1. Patient Reported Outcomes in Oncology Trials Virginia Kwitkowski Clinical Reviewer-- FDA Division of Drug Oncology Products Member OND Patient Reported Outcomes Committee CTEP Program Committee Meeting 03/18/09

2. Objectives Provide a history of the use of PROs in FDA drug approvals Describe FDA draft guidance on Patient Reported Outcomes Discuss the evolution of PROs in toxicity reporting

3. What Is The Regulatory Benchmark Needed? Evidence of drug effectiveness is deemed substantial for claims in product labels if supported by adequate & well-controlled clinical trials using endpoint assessments that are well-defined and reliable to measure the specific concept(s) stated or implied by the claims.

4. What Is A PRO? A measurement of any aspect of a patient’s health status that comes directly from the patient, without interpretation of the patient’s responses by a clinician or research associate

5. Why Do We Need PROs in Cancer Trials? The 1962 amendment to the Federal Food, Drug, and Cosmetic Act requires that new drugs have substantial evidence of effectiveness and specifies that this evidence must be derived from adequate and well-controlled clinical investigations. To provide evidence of clinical benefit, many different endpoints have been utilized in the past.

6. What Endpoints Provide Substantial Evidence of Clinical Benefit?

7. Pathways to FDA Approval Regular Approval Accelerated Approval

8. Pathways To Approval Regular Approval = Approval based on proof of clinical benefit in the proposed indication Accelerated Approval = “Conditional approval” in a serious or life-threatening condition for an agent that demonstrates an improvement over available therapy or provide one where none exists. Accelerated approval is not a method for seeking approval based upon a failed trial, or post-hoc subgroup analyses.

9. Key Points in the Endpoints Guidance Today, in oncology, improvement in overall survival is considered an appropriate measure of clinical benefit for regular approval. Advisory Committee 1980s: Approval based on direct evidence of clinical benefit –Overall Survival advantage –QOL –Improvement in physical functioning –Improvement in tumor-related symptoms

10. How Can Clinical Benefit Be Demonstrated Using PROs? Symptom Endpoints: Patient perspective of direct clinical benefit ; some treatment effects are ONLY known to the patient. Challenges of PROs Blinding is often difficult Data are frequently missing or incomplete Clinical significance of small changes is unknown Multiple analyses (need to adjust alpha) Lack of validated instruments

11. PROs as Trial Endpoints Symptomatic Improvement = Clinical Benefit FDA has approved drugs based upon patient symptom assessments and/or physical signs representing symptomatic improvement (e.g., weight gain, decreased effusion) as the primary efficacy endpoint. However, measures of global health-related quality of life (HRQL) have not served as primary efficacy endpoints in oncology drug approvals. Why not??????

12. Why Doesn’t Global QOL Meet the Need? Global QOL assessments must allow the FDA to differentiate between improvement in tumor symptoms and lack of drug toxicity. Because…an apparent effectiveness advantage based on a global HRQL instrument can simply indicate less toxicity rather than effectiveness.

13. What PROs Could Work? Time to Progression of Cancer Symptoms –Advantages: Measured by the patient; shorter follow-up time than OS; saves cost of independent radiology review; no investigator bias; direct measure of clinical benefit. –Limitations: Missing assessments can limit the ability to accurately measure any “time to event” endpoint; trial blinding necessary to avoid bias; if a delay occurs between objective disease progression and progression of disease symptoms, alternative treatments may be started. –Considerations: For time to symptom progression, patients must have symptoms at baseline to measure change. However, a “time to first symptom” endpoint could be used in an asymptomatic population.

14. History of PROs in FDA Drug Approvals ProductConcept MeasuredContext PorfirmerDysphagia in obstructing esophageal Ca Complement to endoscopic response rate 3 NSCLC symptoms: dyspnea, cough, hemoptysis Complement to bronchoscopic response rate GemcitabinePain/analgesic use/PS/weight gain in pancreatic Ca Complement to overall survival, time-to-progression HRQL in NSCLC (no effect)Complement to safety data MitoxantronePain/analgesic use in HRPCPrimary evidence of efficacy Topotecan9 SCLC symptoms: shortness of breath, interference with daily activities, fatigue, hoarseness, cough, insomnia, anorexia, chest pain, hemoptysis Complement to response rate AmifostineImprovement in xerostomia from radiotherapy Complement to measurement of saliva production ImatinibAbsence of interferon toxicityComplement to PFS PaliferminMucositis preventionPrimary evidence of efficacy Rock et al. J Clin Oncol 2007;25(22):5094-9

15. What Drugs Have Been Approved Based Upon PROs? Eculizumab (Soliris) Indicated for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis

16. Labeling Claim: Soliris Labeling: “…patients reported less fatigue and improved health-related quality of life… FDA Clinical Review: Soliris studies demonstrated persuasive treatment effects as evidenced by changes in the FACIT-fatigue and EORTC QLQ- C30 scores. [SEALD discouraged use of] the word, “fatigue.” During labeling discussions, the sponsor insisted upon the use of “fatigue” and the SEALD team, at one point, acknowledged the size of the treatment effects in FACIT-fatigue and did not object to the use of the word, “fatigue.”

17. http://www.fda.gov/cder/guidance/5460dft.pdf Draft published Feb 2006. Final version currently going through clearance process…. No major policy revisions expected. Clarifies policy in response to comments.

18. Purpose of the PRO Guidance To explain how FDA evaluates PRO instruments for their usefulness in measuring & characterizing treatment benefit as perceived by the patient. To ensure product developers that FDA recognizes the importance of the patient perspective where appropriate. To explain FDA’s evidence requirements when PRO instruments are used as evidence to support claims. The guidance does not address other PRO uses.

19. When is a PRO Instrument adequate to support claims? The adequacy of a PRO instrument as a measure to support medical product labeling claims depends on its documented measurement properties that demonstrate the instrument is “fit for purpose.”

20. FDA Instrument Review FDA can only evaluate an instrument in the context of its intended use (i.e., specific clinical trial, desired labeling claim) In other words, there is no such thing as an instrument “validated” for all uses The most critical consideration is whether content validity has been established with input from patients in the target population demonstrating that the claimed concept is adequately measured by the instrument In the absence of content validity, other measurement properties are inadequate

21. The Evolution of PROs PROs are being integrated into the assessment of toxicities in clinical trials Why? –Current toxicity data derived from unstructured patient interviews –Data capture involves clinician interpretation of patient reporting –Systematic underreporting of symptom number, severity, time of onset/resolution

22. CTCAE-PRO Work is ongoing in the development of a system to accurately assess symptom severity as reported by patients participating in cancer clinical trials Development of patient versions of certain subjective CTCAE toxicity criteria Item development not for use in assessment of the efficacy of an agent

23. Summary PROs are valuable instruments in obtaining information about clinical benefit or toxicity Measurement properties of tool is critical! Patients CAN self-report toxicities more accurately than clinicians

24. Back-Up Slides

25. Measurement Properties of the Instrument Assess the instrument’s ability to measure the intended concept Content validity Reliability –Cronbach’s alpha –Test-retest Construct validity –Convergent –Discriminant Ability to detect change

26. Content Validity Evidence that the items and domains measure: –The intended concept as diagrammed in the conceptual framework –The desired claim Evidence that the items, domains & concepts were developed with patient input & are: –Appropriate –Comprehensive –Interpretable by patients Testing other measurement properties will not replace or rectify problems with content validity

27. Content Validity Documentation In addition to literature and expert opinion, content validity is documented by: –Evidence of patient input in the target patient population (i.e., same population that will be studied in safety/efficacy trials). This is important because disease symptoms are conceptualized differently between medical environments and between patients with differing disease manifestations. –Evidence of diversity in demographic and disease characteristics (within the target population)