Patient-reported outcomes (PROs) provide valuable tools for collecting information on subjective symptomatic effects during clinical trials. They are considered the gold standard for the assessment of health-related quality of life, treatment preferences, and satisfaction with care. PRO results from a well-defined and reliable PRO instrument can be used to support claims in product labeling, which can strengthen side effect data and possibly promote improved safety profiles.

PRO data can be particularly valuable in areas such as oncology, where treatments with secondary complications are frequently accepted due to high mortality rates in untreated populations. However, as treatments and survival rates improve, the patient’s health and quality of life during treatment becomes increasingly important, placing emphasis on high quality PRO data during drug development.

The FDA and PROs

The FDA has acknowledged the importance of utilizing PRO instruments in clinical research, and has made efforts to promote the use of PROs specifically in oncology clinical trials. In 2009, the FDA published a guidance “Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims” to give a cohesive standard that sponsors can use to facilitate the inclusion of PRO data in their label. In addition, recent initiatives within the FDA Office of Hematology and Oncology (OHOD) are designed to improve PRO advice, including building PRO expertise within the divisions, coordinating with the agency’s Study Endpoints and Labeling Development staff, and making efforts to ensure PRO advice is detailed and consistent.

However, there has been a lack of validated PRO instruments and standardization of data collection and analysis. This leads to challenges in interpretation of results and large amounts of missing data, which can result in the denial of a labeling claim. The introduction of NCI’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) addresses these problems.

Challenges of PROs in Oncology

Clinical oncology is one area where the inclusion of PROs in labeling has been particularly rare. Between January 2010 and December 2014, the FDA OHOD approved 40 drugs, and just 3 (7.5%) had patient-reported outcomes in the label. This is compared to 24% reported for all novel drugs and biologics reported between 2006 and 2010. Low inclusion of PRO data in oncology labels, in addition to strict general regulatory requirements, is in a large part due to a unique set of challenges faced by sponsors seeking approval for oncology products.

Clinical trials for cancer indications are by nature often single-arm, open label studies. 37.5% of trials for oncology products are single-arm (vs 8.3% non-oncology) and 67.5% are open-label (vs 8.3%) (Rawson, 2016). In their guidance on PROs, the FDA noted that single-arm, open label studies are “rarely adequate” to support labeling claims, due to the potential for bias. For example, patients who know they are receiving the treatment might overestimate the benefits, making comparative studies difficult. Furthermore, oncology reviews are often expedited, especially with the development of the Breakthrough Therapy designation, and as a result, many programs for oncology therapies do not accommodate the time and patient enrollment necessary for successful PRO incorporation.

In addition, the high level of toxicities associated with most cancer treatments makes data interpretation difficult. There is a wide variety of the onset and character of adverse events (AEs) both within and across trials. Concomitant medications, common in cancer therapy, can also confound interpretation of symptom effects. Symptomatic adverse events are common, and have been increasingly recognized as contributing to patient noncompliance, discontinuation, or dose-reduction in studies.

PRO-CTCAE: Combining patient-reported outcomes with clinician assessments

To address these concerns, the National Cancer Institute developed the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). The PRO-CTCAE is an electronic, patient-reported outcome measure to evaluate the symptomatic toxicity in patients in cancer clinical trials. The PRO-CTCAE was designed to be used in conjunction with the Common Terminology Criteria for Adverse Events (CTCAE), which is the standard method for adverse event reporting in oncology clinical trials.

The CTCAE contains approximately 800 individual AEs that are graded for severity and impact by investigators. To develop the PRO-CTCAE, a consortium comprised of seven cancer centers, five community oncology practice sites, and the NCI systematically analyzed the CTCAE for AEs that were amenable to patient self-reporting. As a result, the PRO-CTCAE includes 78 AEs, with each AE including 1-3 items such as frequency, severity, and interference with daily activities. In addition to providing an accurate and reliable source for adverse events, the PRO-CTCAE also detects baseline symptoms that can be subtracted in the final analysis of a treatment’s toxicity profile.

The National Cancer Institute created the PRO-CTCAE to be user-friendly for patients and sponsors alike. Administration of PRO-CTCAE offers different modes, including screen-based, interactive voice response, and paper, which gives flexibility for patients and operations personnel. (Psychometric evidence justifies comparison of results and pooled analyses across studies that employ different PRO-CTCAE modes of administration). Sponsors have the option to create customized questionnaires that include desired AEs, and data collection can be made easily via the web. The recall reference period for AEs is 7 days, which has been shown to be a reliable timeframe without a substantial loss of information. The PRO-CTCAE also includes patient reminders and clinician alerts for severe symptoms. As an added benefit to sponsors, there is no cost to use any of the PRO-CTCAE items, and the NCI offers resources and advice for its use.

While clinicians are essential for interpreting laboratory or measureable AEs, reports claim that clinicians under-detect the prevalence and severity of subjective symptoms, such as pain or fatigue, compared to patient reports. Empirical evidence also shows that clinical reporting of symptomatic AEs lacks reliability, thus patient reports typically more accurately reflect health status during treatment. As a result, the PRO-CTCAE provides a powerful combination of patient and clinician interpretation of the effects of a given treatment.

Shifting the focus of oncology outcomes

Most oncology endpoints focus on overall survival and reduced tumor growth, which has led to many exciting advances in the field.  But with the positive result of patients living longer with a cancer diagnosis, the push shifts to considering patient experience and quality of life during treatment. This is a direction where PRO-CTCAE can promote vast improvements; inclusion of direct patient reports will result in more accurate toxicity profiles for difficult-to-measure symptomatic AEs. Ultimately, PRO-CTCAE data could potentially be used to support a comparative tolerability labeling claim, giving sponsors a potential edge over competitors.

However, improvements still need to be made before those goals can be reached.  To be able to fully compare one treatment regimen against another, a cohesive method of summing individual adverse events for comparison needs to be developed and implemented. Additional agreements on data collection and data analysis standards need to be put in place to improve uniformity across trials. With those efforts, and with the incorporation of additional languages, the PRO-CTCAE will increase its scope of use.

Increasing the use of PRO data in oncology labeling: benefiting sponsors and patients alike

The benefits of including PROs in clinical trials from the patient’s perspective are clear: they place emphasis on patient quality of life, and more accurately reflect the patient’s experience when taking the proposed product. But what is the added benefit to the Sponsor for adding the time and money required to implement PRO collection in their trials? One of the key goals of the PRO-CTCAE is to provide a way to facilitate the use of PRO data to make formal claims in labeling. As stated above, this has historically been a large challenge for Sponsors in the oncology arena. Between 2010 and 2014, the FDA OHOD approved 13 products in which sponsors included PROs as part of their clinical trials, but denied the inclusion of results of the PROs in the product label (Rawson, 2016). This occurred for various reasons, including missing values and inappropriate choice of instruments. Utilization of the PRO-CTCAE can eliminate some of this ambiguity and improve the chances for getting labeling claim approval. Ultimately, utilizing the PRO-CTCAE can provide an additional way for Sponsors to strengthen the value of their product in their product label.

Premier Consulting has experience in oncology drug development pathways and can assist with development and regulatory strategies specifically focused on 505(b)(2) drug development. Please contact us for more information.

References

Rawson K. Oncology PROs: Limited Use Due To Small Trials, Fast Drug Development. Pink Sheet . 4-27-2016.  Informa Plc.