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Pro Tips for Protocol Writing

September 28, 2018 | Kathryn Tworkoski, PhD, RAC, Senior Clinical Research Scientist  │ Medical Writing Services

Great news; your team has been given the green light to conduct a new clinical study with your favorite compound!  It’s what you’ve been waiting to hear, and now it’s time to seize the opportunity and run full steam ahead!

But first, you have to write a protocol.  The basic structure and content of a protocol are described in the International Council for Harmonisation Good Clinical Practice E6 guideline.  As you would expect, protocols should ultimately outline and justify the planned clinical study.  The type of information presented in protocols includes background information, trial objectives and assessments, trial design, subject selection and treatment, and a brief overview of the planned statistical analyses.

It may seem that writing a protocol would be pretty straightforward.  After all, how hard is it to state what you want to do?  But there are often unexpected hurdles in the design and development of a clinical trial, which can cause delays in the protocol-writing process.  At the same time, there is frequently a sense of urgency to complete the protocol, either because it’s necessary for the submission of an IND or because there’s a rush to initiate the trial itself.

Together, these complications can slow protocol development or necessitate subsequent amendments.  We’ve seen it happen, and over the years, we’ve come up with a few tips to make writing a protocol a bit easier.

Image courtesy of renjith krishnan at

1. Understand where your study fits in

It is important to understand where your study stands in terms of the overall drug program.  Will your study be included in an upcoming submission?  Will your study rely on the results of earlier studies?  What parts of your study are likely to be most important in informing future studies?

Addressing these questions can help determine the timelines for your project and can also help keep the team focused on the “big picture” issues.

2. Assemble a team and determine study goals

It is crucial to assemble a team that can address all aspects of a protocol, from drug formulation to regulatory requirements to safety/efficacy/pharmacokinetic analyses.  As you’re putting your team together, remember to identify individuals who are key decision makers or who can help resolve potential disagreements within the team.

Input from various team members is what ultimately determines how a protocol is written, and forgetting or neglecting a given area of expertise is understandably problematic.  Forgetting to include a team member from a given functional area typically means that you will have to solicit input from that functional area at a later date.  And that usually translates to additional effort needed to re‑write portions of the protocol, as well as delayed timelines while the editing takes place.

Once your team is assembled, it is important to make sure that you all agree on the same study goals.  Is this a bioequivalence study?  Are you trying to find a Phase 2 dose or verify efficacy in a designated population?  These questions may seem obvious, but different team members often have different opinions on what information should ultimately be derived from a study.  Getting everyone on the same page at an early date can prevent confusion and re-writing further down the road.

3. Create a protocol concept

Another excellent way to prevent re-writing and to simplify timelines is to create a protocol concept.  A protocol concept is a short (usually <15 pages long) document that briefly outlines key study aspects, such as trial design, inclusion/exclusion criteria, objectives, and assessments.  This is not a regulatory document and there is no standard format: it can be as simple as a series of bulleted lists!

A protocol concept should be reviewed and/or approved by the team before formal protocol writing begins.  This allows the team to review the “big picture” issues in a small, condensed format, which is typically more efficient than asking the team to review a full-length protocol.  Obtaining team agreement on the protocol concept then streamlines protocol writing, and minimizes the risk of needing large scale edits in the protocol itself.

4. Carefully consider your study design

Ok, this one sounds pretty obvious, but there can be a surprising number of factors at play.  For instance, do you need a placebo or an active comparator for your study?  Should you examine more than one dose level of your drug?  Considering the nature of the drug and the disease in question, what assessments and time points should be used for analysis?

As I mentioned earlier, this is one area where a protocol concept is especially useful.  Determining the study design upfront reduces the likelihood that the study design will be adjusted during protocol writing, which in turn streamlines the production of the protocol.  As you would expect, trials can get more complex at the later stages of development, which makes it all the more important to get all team members on the same page as early as possible.

5. Don’t forget the practicalities of study design and conduct!

It’s very true that the devil is in the details.  There are a lot of potential pitfalls in study design, but there are some issues which seem to recur with startling frequency.  For instance:

And I know I said it earlier, but it bears repeating: remember your study goals!

It can be tempting to try to answer as many questions as possible in a single study.  But unnecessarily complicating a study can be problematic, both in terms of administrative burden and in terms of adding potential confounding variables that may impede the interpretation of data.

6. Remember Your Writing Considerations

Aside from the study design, there are a few additional things to bear in mind during the writing process.  For one thing, it’s always helpful to begin protocol writing using a company template, or using a model protocol from the same (or a similar) clinical program.  In a pinch, it may be possible to adapt online templates for your own use.  For example, the NIH has generated a publically-accessible protocol template that was designed for Phase 2 and Phase 3 clinical studies.

I’ve already mentioned the importance of identifying your team and using a protocol concept to frontload the work.  Additionally, it may be useful to have a designated party review the protocol for feasibility.  A clinical expert or the CRO responsible for conducting the study (if applicable) should be able to advise the team on whether there are likely to be issues implementing the new study design.

Another issue that we often see is the desire to write 2 protocols in parallel (especially for 1 drug that will be used for multiple indications).  But writing in parallel can make it hard to generate consistency between documents.  Parallel writing also increases the overall workload for all team members, which can make it harder for team members to give each study the full scrutiny that it needs.  Collectively, these issues can necessitate substantial edits (and potential delays) in the later writing stages.

Instead, we suggest staggering protocol writing.  Start writing one protocol and allow it to progress through at least 1 draft (preferably 2 drafts) before starting the second protocol.  That way, the overall structure/messaging of the first protocol can be pulled directly into the second protocol and the team can focus on one document at a time.  This staggered process typically allows the second protocol to be written much more quickly than the first, and we’ve found that staggering protocol writing doesn’t necessarily delay document finalization relative to writing the protocols in parallel.

7. Consider planned amendments

Understandably, many teams want to minimize protocol amendments.  But every once in a while, pre‑planning amendments can be a very helpful tool to increase the amount of useful data obtained in a study and to streamline the clinical development program.

Pre-planning an amendment can be done informally, but it is crucial to determine what criteria must be met to trigger the filing of a specific amendment.  A straightforward example may be to add dose cohorts if a maximum tolerated dose is not reached.  But amendments may also be used to acquire additional data to inform future studies.  For instance, if a certain percentage of patients do not meet a designated efficacy endpoint, perhaps an additional endpoint (or time point) may be added to the study.

Good luck!

All right, that’s just a few tips on how to streamline your protocol-writing processes.  Don’t hesitate to contact us if you have any questions or if we can be of any help!  We’d also love it if you follow us on LinkedIn and Twitter.

Category: Medical Writing Services
Keywords:  protocol development, study design, study planning

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