Clinical Trial Safety Data Management (presentation By Tvs Sarma)

Clinical Trial Safety Data Management An introduction

T V S Sarma February 19, 2009

1

What is Safety Data? • Safety data refers to the data about… •

Adverse Events / Experiences (AE)

• •

•

Adverse Event / Experience Serious Adverse Event / Experience (SAE)

Adverse Drug Reactions (ADR)

• • •

Adverse Drug Reaction (ADR) Unexpected ADR Serious ADR 2

What is safety data management? It is the process of capturing, management and reporting of Safety Data.

3

Definition of Terms • Adverse Event / Experience •

Any untoward medical occurrence in a patient or clinical investigation subject, administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment

4

…definition of Terms •

Adverse Drug Reaction

•

•

In case of a pre-approval clinical experience: a noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions For marketed medicinal products: A response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for modification of physiological function 5

…definition of Terms Unexpected Adverse Drug Reaction • An adverse reaction, the nature, intensity or incidence falls outside the information provided in

• •

Investigator's Brochure for an unapproved investigational medicinal product The package insert of a marketed drug.

6

…definition of Terms •

Serious Adverse Event and Serious Adverse Drug Reaction

• • • • •

Any untoward medical occurrence that, at any dose that: Results in death Is life threatening Requires inpatient hospitalization or prolongation of existing hospitalization Results in persistent or significant disability/incapacity, or Is a congenital anomaly/birth defect

7

Minimum standards • • • • •

Ensure compliance with regulations. Ensure that the standard of quality supports the utilization of the data. Ensure that conclusions about the safety profile of a compound can be reliably drawn from the database. Ensure that safety risks are identified and reported accurately. Ensure that normal ranges are properly linked to laboratory data. If normal ranges are unavailable, ensure that the reference ranges used are documented as such. This is especially crucial when normal ranges are updated frequently.

8

Relevant ICH guidelines • •

E1: The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life-Threatening Conditions E2A, E2B and E2C: Clinical Safety Data Management guidelines that provide guidance for definitions and standards for expedited reporting, data elements for transmission of individual case safety reports, and for periodic safety update reports for marketed drugs. 9

…Relevant ICH guidelines • E3: Structure and Content of Clinical Study

• • •

Reports E5(R1): Ethnic Factors in the Acceptability of Foreign Clinical Data E6(R1): Good Clinical Practice, Consolidated Guidelines E9: Statistical Principles for Clinical Trials 10

Safety reporting • • • •

Safety data are reported and examined at various stages of an investigation and by different assessors. IND regulations specify expedited reporting for serious or alarming adverse events Studies generally have Safety Data Management Boards that review data as they are accumulated FDA requires that sponsors provide them with what they need to meet their obligations to Congress and to the public 11

Safety reporting: What Should be Reported? • •

Single Cases of Serious, Unexpected ADRs Other Observations

• • •

For an "expected," serious ADR, an increase in the rate of occurrence which is judged to be clinically important. A significant hazard to the patient population, such as lack of efficacy with a medicinal product used in treating lifethreatening disease. A major safety finding from a newly completed animal study (such as carcinogenicity). 12

Reporting Safety Data Any AE or ADR that is serious or life threatening or fatal need be • …reported by Sponsor to regulatory authority in 15 calendar days • …reported by investigator to sponsor in 24 hours • …reported by Investigator to Ethics committee in 7 days 13

Capture, Management and Reporting Of Safety Data These are the points to consider regarding safety data • Precision

• • •

• •

High Precision Moderate Precision Low Precision

Severity Dictionaries

• • •

WHOART COSTART MedDRA 14

…Capture, Management and Reporting Of Safety Data •

Encoding

• • • • •

Avoid use of adjectives as initial words (e.g., “weeping wound” may be coded to “crying” or “faint rash” may be coded to “syncope”) Avoid use of symbols and abbreviations in the AE text field (symbols may be interpreted by different individuals differently) Avoid inclusion of severity (e.g., “severe headache” in the AE text box inhibits auto-encoding; severity should be recorded in the severity box, not the AE text box) Ensure AE text has clinical meaning (e.g., “bouncing off the walls” and “feeling weird” are difficult to interpret) Ensure AE text has clear meaning (e.g., “cold feeling” may be interpreted as “chills” or “flu symptoms”)

15

Capture, Management, and Reporting of Laboratory Data

• • •

One of the most challenging aspects of managing laboratory data is linking the data to the appropriate normal range In cases where normal ranges are not available or not obtainable, reference ranges may be used Normalization techniques for laboratory data are often employed for convenience of combining data across studies 16

Other Data •

•

Safety data can have forms other than AEs and laboratory values. Capture of data from specialty tests (e.g., electrocardiograms, electroencephalographs) requires understanding the common data derived from the test, the format, precision, and special attributes Physical examinations are customary in clinical trials. In a broad sense, the physical exam is a screening method; if an unexpected, significant abnormality is detected during a physical exam, there is generally a specialty test to confirm the event. The data with greater reliability, then, is the specialty test

17

…other data

•

In considering data capture, free-text commentary boxes are generally discouraged

18

SAE Data

• •

Expedited reports are required by regulatory agencies for certain serious adverse events In many companies, the receiving of SAE reports, computerizing and managing of these reports is the responsibility of a dedicated group, which is often separate from the Data Management group 19

General Safety Data • •

The FDA provides specific guidance to industry that reflects thinking within the Agency about safety data the FDA described the concept of clinical domains for a review of the following systems

• • • • • • • • • • •

Cardiovascular Gastrointestinal Hemic and Lymphatic Metabolic and endocrine Musculoskeletal Nervous Respiratory Dermatological Special Senses Genitourinary Miscellaneous. 20

…general Safety Data FDA specifies that an NDA be reviewed against each clinical domain with two key questions as goals

• •

Are the safety data adequate to assess the influence of the product on the clinical domain? What do the data indicate about the influence of the product on the clinical domain?

21

Center effects on safety data

• • •

The investigator as an individual (the bedside manner, personal biases, peculiar methods of assessment) The environment (equipment, SOPs, staff, etc.) The subject population (those who frequent the hospital or clinic, VA hospital, university hospital, country clinic, etc.) 22

Recommended Standard Operating Procedures

• • • • • •

Coding of adverse events Maintenance of coding dictionaries Reconciliation of serious AEs in SAE database with clinical trial database Management of AE analysis file Management of laboratory data and normal ranges Preparing integrated summaries of safety data 23

Terminology Relevant to Safety Data Management • • • • • • • • • •

AE: Adverse Event or Adverse Experience SAE: Serious Adverse Event/Experience ADR: Adverse Drug Reaction SADR: Serious Adverse Drug Reaction UADR: Unexpected Adverse Drug Reaction SUSAR: Suspected Unexpected SAE EMEA: European Medical Evaluation Agency CDER: Center Drug Evaluation and Research CBER: Center for Biologics Evaluation and Research CRF: Case Report / Record form 24

…terminology • • • • • • • • •

FDA: Food and drug Administration EAB: Ethical Advisory Board IFPMA: International Federation of Pharmaceutical Manufacturers Association ATC: Anatomical Chemical Classification PT: Preferred Terms SOC: System Organ Class HLT: High Level Term HLGT: High Level Group Term LLT: Low Level Term 25

References

• • • •

GCDMP Version 4 Chapter on Safety Data Management and Reporting ICH E2A ICH E2B ICH E2C

26

That will be all

Thank you

27