By Marco Calabresi, MD, PhD, Senior Medical Director, Neuroscience & Ophthalmology at Fortrea and Friedrich Wieser, MD, Medical Director, Neuroscience, Ophthalmology & Women’s Health (NOW) at Fortrea
Key considerations for endpoint protection in pain management clinical trials
Pain is one of the most important symptoms, cutting across every specialty in medicine. Due to the widespread impact and significant burden of pain on the quality of life of pain sufferers and their families, caregivers and communities, pain management has become a worldwide public health priority.
Drugs and medical devices represent important strategies in pain management. Development of these products requires careful consideration during discovery to address disease-specific mechanisms of pain as well as thoughtfully designed clinical development programs.
The role of patient-reported outcomes in pain management trials
Ultimately, one of the goals of a pain management clinical trial is to provide healthcare professionals with the necessary information to thoughtfully balance their patients’ pain relief with a medication’s side effects. Patient-reported outcomes (PROs) are the most important clinical outcome assessments to support that goal by providing drug development sponsors with a comprehensive understanding of a patient’s treatment experiences, side effects and perceived well-being based on their individual experiences, which may differ from clinical measures.
Fortrea has been working with innovative drug developers leveraging the capabilities of electronic PROs to protect the accuracy and integrity of pain clinical endpoints. This involves:
- Identification of critical data - Numerical Rating Scales (NRS) and Visual Analogue Scales (VAS) serve as effective tools for patients to rate their pain intensity and report changes (usually daily) over a period. As the name suggests, NRS uses a numerical scale that typically ranges from 0 (no pain) to 10 (worst pain imaginable). VAS is similar to NRS but uses a line for a patient to mark a point on the line between “no pain” on one end to “worst pain imaginable” on the other end. The difference in NRS or VAS measurements between baseline and post-treatment is the endpoint associated to the primary objective of most pain studies, i.e., the reduction of pain.
- Obtaining accurate pain measurements - Pain measurements must have a precisely defined variable reflecting a pain outcome of interest (e.g., the type of assessment and timing). The timing of pain intensity reporting is important because in several conditions pain has a predictable diurnal pattern. In addition, patients’ perceptions of their pain over recent periods are influenced by their current pain. The use of electronic diaries not only allows accurate timestamping of the time at which records are being taken but also allows alerts to be sent to investigators to measure and ensure compliance. Medical monitors can also send reminders and take appropriate measures through electronic diaries. Finally, it’s important to recognize that the accuracy of measuring of a subjective state, such as pain, depends on the performance of the measurement instrument as well as the study participant (patient-reported outcome) or clinician (clinician-reported measure).
- Selecting an appropriate study design - The selection of a study design for a trial assessing PROs is essential for endpoint protection. Traditionally, standard parallel groups or cross-over designs have been used, however, alternative study designs including enrichment design can be considered in selected cases.
Considerations for patient centricity in a pain management clinical trial
While the NRS and VAS offer a simple method for communicating pain levels, sponsors must ensure that excessive data entry does not represent a burden to study participation as this can lead to decreased compliance or even participant attrition.
An example of an excessive data entry requirement would be providing NRS or VAS pain scores twice daily (or more) over a three-month period (or longer). In contrast, more frequent data entry may be acceptable in the acute (e.g., post-surgical) setting, where the overall duration of the study is usually a few days.
However, the frequency of pain measurements is not the only situation in which unreasonable data entry requirements are placed on the subject. Pain, and especially chronic pain, is frequently associated with other mental health conditions, such as anxiety and depression, and may cause disability and lack of sleep. Therefore, anxiety, depression, disability, and lack of sleep, in this example, could also be measured using PROs, which presents a further burden to study participants.
Traditionally, in clinical practice—as opposed to the clinical study setting—it may be advantageous to have screening instruments that assess several potentially comorbid conditions at once, even at the cost of less depth and precision. When several of these standard clinical instruments are used in a study to measure each of these conditions, there is inevitably a high degree of redundancy. For example, a sleep questionnaire or depression and anxiety scales may ask about pain, which may have been measured separately in a pain clinical study.
Therefore, researchers should isolate the specific and relevant conditions they wish to measure and use measurement instruments with the least possible amount of repetition. A good example of such measurements is the Patient-Reported Outcomes Measurement Information System.
Sponsors can also consider strategies for streamlining data collection methods. Decentralized clinical trial technologies, such as wearables, can ease the patient reporting burden if well-integrated into patients’ daily lives.
Recognizing influences on the interpretation of results
As part of collecting endpoints in a clinical pain study, it is important to consider medical and psychiatric conditions, as pain patients frequently report comorbidities, such as common mental health conditions. These conditions may affect treatment response and intensify pain perception, thus affecting the reporting and interpretation of results.
The use of concomitant and rescue analgesics, in combination with the investigational product, may provide additional pain relief to the patient but can affect results. The frequency and amount of these medications must be well-defined and documented in a trial to ensure patient safety and consistent data collection.
Summary
The patient perspective offers a valuable endpoint in pain clinical trials. With clearly defined, validated patient-report outcomes (PROs), sponsors can apply this reliable method to better understand patient satisfaction with a treatment, measure perceived improvement in pain and gather critical information about a treatment’s effectiveness.
References
- Mullins PM, Yong RJ, Bhattacharyya N. Associations between chronic pain, anxiety, and depression among adults in the United States. Pain Pract. 2023 Jul;23(6):589-594.
- National Institutes of Health. Patient-Reported Outcomes Measurement Information System (PROMIS). https://commonfund.nih.gov/promis/index Accessed June 14, 2024.
- National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Care Services; Committee on Identifying Disabling Medical Conditions Likely to Improve with Treatment. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington (DC): National Academies Press (US); 2020 Apr 21. 2, Cross-Cutting Issues. Available from: https://www.ncbi.nlm.nih.gov/books/NBK559516/.
