Sweet harmony: clinical trials protocol template

26 July 2018

The increasing complexity of clinical trials, combined with the inexperience of many investigators who write the protocol templates, has long caused concerns. In 2017, US officials responded to the lack of consistency across clinical trial protocols by creating their own model template for investigators to use. How well has it gone down? Neil Thompson explores.

Clinical trials are one of the most important ways a modern healthcare system can advance medical knowledge, policies and practices in a robust and coherent fashion.

Unfortunately, the long process of designing, approving and implementing a clinical trial has become bogged down. Inadequate submissions and complex bureaucracy waste the time, money and energy of patients, companies, regulators and investigators alike. Complaints have become especially loud in the US, which still boasts the biggest healthcare sector in the world.

Since 2010, the number of new studies registered with the ClinicalTrials.gov website, from the US Government, has increased by approximately 20,000 per year. This figure includes studies sponsored by pharmaceutical companies, as well as work from academic centres, contract research organisations and members of the US’s National Institutes of Health (NIH), among other parties.

As a result, the US regulatory system is struggling to process the number of applications it receives and stakeholders are being subjected to long delays, even if no errors or oversights are found in their documents. Moreover, such a scenario is unlikely, according to experts familiar with the application process.

“Recent data indicates that 66% of currently submitted protocols are amended, and [10%] of these issues are related to human error,” Dr Rob DiCicco, vice-president of clinical innovation and digital platforms at GlaxoSmithKline, revealed last year. He had previously led several parallel initiatives to tackle problems with protocols at the non-profit research and development body, TranScelerate BioPharma, where he also works as an initiative leader for its Common Protocol Template (CPT) Initiative.

Joined-up thinking

In response to a growing crisis of confidence in the applications system, two US federal agencies, the NIH and FDA, joined together last year to harmonise the way investigators write clinical trial protocols. They produced a document that outlines any proposed trial’s objectives, design, methodology, statistical considerations and organisation. In 2017, the two bodies announced that they had created an official clinical trial protocol template (CTPT), as a suggested format for applicants to follow when designing their own proposals. However, FDA found that up to 85% of these individuals have only participated in one clinical trial during their careers before they decide to sit down and try to design one themselves.

According to regulators, the final version of the CTPT is intended mainly for researchers who are writing protocols for phase II and III NIH-funded studies, requiring investigational new drug or device exemption applications. But it will also provide a valuable guide for other investigators designing studies in areas that are not regulated by FDA. The agencies involved say that expert opinions were sourced from more than 60 individuals before creating their template.

Garnering industry praise

The work was done under the umbrella of the FDA-NHI Joint Leadership Council, and was praised by TranScelerate BioPharma. Before the federal version arrived, the nonprofit organisation had been updating a parallel template for the private sector, the CPT, since 2015.

TranScelerate’s positive response was significant, because its 18 members include some of the biggest biopharmaceutical companies in the US medical scene, including Pfizer, Johnson & Johnson, Lilly, GlaxoSmithKline and Bristol-Myers Squibb. Subsequently, the council and the organisation agreed to harmonise the CTPT and CPT to avoid giving people conflicting information.

“I suspect that the CTPT will become widely used, particularly since it carries a fair amount of credibility from the regulators, from the governmental institutions and a very significant part of the industry,”

TransCelerate’s CEO, Dalvir Gill, predicted when the template was published. His views reflected the importance attached by many medical companies concerning the need to better manage the increasingly complex US clinical trials process.

One simple way the updated template was expected to tackle delays lay in how it addressed the frequent shortfalls made by applicants in their submissions to regulators. Many clinical research enterprises in the US healthcare market struggle to produce high-quality, timely and actionable plans that lay out the process by which any trial for a new medical treatment would take place. By providing a clear CTPT as a starting point, the two US agencies hoped to clarify the often arcane procedures around gaining official approval for one to begin.

In 2017, federal regulatory insiders, including Dr Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, sounded relieved when it became clear that a regulatory advance harmonising applications for FDA or NHI approval was at last in place.

“The FDA and NIH see protocol harmonisation as an essential component to the accelerated delivery of medicines to patients,” Woodcock said when the final draft of CTPT was released. “Having aligned templates will help enable health authorities to receive consistent, high-quality protocols, enable timely review and ultimately ensure trial participant safety.”

Moving forward

Of course, the CTPT alone will not solve the wider issues pharmaceuticals face in the US, such as delays in navigating the regulatory and ethical requirements for studies involving human subjects, problems with recruiting and retaining an appropriate patient population, and the time and cost involved in conducting clinical trials. But the new template will help tackle the widespread perception, which has emerged among stakeholders, of a bottleneck affecting designing and winning approval for a trial to start in the first place.

Moreover, while the CTPT has been designed primarily for a limited range of clinical trials, it is already serving as the basis for specialist tools and adapted versions edited for other areas of research; for example, shortly after the template’s release, the NIH Office of Science Policy announced it had used the CTPT as the basis for an online electronic protocol writing tool. This was intended to help investigators collaborate with one another while developing trial protocols.

The healthcare industry has also not been standing still while regulators do all of the heavy lifting. After ensuring its joint efforts with US regulators were finished, TransCelerate announced that it had released an updated ‘technology-enabled’ copy of its CPT template.

This has constantly evolved since its inception, but still includes a common structure and text, as well as regulator-accepted end point definitions. These can be used across different protocols with little to no editing by the user of the template. TransCelerate BioPharma says the electronic version gives applicants access to the “automated reuse of information and point-and-click population of selected template sections, among other features”. In addition, the organisation has made the template available to the public through the internet, together with digital libraries containing commonly suggested text that is pertinent to certain studies and the implementation tool-kit materials.

“The CPT Initiative has worked to decrease protocol-related issues frequently reported by trial sponsors, investigator sites, regulators and patients by creating common content that can be used by any stakeholder, such as a health authority or investigational review board,” DiCicco explained recently.

While the template created by FDA and the NIH was developed with single-centre NIH sponsored trials in mind, he stated that TransCelerate’s CPT was more flexible, as it had been rewritten to include additional text that supported the increasingly common format of global, multicentre research trials. DiCicco added that it also promoted the reuse of protocol level information for other requirements of clinical trials, such as statistical analysis plans and registry posting.

In the time since its release, the CTPT’s use has spread to different organisations that have used it to craft their own tailored versions. The lack of media announcements notifying patients, clinical trial sponsors and other stakeholders about new modifications or withdrawals suggests that overall, the template and its various offshoots have been a success.

The entrenched problems of cost and lengthy approval times for clinical trials in the US have not gone away, but perhaps the difficulty of starting one in the country has been made as painless as possible.

Removing obstacles and simplifying complexities

Dr Peter Marks, director of FDA’s Center for Biologics Evaluation and Research, recently discussed the importance of the new protocol template.

“Placing relevant information in a standardised location, in a clinical trial protocol, can expedite the development and review of protocols, thus enabling a quicker start of a clinical trial and leading to more timely completion of studies and getting important new treatments to patients more quickly, he said. “What’s more, with the increased complexity of clinical development, such as the use of combinations of different medical products, it is more important than ever that investigators understand protocol development expectations and capture important components right from the start of the application process.”

Source: FDA and Business Wire


The NIH’s Clinical Center in Bethesda, Maryland, is the US’s largest hospital that specialises in clinical research.

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