IND Review Process Seoul National University Dept. of Manufacturing Pharmacy 2001-14451 Sue Hyun Kim

IND Review Process Applicant (Drug Sponsor) IND Medical Chemistry Review by CEDR Medical Chemistry Pharmacology/ Toxicology Statistical Sponsor Submits New Data Safety Review No Clinical Hold Decision Safety Acceptable for Study to Proceed? Yes Yes No Complete Reviews Notify Sponsor No Reviews Complete And Acceptable? Sponsor Notified Of Deficiencies Yes *While Sponsor answers any deficiencies No Deficiencies Study Ongoing*

Applicant (Drug sponsor) The person or entity who assumes responsibility for the investigation of a new drug. (including responsibility for compliance with applicable provisions of the Federal Food, Drug, and Cosmetic Act and related regulations) Usually an individual, partnership, corporation, government agency, manufacturing or scientific institution. Investigational New Drug Application The result of a successful preclinical development program  advances to clinical trials 1’ goal : determine safety for initial use in humans & pharmacological activity for commercial development  collecting data and information  collecting data and information Animal Pharmacology and Toxicology Studies Manufacturing Information Clinical Protocols and Investigator Information IND is not an application for marketing approval. It is a request for an exemption from the Federal statute that prohibits an unapproved drug from being shipped in interstate commerce.

Types of IND Review Process Medical Review Commercial INDs : submitted by companies-obtain marketing approval Noncommercial INDs : vast majority of INDs. - including Investigational INDs, Emergency Use INDs, Treatment INDs. Review Process Medical Review Exclusively physicians. Medical reviewers are responsible for evaluating the clinical sections of submissions (i.e., safety of the clinical protocols in an IND or the results of this testing.) Lead role in the IND or NDA review, Responsible for synthesizing the results of the animal toxicology, human pharmacology and clinical review to formulate the overall basis for a recommended Agency action on the application. Evaluate clinical trial protocols to determine If the participants will be protected from the unnecessary risks If the study design will provide data relevant to the safety and effectiveness of the drug

Pharmacology/Toxicology Review Chemistry Review Reviewing the chemistry and manufacturing control sections of drug applications Issues related to drug identity, manufacturing control, and analysis. Evaluates the manufacturing & processing procedures ? Reproducible ? Stable ? ? Any differences b/w the drug product proposed for clinical use & used in the animal toxicology trials?  should be stated ( whether or not) Pharmacology/Toxicology Review Evaluate the results of animal testing & attempt to relate animal drug effect to potential effects in humans. Pharmacology and Drug distribution Pharmacologic effects and mechanism(s) of action of drug in animals ADME Information  A summary report usually suffices (w/o ind. Animal records or ind. Study results) Toxicology Data Integrated summary of the toxicologic effects of the drug in animals and in vitro. ** particular studies needed depend on the nature of the drug and the phase of human investigation.

Clinical Hold Decision Safety Review 30 calendar days following review of an initial IND submission  clinical hold? Or not? Sponsor hears nothing from CDER  continue the study on day 31 after submission Clinical Hold Decision When CDER does not believe or cannot confirm that the study can be conducted w/o unreasonable risk to the subjects/patients Delay the start of an early-phase trial / stop an ongoing study Sponsor must address the issue (basis of the hold) before the removal of the order Clinical holds are reviewed by upper management of CDER  to assure consistency and scientific quality in the Center’s decisions Notify Sponsor Immediate phone call by the division director A letter send by the division within 5 working days following the phone call : describe the reasons for hold, signature of the division director Response of the sponsor to CDER by sending “ IND CLINICAL HOLD RESPONSE” letter to division

Sponsor Notified of Deficiencies The division reviews the sponsor’s response and decides whether lift the hold or not (Within 30 calendar days) If the hold won’t be lifted, the hold decision is automatically sent to the office director for review  decide within 14 calendar days whether or not to sustain that decision  decision to lift the hold sent by the phone call from division to sponsor, & a letter confirms decision (within 5 working days of the phone call) Sponsor Notified of Deficiencies Other deficiencies that are not serious enough to justify delaying clinical studies Telephone or deficiency letter to the sponsor form the division Study Ongoing Expiration of CDER’s 30-day initial review period  Initiating clinical studies