Preparations for a large Phase 3 clinical trial will always present challenges. In the area of gene therapies, those challenges can be magnified. Gene therapy trials can add more time and cost to a trial, and will also require specific expertise not needed in small molecule and biologics trials.
In a typical clinical trial, patients receive multiple doses of a new treatment. In a gene therapy trial, patients will receive the treatment via a onetime dose. While that sounds like it might simplify a trial, it also makes study design and control more complicated. Ensuring a smooth start-up process means understanding the facilities that will be required, selecting the right CRO, and providing constant oversight of sites.
uniQure, based in Amsterdam and Lexington, MA, is a company focused on delivering treatments to patients based on the promise of gene therapy. The company’s pipeline features treatments for its lead indication, hemophilia B, as well as Huntington’s disease. The lead hemophilia B product, AMT-061, is about to enter a pivotal Phase 3 trial. A recent strategic collaboration with Bristol-Myers Squibb now has the company pursuing gene therapies for cardiovascular diseases as well, which will have uniQure developing gene therapies for chronic and degenerative diseases impacting much larger populations.
Special Facilities Required
“One thing that makes gene therapy trials unique is the need for special facilities at sites in which we administer the treatment,” says Steve Zelenkofske, chief medical officer at uniQure. “The special facilities are required for the safety of the patient, which is our primary concern. This is also critical for getting approval for the study protocol from an institutional review board or ethics committee. But there are also individuals who handle the gene therapy products and will get exposed to them. We have to make sure there are precautions in place to protect them as well.”
The gene therapies employed by uniQure use an engineered, non-replicating viral vector delivery system. Although the biohazard risks inherent in using the system are low, there are still steps that must be completed to ensure both staff and patients are safe and protected.
Gene therapies will generally be administered in in a hospital. The treatment needs to be prepared in an area with biohazard level one, and in some case, level two preparation facilities. The treatments must be transported safely and then handled in a biohazard hood. Some genes and vectors do replicate, and are therefore attenuated viruses that you would not want individuals exposed to.
Although gene therapies must pass the normal institutional review board (IRB) review process, they are also reviewed by an institutional biologic committee (IBC), which evaluates the safety of the use of products at the sites.
Gene therapies will generally go through an NIH review as well to make sure the protocol and the handling of the products are done in a manner that protects the safety of patients and staff. At certain facilities, there will also be additional technology committees that review whether the site has the appropriate technology necessary to handle an attenuated virus.
“This clearly makes for a much more complicated trial,” says Zelenkofske. “Most studies require that your protocol, informed consent, investigator brochure, and patient phasing materials are sent to an IRB. When approved by the IRB, you can begin your usual startup activities. The review process for a gene therapy study requires multiple committees, multiple reviews, and special expertise to navigate the technology in place at facilities. Failing to ensure a hospital or site has the appropriate facilities to carry out the study can stop it dead in its tracks.”
Select The Right Partner
uniQure does have a CRO partner it uses for its clinical programs. Zelenkofske notes the process involved in administering gene therapies makes CRO selection even more important. First, gene therapy companies are generally working with rare diseases. Therefore, the CRO you select must have experience in the disease you are working on but should also have experience in working with sites and investigators that have access to orphan and rare disease patients.
The CRO selection process began by having the head of uniQure’s clinical operations team send out a request for proposal (RFP) to CROs that had previously worked on hemophilia B trials. When the responses were received, representatives of the company’s clinical team met with each CRO, reviewed their proposals, and had them make a verbal bid defense.
The results of those presentations were then shared with senior executives, including Zelenkofske, who then selected the CRO the company would partner with. Zelenkofske states that with gene therapy trials, there is a lot more hands-on work performed with sites. Gene therapy studies generally have far fewer patients than a small molecule trial, but being that these trials are for rare disease patients, there will still be a large number of sites to oversee.
“I have been involved in large clinical trials where a single site might have access to 30 patients,” says Zelenkofske. “In one of our trials, a site might get one or two patients. That also means that patient retention, and making sure we do everything right the first time, is of paramount importance. We require our CROs to keep in very close contact with our sites and that they develop close relationships. We also perform a lot more hands-on work with the sites to ensure every patient is screened appropriately and fits the protocol. In this type of trial, it is difficult to replace patients.”
Zelenkofske also felt the CRO selected would have to be able to handle the appropriate levels of review through a biologics committee. Part of the CRO search involved finding a partner that had previously performed that type of work. The CRO would have to be aware of the different steps that each individual facility might have in place. For example, a university in North Carolina might have a different institutional review program than a university in Michigan. A hospital might not have a review program in place and will need assistance setting up the appropriate levels of review.
uniQure looked for a CRO that was capable of doing that. That partner selected has since determined which sites had review processes in place and which ones did not. It has also helped create review processes at the sites that did not have one in place.
Constant Oversight Is Vital
Constant contact with site personnel is of critical importance to uniQure. Representatives from the company’s CRO partner will work onsite, closely engaging with physicians and nurses. Additionally, a clinical team from uniQure will also spend time on the phone discussing protocol and trial conduct with site personnel. For the Phase 1 and Phase 2 trials conducted in Europe, uniQure even sent pharmacists out to sites to insure the infusions were being properly performed. This same oversight monitoring is planned for the upcoming Phase 3 study.
“We are not performing this oversight because site personnel are incapable of performing the task,” notes Zelenkofske. “Rather, the number of patients in these trials is very small. Maintaining the number of patients in the study is of paramount importance. We cannot afford to allow even one patient to become disengaged from the study. As we do more studies, we gain additional experience. Although there are challenges, they are doable challenges that simply require an experienced team. The more experience you have, the better able you are to anticipate problems. It’s like anything else in clinical operations: If you can anticipate what's coming, the challenges become very manageable.”