A historical switch to reflect FDA’s efforts in Patient-Focused drug development

Professor Donald L. Patrick, Director, Seattle Quality of Life Group and Biobehavioral Cancer Prevention and Training Program, University of Washington, Seattle, Washington, USA

Evolution in Terminology: from Health-Related Quality of Life to Patient-Centered Outcomes

Patients have always been at the center of the Food and Drug Administration’s (FDA) activities and concerns. Historically, the Agency has always made it a point to seek advice from patients about their treatment options and needs. For many years, FDA has included the patient’s perspective at advisory committee meetings and during the review of dossiers seeking approval for new medical products, in selected meetings within the Agency, and with developers and users at national and international conferences.

In the last 15 years, the patient’s perspective in clinical trials was encouraged, and those encouragements were reflected in the changes in terminology over the years. “Patient-reported outcomes” (PRO) was introduced in October 2000 during one of the four PROHarmonization Group meetings held at the FDA1 to go beyond the controversial use of the term “health-related quality of life,” which lacked specific meaning to many stakeholders.
In 2009, the final version of the FDA guidance on PRO measures provided a definition of what is a PRO:2 “A PRO is any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else;” and briefly introduced the notion of caregiver- and clinicianreported outcomes. The objectives of the guidance were to define how the Agency interprets “well-defined and reliable”3 PRO measures intended to provide evidence of treatment benefit, and to summarize good measurement principles applicable to any PRO, ClinRO or ObsRO assessment.

In October 2011, the term Clinical Outcome Assessments (COAs) was introduced at a FDA Workshop4 to better reflect the importance of the source of information in measurements. COAs, which exclude survival and biomarkers, are influenced by human choices, judgment, or motivation, and depend on the cooperation, and reporting of feelings and function by patients (PROs), by clinicians (ClinROs), by observers (ObsROs), and by the use of performance measures.Two years later, the notion of Patient-Centered Outcomes has been implemented to express the FDA’s current efforts to expand the role of the patient perspective in drug development, i.e., the agency’s Patient-Focused Drug Development initiative.5

During the ISPOR 18th international meeting in New Orleans (May 2013), Patient-Centered Outcomes (PCOs) were defined as “Those outcomes important to patients’ survival, function, or feelings as identified or affirmed by patients themselves, or judged to be in patients’ best interest by clinicians and caregivers when patients cannot report for themselves.”.6 At this occasion, “Patient-centeredness” was reminded to all as it was defined by Donald M. Berwick:7 “Patientcenteredness” is a dimension of health care quality in its own right, not just because of its connection with other desired aims, like safety and effectiveness. Its proper incorporation into new health care designs will involve some radical, unfamiliar, and disruptive shifts in control and power, out of the hands of those who give care and into the hands of those who receive it.”

Patient Engagement

During the ISPOR meeting, several reasons why Patient-Centered Outcomes are growing in importance were listed.8
First, Patient-Centered Outcomes provide the information that all stakeholders need.
Second, patients are empowered to be their own best health advocate. Third, how patients feel and function predicts utilization of healthcare services. And finally drug approval decisions are more relevant. When original accelerated approval is based on indirect evidence of treatment benefit using a surrogate endpoint that is not established to predict treatment benefit, approval for an indication can be withdrawn if post-marketing studies fail to verify clinical benefit.
To be used in drug development and research, Patient-Centered Outcomes should meet five requirements:

  1. Patient engagement through all phases of drug development and research
  2. Identification of the concept of interest and rationale for use
  3. Definition of how patient-centered outcome is a treatment benefit within a proposed context of use
  4. Keeping the patient-perspective in mind during conduct of clinical research; and
  5. Qualification of COAs for regulatory purposes or use of COA in clinical trial

The first requirement for Patient-Centered Outcomes is the clear engagement of patients. According to the current direct of the Study Endpoints and Labeling Division of the FDA Laurie Burke,8 patients should be engaged during the pre- IND stage (see Figure 1) with the following objectives in mind: To define the disease in terms of the important patient phenotypes that will contribute to heterogeneity in the outcome (i.e., diagnostic criteria, symptom burden, relationship of symptoms and signs to daily functioning, impact of disease on life, accommodations made by patients to deal with disease, treatments used, patient demographics);

  • To identify the clinical practice variations that may impact treatment and outcomes, and;
  • To identify the appropriate subgroups to target with the enrollment criteria for future clinical trials.

The second requirement is the conceptualization of PCOs for drug development. By definition, a PCO must be identified with the involvement of the targeted patients or patient advocates. In other words, what is the thing that should be measured? The PCO is conceptualized by identifying the thing(s) that determine treatment benefit. Direct evidence of treatment benefit is demonstrated by a positive impact on survival or on how patients feel or function in daily life. Indirect evidence of treatment benefit is useful only when we know the relationship to survival, feelings, or functioning in daily life. In addition, it was reminded that the PCO concept is different from diagnostic criteria, the pathogenesis of the condition, and the mechanism of action of the targeted treatment. The third requirement is measurement. PCO measures can provide evidence of treatment benefit if they are well-defined and reliable measures of a relevant concept of interest in the context of use defined by the study.3 Well defined and reliable evidence applies only to the context of use tested in the qualitative and quantitative studies used to document the measure’s ability to validly and reliably capture the concept of interest.
The fourth requirement is keeping the patient perspective in mind during the conduct of clinical trials. The fifth requirement concerns qualification. The entire process of using PCOs in the regulatory process can be shortened by considering the regulatory qualification of COAs. The FDA and the EMA are harmonizing their processes and standards for COA qualification review. These agencies suggest concurrent submissions of identical dossiers for parallel review of the outcome assessment. Several recommendations for the inclusion of PCOs into drug development can be given:8

  1. Identify the PCO that will provide the best information for patients early in the drug development program.
  2. Ensure that the PCO can be measured validly and reliably in the targeted context of use.
  3. Interact early and regularly with FDA:
  4. FDA is committed to working with submitters to identify and develop PCO measures.
  5. The timing of interaction should allow for incorporation of advice (EOP2a at the latest).

In other words, always start with the end in mind.

Patient-Focused Drug Development Initiative

The analysis of the context of a regulatory decision is an important component of the benefit-risk assessment. These considerations are embodied by the Analysis of Condition and Current Treatment Options sections of the benefit-risk framework. FDA recognizes that patients have a unique and valuable perspective on these considerations and believes that drug development and FDA’s review process could benefit from a more systematic and expansive approach to obtaining the patient perspective. Though several programs exist to facilitate patient representation, there are currently few venues in which the patient perspective is discussed outside of a specific product’s marketing application review. In PDUFA V,5 FDA committed to a new initiative known as Patient-Focused Drug Development with the objective of obtaining the patient perspective on the condition and the currently available therapies for a set of disease areas during FY 2013-2017. This initiative will add to the existing FDA programs designed to integrate patients’ perspectives.

Figure 1. How do we get Patient-Centered Outcomes into Drug Development?
Presented by and adapted from Laurie Burke (Finding the patient in the drug development process: regulatory perspective) at the ISPOR 18th Annual International Meeting May 2013 – New Orleans
For each disease area, FDA is conducting a public meeting and will invite participation from FDA review divisions, the relevant patient advocacy community, and other interested stakeholders. After each meeting, FDA will publish the meeting proceedings and a summary analysis of the input received by FDA that is relevant to FDA’s consideration of disease severity and unmet medical need. This knowledge will be used to more fully develop an understanding of the disease severity and an assessment of the current state of the treatment armamentarium which are both critical components of FDA’s current benefit-risk framework in regulatory decision-making and communication.

Four meeting were held this year:

Each of the meetings was webcasted for those who could not attend. The webcast recording and transcript of each meeting are available on FDA’s website (www.fda.gov). Exact dates for other future meetings have not yet been set, but 13 additional disease areas were selected (for a total of 16 for fiscal years 2013-2015) – see Table 1.
Table 1. Additional diseases for Patient-Focused Drug Development

Meetings Planned for FY 2014 and FY 2015

  • Alpha-1 antitrypsin deficiency
  • Breast cancer
  • Chronic Chagas disease
  • Female sexual dysfunction
  • Fibromyalgia
  • Hemophilia A, Hemophilia B, von Willebrand disease, and other heritable bleeding disorders
  • Idiopathic pulmonary fibrosis
  • Irritable bowel syndrome, gastroparesis, and gastroesophageal reflux disease with persistent regurgitation symptoms on proton-pump inhibitors
  • Neurological manifestations of inborn errors of metabolism
  • Parkinson’s disease and Huntington’s disease
  • Pulmonary arterial hypertension
  • Sickle cell disease

The remaining meeting topics will be selected by the end of fiscal year 2015.


The use of PCOS in drug development and research requires that we change our culture and focus on the difficult work of conceptualizing treatment benefit early in the development of the intervention. PCOs provide the information that all stakeholders need to make difficult decisions on the efficacy of a medical product. Patient engagement makes the entire research process more credible and relevant to the actual use of the intervention. The more closely related the outcome assessment is to how patient feel and function in their daily life, the more likely we shall find treatment benefit that is meaningful to all stakeholders in health care.


  1. Acquadro C, Berzon R, Dubois D, et al. for the PRO Harmonization Group. Incorporating the patient’s perspective into drug development and communication: an ad hoc task force report of the Patient-Reported Outcomes (PRO) Harmonization Group meeting at the Food and Drug Administration, February 16. Value Health 2001;6(5):522-31.
  2. Food and Drug Administration . Patientreported outcome measures: use in medical product development to support labeling claims. Federal Register 2009; 74(35):65132- 133. Available at http://www.fda.gov/ downloads/Drugs/Guidances/UCM193282.pdf.
  3. U.S. Government Printing Office. Code of Federal Regulations. 21 CFR 314.126 – Adequate and well-controlled studies (April 1, 2010). Available at http://www.gpo.gov/fdsys/granule/CFR-2010-title21-vol5/CFR-2010-title21-vol5-sec314-126/content-detail.html
  4. Regnault A, Acquadro C. FDA Workshop: Measurement in Clinical Trials: Review and Qualification of Clinical Outcomes. PRO Newsletter 2012;47:12-17.
  5. PDUFA V Reauthorization Performance Goals and Procedures; Fiscal Years 2013 through 2017. Available at http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM270412.pdf
  6. Patrick DL. What does “Patient-Centered Outcomes” mean? Presented at ISPOR 18th Annual International Meeting May 2013 – New Orleans. Available at http://www.ispor.org/meetings/neworleans0513/releasedpresentations/first_plenary_donald_patrick.pdf
  7. Berwick D. What “Patient-Centered” Should Mean: Confessions of an Extremist. Health Affairs 2009;28(4):555-565. Available at http://content.healthaffairs.org/content/28/4/w555.full.pdf+html.
  8. Burke L. Finding the patient in the drug development process: regulatory perspective. Presented at ISPOR 18th Annual International Meeting May 2013 – New Orleans. Available at http://www.ispor.org/meetings/neworleans0513releasedpresentations/Second_Plenary_Laurie_Burke.pdf