https://www.raps.org/News-and-Articles/News-Articles/2023/10/FDA-guidance-explores-trial-design,-supporting-dat
Illustration of stem cells. (Source: iStock)
In preparation for a potential “paradigm shift” in the management of graft-versus-host disease (GVHD), the US Food and Drug Administration (FDA) is seeking comment on draft guidance for developing drugs, biological products, therapeutic devices, and cell processing devices for the prevention or treatment of acute graft-versus-host disease (aGVHD) or chronic graft-vs-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT).
Traditionally, GVHD in this setting has been addressed with drugs or with physical methods aimed at depleting the reactive immune cells immediately after transplant. But GVHD is potentially a lifelong post-transplant problem; prolonged immunosuppression carries serious health risks, including infections and malignancy that might otherwise be controlled by normal immune function.
Recent advances in understanding the pathophysiologic underpinnings of GVHD have set the stage for developing novel methods of predicting and measuring risk, treating the active form, and preventing it from occurring or persisting, according to draft guidance.
“These scientific advances have provided opportunities for development of biomarkers to identify the specific immune dysfunction present in an individual patient and for development of drugs to modulate the immune system with precision rather than to just suppress the immune system broadly,” the draft guidance states. “Given the complexity of the clinical manifestation of aGVHD and cGVHD and the potential for a paradigm shift in the management of GVHD, FDA is providing this guidance with recommendations regarding the design and conduct of clinical trials and the types of supporting data that could facilitate efficient development of drugs and/or certain devices for the prevention or treatment of aGVHD or cGVHD.”
Biomarkers, dosing and diagnostic devicesFor biomarkers, sponsors may need a Type C meeting to obtain FDA feedback on clinical and analytical validity. Drugs developed in a biomarker-identified population may require a companion in vitro diagnostic device (IVD). The IVD will be considered investigational unless it’s already being used for the same purpose in a cleared indication.
Otherwise, sponsors may ask the Center for Devices and Radiological Health (CDRH) or the Center for Biologics Evaluation and Research (CBER) whether a study risk determination is necessary before the trial can proceed.
Sponsors developing drugs for GVHD should bear in mind that most transplant patients are on numerous concomitant medications, including antifungals and immunosuppressants, the draft guidance notes. Many of these drugs are substrates, inducers, or inhibitors of cytochrome P450 (CYP) enzymes, other metabolizing enzymes, or transporters; these will affect the way other drugs are metabolized. Before any clinical trials, in vitro studies must explore all of these potential metabolic irregularities, as well as how the drugs are excreted in patients who may have impaired kidney function.
Early-phase trials should explore dose escalation to optimize dosing before entering into any large-scale or potentially pivotal study. “Dose-escalation trials with small cohorts may provide information to warrant further dose exploration in dose-expansion cohorts [e.g., exploration of a minimum of two dose levels with at least 20 participants per dose level] and/or in a randomized dosage-finding trial to generate the additional data needed for dose optimization,” FDA wrote.
If a therapeutic drug monitoring device is necessary for safely monitoring dose and response, then that device needs to be codeveloped with the drug, and tested as early as possible, according to the draft guidance.
Trial designClinical trial efficacy endpoints will reflect whether the drug is intended to treat or prevent GVHD. For preventive therapeutics, primary efficacy endpoints should be GVHD-free survival (time from transplant to onset of GVHD or death) and overall survival (time from randomization to death from any cause).
And since preventive therapeutics are considered supportive care, they need to be very safe and highly tolerable, the guidance notes.
“[T]he target regimen should have little-moderate toxicity and no severe toxicity. Anticipated adverse reactions may be informed by nonclinical studies, the first-in-human study in healthy volunteers, and trials in other diseases. However, given that the toxicities of the investigational drug may overlap with those of the preparative regimen, or that the investigational drug may exacerbate toxicities of the preparative regimen, attribution may not be possible. Therefore, the assessment of [dose-limiting toxicities] should reflect the need to not increase the risk of known toxicities in transplant recipients,” FDA wrote.
Trials of drugs treating aGVHD should be at least four weeks long and include at least 180 days of follow-up. Primary endpoints may include systemic response staging (complete, partial or very good partial) with skin, liver and gut endpoints as well. They should also evaluate duration of response and survival.
Trials for drugs intended to treat cGVHD need a minimum of one year follow-up to establish durability of responses. “The planned interval between assessments should be no less frequently than every 2-3 weeks for the first 6 months and at least every 3 months thereafter through completion of 1 year of follow-up,” the guidance notes. “The protocol should specify that the study visit activities should encompass events in the intervening period since the last visit.”
Efficacy endpoints in these trials can include treatment response (complete or partial), durability of response, overall survival and patient-related outcomes (PROs).
PROs should be measured with a validated tool that is contextually- and age-appropriate. “The PRO measure or concept of interest proposed to denote clinical benefit [e.g. change in symptom burden] should be well-defined and reliable. Given the heterogeneity in organ involvement by cGVHD, careful consideration should be given to whether the concept of interest is organ-specific or total score derived from multiple organs. Additionally, adequate follow-up is required to establish that the durability of the observed benefit is clinically meaningful,” FDA wrote.
Sponsors should submit their PRO development package and its proposed statistical analysis plan to the FDA before the trial commences.
Comments on the draft can be submitted to
regulations.govusing Docket number
FDA-2023-D-3900. The deadline to submit comments is 28 November 2023.
https://www.raps.org/News-and-Articles/News-Articles/2023/10/FDA-guidance-explores-trial-design,-supporting-dat
(20min delay)