Chemistry Information Necessary to Support an IND Application : Chemistry Information Necessary to Support an IND Application William C. Timmer, Ph.D.
U.S. Food & Drug Administration
Center for Drug Evaluation & Research (CDER)
Office of New Drug Chemistry
301-827-1522
timmerw@cder.fda.gov
Food & Drug Administration : Food & Drug Administration
Regulatory Submissions* : Regulatory Submissions* IND: Investigational New Drug application:
application to begin testing of a new drug in humans
NDA: New Drug Application
application to market a new
drug in humans *CDER; CBER: INDs & BLAs
IND Clinical Development Phases : IND Clinical Development Phases Phase I: Safety study; first use of drug in humans; 20 - 50 healthy patients.
70% of drugs pass
Phase II: Dose-ranging study; msmt of effectiveness; continued safety studies. 100s of patients.
33% of drugs pass
Phase III: Efficacy study; pivotal clinical trials; 1000s of patients.
25% of drugs pass
file NDA
IND / NDA Review Team : IND / NDA Review Team Recommendation Clinical Chemistry Statistics BioPharm Pharm/Tox IND
NDA
Drug Approval Criteria : Drug Approval Criteria
Two Criteria for NDA Approval : Two Criteria for NDA Approval #1. Drug is safe.
#2. Drug is efficacious.
(mechanism of action: no!)
Simplicity of slide does not imply simple to do.
Drug Development Timeline : Drug Development Timeline PRE-CLINICAL
RESEARCH CLINICAL STUDIES NDA
REVIEW POST
MARKETING DISCOVERY/SCREENING SYNTHESIS AND PURIFICATION ANIMAL
TESTING PHASE III ADVERSE
REACTION
SURVEILLANCE
PRODUCT DEFECT
REPORTING SURVEYS
SAMPLING
TESTING
POST APPROVAL
INSPECTIONS AVG: 18 MOS. AVG: 5 YEARS AVG: 12 MOS. PHASE II PHASE I
Slide9 : CHEMISTRY (CMC)
Chemistry, Manufacturing, and Controls
Office of New Drug Chemistry (ONDC) : Office of New Drug Chemistry (ONDC) To ascertain the: identity, strength, quality & purity of the new drug product
includes evaluation of manufacturing process
stability program
ONDC Staff Profile : ONDC Staff Profile Scientific Staff:
~ 30 Managers and Team Leaders
~ 100 Primary Reviewers
Background: organic, analytical, physical, medicinal and pharmaceutical chemistry, biology, microbiology, biochemistry and pharmacy
Education: Ph.D., M.S., B.S., B. Pharm.
Slide12 : CMC Regulatory Requirements
What’s Important from a Chemistry Perspective? : What’s Important from a Chemistry Perspective? drug substance (DS) can be quantitatively assayed in the drug product (DP).
(drug product = drug substance + excipients)
impurity profile of the DS:
be determined
be determined in the DP
be qualified by Pharm/Tox reviewer
What’s Important from a Chemistry Perspective ? : What’s Important from a Chemistry Perspective ? stability of the DP be determined
i.e., the physico-chemical properties of the DP
have not changed over shelf-life period / clinical trial
analytical test procedures and acceptance criteria are indicative of product quality
batch-to-batch variations are minimized by compliance with cGMP
What is cGMP? : What is cGMP?
regulations that govern:
manufacturing, testing, processing, record keeping, packing, etc.
rationale: assure drug product quality
inspection of manufacturing site performed by trained ORA inspector (new initiative: include reviewers)
compliance with cGMP regulations is required for approval of NDA
GMP becomes more important as drug move to NDA.
GMP is important to address early. (quality
is built in)
What is the Minimum CMC Data Set? : What is the Minimum CMC Data Set? Need assay (generally HPLC) to determine:
purity of DS
purity of DS in DP
impurities
Stability data:
sufficient to cover clinical trial (phase I)
Labeling (Caution statement ….)
Slide17 : OTHER USEFUL
REFERENCES
FDA Guidance Documents : FDA Guidance Documents www.fda.gov/cder/guidance/index.htm
Guideline for the Format and Content of the CMC Section of an Application;
INDs for Phase 2 and 3 Studies: CMC Information Background:
FD&C Act of 1938: “The Act”
21 CFR “The Regulations”
Guidance Documents
FDA Reference: ICH : FDA Reference: ICH ICH: International Conference on Harmonization
www.ich.org
ICH topics divided into four major categories:
Q Quality Topics: relating to chemical &
pharmaceutical Quality Assurance.
Ex: Q1 Stability Testing, Q3 Impurity Testing
These are how to do it manuals.
FDA Reference: ICH : FDA Reference: ICH S Safety Topics: relating to in vitro & in vivo pre- clinical studies.
Ex: S1 Carcinogenicity Testing, S2 Genotoxicity Testing
E Efficacy: relating to clinical studies in humans subject.
M Multidisciplinary Topics: cross-cutting topics which do not fit into one of the above.
ICH is for NDA! (but ….)
Literature Reference : Literature Reference
Literature Reference : Literature Reference Drug Information J. 37, 407-38 (2003)
Slide23 : from: Drug Information J.
37, 407-38 (2003)
Slide24 : from: Drug Information J.
37, 407-38 (2003)
Slide25 : Professional Organizations
1. DIA: Drug Information Association
www.diahome.org
2. PERI: Pharmaceutical Education and Research Institute
www.peri.org
3. RAPS: Regulatory Affairs Professional Society
www.raps.org
4. Regulatory sections within your drug’s
professional association. Organizations
Where to Go for More Information : Where to Go for More Information
FDA !!
Simple Two Step Process:
Step 1: Prepare briefing package outlining plans/questions
Step 2: Request pre-IND meeting from appropriate FDA division.