Safety data is generated throughout the drug development and approval process, including pre-clinical trials, clinical trials, and post-approval monitoring. In pre-clinical trials, exploratory and regulatory toxicology studies provide safety data. Clinical trials involve monitoring adverse events and serious adverse events. Post-approval, safety is monitored through periodic safety update reports, spontaneous reporting, and other methods. Safety data informs the entire process from drug discovery through marketing.

1. Safety Data Generation
Dr. Ramesh Bhandari
Asst. Professor
Department of Pharmacy Practice
KLE College of Pharmacy, Belagavi

2. Safety data generation
Drug
Discovery
Pre-
Clinical
Developm
ent
Clinical
Developm
ent
Regulatory
approval
Drug
Marketed
IND
Application
Developed
Compound
NDA
Submission
Drug Approved
for marketing
Pre-Clinical
Phase
Post
Approval
Phase
Clinical
Phase
1 2 3

3. Safety data generation
• In-vitro, In-vivo
• Safety pharmacology
Pre-Clinical
Phase
• AEs/SAEs
• Subject Follow-ups
Clinical
Phase
• PSURs
• Marketing authorization
holders (MAH) AEs
Post
Approval
Phase

4. Pre-Clinical Phase
4

5. Pre-Clinical Phase Data Generation
◎ Exploratory toxicology:
◎ Regulatory toxicology

6. Pre-Clinical Phase Data Generation
◎ Exploratory toxicology:
 Provide a rough quantitative estimate of
toxicity (acute or repeated dose)
 Provides main organs and systems
involved

7. Pre-Clinical Phase Data Generation
◎ Regulatory toxicology:
 Performed to GLP standards and
comprise regulatory requirement by
authorities
 Performed to support an application
for marketing approval

8. Pre-Clinical Phase Data Generation
◎ Exploratory toxicology: In-vitro and in-
vivo studies:
 Mutagenicity
 Cytotoxicity
 Immunotoxicity
 Hepatotoxicity
 Embryotoxicity

9. Pre-Clinical Phase Data Generation
◎ Regulatory Toxicology:
 Safety pharmacology
 GLP guidelines
 Acute toxicity
 Chronic toxicity
 Reproductive toxicity

10. Pre-Clinical Phase Data Generation
 Safety pharmacology:
 Pharmacological testing to check that the
drug does not produce any obviously
hazardous acute effects known as safety
pharmacology.

11. Pre-Clinical Phase Data Generation
 Safety pharmacology:
 System wise tests
 Follow up tests
 Supplementary tests

12. Pre-Clinical Phase Data Generation
 Safety pharmacology:
 System wise tests
• CVS: BP, Heart rate, ECG changes
• Respiratory: RR, Tidal volume
• CNS: Behavioural Changes, motor
activity, Body temperature

13. Pre-Clinical Phase Data Generation
 Safety pharmacology:
 Follow up tests
 CVS: Cardiac output, ventricular
contractility
 Respiratory: pulmonary arterial
pressure, blood gases

14. Pre-Clinical Phase Data Generation
 Safety pharmacology:
 Supplementary tests:
• Renal function: Urinary volume, pH,
proteinuria, blood urea
• GIT: gastric secretion, pH, GI motility, GI
transit time

15. Pre-Clinical Phase Data Generation
 Acute toxicity:
o28 days repeat dose toxicity and
recovery in 2 species
 Chronic toxicity:
o3-12 months chronic toxicity in 2
species

16. Pre-Clinical Phase Data Generation
 Reproductive toxicity:
oReproductive toxicity in 1 species
 Carcinogenicity:
o24 months carcinogenicity in 2 species

17. Clinical Trial Safety
Data Generation
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18. Clinical Trial Safety Data Generation
• 20–100 People
• Usually 1-2 Years
Phase I (Safety)
• 100-300 People
• 1-2 Years
Phase II (Efficacy
and Safety)
• 1000-3000 Peoples
• 2-3 Years
Phase III
(Efficacy and
Safety)

19. Clinical Trial Safety Data Generation
 Serious adverse events reporting
 Conducting Subjects follow up
 Ensuring subject compliance
 Continue communication

20. Clinical Trial Safety Data Generation
Adverse
Events
Unexpected
adverse
events
Any
laboratory
abnormalities
Serious
Adverse
events
Adverse
events of
special
interest
Adverse drug
reactions

21. Clinical Trial Safety Data Generation
 Adverse Event:
Any untoward medical occurrence observed during treatment while a
pharmaceutical product which does not necessarily have a causal
relationship with the treatment.
• Adverse outcomes after use of the drug
• Any new clinical experience may or may not be linked to the use of
drug
• Eg: any laboratory abnormality or new symptoms after the use of the
drug

22. Clinical Trial Safety Data Generation
 Sources:
Clinical Information sources
Non Clinical Information Sources

23. Clinical Trial Safety Data Generation
 Sources:
Clinical Information sources:
Data from clinical and epidemiological studies
Data from pharmaceutical companies
Safety profile of the drugs of similar class or type
Data from clinical studies

24. Clinical Trial Safety Data Generation
 Sources:
Non Clinical Information Sources:
Chemical structure, class indication, adverse effects, actions
In-vitro studies report
Data from toxicology studies in animals (Cardiotoxicity,
hepatotoxicity, renal toxicity, carcinogenicity, mutagenicity)

25. Clinical Trial Safety Data Generation
 Serious adverse event
 Adverse drug reaction
 Unexpected adverse event:
Nature and severity of which is not consistent
with the risk information described in general
investigational plan of investigator’s brochure

26. Clinical Trial Safety Data Generation
 Reporting timelines:
Any Serious, unexpected or life threatening adverse
events must be reported within 7 days
Any other unexpected AEs that are neither fatal not
life threatening should be reported within 15 days

27. Post Marketing
Safety Data
Generation
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28. Post Marketing Safety Data Generation
 Periodic safety update reports
 PSUR Process
 Intake of ADR information
 Data Retrieval
 Data analysis
 PSURs should be submitted every months for first two
years and annually for subsequent 2 years. (India)

29. Post Marketing Safety Data Generation
PMS
Spontaneous
reporting
Prescription
Event
Monitoring
Electronic
health records
Observational
studies
Registries

30. Post Marketing Safety Data Generation
 Post marketing safety evaluation data source:
Product’s preapproval safety profile
Current FDA approved label
FDA adverse event reports (FAERS)
Reports of vaccine adverse event reporting system
(VAERS)
Periodic submission of safety reports

31. Post Marketing Safety Data Generation
 Post marketing reports timeline:
Serious and unexpected AEs: FDA recommends
report to be submitted within 15 days
Follow up - Up to 15 days alert reports should be
submitted within 15 days

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