Military clinical trials pose unique challenges in subject recruitment

Potential subjects could be deployed

Imagine recruiting for a clinical trial when a big portion of your potential volunteers might be sent to the other side of the world half-way through a study.

Patience is a key philosophy among clinical trial investigators and coordinators for the Naval Medical Research Center (NMRC) Clinical Trials Center in Silver Spring, MD. They need a great deal of patience when dealing with recruiting among a military population.

"When recruiting military personnel, you need to have a supervisor's approval because these individuals are ready to be deployed at any time," says Victoria Steinbeiss, BSN, RN, clinical nurse coordinator for the NMRC. The Clinical Trials Center has been involved in Phase 2a trials that test experimental malaria vaccines.

An ongoing trial is designed to assess the safety, tolerability, immunogenicity, and protective efficacy of a multivalent, adenovirus-vectored Plasmodium falciparum malaria vaccine. Volunteers are healthy adults who have never been exposed to malaria and who will actively participate in the trial for about one year.

Since enlisted men and women often travel to and from countries where malaria is prevalent, there's an additional challenge in finding malaria-naïve military volunteers who will not be sent to another country during the trial's duration.

"So you have a research study that may go from one year to five years, and these individuals might not qualify because they have to be deployment-ready," Steinbeiss explains. "And, often, their supervisors are not at liberty to give them permission."

Also, civilian staff are required to do the actual recruiting for the trials so there isn't the potential or appearance of undue coercion as there might be if an officer were attempting to recruit enlisted men and women for a study.

Since deployment is a ready possibility for many military personnel during wartime, studies also will enroll non-military volunteers.

"We have a military population, but to have more options we can recruit civilian volunteers," says Jose Mendoza-Silveiras, MD, Clinical Trials Center director at NMRC.

"But to recruit civilians we need permission through the Secretary of the Navy [SECNAV] that will allow civilians to participate in the studies with a SECNAV designee status," Mendoza-Silveiras says.

Without this approval, studies are restricted to enrolling only military volunteers or their dependents, says Judith Epstein, MD, CDR MC USN, a clinical investigator at the NMRC.

"In some of the larger trials it can be difficult to recruit enough people," Epstein notes. "So we give a description of the trial, provide all background details, include the protocol, and a whole packet goes through the chain of command."

Once SECNAV designee status has been approved, the trial can recruit civilian volunteers.

"There are a lot of issues to be dealt with in gaining approval, but for us it means we can open our enrollment to civilians," Epstein says.

Traditionally, military trials have been half civilian volunteers and half military volunteers, she notes. "Now we have more civilians because of the issues of deployment," Epstein says.

Steinbeiss has seen how the recruitment challenges are greater now than they were pre-2003.

"I have seen over the past five years of working in the military research community how there has been an impact [from the Iraq war] in recruiting," Steinbeiss says. "There aren't as many [enlisted men and women] stationed in this vicinity right now because they have been deployed."

Most of the NMRC 's studies have been for the development of a malaria vaccine that could one day be used by the military to protect enlisted personnel, Epstein says.

"Also, we're trying to develop vaccines that could be used in the developing world, where it could be given to children," she adds. "Every minute there are two to three children who die of malaria; this is an incredible tragedy worldwide."

Although there are prophylactic prevention strategies for malaria, there always is the issue of compliance, and these options aren't practical in the developing world, Epstein says.

The NMRC is part of the U.S. Military Malaria Vaccine Program, which has a long-established experimental malaria challenge, Epstein says.

Vaccine trial volunteers are given the malaria vaccine. After several weeks, volunteers are challenged. Five mosquitoes carrying malaria are placed on the volunteer's arm, inside an ice cream cup. The malaria strain used is completely susceptible to the most common treatments, Epstein says.

After the volunteer is exposed to the malaria-infected mosquitoes, the volunteer waits for 30 minutes on site. They may then go home and are followed-up by telephone, she says.

"One week after the challenge we have them check into a location where medical staff will watch them closely. They reside there until approximately 18 days after the challenge," Epstein says. "We follow them very closely and do blood smears every day to see if they've developed malaria."

"During the day and evenings the volunteers are free to pursue their normal activities — it's only at night that they are asked to come to the hotel. It can be a lot of fun gathering in the evenings, eating Chinese take-out together," says Epstein. "Volunteers can avail themselves of the hotel's amenities, such as movies and the fitness center."

"As soon as we document that they have malaria, they receive treatment and we ensure that they adhere to treatment," she says. "Volunteers are always cured completely, although they may feel sick for a day or two during treatment. When finished with the study, they are 100% free of malaria, and to date, no volunteers have had long-term consequences from participation in a malaria challenge conducted by the Navy."

In one trial on two sites, the NMRC is recruiting 44 volunteers, Epstein says.

"We estimate it will take us three months to get the initial 18 volunteers we need to start," she adds. "Prior to their first immunization, we have a three-month screening period."

In the first group of the study, there will be 12 volunteers who will receive the vaccine and six controls who will not receive the vaccine, but who will receive the malaria challenge.

As one site's enrollment is underway, another site's enrollment begins: "We usually have rolling enrollment," Epstein says.

Each volunteer, whether military or civilian, receives some financial compensation per visit, in the range of $25 to $50, Mendoza-Silveiras says.

The amount depends upon the procedures and time required, and the compensation is approved by the IRBs, Mendoza-Silveiras says.

"I came into the military after completing all of my training," Epstein says. "When I first thought of the military doing clinical trials, I wondered if there could be a potential for coercion with young, junior officers participating."

The opposite is true, Epstein says. "The military goes to extreme measures to prevent coercion from occurring," she explains. "They realize there's quite a bit of scrutiny, so auditing and monitoring tends to be of a high standard."

Despite challenges posed by military recruiting, the clinical trial work at the NMRC has been rewarding, say Mendoza-Silveiras and Steinbeiss, who are civilian contractors.

"We have a great team," Mendoza-Silveiras says. "We know each other's jobs, and we're capable of doing everything when somebody's out — we cover each other."

Plus, investigators and study coordinators know their vaccine work is meaningful.

"We're a close team, and we enjoy working on these vaccine studies," Steinbeiss says.