SAFETY OF MEDICINES: CLINICAL C TRIALS AND PHARMACOVIGILANCE. Robert Lindblad, M.D. Chief Medical Officer The EMMES Corporation

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1 SAFETY OF MEDICINES: CLINICAL C TRIALS AND PHARMACOVIGILANCE Robert Lindblad, M.D. Chief Medical Officer The EMMES Corporation

2 The Quality of Safety Data Sf Safety vs. efficacy Adverse event reporting Limitations Alternative strategies Methods to implement Examples

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4 Safety and Efficacy Efficacy (Benefit) Moves drug development forward Pre specified Primary outcome for drug approval Structured data collection Safety (Risk) Holds drug development back Primary outcome only in Phase 1 Typically unstructured data collection

5 Adverse Event Collection The safety Gold Standard d Observe safety signals Create Pharmacovigilence il Create separate data base for SAEs Medical review for each SAE report Reconcile with clinical data base Unstructured data

6 Adverse Event Collection Increasing reliability of AE data Site monitoring for unreported AEs and SAEs Standardize di characterization i MedDRA coding

7 Evaluation of Safety Data Specifed safety outcomes High himportance, higher h quality data, increases reliability and reproducibility Laboratory and vital signs Variable importance, higher quality data, increases reliability and reproducibility Adverse events High importance, low quality data, subjective, difficult to reproduce, Limited information regarding protocol, CRFs, site quality and variability Even more limited with postmarketing reports

8 Data Quality Best data Structured Defined data elements Consistent reporting outcome data, laboratory data, vital signs Worst data Spontaneous reporting Unstructured adverse events Two Examples

9 Data Quality AE Reporting Site Variability a Large Multi Site Study Site Total # Total % of Subjects Subjects Randomized with AE with AE subjects A B C D E F G H I

10 Data Quality AE Reporting Site Variability a Large Multi Site Study Site Total # Total % of Subjects Subjects Randomized with AE with AE subjects A B C D E F G H I

11 Data Quality AE Reporting Site Variability a Large Multi Site Study Site Total # Total % of Subjects Subjects Randomized with AE with AE subjects A B C D E F G H I

12 Data Quality AE Reporting Unstructured Data Collection Two clinical trials using adverse event reporting and a structured assessment for suicide Unstructured adverse event MedDRA coded 4 of 480 participants (0.8%) Depression suicidal (1), suicidal ideation (2), suicide attempt (1) Structured assessment Suicidal ideation without intent 82 of 480 participants (17.1%) Suicidal ideation with intent 3 of 480 participants (0.6%) 3 out of 4 participants reporting suicidal adverse events were also captured on the structured assessment

13 Adverse Event Collection What do we see? Maybe we see 100% of events Maybe we see the tip of the iceberg

14 Importance of Safety Reporting 4th Annual Meeting of the Age-Related Eye Disease Study 2: April 2009

15 Importance of Safety Reporting

16 Why Adverse Event Reporting Unknown risks Unknown data elements Mitigate lack of structure MedDRA code terms Standardize di characterization terms Severity Causality Expectedness The Safety Net How well does MedDRA mitigate the variability in reporting?

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19 Background March 14, 2003 FDA issued proposed rule to revise its regulations governing gpre and post marketing safety reporting for human drugs and biological products. 110 comments received from Manufacturers, Trade Representatives, CROs, Universities etc. September 29, 2010 FDA published a final rule amending safety reporting requirements for INDs and Bioavailability/Bioequivalence (BA/BE) Studies. September 2010 Draft Guidance issued to address rule changes March 28, 2011 Final Rule became effective. Post marketing safety reporting requirements will be addressed later by FDA.

20 FDA Guidance Sept 2010 VI. OTHER SAFETY REPORTING ISSUES A. Alternative reporting arrangements (21 CFR (c)(3)) 32(c)(3)) Title 21 of the CFR, (c)(1) and (c)(1)(v) specify the format and timeframe for reporting suspected adverse reactions in an IND safety report (see section VII). Sponsors may request and adopt different reporting formats or frequencies if agreed to in advance by the director of the FDA review division that has responsibility for review of the IND (21 CFR (c)(3)).

21 FDA Guidance Sept 2010 i. Identifying i and monitoring i protocolspecified serious adverse events At the time of protocol development, the sponsor should identify in the protocol the serious adverse events that it does not plan to report individually in an expedited manner because they are anticipated to occur in the study population at some frequency independent of drug exposure.

22 Generating Safety Data Protocol developmentelopment Case report form design Data collection Analysis Reporting

23 Protocol Development Any safety parameters known Collect as specific data points Do not duplicate report as an adverse event Adverse event collection as safety net

24 Example IND food allergy study Administer allergen to achieve tolerance Capture reactions as dosing symptoms Do not report as adverse events If a symptom becomes an SAE report as symptom and as SAE Include all AEs and SAEs and dosing symptoms Include all AEs and SAEs and dosing symptoms in annual safety reports

25 Case Report Form Dosing Symptoms

26 Data Collection Dosing Symptoms

27 Analysis Dosing Symptoms # Any Skin Resp. GI Neur. Circ. Other Visit Type Doses Symptoms Symptoms Symptoms Symptoms Symptoms Symptoms Symptoms Escalation Clinic i Dose 347 Moderate Mild Moderate Moderate None None Mild Non-Escalation Clinic Dose 730 Moderate Moderate Moderate Moderate None None Moderate Home* Moderate Moderate Moderate Moderate None None Moderate All Moderate Moderate Moderate Moderate None None Moderate Symptom Free Symptom Free Excluding Oral Pharyngeal Alone Oral Phary. Skin Respiratory GI Other Symptoms Symptoms Symptoms Symptoms Symptoms Symptoms > 0.5 Hour Treated # Visit Type Doses N % N % N % N % N % N % N % N % N % Escalation Clinic Dose Non-Escalation Clinic Dose Home* All

28 Analysis Dosing Symptoms # Any Skin Resp. GI Neur. Circ. Other Visit Type Doses Symptoms Symptoms Symptoms Symptoms Symptoms Symptoms Symptoms Escalation Clinic i Dose 347 Moderate Mild Moderate Moderate None None Mild Non-Escalation Clinic Dose 730 Moderate Moderate Moderate Moderate None None Moderate Home* Moderate Moderate Moderate Moderate None None Moderate All Moderate Moderate Moderate Moderate None None Moderate Symptom Free Symptom Free Excluding Oral Pharyngeal Alone Oral Phary. Skin Respiratory GI Other Symptoms Symptoms Symptoms Symptoms Symptoms Symptoms > 0.5 Hour Treated # Visit Type Doses N % N % N % N % N % N % N % N % N % Escalation Clinic Dose Non-Escalation Clinic Dose Home* All

29 Analysis Adverse Events 362 AEs reported 4 SAEs reported 2,966 dosing symptoms reported reported as structured data vs. unstructured reported as structured data vs. unstructured adverse events

30 Reporting Publication and clinical i l study report Describe strategy Include both targeted reporting Include adverse events

31 Summary Safety reporting Starts with the protocol Define safety reporting parameters and data collection strategies as carefully as efficacy outcomes

32 Summary Provide structure t to safety reporting to increase data quality, reproducibility and reliability Maintain unstructured adverse event reporting as a safety net Report both sets of data to facilitate interpretation t ti of safety profile and assessment of risk benefit