How Biotech Teams Should Approach Protocol Writing to Avoid Amendments

Get it right the first time—with less rework, fewer delays, and more clarity

Introduction

Biotech teams are often working at full capacity. Writing clinical trial protocols shouldn’t drain your time or distract you from strategic priorities. Yet, when protocols aren’t right the first time, the consequences are real: costly amendments, investigator queries, and missed deadlines.

A well-crafted protocol can minimize amendments and deviations, ensuring a smoother trial process. This guide aims to provide insights into crafting a clear and effective protocol, specifically tailored for the biotech industry. Whether you’re managing clinical operations, overseeing a clinical trial, or simply an individual tasked with writing the study protocol, here’s how to reduce amendments and deviations and run a smoother trial from day one.

What is a Clinical Trial Protocol?

A clinical trial protocol is a document that describes the objectives, design methodology, statistical considerations, and organization of a clinical trial. It provides the background and rationale for the trial, as well as the known benefits and potential risks of the investigational product.

Why Do Protocol Amendments Happen?

Since 2015, the prevalence of amendments in phase I–IV protocols increased substantially (from 57-76%), and the mean number of amendments per protocol has increased by 60% to 3.3, up from 2.1 [1]. In the same study, 23% of amendments were deemed avoidable, potentially due to the quality of the written protocol.

Protocol amendments often result from original protocol versions lacking clarity or thorough planning. Ensuring the protocol is accurate from the outset can help save time on amendments, ultimately leading to more efficient recruitment and a reduced workload for the clinical team.

So, how can you guarantee accuracy from the outset?

How to Write a High-Quality Protocol

Writing a protocol involves multiple stages, from concept and synopsis development to writing and final submission. We’ll focus specifically on the medical writing process of protocol development and its finalization:

1) Gathering the essential source documents for your clinical study protocol

Finalized and up-to-date source documents are vital as they ensure scientific integrity, regulatory compliance, and overall success of the clinical study protocol writing process. To author a protocol, at a minimum, the following documents are needed:

• A final approved synopsis: Ensure you have a final approved synopsis before writing the protocol. This includes forming the central scientific question, developing a concept with critical trial elements, and gathering input from subject matter experts.

• An up-to-date Investigator’s Brochure (IB): Provides key background information, ensures patient safety, and helps maintain overall consistency and quality of the protocol.

• Protocol template: Helps to streamline the writing process, ensuring regulatory compliance and reducing errors and amendments. They’re often based on ICH M11 approved templates, e.g,. Transcelerate

• Style guide: Essential for maintaining consistency, clarity, and quality in protocol writing.

Clinical Trial Protocol Development and Finalization

Protocol development and complexity depend greatly on the type of trial being conducted. For instance, interventional, randomized, double-blind, multi-site trials need more detailed protocols than open-label, single-site, or Phase 1 trials. Despite this, all protocols should be written in accordance with standard operating procedure, and all protocols must follow Good Clinical Practice (GCP) principles:

Start by hosting a Kick-Off Meeting (KOM) with all team members

This includes Project Managers, the medical writing team, Sponsor teams, and External Stakeholders. The KOM informs team members of information exchange methods to draft a protocol and alignment on the process for producing a final version. The meeting is used to review project timelines and confirm reviewers for each draft and their contact details.

Following kick-off, protocol development should follow 2 review drafts, quality control (QC) review, and final approval. Here are more detailed instructions for this development process:

Develop the first draft

Using the approved protocol template, develop Draft 1 of the protocol. Aim to write the protocol with the investigator in mind. Structure the inclusion/exclusion criteria and schedule of assessments logically to make it easy for the investigator to follow.

Ensure the team is notified of the upcoming review. Draft 1 should be as complete as possible for an efficient and feasible review.

Review and comment resolution

Distribute Draft 1 of the protocol to the Sponsor for review. Reviewers must read the entire protocol for consistency. Following this, the Project Manager should schedule a Comment Resolution Meeting (CRM) to ensure all comments from the prior draft are resolved.

With the client's consent, the Project Manager should transcribe the call to accurately capture important discussion points and subsequent action items. This approach allows all participants to be fully engaged in the meeting without the need for the Medical Writer to assume the role of 'note-taker'.

Repeat the review process for subsequent drafts

Repeat the above steps for subsequent drafts as necessary. Reviews of additional drafts should focus exclusively on content changes from the prior draft. You should aim to complete this process within two rounds of review.

QC review

Submit the draft for QC review and incorporate QC findings into the working draft, keeping them as separate files.

Final review and approval

Distribute the protocol and its accompanying files for Sponsor review and approval.

Biotech Reality: When Things Don’t Go to Plan

The biotech environment is unpredictable, often causing unforeseen roadblocks in the protocol writing process. Changes in clinical trial design are common due to emerging scientific data, regulatory feedback, or shifting therapeutic landscapes. As a result, a new draft of the protocol synopsis may become available during the protocol development.

What if there are fundamental design changes during protocol development?

Fundamental design changes during protocol development can present significant challenges. These modifications might arise from new scientific discoveries or shifts in regulatory requirements, necessitating revisions to the clinical trial framework. Biotechs can take the following steps to manage these changes effectively:

• Schedule additional review meetings with key stakeholders, including subject matter experts, clinical operations personnel, and regulatory experts, to discuss the proposed design changes and their implications.

• Thorough reviews of protocol drafts, with effective management of comments that should be tracked in the document.

• Revise the synopsis to reflect the new design changes. Ensure that the updated synopsis is reviewed and approved by all relevant parties before proceeding with further protocol development.

• Involve medical writers in the review and integration of the design changes. Their expertise can help ensure that the changes are accurately reflected in the protocol and that the document remains clear and consistent.

• Document the design changes and the rationale behind them. This helps maintain transparency and provides a clear record of the decision-making process for future reference.

• Recognize that the protocol development process may need to be flexible to accommodate significant design changes. Be prepared to extend timelines if necessary to ensure that the protocol is thoroughly reviewed and finalized.

  
  

  These strategies can help you avoid protocol amendments by preventing the common challenges that come with fundamental study design changes.

How Morula Health Helps Biotechs Write High-Quality Protocols

We combine the right experience with trusted processes to deliver protocols that are clear, consistent, and ready for execution.

We have experienced senior Medical Writers with relevant therapy area expertise and a deep understanding of protocol development. Their clinical research experience grants them insights into the patient pathway and operational aspects of clinical studies, making them adept at capturing crucial details and asking the right questions. We also have in-house project management to help schedule and lead key meetings, like CRMs, that often go beyond discussions and act as brainstorming sessions where protocol design evolves.

To streamline the protocol development process, we offer ready-to-use templates, QC checklists, and style guides that guarantee consistency, quality, and alignment with ICH standards. These resources are instrumental in crafting robust protocols that can withstand amendments.

Morula Health's multitasking ability and effective management of inputs ensure protocol development remains focused and efficient. Our comprehensive experience adds significant value to biotech protocols, making them ready for successful implementation.

Get In Touch

If you’d like to contact us to discuss protocol writing support, you can email our team directly or fill out our website contact form.