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US Regulation for Biologics and Biosimilars Definition: Biologics: Public health service (PHS) act defined as “ Biologics are single or combination of virus, Therapeutic serum, Toxin, Antitoxin, Vaccine, Blood, Blood component or Derivatives, Allergenic product, or Analogues product used for treatment, diagnosis, and prevention of disease condition.
- The most important thing is Hormones such as insulin, glucagon, and human growth Hormones are regulated as a drug under the FDA act, not as a biological product. Both FDA’s centers such as CDER and CBER are responsible for the regulation of the biological product.
- Biologics are also called Biotherapeutics or Biopharmaceutical, these are derived from a living organism.
- The first protein- based biologics, which was made by recombinant technology is insulin and it was approved in the United States in 1982. Biosimilars: Biosimilar is a drug that manufactures from the large-scale operation of a living cell. Biosimilar is very similar to the older drug but not structurally identical.[4] They are isolated from the living source – humans, animals, plants, fungal and microbial. Reference Biologics: Innovator products approved by the FDA for comparison with a Non-US approved Products. Types of Biological Product
- Blood Derivatives
- Whole blood
- Proteins
- Vaccines
- Cellular and gene therapy
- Allergic extracts
- Human tissue
- Xenotransplantation produces Difference between Biologics and Small molecular drugs Biologics Small molecule drugs High Molecular Weight Low Molecular Weight Biologics made by living cells Drug made by chemical synthesis It has a heterogeneous structure It contains a defined structure It is a difficult to characterize It is easy to characterize Size: Large Very small Via injection or infusion Oral Administration Unstable at room temperature Typically, stable at room temperature Can not completely define the structure Can be determined using standard analytical techniques Used as drugs for more complicated diseases such as cancer therapy Suitable for drug development for minor diseases Regulatory Bodies FDA: FDA team was established in 1997 to give quality and safety to biological Products. The biological product comes under two acts as the public health service act (PHSA) and Food and Drug Administration (FDA). Regulatory submission refers to the application to provide the data or information to FDA regarding the development, approval, or post - approval report of biologics. FDA is responsible to gives market approval to biologics in the United States under the authority of the Federal Food, Drug and Cosmetic Act, and section 351 of the Public Health Service Act (PHSA). The review of an application takes place in three major centers of the FDA such as- CDER, CBER, and CDRH.
Public Health Service Act (PHSA) Act was started in 1944. The act established the federal government's quarantine authority for the first time. It gave the United States Public Health Service responsibility for preventing the introduction, transmission, and spread of communicable diseases from foreign countries into the United States. CBER (center for biological evaluation and research) AND CDER (center for drug evaluation and research) It works under FDA and Public Health Service Act (PHSA). The main objective of CBER is to protect and enhance public health by regulating biological products, vaccines, tissue, and gene therapy product. CBER is responsible for assuring the safety, purity, potency, and effectiveness of biologics and related products. Not all biologics are regulated by CBER. Monoclonal antibodies and other therapeutic proteins are regulated by CDER. The following product will be 1) regulated by CBER such as- a) Gene and gene product. b) The allergenic extract is used for the diagnosis and treatment of allergies. c) Venom, antitoxin, and antivenin. d) Blood, several blood products, and the device used for collection, testing, and processing of blood. e) Xenotransplant
f) Human cell, tissue or cellular, and tissue base product
- CDER regulated by certain biologics such as- a) Immunomodulators (except vaccine or allergenic compound). b) Hormones c) Monoclonal antibodies for in vivo use. d) Most protein for therapeutic use (except those specifically noted as being regulated within CBER) CBER procedure having four main criteria for approval of advertising and promotional materials-
- Material must include proper prescribing information.
- Material not required false.
- Material must contain a fair balance.
- material must be consistent with the approved package insert; also, the generic name of the product must be used in advertising. IND (Investigational New Drug Application) After preclinical investigation when the new biological molecules have been screened for pharmacological activity and acute toxicity potential in animals the sponsor required permission from FDA for its clinical trials in humans. The sponsor applies to the conduct of human clinical trials called IND. According to the FD&C act sponsor of biologics are must be required to fill IND application form before biologics products may be given to a human. This is to protect the rights and safety of the subject. The sponsor of an IND takes a responsibility for initial clinical trials. An IND generally goes into effect 30 days after FDA receives it. FDA is taken 30 days for checking the IND application. FDA receives the IND for safety issues.
f. Explanation of the patient observation, measurement, and test to be used. g. The clinical procedure, Laboratory test, and monitoring to be used in minimizing patient risk. h. All information such as the name, address, and credentials of the principal investigator and co- investigator. i. Location and Description of the clinical research facilities to be used. j. Approval of the authorized IR. The application Review process of IND After review by CDER or CBER, CDR, the application is sent to the document control center which is responsible for the review of the application. Acknowledgment letter is sent to the applicant and the project manager is assigned to coordinate the NDA review process. CD is responsible for the distribution of various copies of IND to the different divisions for evaluation. The project manager performs the initial screening of application are refused for feeling. If the concern is found, then a deficiency letter is sent to the applicant. NDA (New Drug Application)
NDA and BLA application is required to market a new drug and biologics product. NDA is used by CDER for the market to drug products. BLA is used by CBER for the market to biologics products. The review and approval of NDA are based on safety, efficacy, according to detailed reports of clinical trials. The pre- NDA meeting between the sponsor and FDA to discuss the content and format of the NDA. The purpose and main mission of NDA are to gain permission to market the drug and biologics. NDA has a specialized review team of highly qualified experts. The review team will decide to approve or disapprove the NDA. Classifies new drug applications according to the type of drug being submitted and its intended use:
- New molecular entity
- New salt of previously approved biologics
- New formulation of previously approved biologics,
- New combination of two or more biologics,
- Already marketed drug product- Duplication (i.e., new manufacturer),
- New indication (claim) for already marketed drug (includes switching marketing status from prescription to OTC),
- Already marketed drug product (no previous approved NDA) Format and Contents a) FDA form 356h b) User fee cover sheet (FDA form 3397) c) Cover letter (comprehensive table of contents for modules 1 to 5) d) Summary e) Chemistry, Manufacturing, and control.
- The CD is responsible for the distribution of various copies of NDA to the different divisions for evaluation.
- Then the acknowledgment letter is sent to the applicant and the project manager is assigned to coordinate the NDA review process.
- The project manager performs the initial screening of application are refused for feeling.
- FDA review team will convene at 45 days meeting to determine the application should be filed or refused. BLA (Biological License Approval) A BLA is “a request for permission to introduce or deliver for introduction biologics product into interstate commerce”. The BLA is regulated under 21 CFR 600 – 680. A BLA is submitted by any legal person or entity who is engaged in the manufacture or an applicant for a license who takes responsibility for compliance with product and establishment standards. Form 356h specifies the requirements for a BLA. This includes:
- Applicant information
- Product/Manufacturing information
- Pre-clinical studies
- Clinical studies
- Labeling The main requirement is to submit the BLA to FDA firstly. All information regarding BLA must be submitted to FDA within 30 days of biological product withdrawal from sale. FDA Review of BLA: 1)The two main agency the BLA such as “Prescription Drug User Fee Act (PDUFA). And FDA Good Review Management Principles and Practices (GRMPs).
- After sponsor submission of BLA, the agency assembles the all-reviewer member and they focus on each content of BLA such as clinical trials and toxicology issues.
- after submission of BLA, within 60 days FDA decide that BLA application file or not.
- Many times, FDA refuses to file when BLA did not show satisfactory information.
- During the filling period, the FDA will also decide whether to choose the BLA as a priority as standard application.
- after the FDA has begun a substantive review of the BLA, reviewers may issue information request (IR) and discipline review (DR) letter to the applicant. Contents of BLA: a) A BLA must contain the following information: Form FDA 356h (cover sheet) b) Applicant information c) Product/manufacturing information Source material / raw materials d) Manufacturing process and controls e) Formulation f) Facility information g) Contamination / cross-contamination information h) Environmental assessment or categorical exclusion i) Safety, efficacy and use pre-clinical studies j) Clinical studies k) Labeling. PMA (Pre-Marketing Approval)
g. Conclusion of studies include safety and effectiveness of the device h. Reference to any performance standard followed i. Labeling j. Result of the non-clinical lab study k. Result of clinical studies on human patients l. Financial certification. 510K The 510k process is rapid, flexible, and adaptable to many devices. The main goal of 510k is “Demonstration of sustained to a device that was on the US market before May 28, 1976, or to a device that has already gone through 510k clearance process”. The device is successfully gone through the 510k process are called “510k cleared”. Types of 510k: There are four main types of 510k are as follows- a) Traditional 510k- Traditional 510k filed when sponsor developed a similar device or equivalence to a device that has been cleared through the 510k processor was already in the market before the 1976 med ical Device Amendments were sighed on May 26, 1976. b) Abbreviated 510k - This 510k is similar to the traditional 510k in function. A sponsor can choose to comply with FDA accepted standards during the testing process. A declaration of conformance included in the 510k, stating that the device meets the specification in the reference standard. c) Special 510k - A special 510k is submitted when a sponsor has made some modification in her/his device and has not added a new indication for use. d) De Novo 510k - The De Novo 510k is a 510k without a predicate device. It is not a commonly used path, but in some circumstances, it is appropriate. Content of 510k:
a) The cover sheet (FDA form 3514). b) The cover letters c) The table of content d) User fee information e) Statement of substantial equivalence f) Labeling g) Advertising and promotional material. h) Comparative information.
