Phases of Drug Development & Regulation, Slides of Chemical Kinetics

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Phases of Drug Development &

Regulation

Akm Khairuzzaman, B.Pharm, M.S. Ph.D. CDER/FDA

Aim of Drug Development

• (^) CMC [21 CFR 312.23(a)(7)]: To assure the proper identification, quality, purity, and strength of the investigational drug.
• (^) Preclinical [21 CFR 312.23(a)(8)]: To assure that it is reasonably safe to conduct the proposed clinical investigations

Drug Development Timeline

Before Administering a Study Drug to

Humans...

• (^) Duration of drug exposure in humans should not exceed duration of exposure in animals.
• (^) Maximum initial dose used in humans should not exceed maximum observed no adverse effect level (NOAEL) dose studied in animals.

IND Regulation (Drugs & Biologics)

Legislative Process

21 F.R. 312 21 U.S.C. 312 21 C.F.R. 312 21 U.F.O. 312 § Resources:

• CFR : www.access.gpo.gov/nara/cfr/index.htm
• Federal Register : www.access.gpo.gov/su_docs/aces/aces140.htm www.fda.gov/ohrms/dockets/default.htm
• Dockets : www.fda.gov/scripts/oc/ohrms/index.cfm
• 􀃅Regulatory Policy Staff (RPS; HFD-007)

Types of IND

• (^) Commercial (Company & NIH)
• (^) Research (Individual Investigators & Academic Institution)
• (^) Individual Patient INDs (21 CFR 312.23) Generally for serious illnesses, but not emergencies
• (^) Emergency INDs (21 CFR 312.36): Emergency situation that does not allow time for submission of IND, normally just for one patient
• (^) Treatment IND (21 CFR 312.23): Drug intended to treat a serious or immediately life-threatening disease

When is an IND needed?

Questions to ask

• Is it a drug?
• Is it being used in a clinical investigation?
• Is it a drug that is lawfully marketed in the U.S. for another use?

Is it a clinical investigation?

• (^) A “clinical investigation” is “any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects.”
• (^) An “experiment” is “any use of a drug except for the use of a marketed drug in the course of medical practice.”
• (^) Not limited to commercial development

Is it a Drug that is Lawfully Marketed

in the U.S. for Another Use?

• (^) Is it lawfully marketed as a drug under one of the two following circumstances?
• marketed under an approved NDA or BLA or
• marketed under an OTC monograph

What happens at FDA after the IND

submission?

• (^) Study cannot proceed until 30 days from FDA receipt (new INDs and reactivated INDs only)
• (^) 30-day safety review
• (^) Decision: safe to proceed or clinical hold?

IND Review Outcome: Clinical Holds

• (^) If there is no advice to the IND sponsor, then after 30 days they can start the clinical trial
• (^) Clinical HOLDS (21 CFR 312.42)
• (^) Partial holds vs full clinical hold

Clinical Hold

• (^) 312.42(b)(1)(i-iv) – Phase 1, 2 or 3 Studies
  • (^) Unreasonable risk
  • (^) Unqualified investigators
  • (^) Misleading erroneous, or incomplete investigator brochure
  • (^) Insufficient information
• (^) 312.42(b)(2)(ii) – Phase 2 or 3 Studies
  • (^) Protocol is deficient in design to meet objectives

Example 1 of a Clinical Hold

A dose escalation study is proposed. Due to safety concerns, the firm is instructed to test the dose levels sequentially and to submit the safety information after each dose level for FDA review. The firm cannot proceed to the next dose level without FDA concurrence