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• General endpoint considerations

• Surrogate endpoints

• Composite endpoints

• Safety outcomes (adverse events)
      Types of Safety Outcomes (1)

• Adverse events that require reporting to regulatory
  – Serious Adverse Events (SAEs)
  – Suspected Unexpected Serious Adverse Reaction

• Adverse events for planned treatment
  – Treatment discontinuation due to adverse effects
  – Severe adverse effects according standard grading
     • Open-ended
     • Side effect check-list
     Types of Safety Outcomes (2)

• Another way of thinking of the
  – 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

• Related – cannot rule out the possibility that
  the treatment caused the adverse event
  (i.e., the investigator cannot check “not

• 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
     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)
   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

• 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
• Most adverse events reported were mild;
  3% were severe; 1% required expedited
• 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

                            A        B
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

       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
      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

• 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

• 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
                     Grade 1       Grade 2        Grade 3          Life-
                      Mild         Moderate       Severe       threatening
Allergic Reaction   Pruritis w/o   Localized    Generalized    Anaphylaxis
                       rash         urticaria   urticaria or

   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

• 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   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
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

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
• Report status of event
• A single event can be of
  multiple types (e.g., life-
  threatening and required

   Event-Driven Form
   Serious Event CRF
• Record one primary
  event per CRF
• Events must be
  followed to
  resolution or
    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
Ischaemic Coronary Artery Disorders   HLT

     Myocardial Infarction             PT

          Heart Attack                 LLT
MedDRA Hierarchical Structure
  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

                        Percent Ever Reporting
 Bloody Stools           Aspirin     Placebo
 Volunteered             1.29          0.45

 Elicited                 4.86         2.99

 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

• 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

• Interim treatment comparisons are the most important
  component of safety monitoring. These must be done
  to supplement the data on individual case summaries.

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