# Presentation: 004337

## Hepatotoxicity: LeflunomideLawrence GoldkindDeputy Division Director Division of Anti-Inflammatory, Analgesic and Ophthalmic Drug Products CDER / FDA

## At approval 1998 hepatic enzyme  elevation (ALT) was noted

- Approved label 1998

##      “Warnings”

           Hepatotoxicity 
    In clinical trials, ARAVA treatment was associated with elevations of liver enzymes, primarily ALT and AST, in a significant number of patients; these effects were generally reversible. Most transaminase elevations were mild 
    (<2-fold ULN) and usually resolved while continuing treatment. Marked elevations (>3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment.  The following table shows liver enzyme elevations seen with monthly monitoring in clinical trials US301 and MN301.  

***           ***_***Hepatotoxicity ***_
*    **In clinical trials, ARAVA treatment was associated with elevations of liver enzymes, primarily ALT and AST, in a significant number of patients; these effects were generally reversible. Most transaminase elevations were mild *
*    **(*_*<*_*2-fold ULN) and usually resolved while continuing treatment. Marked elevations (>3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment.  The following table shows liver enzyme elevations seen with monthly monitoring in clinical trials US301 and MN301.  *

## “Warnings”  (continued)
At minimum, ALT (SGPT) should be performed at baseline and monitored initially at monthly intervals then, if stable, at intervals determined by the individual clinical situation. 

Guidelines for dose adjustment or discontinuation based on the severity and persistence of ALT elevation are recommended as follows: For confirmed ALT elevations >2-fold ULN, dose reduction to 10 mg/day may allow continued administration of ARAVA.  If elevations >2 but <3-fold ULN persist despite dose reduction, liver biopsy is recommended if continued treatment is desired.  If elevations >3-fold ULN persist despite dose reduction, ARAVA should be discontinued and cholestyramine should be administered (see PRECAUTIONS -- General -- Need for Drug Elimination ) with close monitoring, including retreatment with cholestyramine as indicated. 

*At minimum, ALT (SGPT) should be performed at baseline and monitored initially at monthly intervals then, if stable, at intervals determined by the individual clinical situation. *
_***Guidelines for dose adjustment or discontinuation***_* based on the severity and persistence of ALT elevation are recommended as follows: For confirmed ALT elevations >2-fold ULN, dose reduction to 10 mg/day may allow continued administration of ARAVA.  If elevations >2 but *_*<*_*3-fold ULN persist despite dose reduction, liver biopsy is recommended if continued treatment is desired.  If elevations >3-fold ULN persist despite dose reduction, ARAVA should be discontinued and cholestyramine should be administered (see *_PRECAUTIONS_* -- *_General -- Need for Drug Elimination _*) with close monitoring, including retreatment with cholestyramine as indicated**. *

## “Warnings”  (continued)

_**Pre-existing Hepatic Disease**_
-     *Given the possible risk of increased hepatotoxicity, and the role of the liver in drug activation, elimination and recycling, the use of ARAVA is not recommended in patients with significant hepatic impairment or evidence of infection with hepatitis B or C viruses.** *

## “Precautions”

**        **_**Laboratory tests**__*** ***_
*At minimum, ALT (SGPT) should be performed at baseline *
*and monitored initially at monthly intervals then, if stable, at*
*intervals determined by the individual clinical situation.*

## “Precautions” (continued) 

_**Drug interactions**_
**            **_**Hepatotoxic Drugs**__** **_
*  “**Increased side effects may occur when leflunomide is given concomitantly with hepatotoxic substances.  This is also to be considered when leflunomide treatment is followed by such drugs without a drug elimination procedure.”*

## Post-approval

## Post-marketing reports of hepatitis and acute liver failure (ALF) have been received through the Adverse Event Reporting System/Medwatch (AERS)	-ODS review in 2001 identified highly confounded report: 		  hepatotoxicity was referenced in the labelCitizen’s Petition for removal from the market based   primarily on reports of ALF: 2002Exhaustive re-assessment of hepatotoxicity	-Assessment of individual AERS reports	-Controlled clinical trials	-Other databases, sponsor studies and medical literature	-Data mining

## Role of Various Sources of Safety Information

- Controlled clinical trials
- Cohort studies
- AERS database

## Controlled Clinical Trials

- Strengths
- Comparative to placebo and alternative therapies
- Least bias (imbalance in confounding factors)
- Most detailed data, access to medical records
- Denominator and hence, rate calculation
- Weakness
- Not powered for rare to very rare events (<1/100-1/1000)
- Exclusions/limited enrollment vulnerable populations that will be exposed

## Cohort Studies

- Strengths
- Larger size (power to detect less common events)
- “Naturalistic” (includes “all comers”)
- Identify vulnerable groups, drug interactions
- Can provide rates for events and comparative data
- Weakness
- Bias based on channeling, lack of randomization
- Ascertainment less robust (missed cases)
- Lack of access to full medical records (causality)

## Adverse Event Reporting System (AERS)

- Strengths
- Power: can identify rare events not seen in clinical trials or cohort studies
- Can identify toxicity in special populations
- Limits
- Under reporting
- Cannot provide rates for rare events
- Cannot provide comparative data, content
- Limited information may limit causality assessment

## Adverse Event Reporting System (AERS)

- Limits (continued)
- Causality
- inadequate information to assess
- co-morbidities
- other causes of event (hepatic injury)
- infection, vascular, drugs, treated disease, etc.
- clinical judgement required/variability

## Analysis of AERS Database

- Survey by ODS identified 16 cases of “temporally associated acute liver failure” (ALF) in the US and 13 cases outside the US
- Limited data, inherent subjective “clinical” nature of causality assessment warranted consensus approach to analysis of these reports
- Analysis of reports by:
- ODS
- OND: FDA gastroenterologist
- 2 external expert hepatology consultants

## Analysis of Post-marketing Reports of ALF

- CONCLUSIONS
- Rare cases of probable leflunomide induced ALF
- Additional “possible” or “unlikely” cases reported
- Confounding present in all but several cases
- No consistent pattern of clinical and/or biochemical presentation *(unlike other serious hepatotoxins, such as troglitazone or bromfenac)*
- ALF rate cannot be calculated with such small number of events: unknown true numerator or denominator

- Questions
- “Tip of the unreported iceberg” or exceedingly rare event?
- Can we quantitate the risk?
- Is the overall risk:benefit ratio for patients changed by these case reports?
- Are other therapies of similar efficacy “safer”?

## Goal of Presentation

- Assess all available databases for estimates of rates of serious hepatotoxicity

## Outline of Presentation: Serious Hepatotoxicity in Leflunomide Databases

- I.     Clinical Trials Database: Pooled Analysis (PA)
- II.    Post-marketing Studies of Combination Therapy
- III.   Aetna/US Healthcare Cohort Analysis
- IV.   Protocare/Pharmetrics Bi-cohort Analysis
- V.    National Databank for Rheumatic Diseases
- VI.   US Acute Liver Failure Study Group (USALFSG)
- VII.  Data Mining Analysis of AERS

## Definitions of Serious Hepatotoxicity

- Hepatocellular necrosis: 8-10 x ULN
- Hepatocellular necrosis associated with clinical jaundice (Hy’s Rule): 10% mortality
- Hospitalization for hepatocellular necrosis
- ALF
- Death
- (will vary based on database availability)

## Outline of Presentation: Serious Hepatotoxicity in Leflunomide Databases

**I.     Clinical Trials Database: Pooled Analysis (PA)**

##      I.    Clinical Trials Database:  Pooled     	Analysis (PA)

- 17 controlled clinical trials
-  August 1989 - February 2002
-  Kaplan-Meier analysis
-  Rates per 100 patient years
-  Rates of ALT elevations include all causes
- 	 (no causality assessments in these analyses)

## Exposure

## Slide 24

## Slide 25

## ALT >3 ULN Across Clinical Trialscrude rates

-                        Leflunomide    Methotrexate    Placebo
-  US 301:  (12mo)      4.4%                         2.7%                      2.5%
-  MN 301:  (6mo)       1.5%                         ----                         1.1%
-  MN302*:(12mo)      2.6%                       16.7%                     ----
-  4001:        (6mo)       3.8%
-  4002:         (6mo)      3%
*    *** only 10% folate use*
- Note:
-      1.  Limitations of using rates of  “nonspecific” biochemical changes
-      2.  Presence of a background rate for such events

## Assessment of Clinical Trials Database for Serious Drug-Induced Hepatocellular Injury

- “Hy’s Rule” - jaundice associated with hepatocellular
- 	  injury (_>_10% mortality)
- Review of all cases of ALT elevations and bilirubin over     1.5 x ULN in _monotherapy_ clinical trials of 1700 subjects
- 		   - one case of _**treatment related**_ hepatocellular injury (ALT
-                    peak of 2710) but not jaundice (bilirubin peak 1.3 x ULN)
-       	      (patient was hospitalized)
- 		    - no cases of hepatocellular jaundice

## Outline of Presentation: Serious Hepatotoxicity in Leflunomide Databases

- I.     Clinical Trials Database: Pooled Analysis (PA)
**II.    Post-marketing Studies of Combination Therapy**

## II.     Post-marketing Studies of          Combination Therapy 		 

- Study 4001:  260 patients on methotrexate and leflunomide
- Study 4002:  968 patients on leflunomide alone for 6 months 		 followed by 6 months on combination SSZ
-                       and leflunomide in unresponsive group
-     Out of 1200 subjects enrolled in combination studies (6-12 month studies), there were no cases of hepatocellular jaundice

## Conclusion of Review of All Clinical Trials

- ALT elevations >3 x ULN 2-4% range
- ALT elevations >10 x ULN under 1%
- 1/2900 subjects (0.03%) treated with leflunomide experienced treatment related hepatocellular injury and slight elevation of bilirubin
- 0/2900 subjects experienced ALF

## Retrospective Cohort Studies

- Aetna/US Healthcare
- Pharmetrics/Protocare
- National Databank For Rheumatic Diseases

## Outline of Presentation: Serious Hepatotoxicity in Leflunomide Databases

- I.     Clinical Trials Database: Pooled Analysis (PA)
- II.    Post-marketing Studies of Combination Therapy
**III.   Aetna/US Healthcare Cohort Analysis**

## III.  Aetna/US Healthcare Cohort Analysis

- Retrospective cohort study
- Claims database with linkage to medical, pharmacy and laboratory data: claims validation for severe hepatic events
- 40,000 RA patients: 9/98-12/00
-                             _Exposed         Pt yr          Mean exposure __(days)_
-        Leflunomide               2633            4214                585
-        Methotrexate               9514          10682                410
-        DMARD*                  14861          31158               765
- * gold, ssz, penicillamine, TNF, cya, minocycline, steroids, chlorambucil, hydroxychloroquine

## Aetna/US Healthcare

- Strength:
- 		1.  Case validation for severe events (all severe hepatic cases 	       were evaluated with 100% agreement/validation: 20% of all 		       hepatic events were assessed with 83% validation)
-    		2.  Large size (although an even larger size would be needed to   	       	       observe rare events under 1/1000)
- Weakness:
- 		1.   No causality assessment
- 		2.   Channeling bias/Lack of randomization                             		   ? Sicker or refractory to MTX channeled into lef
-                              ? Prior MTX use deplete intolerant patients from 			     current cohort

## Results

-  _Hepatic necrosis__:_    rate/10,000 pt yr  (n)
-            Leflunomide             2.4  (1)
-          Methotrexate             1.9  (2)
- 1/2633 (0.04%) experienced “hepatic necrosis”
- No cases of hepatocellular jaundice
- No data on hospitalization available

## Outline of Presentation: Serious Hepatotoxicity in Leflunomide Databases

- I.     Clinical Trials Database: Pooled Analysis (PA)
- II.    Post-marketing Studies of Combination Therapy
- III.   Aetna/US Healthcare Cohort Analysis
**IV.   Protocare/Pharmetrics Bi-cohort Analysis**

##     IV.    Pharmetrics/Protocare 		Bi-cohort Study Analysis

- Nested retrospective case control study
- Pharmetrics: standardized claims data for managed care organizations
- Protocare: Health benefits claims including Medicaid, Medicare, PPO and HMO
- First prescription: 1/98-12/01
- 130,000 RA patients
- Rate ratios compared to methotrexate

## Pharmetrics/Protocare Bi-cohort Study

- 42000 RA patients on a DMARD
-                   -2800 on started on leflunomide monotherapy
-                   -15000 on methotrexate
- 51000 pt yr exposure
- Mean follow-up: 400-500 days
- Weakness:
- 			1.  Channeling bias, no causality assessment
- 			2.  No clinical information for validation
- 				- limitation of code based analysis
- 				- imprecision obscures differences

## Definition of Hepatic Events

- Hepatic events requiring hospitalization
- 		-Acute or subacute necrosis: ICD-9:   570
- 		-Cirrhosis of liver without mention:    571.5
- 		-Hepatitis-noninfectious toxic:            573.3
- 		-Hepatic coma:				572.2
- “Expanded events” definition: above codes but
-   without hospitalization

## Results: Hospitalization for any hepatic events (Crude relative rate)

## Results: Expanded DefinitionHepatic events not requiring hospitalizations(Crude relative risk)

- 	Pharmetric	 Protocare	Combined
- Lef	      0.9                 1.1 	     0.9
-                (n=45)           (n=11)           (n=56)
- MTX	      1.0 	      1.0 	     1.0
-     	    (n=93)    	    (n=45)           (n=138)

## Conclusions from Bicohort Study

- No cases of leflunomide related serious hepatitis defined by hospitalization for hepatic event (including hepatocellular necrosis)
- Similar risk to methotrexate for overall hepatic events
- Caveat: limitations of lack of causality and bias/absence of randomization may obscure differences

## Outline of Presentation: Serious Hepatotoxicity in Leflunomide Databases

- I.     Clinical Trials Database: Pooled Analysis (PA)
- II.    Post-marketing Studies of Combination Therapy
- III.   Aetna/US Healthcare Cohort Analysis
- IV.   Protocare/Pharmetrics Bi-cohort Analysis
**V.    National Databank for Rheumatic Diseases**

##     V.   National Databank for Rheumatic            Diseases

- Longitudinal patient reported surveillance program
-     recruited from rheumatology practices and Aventis registry
- Adverse events collected from patients by mail survey
-           - participant: at least one semi-annual questionnaire received
-               - 5437 on leflunomide  (12786 responses)
-               - 10527 on methotrexate  (31313 responses)
- Hospitalization and deaths corroborated by physician records and death certificates

## National Databank for Rheumatic Diseases

- Strengths:
- 		    1. Large database
- 		    2. Validation of serious events (hospitalization and
-                     death)
- Weakness:
- 		    1.  Not randomized (confounded by co-therapy and non
-                      drug events)
- 	       2.  Potentially incomplete reporting
- 	      3.  Non-serious events are not assessed for causality
-                     (comparative rates not accurate representation of drug
-                     specific toxicity)

## Results

- Hospitalization rate for ICD-9 related liver codes/100 pt year
- Acute/chronic conditions
- Broad coding definition of all hepatic codes
- Unrelated events add “noise” and may obscure differences
- leflunomide:   0.20
- methotrexate: 0.27
- Hospitalization for probable drug induced hepatocellular necrosis of the liver:
- One on leflunomide (neutropenia, fever and ALT 524)
- Possible septic hepatopathy
- No ALF

## National Databank for Rheumatic Diseases: Conclusions

- One hospitalization for drug related hepatocellular injury (without jaundice) in a database of over 5000 patients on leflunomide (7500 patient years)
- No cases of ALF

## Outline of Presentation: Serious Hepatotoxicity in Leflunomide Databases

- I.     Clinical Trials Database: Pooled Analysis (PA)
- II.    Post-marketing Studies of Combination Therapy
- III.   Aetna/US Healthcare Cohort Analysis
- IV.   Protocare/Pharmetrics Bi-cohort Analysis
- V.    National Databank for Rheumatic Diseases
**VI.   US Acute Liver Failure Study Group (USALFSG)**

## VI.   US Acute Liver Failure Study        Group: Survey of Drug Induced         Liver Failure  	

- “*Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States” *Ann Intern Med 2002
- January 1998-May 2001 (covers first 30 months of leflunomide marketing)
- Approximately 25-40% of transplant capability (not all ALF or serious hepatotoxicity is referred to transplant centers)
- 308 consecutive patients admitted with ALF
- 39% acetaminophen
- 13% (40 cases): bromfenac (4), troglitazone (4), INH (5)

## US Acute Liver Failure Study Group: Survey of Drug Induced Liver Failure

- One case of ALF associated with leflunomide
- This case was captured independently by the FDA AERS database
- The one case of *probable* leflunomide induced ALF not associated with overdose in the AERS review
- Conclusion: The extent of underreporting of ALF associated with leflunomide may well be much lower than generally quoted (90-99%) given the findings from this study.

## Conclusions Hepatotoxicity in available databases

- In studies of 6-12 months duration, ALT elevations (>3 x ULN)
-      are consistently associated with the use of leflunomide (2-4%), methotrexate (2-16%) and placebo (1-2%)
- Clinically significant liver injury (hospitalization) in 4 databases consistently low
- Across studies: for _hospitalization_ for hepatocellular necrosis or hepatocellular jaundice
- 1/2900 Clinical Trials
- 0/2800 Bicohort Study
- 1/5400 National Databank for Rheumatic Diseases

## 0.02% hospitalization for hepatocellular necrosis
NNH: 1:5500 (lower 95% CI ~ 1:2000)

No cases of hepatocellular jaundice: 0/13700
NNH: lower 95% CI, therefore under 1:5000

Using Hy’s Rule - 10% mortality
NNH for hepatic necrosis causing under ~ 1:50,000 (lower 95% CI under 1:15,000)

Caveat:	event ascertainment by self reporting and diagnosis coding in 	health claims and hospitalization susceptible to inaccuracy and 	under reporting

- NNH: 1:5500 (lower 95% CI ~ 1:2000)
- No cases of hepatocellular jaundice: 0/13700
- NNH: lower 95% CI, therefore _under_ 1:5000
- Using Hy’s Rule - 10% mortality
- NNH for hepatic necrosis causing under ~ 1:50,000 (lower 95% CI under 1:15,000)
***Caveat:******	******event ascertainment by self reporting and diagnosis coding in ******	******health claims and hospitalization susceptible to inaccuracy and ******	******under reporting***

- Conclusions (continued)

## Dilemma

- Rare (under 1/5000) hospitalization for hepatic necrosis in controlled studies
- Few probable cases of drug induced ALF in post-marketing reports
- ? Comparative risk to other therapies
- 	           - Redirect therapy from one potential toxicity to another
- 	           - TNF-alpha inhibitors: malignancy, infection . . .
- 	           - Methotrexate: malignancy, pneumonitis, infection,
-                   cirrhosis ...

## Dilemma

- For the patient who experiences ALF, no risk benefit analysis can favor therapy but for prospective prescribers and patients...
- How to interpret magnitude of risk for very rare events in uncontrolled databases and characterize for prescribing physicians and patients
- Back to post-marketing reports . . .

## Outline of Presentation: Serious Hepatotoxicity in Leflunomide Databases

- I.     Clinical Trials Database: Pooled Analysis (PA)
- II.    Post-marketing Studies of Combination Therapy
- III.   Aetna/US Healthcare Cohort Analysis
- IV.   Protocare/Pharmetrics Bi-cohort Analysis
- V.    National Databank for Rheumatic Diseases
- VI.   US Acute Liver Failure Study Group (USALFSG)
**VII.  Data Mining Analysis of AERS**

## What is Data Mining?

A system to allow computer analysis of the AERS database of millions of reports to identify and quantitate “signals” for drug associated adverse events

Currently being evaluated in the Office of Biostatistics as a screening tool to identify drugs and events that require further examination and study

“ Use of Screening Algorithms and Computer Systems to Efficiently Signal Higher than Expected Combinations of Drugs and Events in the US FDA’s Spontaneous Reports Database”
Szarfman, Machado and O’Neill: Drug Safety 2002, 25(6):381-392

- A system to allow computer analysis of the AERS database of millions of reports to identify and quantitate “signals” for drug associated adverse events
- Currently being evaluated in the Office of Biostatistics as a screening tool to identify drugs and events that require further examination and study
- “ Use of Screening Algorithms and Computer Systems to Efficiently Signal Higher than Expected Combinations of Drugs and Events in the US FDA’s Spontaneous Reports Database”
***Szarfman, Machado and O’Neill: Drug Safety 2002, 25(6):381-392***

## Adverse Event Reporting System (AERS)

- Strengths
- Power: can identify rare events not seen in clinical trials or cohort studies
- Can identify toxicity in special populations
- Limits
- Cannot provide rates for rare events
- Cannot provide comparative data for context
- Limited information may limit causality assessment

## Slide 58

## Why Data Mining?

- Coherently organize and interpret a large database!
- Medwatch Database
***	******	***- over 2 million reports
- 		- over 8000 products
- 		- 7000 MedDRA preferred “event terms”***	******	***- 56 million possible drug event combinations
- 		   (cells in a two way table)
-  		- 300,000 new reports per year

## Example

- Data mine across the AERS database for the event code “hepatic failure”
- 	    - Limit to those drugs with at least 3 reports 	  	   - Identify those drugs which have such signals out
-              of proportion to “background” or  “expected”
-              reporting rate for the the overall database of drugs
- Background rate:  gray
- Signals for higher than expected:  blue-purple

## Slide 61

## Slide 62

## Drugs with a Signal for Hepatic Failure

- Include
- troglitazone
- bromfenac
- trovafloxacin
- ketoconazole
- fluconazole
- flutamide

- isoniazid
- nitrofurantoin
- halothane
- isoflurane
- didanosine

## Data Mining for Drugs Used to Treat Rheumatoid Arthritis

- Highlights graphically the complexity of assessing
-           post-marketing serious and life threatening events
- May provide insight into the AERS reports of serious hepatic events for leflunomide

## Data Mining Study of Spectrum of Drugs and Associated Serious Adverse Events Used to Treat RA (plus Control Drugs)

_**RA **__   _
- 	- leflunomide
-      - gold
- 	- etanercept
-      - prednisone
- 	- infliximab
- 	- anakinra
- 	- methotrexate
- 	- hydroxychloroquine
- 	- sulfasalazine

_**Controls**_
-      - bromfenac
-       - acetaminophen
-       - valproate
-       - isoniazid
-       - ketoconazole
-       - troglitazone
-      - chlorzoxazone (parafon)

## Data MiningSpecific Outcome Events of Interest

- Fatal events only
- Liver related events
- Opportunistic infections
- Lymphoma
- Note: only drugs with a signal appear on graph

## Slide 67

## Slide 68

## Leflunomide is not seen in this chart because there is no signal for it

## Conclusions from Data Mining

- Currently under evaluation as a signaling tool in post-marketing safety assessment
- Signals require interpretation and validation based on review of reports
- false positives: based on disease being treated and reporting intensity variability
- false negative: absence of signal?

## Conclusions from Data Mining (continued)

- Highlights graphically the complexity of assessing post-marketing serious and life threatening events
- Highlights graphically the “unique fingerprint” for reported rare events for each drug

## Conclusions from Data Mining (continued)

- Signal for leflunomide not above “threshold” of this data mining system for life threatening acute liver injury
**This does not mean that it does not occur - ALF events have occurred**
- This analysis does suggest that the pattern of reported hepatic failure events for leflunomide is different than that seen for hepatotoxic drugs such as troglitazone, trovafloxacin, valproate, flutamide, isoniazid or bromfenac

## Overall Conclusions Regarding Hepatotoxicity of Leflunomide

- Minor hepatotoxicity defined by ALT elevation is not “uncommon” in clinical trials (2-4%)
- Serious drug induced hepatotoxicity defined by hospitalization for hepatotoxicity in _controlled databases_ is rare (0.02%)
- ALF and death have been reported in post-marketing experience

## Overall Conclusions Regarding Hepatotoxicity of Leflunomide

- A rate for hepatocellular jaundice (Hy’s Rule) cannot be accurately defined but . . .
- Based on absence of cases in a combined database of 13,700
-  lower bound 95% CI very likely under 1:5000
-     exposures
- Based on Hy’s Rule (10% mortality)
-  Estimate for deaths due to ALF 1:50,000

## Overall Conclusions Regarding Hepatotoxicity of Leflunomide(continued)

- When looking across drugs used to treat rheumatoid arthritis, life threatening events are associated with all available therapies
- NSAIDS
- DMARDS (drugs)
- DMARDS (biologic)
- It is important to characterize and communicate these rare but life threatening events as coherently as possible for optimal use

## Finis

## Conclusions from AERS Reports Analysis

- Cases of serious hepatotoxicity including ALF due to leflunomide have occurred
- Cannot calculate a rate based on post-marketing reporting
- Confounding and lack of consistent clinical or biochemical pattern
- Both numerator and denominator difficult to define