Developing Novel Clinical Trial Endpoints

Zoran M Pavlovic MD, CEO Heruka Lifescience & Health Innovations

Clinical outcome assessments (COAs) measure a patient’s symptoms, overall mental state, or the effects of a disease or condition on how the patient functions and can be used to determine whether a drug has demonstrated clinically meaningful treatment benefit.
There are four types of COA measures:

  • Patient-reported outcome (PRO) measures
  • Clinician-reported outcome (ClinRO) measures
  • Observer-reported outcome (ObsRO) measures
  • Performance outcome (PerfO) measures.

Choosing a type of COA (depends on a determination of the most appropriate reporter for the concept of interest and the context of use. For example, if pain intensity is the concept of interest in a patient population that can respond themselves, a PRO is most appropriate.

Recently after the introduction of personalized medicine and patient-centric approach to contemporary clinical practice, pharmaceutical and biotech companies decided for the first time to engage patient advocacy groups in their drug development process, with the aim to produce novel drugs which will have high impact not just on clinical symptoms, but also on patient’s quality of life and overall daily functioning. One of the challenges to this approach is the “know-how” about capturing large amounts of patient-generated clinical trial data outside of the hospital or a medical practice. Currently, the most credible solution to solve this problem, turn out to be the use of various mobile devices and wearables as important tools that will contribute to conducting a successful clinical study. In addition, their application would also add-value by increasing quality of gathered clinical trial information, enhancing patients’ compliance and trial engagement, reducing of barriers to trial participation, and lowering of costs associated with conducting clinical trials together with minimal interference with trial participant’s daily lives.

In a special event recently organized by the FDA and Clinical Trials Transformation Initiative (CTTI) Pamela Tenaerts, executive director at CTTI addressed meeting participants by saying “The clinical research community has long discussed an exciting future of using mobile technologies to collect objective, reliable data in clinical trials and today, we are excited to start making this vision a reality”—sharing recommendations for capturing more informative real-world data from patients, reducing barriers to trial participation, and lowering costs associated with conducting clinical trials.”

I listed below the CTTI recommendation criteria which were recently adopted and include suggestions about the creation of novel clinical trial endpoints and selection of adequate mobile/wearable clinical trial devices:

CTTI RECOMMENDATIONS FOR OPTIMIZING NOVEL ENDPOINT SELECTION

1. Focus on measures that are meaningful to patients

Selection of clinical trial measures should address an unmet need for assessments that directly measure or indirectly reflect an aspect of the disease or illness that, if relieved, improved, or prevented would be meaningful to patients. The first two steps outlined in the US Food and Drug Administration’s (FDA’s) Roadmap to Patient-Focused Outcome Measurement in Clinical Trials are namely 1) understanding the disease or condition and 2) conceptualizing treatment benefit, when considering a mobile technology-derived assessment. Specifically, the mobile technology-derived assessment should be better than the alternative measure(s) in one or more ways: for example, the measure should be more informative or meaningful to patients. Effective engagement of patient groups in clinical trials demands that the “patient voice” by establishing partnerships from the beginning of the research and development program to improve trial design and execution. Include the perspective of patients (i.e., the patients’ voice) in the early stages of disease targeting, making full use of PG input while clinical trials are still in the planning phase to help shape and refine the study protocol. Soliciting PG input early in development benefits both sponsors and patients. Sponsors benefit by a clearer, more focused understanding of unmet need, therapeutic burden, opportunities for expanding indications, and better targets; by improved clinical trial design, selection of optimum subjects, endpoints, and clinical sites; by faster trial recruitment and greater patient compliance with the protocol; and by alleviating the need for costly and time-consuming adjustments later. Patients benefit by less burdensome study protocols and more meaningful and relevant endpoints, thus increasing the likelihood they will participate in the trials and potentially help to develop a meaningful treatment for their disease. The patient voice as communicated by PGs is key to understanding the day-to-day effects of the condition and the acceptable benefit-risk trade-off of treatment. The FDA appropriately places a high priority on minimizing risk to trial participants, but PGs can speak to and provide data on the high risk to patients of living with the condition and, therefore, the risks patients are willing to take to test truly promising therapies. Engaging PGs is a means for research sponsors to understand patient and family needs so that sponsors can develop not only new treatments but also services that demonstrate a commitment to the well-being of patients. At the CTTI Patient Groups & Clinical Trials Expert Meeting Janet Woodcock of the FDA stated that it is critical for the clinical research community to recognize the shift from “patients as consumers” to “patients as partners”.

2. Select the technology after selecting an outcome assessment.

Selecting a suitable mobile technology for data capture should occur only after the clinical outcome assessment or biomarker is identified. This will ensure the evaluation of the assessment is separate from evaluation of the technology. Minimum criteria for technology selection should include:

  1. Establishing tolerability and acceptability of the technology by participants;and
  2. Verifying the technology. Specifically, ensure that the technology is acceptable in terms of its sensitivity, specificity, accuracy, precision and other relevant performance characteristics related to the primary data collected by the technology.

CTTI RECOMMENDATIONS ON PRACTICAL APPROACHES TO THE NOVEL ENDPOINT DEVELOPMENT PROCESS

1. Foster collaboration among key stakeholders.

Sponsors, patients, clinicians, technology companies, and regulators should collaborate in a pre-competitive environment to identify and advance consensus on the mobile technology-derived outcome measures that are most valuable and warrant development.

2. Create technical standards for mobile technology-derived assessments.

In order to promote the scientific, technical, and medical benefits of novel endpoints, shorten development time, and increase the quality and usefulness of mobile technology-derived assessments, CTTI recommends establishing industry-wide standards related to 1) terminology, 2) the collection and reporting of data captured by mobile technologies, and 3) transparency requirements for the algorithms used to convert the data into physiologically and medically useful endpoints. CTTI recommends that stakeholders, including mobile technology companies and sponsors who may produce competing tools or develop competing therapies, collaborate in a pre-competitive space to set these standards.

3. Engage with regulators.

Regulators can and should provide critical input throughout the process of developing novel endpoints. Stakeholders including technology companies, patient groups, and consortia working to develop technology-derived novel endpoints should engage regulators early in the process. For drug sponsors and therapeutic medical device sponsors planning to use a novel endpoint in a pivotal trial, interactions should continue during the Investigational New Drug (IND) application or Investigational Device Exemption (IDE) reviews. There are several opportunities to interact with FDA review staff to discuss how novel endpoints will be used within proposed clinical investigations. It is advantageous to interact with FDA staff early and frequently to improve the FDA’s understanding of the clinical investigation, the mobile technology, and how the data collected will be analyzed and used to support subsequent applications to the FDA.

4. Include novel endpoints as exploratory endpoints in existing clinical trials and observational cohort studies.

CTTI recommends including novel endpoints as exploratory endpoints in existing studies in preference to solely conducting unique pilot studies. This approach not only eliminates the need for the development and execution of additional protocols but allows sponsors and investigators to gather information about scientific and operational considerations related to using mobile technologies for data capture in a large study or trial. These considerations may include patient compliance with, and tolerance of, the technology; identification of the appropriately sensitive sensors required to maximize signal-to-noise ratios in measurement; and data properties, all of which inform correct protocol design and sample size. CTTI also recommends including novel endpoints as exploratory endpoints in natural history and observational studies, including those conducted by patient groups and academics. Data collected by including mobile technology-derived assessments as exploratory endpoints in clinical studies can contribute to the body of evidence required to successfully develop them for use as primary or secondary endpoints.

5. Think critically about how to optimally position novel endpoints in interventional trials

Where novel endpoints address unmet need, they may be uniquely important as primary efficacy endpoints. However, when well-established, endpoints that effectively demonstrate clinical benefit already exist, novel endpoints may be most valuable as complementary assessments. Novel endpoints are unique in their ability to objectively capture data about patients outside of the clinic in the context of their activities of daily living. As such, novel endpoints may offer valuable data in support of labeling claims for new therapies. Similarly, novel endpoint data may provide evidence to support the roles of other stakeholders in the healthcare ecosystem, including providers and payers who make coverage decisions related to the use of medical products. CTTI recommends that trial sponsors think critically about how to optimally position novel endpoints in pivotal trials. Where appropriate, sponsors should also include novel endpoints in phase II studies. Promising drugs may be terminated prematurely in phase II due to lack of evidence that they could succeed. By measuring concepts that previously could not be assessed, or were measured inadequately, novel endpoints offer the ability to improve our understanding of the safety and efficacy profile of a drug, which may in turn lead to greater success from phase II to phase III. As such, novel endpoints may be particularly impactful in phase II studies in therapeutic areas where there is significant unmet need for treatments.

Conclusion

Mobile technology offers unique opportunities for provision of novel clinical outcomes developed in collaboration with patients and patient’s groups, for improvement of the quality and efficiency of clinical trials by enhancing patient compliance and engagement, thus providing better and more informative real-world data capture, reducing of barriers to trial participation, and lowering costs associated with conducting clinical trials.

 

Author

Zoran M Pavlovic

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