SAE Reporting Timelines, Causality Assessment And Compensation

Pawandeep Kaur DhawanAssociate Medical Director

CDSA

Objective

• Important definitions

• SAE Reporting Timelines

• Causality Assessment

• Compensation

Important Definitions

Adverse Events

• Adverse event means any untoward medical occurrence that may appear during treatment with a pharmaceutical product (drug, biologic, vaccine, device) in humans, whether or not it has a causal relationship to the treatment.

Side Effects• Any unintended effect of a pharmaceutical product

occurring at a dose normally used in man, which is related to the pharmacological properties of the drug. NOTE: The term “side effect” may only be used after the pharmaceutical product has been approved by the regulatory authorities.

Serious Adverse Event (SAE)• An adverse event or suspected adverse reaction is considered

"serious" if, in the view of either the investigator or sponsor, it results in any of the following:– Death– A life-threatening adverse event– Inpatient hospitalization or prolongation of existing

hospitalization,– A persistent or significant incapacity or disability or

substantial disruption of the ability to conduct normal life functions, or

– A congenital anomaly/birth defect

Unexpected Adverse Events• An adverse reaction, the nature or severity of

which is not consistent with the applicable product information.

SAE Reporting Timelines

Initial Report (by Investigator)

• 24 hours of occurrence of SAE

Licensing Authority (DCGI)

Chairman of Ethics Committee

Sponsor

Detailed SAE Report (14 Days of Occurrence of SAE)

Detailed Report by EC (30 Days of Occurrence of SAE)

Licensing Authority

SAE of Death

Gazette notifications [GSR 72(E)), GSR 53(E), GSR 364 (E), G.S.R. 292 (E), G.S.R. 889 (E)]

SAE Other Than Death

Gazette notifications [GSR 72(E)), GSR 53(E), GSR 364 (E), G.S.R. 292 (E), G.S.R. 889 (E)]

Causality Assessment

Causality

• Cause: Something that produces an effect, result, or condition; something that makes something exist or happen: (if A, then B)

Causality assessment

• Investigator• Institutional ethics committee • Pharmaceutical company/Sponsor • Regulatory authorities

– DCGI Order dated 1 Jul 2014• Constitution of Independent Expert Committee (Cardiology,

Oncology, General) for examination of reports of SAEs of deaths occurred during CT

• Expert Judgment• Algorithms• Bayesian approaches

Adverse Drug Reactions:Methods for Evaluation of Causality

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Common Methods to Assess Causality

• Expert Judgments: – causality inference obtained via clinical judgment,

such as with an expert panel– These are individual assessments based on

previous knowledge & experience

Common Methods to Assess Causality

• Structured algorithms with or without scoring:– Algorithms are set of specific questions with

associated scores for calculating the likelihood ofcause effect relationship.

– Transparent and consistent– Reduced ability to apply clinical judgment

Algorithms/Scales/Systems

Lots of algorithms have been developed (>30)Some examples of algorithms/scales used for causality assessment:

– WHO assessment scale – Karch and Lasagna’s scale – Naranjo’s scale– Kramer scale – Yale logarithm – European ABO system – Spanish imputation system

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Common Methods to Assess Causality

• Bayesian approaches – need a probability for causality calculated

from available knowledge (prior estimate)– need the specific findings in a case, which

combined with the background information, determines the probability of drug causation for the case (posterior estimate)

WHO-UMC System for Causality Assessment • Certain• Probable• Possible• Unlikely• Conditional/ Unclassified• Unassessable/ unclassifiable

‘un-assessable / un-classifiable’ category is for cases with insufficient or contradictory information

• The 3 methods of causality assessments while different share common factors for consideration:– Temporal relationship– Dose relationship– De-challenge/Re-challenge– Recognized association with the product/class– Pharmacological Plausibility– Underlying illness/concurrent conditions– Other medications

Note: Regardless of number of factors present, the quality of the information is critical to the assessment

Causality Assessment: Important Factors

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What if SAE is ‘related’

• Financial compensation for death

• Financial compensation and free management in case of injuries

Compensation

Guidelines on compensation

Declaration of Helsinki The protocol should include information regarding ……….. provisions for treating and/or compensating subjects who are harmed as a consequence of participation in the research study.

ICH –GCP Guideline Para 5.8: Compensation to subjects and investigatorsPara 4.8.10: Written and other information to be given to participants.

Indian GCP guidelines Para 2.4.5. Compensation for ParticipationPara 2.4.7. Compensation for Accidental Injury

GSR No 53(E) dt 30 Jan 2013

• Insertion of Rule 122 DAB: Compensation in case of injury or death during Clinical trial

• Injury to the trial subject – Free medical management as long as required• Trial related injury – Medical cost + compensation• Trial related death: Compensation to nominee

• Cost of compensation to be borne by sponsor

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Quantum of compensation - Formula

• Compensation =

(8 lacs *Age factor*Risk factor)/99.37

• Compensation for terminally ill patient of 16 yrs of age: (8 X 228.54 X 0.5)/99.37 = Approx 9 lacs

• Compensation for terminally ill patient of 67 yrs of age: (8 X 99.37 X 0.5)/99.37 = 4 lacs

Expected mortality > 90% in 30 days – Fixed amount of 2 lacs

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Criteria for Determining the Quantum of Compensation• Age of the Subject• Risk of death• Income of the Subject• Co- morbidity of the subject at the time of SAE (Death)• Expected Survival• Dependency on the deceased • Concomitant medication • Gender of the subject• Negligence during the conduct of Clinical Trial • Duration of the disease• Industry V/s Academia V/s Institute v/s Sponsor• Expectedness of drug to cause death.

Factors

• B = Base amount (i.e. 8 lacs)• F = Factor depending on the age of the subject as

per Workmen Compensation Act• R = Risk Factor depending on the seriousness and

severity of the disease, presence of co-morbidity and duration of disease of the subject at the time of enrolment in the clinical trial

Risk Factor

• 0.50 terminally ill patient (expected survival not more than (NMT) 6 months)

• 1.0 Patient with high risk (expected survival between 6 to 24 months)

• 2.0 Patient with moderate risk• 3.0 Patient with mild risk• 4.0 Healthy Volunteers or subject of no risk

Trial related SAE (Serious Adverse Event) of Death

Compensation = (B x F x R) / 99.37

Trial related SAE causing Permanent Disability to the Subject

Compensation = (D x 90 x C) / 100*100

• D= % of Disability• C= Quantum of Death compensation as

calculated above

Trial related SAE causing Congenital Anomaly or Birth Defect• Quantum of compensation will be calculated

with half base amount ie., 4 lacs

Compensation = {(B/2) x F x R} / 99.37

Trial related SAE causing Life-threatening Disease

Compensation = 2*N*W

• N= No of days the subject under life threatening Situation requiring medical care, irrespective of number of days of hospitalization

• W= Minimum Wages per day of Unskilled worker (in Delhi)

Trial related Reversible Resolved SAE

Compensation = 2*N*W

• N= No of days of hospitalization• W= Minimum Wages per day of Unskilled worker

Tool to Calculate Compensationhttp://cdsaindia.in/tool-calculate-compensation

Thank You