Improving Adverse Drug Reaction Information in Product Labels. EFSPI IDA Webinar 28 th Sept 2017 Sally Lettis
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1 Improving Adverse Drug Reaction Information in Product Labels EFSPI IDA Webinar 28 th Sept 2017 Sally Lettis
2 Improving Adverse Drug Reaction Information in Product Labels 2
3 Outline Current Labelling Practice Current Labelling Limitations The problem to solve The proposed solution Improving Adverse Drug Reaction Information in Product Labels 3
4 Current Labelling Practice Product labels are intended to provide health care professionals with clear and concise prescribing information that will enhance the safe and effective use of drug products. Improving Adverse Drug Reaction Information in Product Labels 4
5 Current Labelling Practice: US Product Label Quantitative approach used in the Adverse Reactions section Incidence of common ADRs presented Common defined as an ADR that occurs at or above a specified incidence e.g. >=3% A comparator must be provided, except in exceptional circumstances. Typically, a single ADR table is included; however, more than 1 can be included when the ADR profile differs substantially from one setting or population to another Improving Adverse Drug Reaction Information in Product Labels 5
6 Current Labelling Practice: EU SPc ADRs (from RCTs) placed into frequency categories Convention for classification: very common (1/10), common (1/100 to <1/10), uncommon (1/1,000 to <1/100), rare (1/10,000 to <1/1,000), and very rare (<1/10,000); (CIOMS III and V) Comparator typically not included Category based on crude incidence on drug. Studies included don t need common comparator For drugs for long-term use, there is no representative duration; in practice, studies of differing durations are combined together Only in exceptional cases is more than 1 table included for different populations Improving Adverse Drug Reaction Information in Product Labels 6
7 Current Labelling Limitations: The issue with no comparator data in label Disease Severity Duration Incidence on drug In label it is an ADR and is common Category X Moderate 3 months 0.6% Uncommon - X Moderate 6 months 1.5% Common 1.7% X Severe 12 months 6.3% Common 3.3% X Pooled 3.0% Common 2.6% Heterogeneity? Appropriate to combine? Helpful for patient? If two similar drugs tested in different populations very different incidences with no comparator data to contextualise Incidence on Comparator Y Pooled 0.5% Uncommon Different X+Y Pooled 1.0% Common Multiple Improving Adverse Drug Reaction Information in Product Labels 7
8 Current Labelling Limitations: The issue with crude pooling Data presented is based on crude pooling of data across multiple studies: pooling data as if from a single study Can lead to Simpson s Paradox : When studies combined, trend seen in the individual studies either disappears or is reversed Why? Can result in an overall baseline risk that is different among treatment groups due to differing randomization allocations within a study and different study populations across studies Differences that could affect the incidence include age, sex, race, medical practice, differing time on study Common for reporting proportions with an ADR in labels Not a new issue (Chuang-Stein and Beltangady (2010)) E.g. Cochran-Mantel-Haenszel to produce a common odds ratio across strata If used, applied in Integrated Summaries of Safety Too complicated for Product Labels which revert to crude incidences Improving Adverse Drug Reaction Information in Product Labels 8
9 Current Labelling Limitations: Example showing misleading incidence proportion from crude pooling New treatment, Placebo, Total patients in study Phase 2 study 30/300 (10%) 10/100 (10%) 400 Phase 3 study 133/700 (19%) 67/350 (19%) 1050 Phase 3 study in refractory patients Incidence proportion: crude pooling 200/500 (40%) 200/500 (40%) /1500 (24%) 277/950 (29%) 2450 N = total number of patients in the group; n = the number in the group that experienced the event The last row gives the impression the new drug has a beneficial effect, though the AE incidences are equal in each study. If you were to do a statistical test -> p=0.007 Improving Adverse Drug Reaction Information in Product Labels 9
10 Current Labelling Limitations: Why did crude pooling go wrong? New treatment, Placebo, Total patients in study Allocation Ratio Phase 2 study 30/300 (10%) 10/100 (10%) 400 3:1 Phase 3 study 133/700 (19%) 67/350 (19%) :1 Phase 3 study in refractory patients Incidence proportion: crude pooling 200/500 (40%) 200/500 (40%) :1 363/1500 (24%) 277/950 (29%) 2450 N = total number of patients in the group; n = the number in the group that experienced the event Studies with uniformly lower ADR proportions (e.g. Phase 2) have more subjects on new treatment than placebo Improving Adverse Drug Reaction Information in Product Labels 10
11 The problem to solve: So what do we do? We can see what the issue is How should we present adjusted proportions? Conclusions from crude pooling misleading Meta-analytic techniques: e.g. Cochran-Mantel-Haenszel weights Not easy for non-statistician to understand Improving Adverse Drug Reaction Information in Product Labels 11
12 The Proposed Solution: A better way to go Study-size Adjusted Percentages New treatment, Placebo, Total patients in study Proportion of total patients in study Phase 2 study 30/300 (10%) 10/100 (10%) 400 w 1 = 400/2450 (16%) Phase 3 study 133/700 (19%) 67/350 (19%) 1050 w 2 = 1050/2450 (43%) Phase 3 study in refractory patients Incidence proportion from crude pooling 200/500 (40%) 200/500 (40%) 1000 w 3 = 1000/2450 (41%) 363/1500 (24%) 277/950 (29%) 2450 Improving Adverse Drug Reaction Information in Product Labels 12
13 The Proposed Solution: A better way to go Study-size Adjusted Percentages New treatment, Placebo, Total patients in study Proportion of total patients in study Phase 2 study 30/300 (10%) 10/100 (10%) 400 w 1 = 400/2450 (16%) Phase 3 study 133/700 (19%) 67/350 (19%) 1050 w 2 = 1050/2450 (43%) Phase 3 study in refractory patients Incidence proportion from crude pooling Study-sizeadjusted incidence proportions 200/500 (40%) 200/500 (40%) 1000 w 3 = 1000/2450 (41%) 363/1500 (24%) 277/950 (29%) 2450 w 1 x (30/300) + w 2 x (133/700) + w 3 x (200/500) = 26% w 1 x (10/100) + w 2 x (67/350) + w 3 x (200/500) = 26% Improving Adverse Drug Reaction Information in Product Labels 13
14 Comparison of Weights for New Treatment New treatment Study Size Weights in Crude Pooling = Proportion of total patients on new drug Weights in Study sized pooling = Proportion of patients in study Weights using CMH a j = (n 1j n 2j )/ (n 1j +n 2j ) Study 1 30/300 (10%) Study 2 133/700 (19%) Study 3 200/500 (40%) N w 1 = 300/ % 1050 w 2 = 700/ % 1000 w 3 = 500/ % w 1 = 400/ % w 2 = 1050/ % w 3 = 1000/ % w 1 = a 1 / a j 13% w 2 = a 2 / a j 42% w 3 = a 3 / a j 45% w 1 x (30/300) + w 2 x (133/700) + w 3 x (200/500) = 24% w 1 x (30/300) + w 2 x (133/700) + w 3 x (200/500) = 26% w 1 x (30/300) + w 2 x (133/700) + w 3 x (200/500) = 27% Study Adjusted Size and CMH weights same for each treatment; Crude pooling weights are not 14
15 Comparison of Weights for Placebo Placebo Study Size Weights in Crude Pooling = Proportion of total patients on placebo Weights in Study sized pooling = Proportion of patients in study Weights using CMH a j = (n 1j n 2j )/ (n 1j +n 2j ) Study 1 10/100 (10%) Study 2 67/350 (19%) Study 3 200/500 (40%) N w 1 = 100/950 11% 1050 w 2 = 350/950 37% 1000 w 3 = 500/950 53% w 1 = 400/ % w 2 = 1050/ % w 3 = 1000/ % w 1 = a 1 / a j 13% w 2 = a 2 / a j 42% w 3 = a 3 / a j 45% w 1 x (10/300) + w 2 x (67/350) + w 3 x (200/500) = 29% w 1 x (10/100) + w 2 x (67/350) + w 3 x (200/500) = 26% w 1 x (10/100) + w 2 x (67/350) + w 3 x (200/500) = 27% Study Adjusted Size and CMH weights same for each treatment; Crude pooling weights are not 15
16 Current labelling limitations: The Issue with Rule of 3 If ADR not observed in clinical trials but determined to be causally related post authorization based on spontaneous reports, Rule of 3 used to estimate category using sample sizes from clinical trials If X is number of patients exposed to drug in all relevant clinical trials, then frequency category would be 3/X, the upper limit of a 95% CI for the true incidence proportion of the event in question This method estimates the incidence proportion by the upper end of a range of plausible values for the incidence proportion. By doing so, ADRs that were never reported in clinical trials can be assigned to a frequency category that is higher than the category for ADRs that were reported in clinical trials. Anomalies arise when AE was observed in clinical trials at same or lower incidence than placebo and so not considered ADR. Subsequently included as ADR based on spontaneous reports. Frequency? Improving Adverse Drug Reaction Information in Product Labels 16
17 Recommendations That product labels that include comparator data be changed to include adjusted incidence proportions (or rates) when needed for adverse drug reactions (ADR) that are somewhat common. Product labels better reflect the risk of a drug relative to a comparator Not needed if: The ratio of patients receiving the new drug to that receiving the comparator is approximately the same across all the studies included or Incidences of AEs in the comparator group are nearly the same across the studies If crude pooling be sure to look at the individual study results to check that pooled results are consistent with the individual studies Including comparator incidence in product labels gives health care providers and patients appropriate information to put the absolute risks in perspective Move from reporting extremely rare events using Rule of 3. Suggest using a separate table for ADRs from PM Reports Improving Adverse Drug Reaction Information in Product Labels 17
18 References Crowe, B., Chuang-Stein, C., Lettis, S., & Brueckner, A. (2016). Reporting Adverse Drug Reactions in Product Labels. Therapeutic Innovation & Regulatory Science, 50(4), Chuang-Stein, C., and Beltangady, M. (2010). Reporting Cumulative Proportion of Subjects With an Adverse Event Based on Data From Multiple Studies. Pharmaceutical Statistics, 10, 3 7. Improving Adverse Drug Reaction Information in Product Labels 18
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