# Presentation: 359819

## The Analysis of Adverse Drug Reactions in Clinical Trials:A Basis for Communicating and Managing  Risk

**Robert T. O’Neill Ph.D.**
**Director, Office of Biostatistics, CDER, FDA**

**To be presented May 22, 2001 **
**at the Society for Clinical Trials 22 ****nd **** Annual Meeting, Denver, Colorado**

## Outline of talk

**Will focus on the estimation of event rates for serious events whose characterization in RCT’s is critical to communicating and managing risk**
**Concepts and measures of event rates and their estimation**
**Communicating and managing risk : reporting adverse event rates in the label of a new drug**
**Impact of misclassification on detection of ADR’s**
**Challenges in the future to improve the understanding and analysis of adverse drug reaction information**

## Managing risk by preventing known risks of serious events

**Options:**
**Approval/non -approval**
**Limit the population exposed**
**Search for predictive risk factors that can be communicated in a drug label to inform patient prescribing and management**

## Communicating the risk of known serious events to the patient and physician in quantitative terms

**Types of exposure (Acute, Chronic, interactions of two or more drugs)**
**Types of adverse events (serious; usually associated with hospitalization, morbidity and/or mortality (withdrawal from RCT)**
**The drug label (Incidence rates,Time dependencies, Monitoring strategies to prevent/ minimize the occurrence)  **

## Metrics of risk : Quantifying adverse event rates

**Crude rate  R = X / N**
**Occurrences per unit time of exposure - constant hazard rate; delayed events**
**Life table or cumulative rates**
**Hazard rates and functions**
**Competing risks - death , GI bleeding**
**Accounting for differential exposure time -acute and chronically administered drugs**

##   Quantifying the incidence When you don’t observe an adverse event in a defined cohort of size N

**The ‘ *****rule of three***** ’ for upper 95% confidence limit : 3 / (N + 1)**
**The ‘ *****rule of seven***** ‘ for the upper 99% confidence limit : 7 / (N + 1)**
**References**
**Jovanovic and Levy, ‘A Look at the Rule of Three, American Statistician, V 51, 1997, 137-139**
**Jovanovic and Viana, Upper Confidence Bounds for Binomial Probability in Safety Evaluation (1997), Amer. Stat. Assoc. 1996 Proceedings of the Section  on Biopharmaceuticals, 140 - 144**

## Incidence of Adverse Drug Events and Potential Adverse Drug Events - Implications for Prevention;  Bates, et al, JAMA, July 5, 1995, Vol 274 29-34.
Incidence and Clinical Course of Thrombotic Thrombocytopenic Purpura Due to Ticlopidine Following Coronary Stenting;   Steinhubl, et al, JAMA, March 3, 1999, Vol 281, 806-810

**Incidence and Clinical Course of Thrombotic Thrombocytopenic Purpura Due to Ticlopidine Following Coronary Stenting;   Steinhubl, et al, JAMA, March 3, 1999, Vol 281, 806-810**

**Incidence:   The simplistic view-**** A single number, without reference to time frame,  duration of exposure , or other factors**

**Incidence of Adverse Drug Reactions in Hospitalized Patients - A Meta-analysis of prospective studies; Lazarou, et al, JAMA, April 15, 1998, Vol 279, 1200-1205**
**Age and sex distribution of suspected adverse drug reactions to newly marketed drugs in general practice in England: analysis of 48 cohort studies; Martin, et al, British J Clinical Pharmacology, 1998, V 46, 505-511**

## Incidence: The misunderstood view -The concept that risk is not constant and is a function of several identifiable factors, especially exposure time

**Behavior of the Exposure Odds Ratio in Case - Control Study When the Hazard Function is Not Constant Over Time**
**Guess; J. Clinical Epidemiology, V42, No12, 1989, 1179-1184**
**A Population-Based Study of Appetite-Suppressant Drugs and the Risk of Cardiac-valve Regurgitation**
**Jick et al;  NEJM, 1998, V 339, 719-724**

## Some basic concepts on cumulative risk and time

## DURATION OF EXPOSURE PATTERN

**O'Neill RT 1988**

**DURATION OF EXPOSURE PATTERN**
**FOR SUBJECT FOLLOW UP**

## FREQUENCY OF OCCURRENCE OF 30

**ADVERSE EVENTS: 3 PATTERNS**

**O'Neill RT 1988**

## ESTIMATED CUMULATIVE ADVERSE EVENTS FOR 

**ESTIMATED CUMULATIVE ADVERSE EVENTS FOR **
**THREE PATTERNS OF ADVERSE EVENTS OCCURRENCE**

**O'Neill RT 1988**

## HAZARD FUNCTIONS FOR THREE PATTERNS

**OF DRUG-INDUCED CLINICAL EVENTS**

**O'Neill RT 1988**

*** OR  RISK PER UNIT TIME**

**MONTHS FROM INITIAL DRUG EXPOSURE**

***HAZARD RATE**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**10**

**11**

**12**

**DECREASING**

**DELAYED (INCREASING)**

**CONSTANT**

## Rational Risk Management requires us to distinguish between the two views of incidence :    Why ?

**Detecting risk can depend on it - obscure signal**
**Proper characterizing and quantifying the pattern of risk is important to:**
**Communicating risk**
**Preventing or minimizing risk**

## Other considerations impacting reliable  safety analysis 

**The Combining of adverse event rates from several trials as in an integrated safety analysis ( The Combining of relative risks (odds ratios) from several trials to estimate overall relative risk or to detect increased risk)**
**Especially for events of low incidence and when duration of exposure is important to control**

##  An Example of Combining Adverse Event Rates From Three Trials : The Issue of  taking time into account

**Trial****	****	****Measure****	****	****	**** 1****	**** 2****	****  3**
**    ****1****	****	****No. with event****	****	****	****  5**
**	****	****No. exposed****	****	****	****500**
**	****	****Cumulative rate****	****	****0.01**
**	****	****Crude rate =                     5/500 = 0.01**
**    ****2****	****	****No. with event****	****	****	****  2****	****  2**
**	****	****No. exposed****	****	****	****200****	****100**
**	****	****Cumulative rate****	****	****0.01****	****0.03**
**	****	****Crude rate =                      4/200 = 0.02**
**    ****3****	****	****No. with event****	****	****	****  1****	****  1****	****  1**
**	****	****No. exposed****	****	****	****100****	**** 50****	**** 25**
**	****	****Cumulative rate****	****              0.01       0.03****	**** 0.069**
**	****	****Crude rate =                       3/100 = 0.03**

**Months of Exposure**

##  An Example of Combining Adverse Events From Three Trials : The Issue of  taking time into accountThe  Combined Studies

**Combined ****	****Measure****	****	****	**** 1****	**** 2****	****  3**
**    ****	****	****No. with event****	****	****	****  8            3             1**
**	****	****No. exposed****	****	****	****800       150          25**
**	****	****Cumulative rate****	****	****0.01      0.03       0.69**
**	****	****Crude rate =                    12/800 = 0.015**
**    **

**Months of Exposure**

**3 Studies**

## 95% CONFIDENCE INTERVALS FOR

**95% CONFIDENCE INTERVALS FOR**
**THE CUMULATIVE ADVERSE EVENT RATE**

**O'Neill RT 1988**

## Issues that can obscure detection and evaluation

**Lack of Standard definitions of adverse events, terms, coding conventions, terminology usage,  and the combining / splitting of terms without any prospective plans, lax protocol follow-up procedures, adjudication of ADR standards **
**The impact of imprecise terminology,  event ascertainment, and classification on detecting increased risk of adverse reactions- sensitivity and specificity of ADR classification - a bias in detection of risk **

## The impact of all sources of imprecision on risk detection- To dampen the chances of detection and lower the estimate of relative risk

## BIAS IN THE ESTIMATE OF TRUE RELATIVE RISK EQUAL 

**BIAS IN THE ESTIMATE OF TRUE RELATIVE RISK EQUAL **
**TO 5 AS A FUNCTION OF SPECIFICITY OF THE ADVERSE EVENT **
**CLASSIFICATION  FOR THE COHORT STUDY**

**O'Neill RT 1988**

**SENSITIVITY OF CLASSIFICATION IS .95   TRUE  RELATIVE RISK IS 5**

## BIAS IN THE ESTIMATE OF TRUE RELATIVE RISK EQUAL 

**BIAS IN THE ESTIMATE OF TRUE RELATIVE RISK EQUAL **
**TO 2 AS A FUNCTION OF SPECIFICITY OF THE ADVERSE EVENT **
**CLASSIFICATION  FOR THE COHORT STUDY**

**O'Neill RT 1988**

**SENSITIVITY OF CLASSIFICATION IS .95   TRUE  RELATIVE RISK IS 2**

## Communicating risk to patients and health providers through the drug label

**Non-steroidal anti-inflammatory drugs and gastrointestinal adverse events**
**Ticlid  for anti-platelet function and serious hematological events**

## WARNINGS

**Risk of GI Ulceration, Bleeding and Perforation with NSAID Therapy**
**Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation, *****can occur at any time***** without warning symptoms, in patients treated chronically with NSAID therapy. ... In patients observed in clinical trials of several months to two years duration, symptomatic upper GI ulcers, gross bleeding or perforation appear to *****occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year.***** Physicians should inform patients about the signs and/or symptoms of serious GI toxicity and what steps to take if they occur.**

## The data

**Clinical trial data**
**Data pooled from several cohorts**
**Estimation of event rate**

## WARNING

**      ****Ticlid can cause life-threatening hematological adverse reactions, including neutropenia/agranulocytosis and thrombocytopenic purpora (TTP)**

## Neutropenia/agranulocytosis:

**This is what is derived and taken from clinical trials in pre-marketing**

**       ****Among 2048 patients in clinical trials, there ****were 50 cases (2.4%)**** of neutropenia (less than  1200 neutrophils/mm3) and the neutrophil count was below 450/ mm3 ****in 17 of these patients (0.8% of the total population).**

## TTP:

**       ****This is what is known from post-marketing reports from physicians**

**TTP was not seen during clinical trials, but US physicians reported about 100 cases between 1992 and 1997. *****Based on an estimated patient exposure of 2 million to 4 million , and assuming an event reporting rate of 10% (the true rate is not known), the incidence of  ticlopodine-associated TTP may be as high as one case in every 2000 to 4000 patients exposed*****.**

## Monitoring of Clinical and Hematological Status:Instructions to physicians for preventing the adverse event

**       **

**Severe hematological adverse events may occur within several days of the start of therapy. The *****incidence  of TTP peaks after about 3-4 weeks of therapy and neutropenia peaks at approximately 4-6 weeks with both declining thereafter.***** Only a few case have arisen after more than three months of therapy. ... *****During the first 3 months of treatment***** patients receiving TICLID must, therefore, be hematologically and clinically *****monitored for evidence of neutropenia or TTP.***** If any such evidence is seen, TICLID should be immediately discontinued.**

## The clinical trial data base : Two comparative studies

**The Canadian American Ticlopidine Study - CATS**
**Placebo controlled**
** ****1073 patients**
**designed to treat patients *****up to 3 years***

**The Ticlopodine Aspirin Stroke Study -TASS**
**3069 patients**
**designed to follow patients for *****at least 2 years***** and up to 5 years**

## Importance of duration of follow-up to characterizing hazard rate

**TASS had complete follow-up for at least two years**
**Same chances of identifying crucial adverse event in each per unit of time**
**CATS had decreasing denominators per unit of time - not able to rule out constant hazard rate - implications for monitoring of clinical and hematological status**

## The Data

## Slide 33

## Slide 34

## Future challenges

**Assessing the relationship of surrogate marker methodology to adverse reaction analysis, to predict serious events**
**Liver toxicity monitoring**
**QT interval monitoring**
**Gastrointestinal bleeding and ulcers**
**Hazard rate analysis to understand the mechanism of action leading to ADRs**
**Risk factors, timing, dosing, **

## Concluding remarks

**Improve the protocol considerations for adverse event recording, terminology, and event categories - including how to treat the event or continue exposure**
**Improve the data analysis, event summarization and reporting**
**Bring adverse event analysis to the level of efficacy evaluation and data analysis**
**There remains many amateur, naïve views of  safety summarization, event rates, and reporting - these impact risk management**