reducing the amount of extra work and submission time for your team in the long run.
All experienced protocol writers know that some words that seem very similar, might actually mean something different entirely (for example, describing “severe” versus “serious” adverse events). In contrast, words or abbreviations that look very different can mean the same thing (for example, DMC versus DSMB and DSMC).
A clinical investigation expert or protocol writer should be able to write a seamless document for you and your team to achieve regulatory approval.
The Good Clinical Practice ISO 14155 standard states that the clinical investigation shall be designed to evaluate whether the investigational product is suitable for the purpose(s) and the population(s) for which it is intended. It shall be designed in such a way as to ensure that the results obtained have clinical relevance and scientific validity, and they also address the clinical investigation objectives, in particular, the benefit-risk profile of the investigational product.
Several factors are important when designing any clinical investigation, including general considerations of sources of bias and bias minimization, as well as specific considerations related to clinical investigation objectives, subject selection, subject endpoint(s), stratification, investigation site selection, and comparative clinical investigation designs.
The clinical investigation should be designed to allow confirmation of the benefit-risk analysis of the investigational product as outlined in the product’s risk management report. The protocol shall clearly outline the objectives of the clinical investigation and the design shall be adequately justified based on scientific and ethical principles.
Annex A of the ISO 14155 standard provides a protocol outline for you, which can be extremely helpful for Sponsors who are writing their first protocol. This template is a good start but does not include everything necessary for a particular regulatory authority; therefore, working with an experienced CRO pays off to achieve your objectives.
When writing the clinical investigation’s schedule of events section, you should carefully consider how the events affect and relate to your protocol’s primary and secondary objectives and endpoints.
Sponsors often add extra procedures and visits without considering how this might help (or even hurt) their intervention and overall budget. It can result in extra work for the site, causing inessential monitoring of unnecessary data for analysis that does not end up being used, creating an abundance of additional costs associated with each unnecessary procedure.
Usually, when the Sponsor recognizes the oversight, it is later in the investigation, and a protocol modification is sent to the regulatory body and EC/IRB for a new approval. It usually causes confusion with data analysis, site training, etc. (not to mention the extra time it may take for the modification approval).
Thinking through the schedule of events section is essential during the protocol’s draft phase to avoid unnecessary modifications and confusion. Your schedule of events section does not have to explicitly display all related case report forms (CRFs) and their data entry time frames, but this can be helpful for your investigational site to follow as they relate to each scheduled visit.
It is also important to decide on appropriate visit window times.
Visit windows should be as large as possible without affecting the evaluation of clinical investigation objectives and endpoints. An Early Termination (ET) visit can be established to capture last-minute data points from a subject before their early termination in the investigation if they agree to do so.
Carefully consider which visits can be done over the phone versus in person, a decision that can significantly affect your budget. Adverse events are commonly collected over the phone from the subject directly.; however, note that subjects can often underreport, overreport, or falsely report adverse event descriptions over the phone.
Having your site(s) go through a trial run with your proposed protocol’s schedule of events and case report forms before regulatory body submission (without using actual patients) can be helpful. As the Sponsor, it allows you to decide what is possible, what is unnecessary, and what should be added to the scheduled events before the enrollment phase.
Below is a sample Schedule of Events table:
Monitoring is defined as a systematic and independent examination of clinical investigation-related activities and documents to determine whether the clinical investigation was conducted correctly, and that the data was recorded, analyzed, and accurately reported according to the protocol, Sponsor QOP and SOPs, GCP requirements, and applicable regulatory requirements. Audits are also used to ensure the rights and well-being of human subjects are protected.
Monitoring needs to be tailored according to the device and investigation's risk assessment, stage of clinical development, and the type of clinical investigation. The plan also needs to be referenced in the protocol.
There are a variety of different risk-based monitoring techniques. The best strategy to use depends on the specific needs and budget of the Sponsor and the clinical investigation.
It is recommended to use a combination of the following techniques:
Analyzes and collects data in real-time to identify potential errors in data entry, allowing the Sponsor or monitor to select which subjects or data fields to focus on.
Allows the Sponsor or monitor to be triggered by certain events, such as a specific number of SAEs, severe site non-compliance with data entry, etc.
Allows a Sponsor or monitor to specifically select subjects to monitor for 100% data verification.
Selecting subjects to monitor can be done using subject data entry non-compliance, a specific number of AEs experienced by the subject, the number of minor/major deviations or violations filled for a subject, or any other reason a Sponsor or monitor may have to audit a specific subject's data over another).
The strategies mentioned in this blog can be valuable when writing your protocol. It is also important to acknowledge any additional challenges and their potential solutions to ensure regulatory body and EC/IRB approval of your protocol.
The FDA recognizes that involving patient and Investigator advisors can be helpful in the design and conduct of your clinical trial documentation. Engaging advisors can increase enrollment odds, impact efficient data collection, and influence the quality of the design and conduct of the investigation. It can also be helpful to obtain feedback from the relevant FDA office/division on appropriate design and any applicable regulatory requirements.
The Biotex CRO+ is committed to collaborating with a vast amount of patient and Investigator advisors during the protocol development process. Additionally, our CRO staff are proficient in protocol writing and ensure that documents are approved as quickly as possible by the applicable regulatory body and EC/IRB.
Our clinical team is experienced with protocol writing for the FDA, EU, and various regions around the world. If you need assistance writing your next protocol, Biotex CRO+ is committed and ready to help. Contact our team to explore how we can work together.
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Britnee Ochabski is a Senior Clinical Research Associate (CRA) with an ACRP certification for CCRA and CP who developed the clinical program at Biotex and currently manages the Biotex CRO+. Since 2015, Britnee has managed several clinical investigations involving devices and drugs at various institutions and sites inside and outside the U.S., involving national and international travel. She is a reliable CRA with knowledge in all research areas, including clinical and regulatory requirements for a seamless U.S. or OUS EC/IRB approval. She is known for her strong ethics and commitment to quality patient care.
