The Elephant in the Room: Meaningful Communication of Near Synonyms as Suspected Adverse - PowerPoint Presentation

The Elephant in the Room: Meaningful Communication of Near Synonyms as Suspected Adverse ReactionsA Perspicacious CIOMS View of a Sometimes Tangled Mass of Adverse Reaction Communication ChallengesSession #282Tuesday, 25 June 2019, 4:15-5:30 pm, Room 6D William W. Gregory for the CIOMS MLG Exploratory Team Pfizer Inc

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Clinicians and the healthcare community need clear, consistent, and understandable information in RSI for biopharmaceuticalsLarge amounts of important safety evidence must be distilled for pragmatic (and regulatory) use in RSIExisting regulatory guidance on how to express suspected adverse reactions in RSI permits needed flexibilityPresentation of some data may be straightforward, whereas certain other data may be more challengingWhen existing terminology, e.g., MedDRA, is not appropriate, little guidance is available on how to achieve the desired representations in RSI and outcomes in healthcareHarmonized, consensus principles for grouping of terms and simplification of RSI are needed Independent “one-off” approaches are emerging Problem Statement

“In general, the ADVERSE REACTIONS section includes only information that would be useful to health care practitioners making treatment decisions and monitoring and advising patients. Exhaustive lists of every reported adverse event, including those that are infrequent and minor, commonly observed in the absence of drug therapy or not plausibly related to drug therapy should be avoided …. Such lists are not informative and tend to obscure the more clinically meaningful information.” (p 2) Guidance for Industry Adverse Reactions Section of Labeling for Human Prescription Drug and Biological Products — Content and Format, January 2006 (16 pp)Requirements are in 21 CFR 201.57(c)(7)Current Guidance: US FDA

“The SmPC is the basis of information for healthcare professionals on how to use the medicinal product safely and effectively.” (p 2)“Consistent medical terminology should be used throughout the SmPC. For example, the use of MedDRA as described in the annex for section 4.8 should be applied though [sic] the SmPC, in particular for sections 4.3 and 4.4 and 4.8.” (p 3)Undesirable effects (Section 4.8), “It is important that the whole section is worded in concise and specific language …” (p 15)“Frequencies of cited adverse reactions should be stated as accurately as possible.” (p 16)European Commission Notice to Applicants (Rev 2): A guideline on Summary of Product Characteristics (SmPC), September 2009 (29 pp) Current Guidance: European Commission

“Adverse reactions that are reported under different terms in the database, but that represent the same phenomenon (e.g., sedation, somnolence, drowsiness) or disease pathophysiology in more than one body system (e.g., congestive heart failure: nocturnal dyspnoea, angina, pedal oedema) should be grouped together as a single adverse reaction to avoid diluting or obscuring the true effect.” (p 22) Health Canada Guidance Document: Product Monograph, June 2016Current Guidance: Health Canada

Regulated adverse event data are coded with MedDRAIs a single PT appropriate? A grouping of PTs at a higher level may be suitable for direct representation of a clinically-meaningful concept in RSIHigh Level Term (HLT) Renal lithiasis (10038478)Three PTs (v 21.1): PT Nephrocalcinosis (10029146)PT Nephrolithiasis (10029148) PT Stag horn calculus (10041900) First: Use the Existing MedDRA Hierarchy

Clinical trial data a Assume only one report of dizziness applies to each subject What RSI is useful to a clinician?Next: “… useful to healthcare practitioners …” Suspected adverse reaction Frequency a Dizziness 6%

MedDRA coding and data analysis have matured in the regulated data spaceExisting regulatory guidance focuses on communication of useful information in RSIProblem statement from a CIOMS exploratory teamReference Safety Information (RSI) is intended for communication and has regulatory and practical goalsThe MedDRA hierarchy may often be sufficient to convey clear medical concepts to the healthcare community, but sometimes notMedDRA is foreign to most practicing cliniciansNon-hierarchical groupings of closely-related concepts may sometimes be needed Is it feasible to develop harmonized principles to group near synonyms for communication purposes?Summary of Introductory Comments

William W. Gregory for the CIOMS MLG Exploratory GroupPfizer IncJoin the conversation #DIA2019Thank You