Selecting Endpoints for an Early Phase Cell or Gene Study​

The selection of endpoints for a clinical trial relies on clinical relevance combined with statistical reasoning. Robin Bliss, PhD, and VP of Strategic Consulting for Veristat, takes us through the how-to’s of selecting appropriate endpoints for an early phase study, the importance of considering endpoints in the context of clinical meaning, and the value of ensuring that endpoints are measurable within a reasonable amount of time for continued progression of the clinical development plan.

Transcript

Speaker 1: 0:00

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Speaker 2: 0:15

Welcome to art podcasts, advancing revolutionary therapies, a podcast presented by the center of excellence for cell and gene therapies by verus debt. My name is Robin bliss, vice president of strategic consulting with Veristat working with our clients in cell and gene therapies by training. I'm a statistician. And my role is to help sponsors to develop efficient study designs and effectively plan and progress through their clinical development path. Today, I will discuss selecting end points for an early phase cell or gene study and point selection within cell and gene therapy. Studies can be a uniquely different exercise from the choice in a more traditional study. Often in more traditional study, examples selection may follow an agreed upon precedence of endpoints that denote meaningful clinical impact within the disease space. Based on studies of available therapies, early cell and gene therapy studies, however are often focused on rare diseases that do not have alternative therapies. There may be limited prior research on the specific disease indication and on measures of disease progression over time, given that the outcome of cell or gene therapy may be irreversible, it is critical to use an endpoint that is most attuned to seeing the biological and clinical impact to gain the most information from each patient treated with a novel product. Furthermore, in the FDA guidance on human gene therapy for rare diseases, the FDA states that sponsors should consider designing their first in-human studies to be adequate and well-controlled investigation that has the potential, depending on the study results to provide evidence for effectiveness to support a marketing application. If this is the intention for your novel product, this makes the selection of end points even more critical as they will be under direct scrutiny by regulatory agencies and will need to be sufficiently well-developed and well-planned to demonstrate the overall biological and clinical benefit of the novel product. With that in mind, the objectives of today's podcast are first to identify appropriate end points for an early phase study, based on the study objectives. Second to consider endpoints in the context of clinical meaning and in relation to the longer term clinical development plan for your novel product. And third, to ensure that the end points are measurable within a reasonable amount of time to allow continued progression of the clinical development plan. When we begin the process of endpoint selection, we first want to align with the study objectives. For example, if your primary objective is to assess the overall safety and toxicity of the novel product, the corresponding end points should be focused on the respect of safety profile, providing a measurement criteria to ensure safety for your patients. Secondary objectives may relate to biomarker measurements, clinical impact, or disease progression, the corresponding endpoint or multiple end points for each objective should define the measurement of that corresponding item. Whether it be mean biomarker values at dichotomized response change from baseline in a quantitative functional or ambulatory measurement or some other measurement of disease activity. I think it's important to take a moment to emphasize that end points must be measurable in consistently measurable over time between patients and at different study sites. The timing of the measurements must also be clearly defined whether it is a change from baseline to six months or 12 months or five years, the time point or time points of interest must be planned and clearly defined consistent repeatable. And clearly time to measurements are critical to ensuring the appropriate analysis and interpretation of results from a clinical study. Second, we want to ensure the end points we select have direct clinical meaning or are translatable to clinical meeting by some hypothesis that can be evaluated within our clinical development program to achieve this. We may measure one or more biomarkers that may be indicative of a clinically meaningful response while the relationship may be hypothetical. As we start the early phase study, we will want to test the hypothesis of that relationship through the collection of biomarker results and through the longer term follow-up to better understand the relationship of the hypothesized biomarkers with the possible impact on disease activity, the impact of your novel product on biomarker presentation and on disease activity can be directly assessed in a relatively straightforward manner. When your study includes a control arm, especially in an early phase study with a novel product, with unknown safety biomarker impact and or modification to disease activity, a small concurrent control group can provide valuable information on the timeliness and magnitude of effect against what would otherwise be expected among patients. This can be additionally informative. One little research has been done previously among the patient population. If the disease is quite rare, fast progressing, or very severe, a concurrent control group may not be feasible in such cases, a patient registry or natural history study can provide useful information. A patient registry may help guide clinical measures for assessment of disease activity, as well as the expected disease progression among patients treated with standard of care or not treated at all, depending on the volume of information and how it was collected. Use of a registry as a control group can be challenging to the candidate and point measures may not be available information for some or all patients, or they may not be available at the time points for comparison to the intervention trial. Despite these challenges at minimum, a patient registry can provide useful hypothesis generation for end point selection and natural history study is a valuable tool for early phase design in a rare disease indication, similar to a registry, a natural history study can provide useful information on targeted biomarkers and disease activity. And it can be specifically oriented towards the end point or end points you wish to measure at the times you wish to measure them in the intervention trial. A natural history study can provide a baseline observation period for patients who could then participate in your intervention trial, pending their meeting, the trial eligibility criteria. This can be used to inform change over time and biomarker quality of life or other clinical endpoints. While this is a larger topic for a different day. The natural history study could also be used as a source for matched control subjects. For comparison to that interventional trial, returning to endpoint selection, we will want to ensure that the end points can be assessed within a reasonable amount of time to allow for inferential conclusions and next step planning of clinical development, both supported by the application of appropriate and valid statistical methods and an understanding of the clinical effect of the novel treatment. The use of early markers to identify proof of concept for the hypothesized biological mechanism can be helpful to expedite advancements in the clinical development program. We must ensure that we do not lose sight of the longer term investigations of the clinically meaningful impact here. Again, a natural history study can be a valuable tool to measure the course of disease over time, alongside targeted biomarkers among untreated patients to better inform conclusions on those early markers and expedite the assessment of association between those markers and clinically meaningful disease assessments. In summary, when selecting end points for an early phase cell or gene therapy study, the goals are to select endpoints that align with study objectives have, or are indicative of clinically meaningful impact on disease and are measurable at one or more pre-specified time points that occur within a reasonable timeframe for both the development of your product and the treatment of the patients in need that endpoint or endpoints should be attuned to measure the biological and clinical impact to gain the most information from each patient with your novel product. Before I close, I would like to point the audience members toward the FDA regulatory guidance documents that are available on the FDA website. These provide additional information on study design and product development. They are particularly important reference for our industry and will provide you with a lot of useful information. Art podcasts are intended to be brief overviews of complex topics. There are many additional aspects surrounding effective planning for a novel product, and we hope you will join us as we continue to discuss such topics in future podcasts. The Veristat team has extensive experience in cell and gene therapy trials and are actively involved in the field. I hope that this has been valuable to you. Please reach out through the links available on the verus step website for additional information. Should you have questions? We will be back and hope to talk to you again soon. Thank you.

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