1. Background and history
The FDA (U.S Food & Drug Administration) was established in 1901 as a bureau of the Chemistry Department of Agriculture. Five years later, a regulatory function was added to this bureau. By 1953, the FDA was affiliated to the department of Health Education & Welfare. After the elixir of the tragic Sulfanilamide accident that killed 107 patients, a year later the Federal Food and Drug law passed in the U.S congress, regulating cosmetic and therapeutic devices. Since then, every new pharmaceutical product’s safety has to be approved by manufacturers. As part of these new regulations, material’s concentration specifications had to be established and tested in order to increase product safety. Moreover, standards of pharmaceutical materials identity and quality were established. In 1962, as a result of Thalidomide that caused birth defects in thousands of new borns in western Europe, drug efficacy and improved safety regulations were established. For the first time, the U.S, drug manufacturers were required to prove to the FDA the effectiveness of their product before marketing. Back to 2014, FDA covers drugs, devices, biologics, food, dietary supplements, cosmetics, combination products and veterinary products regulation and registration. The FDA today is divided to five product based centers:
- CDER – Center of Drug Evaluation and Research
- CBER – Center of Biological Evaluation and Research
- CDRH – Center of Device Evaluation and Research
- CFSAN – Center of Food Evaluation and Research
- CVM – Center for Veterinary Medicine
2. Code of Federal Regulation
The FDA receives its authority from the U.S congress in order to enforce safety laws. The FDA interpretation of the U.S laws which are being written by the U.S congress are reflected in the understandings and uses accordingly, in order to write formal regulations as a response to these laws. The FDA communicates with the Food and Pharmaceutical industries via federal register and relevant industries are being asked to supply their input on the new FDA drafts. After a predetermined time period, new laws and regulations are entered into the CFR (Code Federal Regulation). Usually, every year (around April) new regulations are supposed to be added into the CFR and are published. All final regulations are being added and codified into the CFR and details FDA expectations from relevant industries for the new laws’ implementation. 21CFR codifies all food and drug regulations (as result of federal laws) and includes several volumes collected from each relevant FDA center. It is important to clarify that the guidelines are considered as recommendation and in case there is a better way for new law understanding, interpretation, implementation and approval, it can be performed accordingly based on a risk based approach.
3. Center of Drug Evaluation and Research (CDER)
3.1 What is a pharmaceutical drug?
- A chemically synthesized known structure product used to diagnose, cure, mitigate, treat or prevent a disease
- Articles recognized in the official USP (United State Pharmacopeia) or other compendia (NF)
- Articles intended for use in the diagnostics, cure, mitigation, treatment or prevention of disease in man or any other animals
- Articles intended to affect the structure or any function of the body of man or other animals
3.2 CDER include six offices of drug evaluation and is responsible for reviewing drug evaluation such Pharmaceutical science offices that provide the scientific perspective for the center. CDER is responsible for reviewing safety and efficacy data before, during and after new drug approval. Since 2003, new drugs and biological submission requests are being handled by the office of new drugs (prescription, generic or over the counter OTC products) for safety and effectiveness before marketing. After marketing, CDER will monitor marketed products and will remove and recall low quality/risky products. As in recent years a lot of biological pharmaceutical products are being developed and submitted, parts of the products registered in the CDER were moved to the CBER as it is similar process. CDER regulations are mainly included in sections 200-300 of the 21 CFR.
4. Center of Biological Evaluation and Research (CBER)
4.1 What is a biological pharmaceutical product? A biological product is a product from a living source such as humans, animals, plants and microorganisms, that prevent, treat or cure disease or injuries in humans. Biological products are subjected to license under the public health service act. 4.2 CBER regulations are mainly included in sections 600 of the 21 CFR
5. New drug development
5.1 General New drug discovery and development is prolonged process that requires high capital investments. New drug development begins with drug discovery, synthesis and screening process. The screening process usually will be supported by software and may include thousands of chemical and biological compounds that will be screened on in-vitro and other models that will supply “go” / “no-go” indications. The screening process can include synthetic or natural compounds, existing drugs or investigational drugs that failed in various clinical stages and that may be found suitable for other Pharmacological indications. At the end of the drug candidates screening process, the lead candidates are being chosen based on bioinformatics and statistical techniques and models for further research.
After several drug candidates are discovered, a study on the chemical/biological/physical and other relevant properties of the investigational drug product is conducted. Moreover, investigational drug product synthesis and purification methods should be developed. Drug candidates are being tested and screened usually using in-vitro models. After in-vitro models testing, potential drug candidates are being tested using in-vivo models (pre-clinical stage) using experimental animals studies (short terms and long term studies) for discovering new investigational drug product efficacy and adverse effects (safety). In short term animal studies, the researcher will collect data regarding investigational drug product absorption, metabolism, extraction and short term toxicity (“ADME” / “Tox study”). Long term animal studies will analyze single and repeated dose effect on reproductive toxicity, teratogenicity, carcinogenicity and geno-toxicity (mutations), immune-toxicity, local tolerance and environmental effects of the investigational drug product usually in to different animal species.
The FDA’s minimal requirements at the pre-clinical stages are 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. Good Laboratory Practice (GLP) based documentation will be essential for regulatory submission. The 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 21CFR part 58 “Good Laboratory Practice for non-clinical laboratory studies” in order to ensure with high confidence level that the investigational drug product is safe for clinical trials in humans.
GLP enable the regulatory authorities to assure that the data submitted is a true reflection of the results obtained as part of the study and can therefore be relied upon as part of safety and Risk Assessments. Moreover, keeping a high level and working according to the GMP/GLP principles and standards at the pre-clinical stage will ensure that the results are reliable and may also give higher confidence levels and more solid information for the company during any potential investors due diligence process. Although no FDA approval is required in the pre-clinical stages, in the IND (Investigational New Drug) stage, retrospective review of the pre-clinical data will be conducted be the FDA, therefore, Good Laboratory Practice (GLP) and GMP (Good Manufacturing Practice) standards including Good Documentation Practices (GDP) and other GxP standards should be kept, unless any additional animal testing may be required by the FDA before clinical stage initiation. All FDA pre-clinical guidelines are detailed in 21CFR part 312.160. 5.2 Pharmacodynamic & Pharmacokinetics (PD & PK) Pharmacodynamic (PD) studies analyze drug effect on the body, while Pharmacokinetics (PK) studies analyze the body’s effect on the drug (absorption, distribution, metabolism and excretion). 5.3 Pre-clinical stage termination. Actually, the main purpose of the pre-clinical trial is to prove the investigational drug product is safe (toxicity) prior clinical stage initiation in addition to efficacy (pharmacology).
The FDA will not be involved at these stages but may review the new drug development stages retrospectively as part of the new investigational drug clinical stage, usually focused 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 the FDA, and then send documents and questions for the clinical stage of the investigational drug product. 5.4 Quality Assurance (QA) function as part of drug development in a company is responsible for assuring the development process stages are being conducted in compliance with the regulatory standards required at the various development stages. Quality Assurance function should cover quality issues related to utilities, equipment, personnel, analytical methods, stability studies, procedures, records, monitoring, inspection and control, qualifications and others.
6. Investigational New Drug application (IND)
6.1 General After pre-clinical stage termination, all pre-clinical data and a detailed clinical trials 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” for information about possible drug effects to the Institutional Review Board (IRB) and clinicians that will perform the clinical trial. In case no response is being received from the FDA, clinical trial can be initiated. 6.2 Clinical Trial Application (CAT) The equivalent European to the IND is called CAT (Clinical Trial Application). In Europe, Qualified person (QP) should approve clinical batch release before using the investigational drug usage in clinical trials. 6.3 IND requirements and content The IND will include introduction, investigator brochure, study protocols, investigational plan, previous human experience, pharmacology and toxicology, investigator, facilities and IRB, manufacturing and control and additional information sections. The IND will include data that will cover the investigational drug chemical composition, pre-clinical data, investigators qualification, clinical studies protocols, informed consent and IRB information, animal pharmacology and toxicology data, chemistry manufacturing and controls (CMC), previous human experience in case exist. For every clinical investigator, FDA form No. 1572 should be submitted. Informed consent as defined in 21CFR part 50, IRB review, approval and reporting defined in 21CFR part 56 are required. The clinical study must be followed based on the relevant, current, approved protocol version only. Changes in protocol must be controlled, reviewed and approved by the sponsor. Records should follow Good Documentation Practices (GDP) and managed in controlled manner and comply with 21CFR part 312 requirements.