A prescription for regulatory fatigue
Protocol navigation relieves the symptoms
IRB, FDA, IBC, RAC, DSMB — just a few of the alphabet soup organizations and regulatory body steps a researcher must go through to get a protocol written, reviewed, and approved. This can lead researchers to burnout dubbed by some at the National Institutes of Health (NIH) as "regulatory fatigue syndrome."
"There are many steps to getting it [protocol] through the regulatory process," says Sara Albert, MPH, protocol navigator at the National Institute of Allergy and Infectious Diseases (NIAID) at NIH in Bethesda, MD.
To help alleviate investigators’ regulatory fatigue and get protocols through the intramural approval process at NIAID, the institute developed the Protocol Navigation/Protocol Development Program (PN/PDP). The program assists NIAID intramural researchers in navigating the cumbersome protocol approval process. The PN/PDP was developed five years ago in response to a survey on clinical research barriers, says Tracey Miller, RN, CCRP, PN/PDP manager at Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD.
"IRBs are perceived as barriers, and researchers said there were not enough clinical research support services to get protocols up and running," she says. "The clinical director wanted to be proactive and to help intramural investigators develop clinical studies."
The PN/PDP tracked the development of an HIV vaccine clinical research protocol that worked its way through the program in 2013. The protocol required review and approval from a slew of regulatory bodies including the Food and Drug Administration (FDA), the NIAID IRB, a scientific review committee, Data and Safety Monitoring Board (DSMB), Institutional Biosafety Committee (IBC), and Recombinant DNA Advisory Committee (RAC). "This particular investigator [for the vaccine protocol] asked for help navigating through the offices needed," Miller says. "If you all work together, you can get something done in a relatively short amount of time, given the complexity."
When a researcher reaches out to the PN/PDP, he or she is asked to provide a study concept and hypothesis, and a sit-down meeting is scheduled to review logistics and see what services are required. "Some people need help with aspects of protocol development, such as consent writing, while some need full-scale navigation through the whole process of development, review, and approval," Albert says. "We usually start setting up timelines and the goal for study start if there is something they need to keep in mind, such as budgeting or funding issues. We try to work out what the game plan is going to look like, what approvals they need, and other logistical steps in that timeline, such as target dates for scientific review and IRB meetings." They also discuss issues in the concept that will need further delineation in the protocol, such as identifying special populations, eligibility requirements, recruitment needs, sample collection and storage, and required oversight, such as monitoring and safety reporting. "I think it really helps if we have a good concept that’s fleshed out. The IRB has several templates for protocols and our initial step is to put it in the appropriate template, based on study design," Miller says. "We work on filling in the holes of that template."
"The investigator is the driver of the whole process," Miller continues. "We are mini project managers for the protocol. If there’s a contract that needs to be written, we engage that department and keep everyone on pace and push people along who need to be pushed."
The timeline milestones for the HIV vaccine protocol hinged on initial protocol document drafting and revisions after each of the previous reviews. The PN/PDP participated in biweekly meetings between the study team and the pharmaceutical company during protocol development to discuss the status of various reviews and ability to meet deadlines in order to keep moving forward.
The first milestone was the scientific review, which involved a team of investigators reviewing the protocol for scientific merit. Once the medical writer from the PN/PDP drafted the protocol, incorporating edits from all parties involved, the review occurred. The scientific reviewers addressed the stipulations in the protocol and approved it in February 2013.
Once final details of the protocol and consent were solidified, an IRB-required regulatory review of the protocol occurred about two weeks prior to the anticipated submission date to the IRB. Representatives from the regulatory, safety, and monitoring offices reviewed the protocol to ensure documents included sponsor-required information. "The medical monitor then issues a no regulatory concern email. The researcher has to have that in hand prior to [IRB] submission," Miller says. The NIAID IRB office has a Web-based submission system and PN/PDP staff assist investigators with filling out the application and uploading the documents to the system. "Once the IRB receives the completed application, the IRB staff administratively reviews the protocol and if there are issues or concerns they talk with us about it," Miller says.
The PN/PDP and the investigator submitted the vaccine protocol on schedule to the IRB two weeks before the meeting, with IRB stipulations given a week later. IRB discussions of the protocol focused on ethical use of a placebo, analytical treatment stop, and risk-benefit analysis. The PN/PDP assisted the investigator with responding to the stipulations and the final protocol was approved in May 2013, three months after completing scientific review.
When possible, the protocol was submitted for other reviews concurrently with IRB review to cut down on lag time between submissions, meeting dates, and approvals:
- FDA: The PN/PDP assisted in preparing the investigational new drug application and other necessary documents. The FDA determine it safe to proceed in May 2013.
- IBC: Pending RAC outcome, the committee approved the protocol with stipulations, in May 2013.
- RAC: The PN/PDP assisted with the RAC application, which was submitted in April. The committee provided written comments in advance of the public meeting held in June 2013. The committee provided additional recommendations at the meeting, and the protocol moved forward.
- DSMB: The board reviewed the protocol in May 2013 and in June, made recommendations allowing it to proceed.
Metrics collected by the PN/PDP showed that the approval process took about seven months for the study, including five handoffs prior to scientific review and eight handoffs prior to IRB approval.
"We do collect a lot of metrics for the program and look at the stipulations received and try to avoid them in the future," Miller says. "We also try to eliminate redundancies in reviews. Navigated studies tend to run about a month faster than non-navigated studies."
"This protocol moved faster than most with these types of logistics involved," Albert adds. "There were a lot of people to appease in the process. It was definitely smoother and it finished as quickly as we could have gotten it done; RAC only meets quarterly, so we had no control over that."
The symptoms of regulatory fatigue syndrome may be unavoidable but were substantially decreased for the investigator as a result of interactions and communications with the PN/PDP, Albert says. "The time lines helped the investigator manage expectations and set up a game plan early on and keep the stakeholders engaged and on track so that this would move along," she says.
The NIAID IRB has also benefitted from the PN/PDP, Miller says, and even refers investigators to the program.
"That has been very key to our success — they [IRB] say it’s so much easier to read the consent documents and protocols and they know all the I’s will be dotted and T’s crossed," Miller says. "If the protocol hasn’t gone through our process, the IRB might stipulate to seek out the services of the PN/PDP to condense or rework the wording or help with stipulation responses. Our IRB chair does seek out our service for his studies."
Elements of the PN/PDP program are adaptable to other research programs, Miller says. "There are elements that are unique to us, but quite a lot of people have been curious about our program and how they can help investigators because they hear the same complaints about inefficiencies and the onerous approval processes," she says. "Since we all have the same goal of getting protocols up and running, they [other IRBs] could take pieces of the program to fit with their own institutions." n