Outline • General endpoint considerations • Surrogate endpoints • Composite endpoints • Safety outcomes (adverse events) Types of Safety Outcomes (1) • Adverse events that require reporting to regulatory authorities – Serious Adverse Events (SAEs) – Suspected Unexpected Serious Adverse Reaction (SUSARs) • Adverse events for planned treatment comparisons – Treatment discontinuation due to adverse effects – Severe adverse effects according standard grading table • Open-ended • Side effect check-list Types of Safety Outcomes (2) • Another way of thinking of the categorization: – Case reports of individual events – Data on case report form with which to compute counts and rates by treatment group • Both are important (refer to week 1 notes for discussion of case summaries) Guidance Documents • International Conference on Harmonization (ICH) of Technical Requirements of Pharmaceuticals for Human Use – Clinical Safety Data Management: Definitions and Standards for Expedited Reporting E2A • Regulatory authorities have reporting requirements for adverse events – Code of Federal Regulations (CFR) Title 21, Part 312 describes safety reporting for investigational drugs (trials being carried out under an IND with the FDA) – EU Directive provides guidance for reporting safety data for investigational medicinal products Serious Events Definition – ICH Guidelines • Events resulting in death • Life-threatening events • Events leading to hospitalization or prolonging existing hospitalization • Events leading to persistent/significant disability or incapacity • Congenital abnormalities/birth defects • • Other important medical events that may jeopardize the participant or require intervention to prevent one of the other outcomes above Other Definitions • Unexpected – an adverse drug experience which is not consistent with the current investigator brochure (or label for approved drug) • Related – cannot rule out the possibility that the treatment caused the adverse event (i.e., the investigator cannot check “not related”) SUSARs • SUSAR=Suspected Unexpected Serious Adverse Reaction • SUSAR reporting is required by the European Union (EU) Directive 2001/20/EC for all trials being conducted at sites in the European Economic Area (EEA) that use investigational medicinal products (IMPs) What is a SUSAR? • Serious: per ICH GCP Guideline E2A • Unexpected: per labeling of the suspect agent • Suspected adverse reaction: related to treatment Reporting Serious Adverse Events • For trials that we do we require serious events to be reported on all participants, regardless of treatment status or relationship to study treatment (attribution is unreliable and hard to standardize). • This allows a randomized comparison of the occurrence of serious events over the course of the trial • Other expedited reporting requirements (within 7 days of awareness) – IND safety reports for serious adverse events associated with the treatment and unexpected (e.g., see 21 CFR 312.32 for drugs) – SUSARS Informing Investigators, IRBs and Ethics Committees • Individual case reports sent to all investigators using the investigational product by sponsor or designee (e.g., an investigator may receive safety reports for patients in another institution and in another trial) • Investigators notify IRB/EC • Sponsor updates investigator brochure on a regular basis Safety Outcomes - Considerations • Where do you draw the line? – Collect all adverse events irrespective of severity? – Only serious adverse events? – Only why the participants is taking the study treatment? • Standardization – Tables for grading AEs for severity – Open-ended or checklist – MedDRA coding – Event review committee • Describe safety data collection and reporting in the protocol and in the trial report Adverse Events in Cancer Treatment Trials: An Evaluation • Evaluation of 75, 598 “routine” adverse events collected on 1,181 patients between 1999 and 2001. • An average of 2,588 adverse events per study. • Most adverse events reported were mild; 3% were severe; 1% required expedited reporting • Much of what is collected is not reported. J Clin Oncol 2005; 23:9275-9281 Do Not Try to Collect All Adverse Events • You will fail! • Bradford Hill suggested the following 3 questions be asked by the person developing a case report form: – Is this question essential? – Can I obtain useful answers to it? – Can I analyze them usefully at the end? • Peto is less diplomatic: “…the statistician should, at the design stage, cross out most of the things that the trial organizer wants to ask.” Principles of Medical Statistics and Biomedicine 28:24-36, 1978. A Minimalist’s Approach: Composite Hierarchical Outcomes for Safety Treatment A B Death Death or SAE Death, SAE, or Severe AE Death, SAE, Severe AE, or Treatment D/C due to AE Reporting Methods: ESPRIT Report “Grade 4 events were reported irrespective of their perceived relationship to the use of interleukin-2 or antiretroviral therapy and were coded according to the Medical Dictionary for Regulatory Activities (version 12.0)” N Engl J Med 2009; 361:1548-59. Questions to Consider in Reviewing a Report Was event ascertainment similar for the treatments under study? When did collection of AEs begin and end? How were AEs defined? Were severe events centrally reviewed and adjudicated? Problems with Collection and Reporting of Safety Data (1) “We used a five-point scale…to grade adverse events occurring while the patient was taking study drugs and during the eight weeks after their permanent discontinuation”. “All analyses were performed according to intention to treat”. N Engl J Med 1996;335:1099-1106. Problems with Collection and Reporting of Safety Data (2) “The study was designed as an intention-to-treat analysis with data of clinical events (excluding survival) and each subject’s tolerance censored at the termination of the study medication.” AIDS 1994;8:1185. Recommendation: Collect Efficacy and Safety Data for Entire Trial Duration • Some treatments, even if taken for a short period of time, may delay or reverse disease progression. • Likewise, some treatments, even if taken for a short time, may cause toxicities (e.g., liver damage, an acceleration of atherosclerosis) that may not manifest themselves while taking the treatment. • It is important to be able to do a true intent-to- treat analysis. Sample Toxicity Table for Grading Severity of Adverse Events Grade 4 Potentially Grade 1 Grade 2 Grade 3 Life- Mild Moderate Severe threatening Allergic Reaction Pruritis w/o Localized Generalized Anaphylaxis rash urticaria urticaria or angiodema Creatinine >1 – 1.5 >1.5 – 3 >3.0 – 6 ULN > 6.0 ULN ULN ULN Generic Grades Structured (Checklist) vs. Unstructured (Open-Ended) Data Collection • Structured data collection is easier to standardize, process and analyze • Structured data is easier to combine across investigators/studies • Greater chance of missing something with structured data collection • No or less freedom of expression with structured data collection Checklist versus Open Response 1) “Did you look at any of the following newspapers or magazines or journals yesterday? Put a tick (√) against each of them that you definitely looked at yesterday. Put a cross (X) if you did not look at it yesterday.” Daily Mail [ ] The Times [ ] Daily Herald [ ] • • List all others: Belson W., Duncan J. Applied Statistics, 1962. 2) “Did you look at any newspapers or magazines or journals yesterday? This would include daily papers, Sunday papers, weeklies and any that come out monthly. Write down the name of each that you definitely looked at yesterday.” Average Number of Publications Identified in the √ List Group 1 Group 2 Type of Open Open Publication √ List Response √ List Response Daily - - 1.52 1.12 Sunday 1.72 1.23 - - Weekly & Monthly 0.78 0.17 0.90 0.23 Daily Papers on the √ List Percent Percent Mentioned with √’d Open Response Ratio* Daily Mail 16 12 0.78 The Times 4 3 0.70 Daily Herald 9 5 0.54 Evening News 39 27 0.70 Daily Mirror 46 39 0.85 Star 21 12 0.56 Daily Telegraph 17 13 0.77 * Before rounding Average Number of Publications Identified Which Did Not Appear in the √ List Group 1 Group 2 Type of Open Open Publication √ List Response √ List Response Daily - 0.06 0.35 0.61 Sunday 0.18 0.26 - - Weekly & Monthly 0.29 0.39 0.33 0.57 ALL 0.47 0.71 0.68 1.18 Daily Papers Mentioned Under “All Others” on the √ List Percent Percent Mentioned Under Mentioned with “All Others” Open Response Ratio* News Chronicle 6 7 1.12 Daily Express 15 25 1.72 Daily Sketch 7 13 1.95 Evening Standard 5 10 1.94 All Others 3 5 1.99 * Before rounding Conclusions 1. There is a sharp difference in the two methods indicating that at least one of them may be in error when assessing yesterday’s behavior. 2. The yields from the two systems cannot be compared or pooled either within a survey or between surveys. 3. One cannot assume that by using an “all others” response in √ list that the problem of not having an exhaustive √ list is solved. 4. Unstructured questions provide more freedom of expression and structured questions allow less expression of individuality. 5. Some TV programs which were not broadcast the day before were included in the √ list and actually checked by some respondents. They were not mentioned in the open response suggesting an inflating tendency with the √ list. Visit-Driven Questionnaire Serious Event CRF for START study • “Date event became reportable” = date event met criteria for “serious” • Multiple events on same day require multiple CRFs • Complete as soon as possible upon awareness of event • Report status of event • A single event can be of multiple types (e.g., life- threatening and required hospitalization) Event-Driven Form Serious Event CRF (cont) • Record one primary event per CRF • Events must be followed to resolution or stability Serious Event CRF, page 2 • Report any additional clinically significant events related to primary event • If the participant has ever taken ART at any time during the study, proceed to pages 3 & 4 • If the participant has not taken ART, sign and submit only pages 1 & 2 MedDRA Medical Event Coding • Medical Dictionary for Regulatory Activities • Used in U.S., EU, and Japan; mandated for safety reporting in EU and Japan • Each event assigned an 8-digit number • Multi-axial: one event may be linked to multiple System Organ Classes MedDRA Example Cardiac Disorders SOC Coronary Artery HLGT Disorders Ischaemic Coronary Artery Disorders HLT Myocardial Infarction PT Heart Attack LLT MedDRA Hierarchical Structure SOC System Organ Class (n=26) High Level Group Term HLGT (n > 300) High Level Term HLT (n > 1,600) Preferred Term PT (n > 18,000) Lowest Level Term LLT (n > 66,000) Example: Aspirin vs. Placebo in AMIS Study (See Chapter 11 of Friedman, Furberg, and DeMets) Percent Ever Reporting Bloody Stools Aspirin Placebo Volunteered 1.29 0.45 (open-ended) Elicited 4.86 2.99 (√-list) Reason for 0.22 0.04 dosage reduction Summary (1) • Collect less, better. • A “Consumer Reports” analysis of safety and efficacy outcomes is helpful, but cannot be done unless you collect data on all patients for the duration of the study. • More rigorous assessment of safety is necessary in some trials to weigh risks and benefits. • Often a combination of “visit-driven” and “event- driven” data collection is optimal with use of both a checklist and open-ended response questions. Summary (2) • Composite hierarchical safety outcomes can be useful to supplement an analysis of the individual safety components. • Interim treatment comparisons are the most important component of safety monitoring. These must be done to supplement the data on individual case summaries.