FDA minimal requirements at the pre-clinical stages are a drug pharmacological profile, acute toxicity in two species and short-term toxicity studies. Usually, no formal obligation for good manufacturing practice (GMP) is required by the FDA at this stage. However, good laboratory practice (GLP) documentation is essential for regulatory submission. FDA requires GLP documentation for safety studies only (not for in vitro/in vivo efficacy studies) including animal toxicity, genotoxicity, supporting toxicokinetic and safety pharmacology studies in the pre-clinical stage, based on 21 CFR part 58 “Good Laboratory Practice for non-clinical laboratory studies”, to ensure with a high level of confidence that the investigational drug product is safe for clinical trials in humans.
GLP enables regulatory authorities to assure that the data submitted is a true reflection of the results obtained from study and can therefore be relied upon as part of the product safety and risk assessments. Moreover, adhering to a high standard of work and according to GMP/GLP principles at the pre-clinical stage will ensure that the results are reliable, and may also provide higher levels of confidence and solid information for the company during any due diligence processes by potential investors. Although no FDA approval is required for pre-clinical stages, at he IND (Investigational New Drug) stage, retrospective review of the pre-clinical data will be conducted be the FDA. Therefore, GLP and GMP including good documentation practices (GDP) and other GxP requirements should be met, unless any additional animal testing may be required by the FDA before initiation of the (human) clinical stage.
FDA pre-clinical guidelines are detailed in 21 CFR part 312.160.
Pharmacodynamic (PD) & Pharmacokinetics (PK) studies: PD studies analyze the effect of a drug on the body, while PK studies analyze the body on the drug (ADME; absorption, distribution, metabolism and excretion).
Pre-clinical stage termination: The main purpose of pre-clinical trials is to prove that the investigational drug product is safe (non-toxic) prior to clinical stage initiation, in addition to efficacy (pharmacology).
FDA is not involved at the pre-clinical stages, but may retrospectively review the new drug development stages as part of the new investigational drug clinical stage, and usually focus on the pre-clinical drug safety results. After the pharmacodynamic (desired and non-desired effects) and toxicity profiles of the investigational drug product data are received, the clinical stage can be initiated. At the end of the pre-clinical stage, the sponsor can arrange a meeting with FDA, and then send documents and questions for the clinical stage of the investigational drug product.
The Quality Assurance (QA) function at a company pursuing drug development is responsible for assuring the development process stages are being conducted in compliance with the regulatory standards required at the various development stages. QA should cover quality issues related to, among others, utilities, equipment, personnel, analytical methods, stability studies, procedures, records, monitoring, inspection and control and qualifications.
Investigational New Drug application (IND)
After termination of the pre-clinical stage all pre-clinical data and a detailed clinical trial plan (in humans) are submitted to the FDA as part of the Investigational New Drug application (IND). It is recommended to add to the IND an “investigator brochure” with information about possible drug effects for use by the Institutional Review Board (IRB) and clinicians that will perform the clinical trial. If no response is received from the FDA within 30 calendar days, the clinical trial can be initiated.
IND requirements and content: The IND will include introduction, investigator brochure, study protocols, investigational plan, previous human experience, pharmacology and toxicology, investigator, facilities and navigational review board (IRB /ethics committee), manufacturing and control and additional information sections. The IND will include data that will cover the investigational drug chemical composition, pre-clinical data, investigator(s) qualification, clinical studies protocols, informed consent and IRB information, animal pharmacology and toxicology data, chemistry manufacturing and controls (CMC), previous human experience. For every clinical investigator, FDA form No. 1572 should be submitted. Informed consent is as defined in 21 CFR part 50, IRB review, and approval and reporting as defined in 21 CFR part 56 are required. The clinical study must be conducted according only to the relevant, current, approved protocol version. Changes in the protocol must be controlled, reviewed and approved by the sponsor. Records should follow good documentation practices (GDP), managed in a controlled manner and comply with 21 CFR part 312 requirements.
EU Clinical Trial Application (CTA): The CTA is the European equivalent to the IND. In Europe, the Qualified Person (QP) should approve clinical batch release before using the investigational drug in clinical trials.
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