1. IND CASE STUDY
NITHYA RAJAN
RGA 6201:New Drug Development
Mid-Term Writing Assignment

2. IND CASE STUDY
NITHYA RAJAN
RGA 6201:New Drug Development
Mid-Term Writing Assignment

3. CASE: IND for a new Anticoagulant
Product is Novel
Oral anticoagulant in a class of Direct Thrombin Inhibitors
Existing anticoagulants are limited by a narrow therapeutic
window and highly variable dose-response relation
Planned study is Phase 1 PK/PD study, multi center
A Pre-IND request was not submitted

4. CASE: IND for a new Anticoagulant
Product is Novel
Oral anticoagulant in a class of Direct Thrombin Inhibitors
Existing anticoagulants are limited by a narrow therapeutic
window and highly variable dose-response relation
Planned study is Phase 1 PK/PD study, multi center
A Pre-IND request was not submitted

5. FDA IND Review - Preclinical studies submitted
Final study reports for nonclinical pharmacology and toxicology studies
submitted in the IND.
Pharmacology screening
in vitro and in vivo assays
Pharmacodynamics & Pharmacokinetics
quantitative data on drug compound
systemic exposure of the drug
Drug Absorption, Distribution, Metabolism and Excretion

6. FDA IND Review - Preclinical studies submitted
Final study reports for nonclinical pharmacology and toxicology studies
submitted in the IND.
Pharmacology screening
in vitro and in vivo assays
Pharmacodynamics & Pharmacokinetics
quantitative data on drug compound
systemic exposure of the drug
Drug Absorption, Distribution, Metabolism and Excretion

7. FDA IND Review - Preclinical issues identified
Acute Toxicity studies are missing
Identify species-specific differences in toxicology
in vitro and in vivo assays
Summary of Pharmacological and Toxicological effects of the
drug in animals incomplete

8. FDA IND Review - Preclinical issues identified
Acute Toxicity studies are missing
Identify species-specific differences in toxicology
in vitro and in vivo assays
Summary of Pharmacological and Toxicological effects of the
drug in animals incomplete

9. FDA IND Review - Clinical data submitted
Outline of the investigation protocol was submitted with an estimated
number of participating test subjects.
Dosing plan and duration
Monitoring of vital signs and blood chemistry of test subjects
Prothrombin time assay to monitor therapy on a daily basis
International Sensitivity Index used to measure and compare the
variability in thromboplastin responsiveness

10. FDA IND Review - Clinical data submitted
Outline of the investigation protocol was submitted with an estimated
number of participating test subjects.
Dosing plan and duration
Monitoring of vital signs and blood chemistry of test subjects
Prothrombin time assay to monitor therapy on a daily basis
International Sensitivity Index used to measure and compare the
variability in thromboplastin responsiveness

11. FDA IND Review - Clinical issues identified
Proposed Phase 1 trial is a open-label, single center, PK/PD study
Evaluate safety and anticoagulation activity of the new drug
compound in humans
Primary outline of the investigation
Toxicity based stopping or dose adjustment rules
missing

12. FDA IND Review - Clinical issues identified
Proposed Phase 1 trial is a open-label, single center, PK/PD study
Evaluate safety and anticoagulation activity of the new drug
compound in humans
Primary outline of the investigation
Toxicity based stopping or dose adjustment rules
missing

13. FDA IND Review - CMC issues identified
CGCP compliance not provided for Phase I
Manufacturer must produce the drug in a qualified
facility, using laboratory equipment that has been
qualified and validated.

14. FDA IND Review - CMC issues identified
CGCP compliance not provided for Phase I
Manufacturer must produce the drug in a qualified
facility, using laboratory equipment that has been
qualified and validated.

15. Initial IND 30 Day Review Cycle
Complete Clinical Hold issued (21 CFR §312.42(b)(i))
The IND does not contain sufficient information required under
federal regulations to assess the risks that the proposed studies
present to subjects.
Investigator Brochure is materially incomplete
Telephone call placed with sponsor
Letter sent to sponsor within 7 calendar days of telephone call

16. Initial IND 30 Day Review Cycle
Complete Clinical Hold issued (21 CFR §312.42(b)(i))
The IND does not contain sufficient information required under
federal regulations to assess the risks that the proposed studies
present to subjects.
Investigator Brochure is materially incomplete
Telephone call placed with sponsor
Letter sent to sponsor within 7 calendar days of telephone call

17. Resolution: Pre-Clinical issues
Sponsor conducted in vitro and in vivo toxicity
studies in mice and rabbits.
Sponsor submitted a complete Summary of
Pharmacological and Toxicological effects of the drug
for Investigator's Brochure.

18. Resolution: Pre-Clinical issues
Sponsor conducted in vitro and in vivo toxicity
studies in mice and rabbits.
Sponsor submitted a complete Summary of
Pharmacological and Toxicological effects of the drug
for Investigator's Brochure.

19. Resolution: Clinical issues
Sponsor included dose adjustment rules in the investigation
Sponsor amended the protocol to include single dose and
escalated dose studies within the investigation

20. Resolution: Clinical issues
Sponsor included dose adjustment rules in the investigation
Sponsor amended the protocol to include single dose and
escalated dose studies within the investigation

21. Resolution: CMC Issues
CGCP Compliance
Sponsor implemented appropriate QC
procedures
Established an acceptance criteria for control
components
implemented manufacturing controls at
appropriate stages of drug development

22. Resolution: CMC Issues
CGCP Compliance
Sponsor implemented appropriate QC
procedures
Established an acceptance criteria for control
components
implemented manufacturing controls at
appropriate stages of drug development

23. Response to FDA
Sponsor responds to the Clinical hold
Faxed letter labeled “ Clinical Hold Complete
Response” to the division project manager.
Discusses unresolved issues with FDA reviewers
Clinical Hold is removed

24. Response to FDA
Sponsor responds to the Clinical hold
Faxed letter labeled “ Clinical Hold Complete
Response” to the division project manager.
Discusses unresolved issues with FDA reviewers
Clinical Hold is removed

25. FDA IND Review - Lessons Learned
I learned to request a Pre-IND meeting with the FDA before
submission of the IND application
Describe in detail Pre-clinical, Clinical investigations and CMC
measures in supplemental documents
It is also important to have knowledgeable RA associates
handling communication between the FDA and Sponsor

26. FDA IND Review - Lessons Learned
I learned to request a Pre-IND meeting with the FDA before
submission of the IND application
Describe in detail Pre-clinical, Clinical investigations and CMC
measures in supplemental documents
It is also important to have knowledgeable RA associates
handling communication between the FDA and Sponsor