The US Food and Drug Administration (FDA) has released a new draft guidance document intended to outline the considerations industry should take into account when designing early-phase clinical trials for cellular therapy (CT) and gene therapy (GT) products.
The draft guidance, released on 2 July 2013 by FDA's Center for Biologics Evaluation and Research (CBER), is specifically targeted at investigational new drug applications (INDs), which are used by companies to obtain FDA approval to begin clinical testing. Because the Federal Food, Drug and Cosmetic Act (FD&C Act) prohibits the interstate shipment of drug products that have not received FDA approval, an IND effectively acts as a temporary suspension of the Act for the purposes of that particular drug so long as it adheres to various restrictions regarding its use (i.e. only for use in approved clinical settings).
While most IND submissions have historically been for traditional drug products like chemical or biological drugs, cellular and gene therapies are increasingly being explored as treatment options for various diseases, thus requiring clinical testing.
The process for obtaining that IND is substantially different for CT and GT products than it is for chemical or biological drugs, FDA explained. "Differences in trial design are necessitated by the distinctive features of these products, and also may reflect previous clinical experience," it wrote. "Early experiences with cellular and gene therapy (CGT) products indicate that some CGT products may pose substantial risks to subjects," including multiple organ failure, death, cancer and tumors.
"These events illustrate that the nature of the risks of CGT products can be different from those typically associated with other types of pharmaceuticals," FDA noted. Those risks largely result from the product's potential to trigger immune system responses in patients, as well as the "relatively invasive procedures" needed to administer the products.
Another key set of differences between chemical/biological drugs and CGTs are manufacturing concerns, FDA said. Consistently manufacturing products to meet quality standards can be difficult, as can ensuring that a product makes it to its destination on time and properly preserved.
"The scientific or logistical complexities of manufacturing CGT products may impose practical limits on the dose of the product that can be produced, or may limit the concentration or volume of product that can be delivered," FDA explained. "These factors might therefore restrict the range of doses that are feasible in an early-phase trial."
In addition, because many CGT products are manufactured to the specifications of a particular patient, delays or manufacturing failures could result in a patient not being treated as intended, complicating clinical trial protocols.
FDA also explained that preclinical data is not always as informative in CGT products as it is in small molecule pharmaceutical ones. "It usually is not feasible to conduct traditional preclinical pharmacokinetic (PK) studies with CGT products," it wrote. In addition, while chemical drugs have the benefit of years of studies and data that can be used to make nuanced determinations about drug safety, CTG products have a "relative lack of clinical experience," leaving regulators uncertain about "the nature and frequency of safety problems" that might occur.
Similarly, while chemical drugs are generally only present in the body for a short period of time, CGT products may persist for an extended period, even proliferating in some cases (e.g. stem cells). "Therefore, evaluation of safety might require observation of subjects for a substantial period of time to understand the safety profile," FDA explained.
That said, the guidance notes that "some toxicities may be expected and acceptable" to regulators. Dose-finding studies should identify the maximum tolerated dose (MTD) able to be given without experiencing toxicities using a similar dose-escalation protocol used in chemical drug studies. However, some products will need to utilize a safety profile characterization approach for a feasible dose rather than finding the MTD, FDA wrote. In general, healthy volunteers will not be used in early-phase clinical studies due to the inherent risks of using the product, FDA added.
Other Safety Considerations
Another noted difficulty is that as opposed to chemical drugs, CGT therapy is typically a last-resort treatment. FDA said that for some CGTs, enrollment may only begin if and when a sponsor can prove that no other treatment options are viable.
FDA also recommended using a staggered administration approach when studying a product with no previous human experience. This will involve a single (or small number of) subjects being treated, followed by a delay before treatment begins in the next cohort. This is intended to identify any acute adverse side effects before they affect the larger study population.
Study patients should also be tracked after the end of treatment to ensure that no long-term side effects are present.
The draft guidance, Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products, may be found here.
Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products