Development of a Consensus Document as a Supporting Document for FDA and Other Health Regulatory Authorities on Health-Related Quality of Life Guidances

Since ISPOR membership represents both producer and the user of outcomes research information, the Society has a unique role in facilitating the translation of outcomes research into practice.

ISPOR is developing a supporting a document which can be used by the FDA and other health regulatory authorities in the development of guidances for health-related quality of life claims for labeling and promotion of drugs, biologicals, and devices. This ISPOR initiative is part of an ongoing consensus development process to identify contentious outcomes research issues, develop discussion points, points of concurrence, points of controversy, and recommendations to these issues.


Quality of Life Regulatory Guidance Supporting Document Development Process:

January, 1999, ISPOR leadership (Robert Epstein MD, MS, Bryan Luce PhD, and Marilyn Dix Smith RPh, PhD) met with the FDA (Laurie Beth Burke RPh,MS, DDMAC staff and members of the FDA HRQL Work Group) to identify quality of life labeling and promotional claims issues.

A paper published in Value in Health, Vol. 2, No. 2 (March/April 1999), pp 113-127 titled ‘Recommendations for Evaluating the Validity of Quality of Life Claims for Labeling and Promotion’ by Nancy Leidy PhD, Dennis Revicki PhD, and Bernard Geneste, was used as a basis of discussion at meetings with the FDA and ISPOR leadership. For a copy of this issue see: https://www.ispor.org/valueinhealth_index.asp.

The health-related quality of life claims issues regarding labeling and promotion of drugs, biologicals, and devices issues given below were identified.

An ISPOR Ad Hoc Quality of Life Guidance Committee commented on these issues. Committee members were Catherine Acquadro MD (MAPI Research Institute, Lyon, France, representing the ERIQA Group, responders: Professor Ingela Wiklund and Steven Fullerton, Astra Hässle Quality of Life Research, Mönldal, Sweden), Stephen Coons PhD (The University of Arizona, Tucson, Arizona), Pennifer Erickson PhD (O.L.G.A, State College, PA), Paul Kind PhD (University of York, York, England), Eva Lydick PhD (SmithKline Beecham, Collegeville, PA), and Jane Osterhaus PhD (G.D. Searle, Skokie, IL). Louis Morris PhD (PRR INC, Melville, NY) and Robert Epstein MD, MS (Merck-Medco Managed Care, Montvale, NJ) summarized the committee comments.

For the final document developed by the Ad Hoc Task Force from the Patient-Reported Outcomes (PRO) Harmonization Group Meeting at the Food and Drug Administration, February 16, 2001, see: http://www.ispor.org/workpaper/research_practices/PRO_mc.asp

For good research practices in conducting PRO and health-related quality of life studies for labeling and promotion of drugs, biologicals, and devices, see: http://www.ispor.org/workpaper/practices_index.asp

Quality of Life Promotional and Label Claim Issues for Drugs, Biologicals, and Devices

Issue 1: Terminology - Do we need to use the term ‘quality of life’ for labeling purposes? While it is in the vernacular today, most measures stem from health status assessments, and this may be a more accurate description of the measures.

Issue 2: Stand-alone claims - Can a study that is powered solely to detect QoL be enough for labeling/promotion when there is not enough power to detect a (secondary) clinical endpoint?

Issue 3: Safety

Issue 3a: Should QoL be a substitute for adverse events (AE) reports?
Issue 3b:
When does a question inside a QoL instrument trigger AE reporting?
Issue 3c:
Can one ‘drop’ a QoL question if it would be the type to trigger AE reporting?

Issue 4: Domains

Issue 4a: Three domains are useful, but is there concurrence that these three are it (i.e. physical, psychological, social)?
Issue 4b:
How does satisfaction play in - or is that not a part of QoL?

Issue 5: Side-effects

Issue 5a: Are side-effects part of QoL assessment or separate?
Issue 5b: Should a QoL questionnaire ask about how drugs effect QoL - or should this be disease-specific only?

Issue 6: Clinical trial administration

Issue 6a: Should there always be a generic and disease-specific questionnaire used in clinical trials?
Issue 6b:
How does one ensure follow-up on treatment protocol violators/drop-outs for QoL measurement?

Issue 7: Timing / administration of measurement

Issue 7a: What is the appropriate time frame for the measures to be collected? Should it correspond to when clinical measures are obtained - more frequently or less - if it’s a chronic drug, is 6 weeks long enough, etc?
Issue 7b:
Should the questionnaires be administered at the beginning of clinic visits or after the patients have already had other tests done?
Issue 7c: Should the respondents see their prior answers?

Issue 8: Blinding - Under what circumstances could results from an unblinded evaluation ever be used for marketing or promotion?

Issue 9: Development

Issue 9a: Can an instrument be truly valid if it is comprised of a battery of scales that an investigator put together without patient input?
Issue 9b:
What could be the rationale or the validation associated with a battery-of-scales approach?

Issue 10: Evidence of proper development and validation

Issue 10a: What is needed to be submitted with CT data to FDA?
Issue 10b:
How much correlation should there be between QoL measures and clinical measures?

Issue 11: Responsiveness - Should responsiveness be proven prior to a clinical trial being undertaken — or, if discovered in the trial, is this good enough?

Issue 12: Clinical significance

Issue 12a: How is clinical significance determined?
Issue 12b:
Should a trial be powered to detect clinical significance up-front?
Issue 12c:
If a difference is found to be statistically significant but it is not ‘clinically significant’ - can a claim be filed?

Issue 13: Statistical analysis

Issue 13 a: What is the role of summary scores across domains vs domain specific?
Issue 13b:
Should QoL be analyzed with intention-to-treat and per-protocol, like all other endpoints?
Issue 13c:
Should missing data be handled the same way it is handled in symptom scores?
Issue 13d:
Is there any circumstance where a different p-value could be used (eg.10)?
Issue 13e:
How many clinical trials to support a label claim - one vs two?
Issue 13f:
Why should QoL endpoints be statistically treated differently than clinical endpoint (i.e. multiplicity)?
Issue 13g: Under what circumstances can a claim be filed for equivalence?