Adverse Events in Clinical Research - the what, when and how of reporting

ITHS Clinical Research Education Series Adverse Events in Clinical Research - the what, when and how of reporting Ann J. Melvin MD, MPH Co-Director ...
Author: Noah Hodges
0 downloads 0 Views 421KB Size
ITHS Clinical Research Education Series

Adverse Events in Clinical Research - the what, when and how of reporting

Ann J. Melvin MD, MPH Co-Director ITHS Regulatory Support and Bioethics Core September 10, 2008

What is an adverse event?

Any unfavorable and unintended medical occurrence, including any abnormal sign (eg physical exam or laboratory finding), symptom or disease temporally associated with the use of a medical treatment* whether or not it is considered related to the medical treatment*. ICH OHRP – *a subject’s participation in the research

Purpose of adverse event reporting 

Monitor safety of study – Drug toxicities – Risks of procedures – Identify events that may impact subject risk







Inform regulators, investigators and others of events associated with risk Allows for timely intervention if risks of study change Inform subjects of any changes in risk

4

Purpose of adverse event capture/reporting   

Data analysis Publications Develop package insert for new agents

5

Cox-2 inhibitors 





Selective Cox-2 inhibitors developed to provide relief from inflammation with less GI toxicity 2000 – 2 large studies (CLASS – celecoxib and VIGOR- rofecoxib) concluding that Cox2 inhibitors had fewer side effects than conventional NSAIDS. ~$3 billion dollars/yr in sales of celecoxib (2001) and $2.5 billion/yr for rofecoxib (2002-2003)

6



2001 – updated full data sets for both trials posted by FDA – indicated that the initial publications of results of both trials were misleading 6

month vs 12 month results CLASS study  Publication of VIGOR results did not include all known MI data 

2001-2004 multiple publications reviewing data sets from these trials and others questioned both safety and efficacy of celecoxib and rofecoxib

Curfman et al, NEJM 2000;343:1520

Berg Hrachovec et al, JAMA 2001;286:2398

Mukherjee et al, JAMA 2001;286:954

James et al, Curr Op Clin Nutr Metab Care 2006;9:89

7





2004 – APPROVe (Adenomatous Polyp Prevention on VIOXX) trial terminated early by DSMC due to increased adverse cardiovascular events in the treatment group (trial start- 2000) September 2004 – rofecoxib removed from the market

James et al, Curr Op Clin Nutr Metab Care 2006;9:89 Bresalier et al, NEJM 2005;352:1092

8





2004- APC (Adenoma Prevention with Celecoxib trial) was terminated early by the DSMC due to increased adverse cardiovascular events in the treatment group (trial start 1999) August 2005 – black-box warning disseminated for celecoxib

James et al, Curr Op Clin Nutr Metab Care 2006;9:89 Solomon et al, NEJM 2005;352:1071

9

Lessons learned 

Record/report all adverse events – Attribution complicated by underlying risk of study population – Many follow-on trials only focused on GI toxicity





Include analysis of full data set in trial reports Know the biology of the drug under investigation

10

Other important definitions

Expected Adverse Events  Those

experiences that have been identified in nature, severity, or frequency in the current investigator brochure, investigational plan/protocol and current consent form. 12

Unexpected Adverse Events – Any adverse event, the specificity or severity of which is not consistent with the current investigator brochure or with the risk information described in the investigational plan or elsewhere in the application CFR 312.32

13

Unexpected Adverse Events 

Not consistent with: – – – –



Current product sheet Current investigator’s brochure Investigative Plan/Protocol Informed consent

Includes events that are more serious than expected or occur more frequently than expected – eg – renal failure if protocol/consent indicates risk of mild increase in creatinine 14

Definitions of relatedness  ICH

- evidence to suggest a causal

relationship  FDA

– Reasonable possibility

 HHS/IRB

– Associated with the use of

the drug

15

Definitions of relatedness  NCI

– Not related – Unlikely related – Possibly related – Probably related – Definitely related

16

Determining attribution  



  

Is the AE a known reaction? What is the temporal relationship to the study treatment? Did the AE improve with treatment discontinuation? Did the AE reappear upon rechallenge? Was it a worsening of a baseline symptom? Were there other treatments being given at the same time? 17









Adults with hepatitis B treated with an IND agent developed increased liver enzymes Investigators assessment was “unrelated to study drug” Longer trial initiated – 13 weeks into the trial a subject dies of liver failure Drug stopped in all subjects but 7/15 developed severe liver damage with 5 deaths 18

Serious Adverse Events 

Any adverse event that results in any of the following outcomes: – Death – Life-threatening adverse event – Requires inpatient hospitalization or prolongation of existing hospitalization – Persistent or significant disability/incapacity – Congenital anomaly/birth defect – Important medical event requiring intervention to prevent one of the above outcomes ICH

21CFR312

19

Life-threatening 

An experience that in the opinion of the Investigator places the subject at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that, had it occurred in a more severe form, might have caused death. 20

 Subject

presents to ED with swollen lips and difficulty breathing – responds to inhaled albuterol and subcutaneous epinephrine – Resolved after 2 hours and goes home without admission Adverse event? Grade? Serious Adverse Event? 21

Important medical events that might not otherwise fit the definition of a serious adverse event may be considered an SAE when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in the definition. Examples include allergic bronchospasm requiring intensive treatment in an emergency room. 21 CFR 312.32 IND safety reports

22

Serious vs Severe 

Seriousness – based on patient/event outcome or action criteria



Severity – refers to intensity of specific event (mild, moderate, severe)



Reporting requirements usually based on seriousness not severity

ICH E2A

23

Adverse Events – grading scales  Severity

of event – a quantitative assessment – Mild: an experience that is usually transient, & requires no special treatment or intervention – Moderate: an experience that is alleviated with simple therapeutic treatments – Severe: an experience that requires therapeutic intervention

24

Serious vs Severe 

Moderate myocardial infarction



Severe headache – Which would be considered a serious adverse event?

25

Adverse Events – grading scales 

NCI Common Toxicity Criteria – http://ctep.cancer.gov/reporting/ctc_v 30.html



DAIDS Toxicity Scales

26

Examples of NCI CTC grading scales (3.0) Adverse Event

1

Hg

Mucositis

2

3

4

5