Potential of patient-reported outcomes as nonprimary endpoints in clinical trials

Patient-reported outcome (PRO) is an umbrella term used to describe data collected directly from the patient without interpretation by clinicians or others [1‐3]. PRO data are collected using standardized questionnaires, diaries, or event logs that are designed to measure an explicit concept (construct), such as signs and symptoms of disease, functioning (activity limitations), health status/health-related quality of life (HRQOL), and treatment satisfaction. PROs are frequently included in registration clinical trials for multiple purposes, including support of product approvals and labeling claims of treatment benefit, support of primary endpoints, and to provide a basis for publication and communication strategies. Also, increased competition in a global market requires pharmaceutical companies to seek methods to differentiate their products from those of competitors. One way of achieving this goal is to generate value propositions that extend beyond the traditional safety and clinical efficacy messages and allow competition on something other than price alone. PRO measures provide this necessary insight into patient experience of treatment benefit.

Primary endpoints are intended to address the most important research being addressed by a trial. In the absence of objective clinical endpoints to support efficacy, PRO measures may be used as primary endpoints. PROs used as primary endpoints are typically those that directly assess drug efficacy by measuring disease-defining signs and symptoms. Examples of indications for which PROs consistently serve as primary endpoints include painful conditions, such as migraine and neuropathic pain, as well as functional gastrointestinal disorders.

PROs may also be used in clinical trials as nonprimary endpoints to provide support for primary endpoints. For example, among conditions for which there are well-accepted clinician-reported primary endpoints, such as depression and other psychiatric indications, PRO measures addressing patients’ perceptions of their symptom severity, such as the Beck Depression Inventory or the Zung Self-Rating Depression Scale, are often used as key secondary endpoints. In addition to signs and symptoms, nonprimary PRO endpoints often assess higher order constructs such as functional status and HRQOL. In many instances, PROs are included in confirmatory trials at the request of regulatory bodies, such as the FDA and the European Medicines Agency (EMA) [4] or to secure reimbursement [5].

Sponsors commonly include nonprimary PRO endpoints to demonstrate value propositions of new medicines to stakeholders other than regulatory agencies [6, 7]. For example, demonstration of improvement in work productivity is important in the treatment of rheumatoid arthritis [8]. Nonprimary PRO endpoints also may be included in clinical trials to satisfy health technology assessment (HTA) requirements. For example, the National Institute for Health and Clinical Excellence (NICE) has recommended patient scores in Adult Growth Hormone Deficiency scale (QoL-AGHDA) as one of the three criteria for judging patient suitability for treatment with recombinant human growth hormone [6], and the EQ-5D is included in most confirmatory clinical trials to demonstrate the economic value propositions of new medicines. Risks of not including a PRO include inaccurate reporting or understanding of patient symptoms and symptom severity related to treatment, important prognostic information, and insight into patient decision making and adherence to therapy [9].

A recent review of PRO labels between 2006 and 2010 found that almost half (45%) of all drug approval package submissions included PROs and that a vast majority of PRO labeling claims (71%) were granted for evidence based on the primary endpoint [10]. The purpose of this research is to fully explore the impact of endpoint type (primary vs. nonprimary) on resultant labeling claims over a 12 ½ -year period supported by PRO measures and determine if nonprimary endpoints are being fully optimized. This review will further contribute to continued analyses of the role of PROs in clinical trials and provide a broader perspective, including an examination of the nonprimary endpoints pre- and postrelease of the FDA PRO guidance [3].

The methods for the data collection component for this research are fully described in a previous publication [10] and are similar to those published by Willke and colleagues [11]. Briefly, all new molecular entities (NMEs) and biological license applications (BLAs) for new prescription drugs approved in the United States (US) from January 2000 through June 2012 were reviewed. Products were excluded if they contained substances previously marketed with a different brand name or set of indications, in a different dosage form or strength, or as a combination product of previously marketed entities.

Once products were identified, drug approval packages (DAP) and approved product labels were extracted by a single researcher and reviewed by all authors. As available, information was retrieved from the medical review, summary review, cross-discipline team leader review, and other review sections from the DAP, as well as the indication and clinical studies section of the approved product label. The DAPs were located on the FDA Web site, Drugs@FDA [12]. In most cases, the label was found on the FDA Web site under approval history for the drug at time of approval. In the event the approved label was unavailable for the specified timeframe, the current label was used. Relevant information was scrutinized for each product to determine the indication, use of PRO, and PRO claim language. Statistical analysis consisted of simple frequencies and cross-tabulations of measured characteristics. Calculations were performed using Microsoft Excel 2007.

A total of 308 NMEs/BLAs were identified between the years 2000 and 2012. Of these, 70 (23%) NMEs/BLAs were granted a total of 83 PRO claims. A PRO was included as a primary endpoint for 57 of the 70 products (81%). The majority of product claims granted were for disease- or condition-specific signs and symptoms. Fewer claims included higher order measures such as functioning, HRQOL, or patient global ratings. Table 1 depicts the products that were granted PRO labeling claims by type of claim.

Additionally, 19 products received a total of 29 PRO labeling claims using a PRO that was a nonprimary endpoint. These claim types included signs and symptoms (n = 19), functioning (n = 2), HRQOL (n = 3), and other (n = 5) (3 for rescue medication use, 1 for treatment satisfaction, and 1 for belly appearance distress). Importantly, of these, the vast majority were claims based on signs or symptoms, as compared with higher order claims, and were supportive of (but not redundant with) the primary endpoint. However, nonprimary endpoints were more likely to represent claims based on concepts other than signs and symptoms as compared with primary PRO endpoints (Figure 1).

Protonix received a labeling claim of “complete relief of daytime and nighttime heartburn and the absence of regurgitation” based on the patient daily diary as well as an indication of “symptomatic relief.” The primary endpoint in the clinical studies was resolution of macroscopic esophageal lesion. Foradil, Nexium, and Frova followed similar patterns, where the nonprimary PRO endpoint provided key support to a clinical, objective endpoint. Foradil, indicated for “maintenance treatment of asthma and in the prevention of bronchospasm in adults and children” is notable, because the labeling claim specifically denotes, “Foradil demonstrated improvement in many secondary efficacy endpoints, including combined and nocturnal asthma symptom scores, fewer nighttime awakenings and fewer nights in which patients used rescue medication.” Emend (aprepitant) was granted a higher order claim of “A higher proportion of patients receiving Emend reported minimal or no impact of nausea and vomiting on daily life” based on the Functional Living Index-Emesis (FLIE), whereas the primary endpoint was “complete response” or no emesis. Soliris and Letairis also received higher order claims, though in these instances they were in support of HRQOL. Table 2 describes the claim granted and PRO used by product for the 19 products with PRO labeling claims based on nonprimary PRO endpoints.

In the absence of objective clinical endpoints to support efficacy, PRO measures are often used as primary endpoints. PROs may also offer support to a primary endpoint as key secondary, secondary, or exploratory endpoints, which may be either independent of or closely associated with the primary endpoint. Based on this review, PRO labeling claims are more likely to be granted for PROs specified as primary endpoints in confirmatory clinical trials. A variety of reasons could explain the limited number of claims granted based on nonprimary endpoints. The three most prominent reasons are overlapping concepts, commitment to resource, and logistical complexities.

This review based on 70 PRO labeling claims granted by the FDA between 2000 and 2012 shows that successful PRO labeling claims are typically based on primary endpoints assessing signs and symptoms (81.4%). Although inclusion of PROs as nonprimary endpoints in clinical trials has its challenges, recent PRO labels granted by the FDA show that they can indeed be candidates for PRO labeling claims as long as they can be supported by evidence. The PRO guidance by the FDA has provided the industry with a blueprint for obtaining PRO labels [3]. It is now left to the industry to accept the challenge and recognize the importance of outcomes that matter to all stakeholders, including patients.