Talking to Elektra Papadopoulos, M.D., MPH, Associate Director, Clinical Outcome Assessments Staff, Office of New Drugs, CDER, FDA

Note: This page has been updated from its original version. The original version can be found here.

As part of its continued effort to foster patient-focused drug development, FDA’s Center for Drug Evaluation and Research (CDER) is announcing the publication of an updated compendium of clinical outcome assessments (COAs) since launch of a pilot program in 2016 to promote the use of patient-focused outcome measurement in drug development.

Elektra Papadopoulos, who is the Deputy Director of the Division of Clinical Outcomes Assessment in CDER’s Office of New Drugs, provides details about the COA Compendium.

Let’s start with the basics.  What is patient-focused outcome measurement about?

Patient-focused outcome measurement starts with an understanding of the impact of a disease and its treatment on patients, and what they value from a treatment perspective. It is about measuring things that are important to patients, such as how a treatment will affect symptoms, day-to-day functioning and overall survival. This information can then be used to develop tools that assess the factors that patients most care about. Patients and prescribers need meaningful information about a drug’s benefits and risks to make important treatment decisions.

How does patient input influence the choice of outcome measures in drug development?

Selecting the right outcomes to measure is a very important aspect of drug development. Patient input into the selection of outcomes that are meaningful to them can profoundly influence drug development by ensuring that the patient’s voice is captured. Patient input also helps to ensure that the instruments used to collect this information in a trial are appropriate and are measuring the outcomes in the right way. As a result, the treatment benefit information can be included in labeling in a way that is accurate and not misleading.

What are COAs and how are they captured in drug development?

COAs are tools that we use as part of our assessments of clinical outcomes, such as how patients feel or function in their daily lives. These measurements of patient outcomes provide essential information about benefits and risks of a drug. COA measures can be patient-reported, clinician-reported, non-clinician observer-reported (e.g., caregiver) and performance-based (e.g., test of cognition or walking ability). Digital health technology tools (e.g., activity monitors) can also be used to measure outcomes of importance to patients. The type of COA that is used depends on the research question and the context in which it will be used.

COAs can be used to support product approval and claims of treatment benefit in drug labeling. Just as with any other tool, a COA measure must be fit for its intended purpose in drug development. FDA regulations state that assessments used to support labeling claims of treatment benefit must be well-defined and reliable so that changes seen in the outcome assessment can be interpreted and accurately communicated to patients and prescribers.

What are patient-reported outcomes?

Patient-reported outcomes (PROs) assess how patients feel and function as a result of treatment and are based on reports coming directly from the patient. The patient’s report is documented without changes or interpretation by a health care professional or anyone else. A PRO can be self-reported by a patient using a journal or by answering written questions in a questionnaire, or a patient can verbally describe it in an interview. An example of a PRO is a patient’s self-report of pain intensity over the past 24 hours on a numeric pain rating scale of 0 (no pain) to 10 (worst pain imaginable). Symptoms known only by the patient, like pain severity, can only be measured by patient reports.

There has been increasing interest among patients, drug developers, health care professionals, insurance payers, and regulators in the development and application of PRO instruments in drug development, particularly to support product labeling claims. However, PRO measures may not always be feasible or appropriate depending on the context, and other types of COAs may be used to assess outcomes of importance to patients.

What is the COA Compendium and what is its purpose?

Recently, FDA has been undertaking multiple efforts in patient-focused drug development (PFDD). One component of these efforts is the COA Compendium, which was launched in January 2016. This is the second update of the Compendium since it was initially introduced in 2016.

The Compendium is intended to provide clarity and transparency, as well as facilitate communication between the drug development community and the agency. It collates and summarizes information for many different disease states and conditions into a single resource. The COA Compendium covers all COA types, including COAs that have been used in clinical trials to measure the patient’s experience (such as disease-related symptoms) and to support labeling claims. The Compendium also identifies COAs that have been qualified for potential use in future drug development programs under CDER’s COA Drug Development Tool (DDT) Qualification Program.

The Compendium is designed to be used as a starting point when considering the use of COAs in clinical trials and to promote early engagement and discussions with the FDA around selection of COAs that are most appropriate for a drug development program. We envision that it will be most helpful in the very early phases of drug development when drug developers are planning future trials. We also aim to facilitate discussion about how COAs can be used in clinical trials and spur innovation and development of COAs in needed therapeutic areas.

Some revisions are noted in the updated version of the COA Compendium. For example, some of the public comments we received through a public docket following the 2016 launch of the pilot Compendium are reflected. In addition, to provide further transparency regarding the origin of COAs, the drug’s name and approval date that corresponds to the labeling is included. The COA Compendium update does not refer to the COAs in development or under review within FDA’s DDT Qualification program because these instruments have not received full FDA review for the proposed use and may not yet be publicly available.

Ongoing qualification projects are listed separately on the public COA DDT Qualification website. The only instruments related to the COA DDT Qualification Program that are referenced in the updated COA Compendium are those that have been qualified for the intended context of use and made publicly available.   

Why is the COA Compendium important and what does it mean for patients?

Capturing outcomes that are important to patients is a high priority for CDER. As I mentioned earlier, the COA Compendium is another tool to foster our patient-focused drug development mission. We hope this tool will make it easier to see the knowledge gaps and where attention is needed to develop patient-focused outcome assessments. Before a product can be developed to treat a disease or condition, we must know how the disease or condition is affecting the patient. After gathering this information from patients, we can define the specific aspects of a disease or condition that we aim to treat and select appropriate outcome measures.

Many COAs have been in use for many years in drug development and are accepted by the FDA and the relevant research community. Existing instruments that have successfully supported previous regulatory decisions and were included in drug labeling generally would not be removed from consideration unless there is a more appropriate replacement, so as not to potentially hinder or stall drug development. It is important to consider the 2009 PRO guidance for industry, which is the best practice guidance that describes one approach to PRO development. However, tools developed prior to this guidance may still be useful in drug development and can support labeling claims. FDA continues to review all instruments intended for use as registrational endpoints to ensure that they are well-defined and reliable, and that they can support regulatory decision-making.

We hope that collating and listing outcome measures for many diseases and conditions in the COA Compendium will encourage the use and development of patient-focused outcomes in future clinical trials. We plan to continue engaging with the public and the scientific community to support pertinent future program and policy development activities.

Is FDA encouraging drug companies to consider using PRO measures in trials that support approval of a drug?

Yes, we want to encourage development and use of clinical trial endpoints that provide information that is meaningful to patients who are considering taking a drug. These often include PROs, but they may also include other COAs, overall survival, or biomarkers, depending on the particular circumstances in which they will be used. We encourage drug developers to consider incorporating adequate, well-defined, and reliable outcome measures and to discuss those measures with us as early as possible in product development.

Will this compendium be an all-inclusive list of COAs?

No, a comprehensive table of all COAs is not our goal with this project. It is also not meant to be a replacement for existing communication channels with CDER review divisions, nor is it a replacement for existing, disease-specific guidance or qualification efforts. The updated COA Compendium includes a small proportion of COAs from new drug labeling and efficacy supplements. The COA Compendium is a communication tool that is intended to serve as a living document which will be updated on a regular basis.

Where can I find more information about the COA Compendium?

More information, including a user guide, is available on the COA Compendium web page.