Bernadette Howlett, PhD
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Publishing Clinical Trial Protocols

Why Clinical Trial Protocols Are - or Should be - Published in Advance

by Bernadette Howlett, PhD | 23 Sept. 2018

Researchers following known, previously established (published in a peer-reviewed journal) protocols may increase safety, quality, and efficacy of clinical trials. When there is not already an established protocol for conducting a particular type of study, the best thing for researchers to do is develop a protocol and publish it.

A clinical trial protocol, also called a research protocol, is a type of article in which the authors describe the methods and procedures that will be used when the study is administered. Chan, Tetzlaff, Altman et al (2013) provide the following definition:

[T]he protocol is defined as a document that provides sufficient detail to enable understanding of the background, rationale, objectives, study population, interventions, methods, statistical analyses, ethical considerations, dissemination plans, and administration of the trial; replication of key aspects of trial methods and conduct; and appraisal of the trial's scientific and ethical rigor from ethics approval to dissemination of results.

Protocols are submitted to institutional review boards (IRB) as part of the process to gain authorization to conduct a study. Under Food and Drug Administration Regulations (2018), an IRB is:

[A]n appropriately constituted group that has been formally designated to review and monitor biomedical research involving human subjects.

Some IRBs will not allow research involving human subjects to be conducted unless the authors utilize a published protocol. Protocol publication is a fairly recent phenomenon, developed out of increasing interest for protecting research participants from unnecessary risk or study design flaws. The U.S. National Institutes of Health (NIH) have adopted a number of policies to improve the quality, efficacy, and efficiency of clinical trials. Part of this quality improvement effort is to require protocol publication, in certain circumstances. Publication of a protocol is especially important when conducting research on a new idea, when an intervention involves more risk than usual, or with subjects who represent a vulnerable population (for example, performing research involving pregnant women).

Even in the case of a study being minimal risk in terms of the intervention, it is important for the design to have a good likelihood of producing usable data and providing valid results. The IRB will be unlikely to approve any study design that is not based on sound principles or is unlikely to produce trustworthy findings. There is little reason to expose research subjects to any intervention if a study is not well designed.

Another important function of publishing protocols is to increase the likelihood of the results being made publicly available. According to Hudson, Lauer, and Collins (2016):

[T]oo often clinical trials are overly complex, have small sample sizes, rely on surrogate end points that lack clinical relevance, have unrealistic accrual rates, and have inadequate budgets. Of particular concern is the existence of trials from which the results are never published or data submitted to a public database.

Including a Pilot Study

Some researchers run a protocol with a small sample of subjects in a pilot study. Conducting a pilot study as part of the development of a protocol is usually done when there is minimal risk to subjects. Leon, Davis, and Kraemer (2011) defined the concept and discussed the purpose for pilot studies as follows:

The purpose of conducting a pilot study is to examine the feasibility of an approach that is intended to be used in a larger scale study . . . A pilot study is not a hypothesis testing study . . . Pilot results can inform feasibility and identify modifications needed in the design of a larger, ensuing hypothesis testing study.

Study Registration

In addition to publishing a protocol in advance, with or without a pilot study, it is becoming more common for researchers to pre-register a study with an appropriate entity, such as clinicaltrials.gov. It has for some time been expected for clinical trials to be registered after a study begins, as part of the process for informing the public of a study and recruiting subjects. In fact, it may be required for funding purposes, as explained by NIH policy (National Library of Medicine, 2018):

[E]very clinical trial funded in whole or in part by NIH is expected to be registered on ClinicalTrials.gov and have summary results information submitted and posted in a timely manner.

It is becoming increasingly suggested that trials will be registered far enough in advance to allow the protocol to be subjected to peer review prior to the study beginning to enroll subjects (Couzin-Frankel, 2018; Kupferschmidt, 2018). However, NIH policy does not require pre-registration, but instead that investigators register with clinicaltrials.gov within 21 days of enrolling the first participant (Hudson, Lauer, & Collins, 2016).

Alone, registering a study is not adequate to achieve the same objectives as publishing a protocol. Study registration does not go through the same rigors of peer review as publication, at least when a protocol is published in a reputable journal. There has been an alarming proliferation of so-called predatory journals, which release articles with little or no peer review (Couzin-Frankel, 2018).

Application to Evidence-based Practice

When the word "protocol" appears in the title or abstract of an article, the reader needs to look carefully to see if the researchers collected data (performed a pilot study) or if all they strictly published the design of a proposed study. It is important that health professionals accessing the published protocol recognize and treat it as such, not as evidence but as information. Even when a pilot study is conducted the results are not generalizable.

Although the publication of clinical trial protocols can help increase safety, quality, and efficacy, it can also introduce confusion to readers. A published protocol might sound to a patient like evidence of an effective intervention. Providers need to be aware of the potential for the public to misinterpret a protocol and request treatment based on the information contained in the protocol publication.

Furthermore, there is some indication that clinical trial registration has been misused, potentially to take advantage of a lack of awareness about the fact that such a listing does not represent evidence of efficacy. According to Allday (2018) the FDA is proposing new rules to crack down on organizations that misuse clinicaltrials.gov as a marketing tool.

Scientists have warned in recent years that for-profit companies, especially in the rapidly growing consumer stem cell industry, are listing clinical trials that are not federally sanctioned and don’t meet basic standards for how trials should be conducted.

Health care professionals need to be aware their patients/clients may be induced to participate in research through questionable practices, and even asked to pay to participate Allday (2018). Furthermore, it is important for health professionals to be aware that a study published through a clinical trial registry might not have been subjected to sufficient safety review, not to mention that registration does not include peer review.

Key Takeaways

  1. When reading a research article look to see if the study followed a protocol that was published in a reputable, peer-reviewed source.

  2. Be cognizant of the fact that a published protocol is not, itself, adequate research evidence on which to base a clinical decision.

  3. Watch for predatory journals publishing studies that have not been subjected to rigorous peer review.

  4. Look to see if a study was pre-registered and if the pre-registration period was utilized to improve the design of the study.

  5. Be prepared to address questions from patients/clients being recruited to participate in clinical research.

References

Research, Clinical TrialsBernadette HowlettDHS4426, 4426, clinical trials, protocol, publishing clinical trial