Patient-Reported Outcomes and Clinical Outcome Assessments

Patient Input Impact on Drug Development

Patient-reported outcomes (PROs) have become a valuable tool for incorporating patient input in clinical research. Whether in academic research or commercial medical product development, the use of PROs facilitates the systematic collection of patient perspectives and provides scientific evidence to support the healthcare and regulatory decision-making process.

A recent assessment report by Eastern Research Group, Inc., commissioned by the U.S. FDA, indicates that PROs and other types of clinical outcome assessments (COAs) play an important role in the FDA’s decision whether to approve a drug or biologic, particularly when those PROs/COAs are used as primary endpoints in clinical trials. As one example, the report points to new molecular entity (NME) new drug applications (NDAs) and biologics licence applications (BLAs) approved by the FDA between 2017 and 2020. Of that group, 30 percent of approved product labeling mentions patient experience data and within that subgroup, nearly all mention COAs (92 percent), with the majority of those COAs being PROs (67 percent).

The growing recognition of the role of PROs is the result of a wider global initiative for patient-focused drug development. Both the FDA and European Medicines Agency (EMA) have established frameworks to ensure that “patient voice” is captured and meaningfully incorporated into drug development.

This idea has also been gaining traction with other regulators worldwide. The latest example of this is the release of a draft guidance on the application of PROs in clinical research by China’s Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA). While still in development, the draft guidance sends a clear message of the NMPA’s support of the concept of patient centricity and thus strengthens the basis for a future uptake of PROs in the development of new drugs in this market.

Embracing ePRO/eCOA solutions

The impact of the COVID-19 public health emergency on the conduct of clinical trials has sped up a wider adoption of digital and remote clinical trial solutions, electronic PROs (ePROs)/electronic COAs (eCOAs) being one of them. ePROs are the standardised questionnaires, assessments, and diaries that are completed by trial participants using electronic devices, such as smartphones or computer tablets, or via telephone-based technologies, such as interactive voice response systems. The need for the remote application of PROs brought to light a wide range of considerations for trial sponsors. Various guidance documents issued by the regulators have provided the essential advice to the industry to enable trial continuity during the pandemic. The question that remains is how many of the regulatory flexibilities afforded for the remote data acquisition and execution of clinical trials will survive beyond the COVID-19 emergency. The FDA’s anticipated draft guidance on decentralized clinical trials (projected for publication in 2021) should give an indication of that as well as of future regulatory direction and developments in this space.

PROs Influencing Medical Device Development Regulations and Manufacture

Drug development is not the only domain where PROs are increasingly seen as a valuable tool in the evaluation of interventions from the patient perspective. The relevance of PROs in the development, evaluation, and surveillance of medical devices has also been steadily growing.

The medical technology industry is one of the most dynamic fields of the healthcare sector. The United States leads the way as the largest medical device market in the world, which is expected to grow to $280 billion by 2023. The industry creates products of varying complexity — from the most common types of thermometers to the state-of-the-art implantable devices — and plays an essential role in improving the ability of health care systems across the globe to diagnose, treat, and prevent illness.

In recent years, the importance of understanding and incorporating the “patient’s voice” throughout the entire product life cycle has gained momentum, with device manufacturers and regulators increasingly seeking to leverage patient insights in the development and evaluation of medical devices.

Achieving Value for Patients

The FDA’s Center for Devices and Radiological Health (CDRH), which regulates medical devices and radiation-emitting products in the U.S., promotes the patient-centric approach by encouraging the usage of patient-reported outcome measures (PROs). PROs facilitate the systematic collection of how patients feel, function, and survive as valid scientific evidence to inform regulatory decisions across a wide variety of devices and indications. Within the medical device regulatory framework, PROs and other types of clinical outcome assessments (COAs) are also known as “medical device development tools (MDDTs)”. An MDDT is “a method, material, or measurement used to assess the effectiveness, safety, or performance of a medical device”. To this point, the CDRH PRO Compendium serves as reference to help device manufacturers understand how certain PROs (and other COAs) have been used in clinical trials to measure patient experiences and to support labelling claims.

PRO data can be captured using various PRO instruments. The so-called “generic” PROs may be used to capture the data concerning the patient’s physical, mental, and emotional health, whilst “disease-specific” PROs are tailored to measure symptoms, effects of treatment, or other aspects related to a specific disease, condition, or treatment.

For instance, trials with ophthalmic devices may use PROs to assess the patient’s vision, symptoms, and satisfaction after surgical procedure. In trials with orthopaedic devices, pain, and physical function are important indicators in the evaluation of device safety and effectiveness. As these concepts are best measured from the patient’s perspective, the use of PROs enables medical device developers to capture and, subsequently, quantify the information received directly from the patients. In this way, PROs serve as tools for communicating patient preferences and the outcomes that matter to them.

Creating Market Differentiation for Device Manufacturers

Innovation, shorter regulatory cycles for novel devices (as compared with novel drugs) as well as the rapid commercialisation of new devices developed on the premise of substantial equivalency with the already marketed products have been fuelling a high output of diverse products to the markets.

Faced with the continued pressure to increase efficiencies and reduce costs, payers, such as national health systems or healthcare providers, have been tightening their standards for covering new technology. For instance, it was reported that private health insurers in the Unites States had been requesting device companies to “provide stronger evidence of the clinical benefits of new devices and information on how their performance compares with existing products.” In the European Union, a legislative change in the form of directive on public procurement (Directive 2014/24/EU) had shifted the approach to purchasing of medical devices by placing greater focus on outcomes and value.

PRO data can provide important information on the advantages of using a device that otherwise would not be captured through other non-PRO endpoints (for example, improvement in ability to perform activities of daily living). As patients are becoming more empowered and involved in the decisions about their health care, their “voice” turns into a potent driver that is shaping consumer demand. Combining technology with patient insights and offering a product that focuses on the attributes and outcomes that are meaningful and relevant to the target patient base is bound to boost product value and differentiate it among the competition. In turn, such market differentiation may positively influence purchasing recommendations and decisions and drive acceptance by healthcare providers and patients.

Opportunities to Incorporating PROs in Medical Device Clinical Studies

The FDA’s regulatory controls or, in other words, requirements necessary to provide reasonable assurance of device safety and effectiveness, are based on device risk classification (Class I, II, or III). Class I devices generally represent the lowest risk, Class II devices pose moderate risk, and Class III devices pose the highest risk. The higher the risk is the more extensive and stringent regulatory controls are. For instance, Class III devices would typically undergo the most rigorous pre-market approval (PMA) process, which includes the requirement for device developers to conduct trials and provide clinical evidence to support their application. These applications are among the most likely to include PROs.

It would be remiss not to mention that the inclusion of PROs and other types of COAs in the medical device studies is voluntary — though strongly encouraged by the FDA — and that study sponsors may propose other approaches to measure key outcomes of interest. With that, the extent of opportunities for incorporating PROs into medical device development and evaluation would, by and large, be shaped by study sponsors’ interest in obtaining PRO data and by the regulatory requirements as pertinent to the individual device and specific pathway under which market approval is sought (which may also include post-approval requirements where and as applicable).

Ensuring that PRO instruments are fit for purpose

When PRO data are used in the evaluation of medical devices, regulatory concerns are often around the evidence provided by study sponsors that these data present relevant, reliable, and sufficiently robust information. To proactively address these concerns, the FDA has established, by way of the draft guidance for industry, a set of recommendations and expectations for selecting, developing, modifying, and adapting PRO instruments for use in medical device evaluation. Similar to the guidance on PROs for use in medical product development, this document puts the message across to study sponsors that each PRO instrument should be selected (and will be evaluated by the FDA) based on the concept(s) of interest that it needs to measure and the context of its intended use, including clinical trial design, target patient population, and desired labelling claim.

The guidance also highlights the importance of ensuring that PRO instruments are comprehensive and are understood by the patient populations that will use them in the trials. Drawing on input from patients (for instance, to help identify or confirm concepts), using plain language and at the appropriate readability level, providing translated and culturally adapted PROs (where applicable) will help ensure that patients with varying levels of literacy are able to provide informed responses.

Having grown in their importance as the source of evidence in regulatory decisions and beyond, PROs are primed to continue gaining greater prominence and recognition in the product lifecycle of medical devices.