FDA

What is New Chemical Entity (NCE)?

"Active moiety means the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt, or other non-covalent derivative of the molecule responsible for physiological or pharmacological action of the drug substance." [21 CFR § 314.108(a)] "New chemical entity means a drug that contains no active moiety that has been approved by FDA in any other application submitted under section 505(b) of the Act." [21 CFR of § 314.108(a)]

What is Device (21 U.S.C. § 321 (h))

A device is defined as an instrument, apparatus, machine, implant, in vitro agent, or other similar or related article which is Recognized in the official National Formulary of US pharmacopeia. Intended for use in diagnosis of disease, cure, mitigation, treatment, or prevention of disease (in man or animals). Intended to affect structure or any function of body of man (or animal). In contrast to a drug, a device does not achieve its intended purpose through chemical action within or on the body and is not being metabolized to achieve its intended purpose.

Prescription Drugs (21 U.S.C. § 353(b))

A drug for use by a human subject which shall be dispensed by written or oral prescription and be filled by pharmacist. Prescription drug is not considered safe unless except under supervision of a healthcare practitioner.

Difference between Drug & Biologic

A drug is: •Small molecule and is regulated by Center for Drug Evaluation and Research (CDER). •Less complex, well-characterized biological products (monoclonal antibodies) are now reviewed by CDER. •A drug is developed and marketed by sponsor. A Biologic is: •Regulated by CBER and requires specific non-clinical and clinical testing due to immunogenicity issues that may arise. •Can be introduced into interstate commerce under 21 CFR 601.2. •Made from virus, serum, toxin, blood component, protein, vaccines, human cells and tissues, gene therapy. •Historically, the PHS Act (1944) gave authority to NIH to perform research, development, and to regulate biological products. •Drug and biologic should be safe, effective. •Biologics & Biologics License Application (BLA) under PHS Act. •Biologic should be pure. •Under the PHS Act, two types of biological product applications: •Original BLA (§351(a) of the Act) and Biosimilar BLA (§351(k) of the Act). •BLA is regulated under 21 CFR 600-680. •BLA has the same content and structure to NDA. •However, NDA is regulated under 21 CFR 314.

What is a drug?

According to FD&C Act (21 U.S.C. § 321(g)(1), a drug means: A. Articles recognized in the US pharmacopoeia, the US Homeopathic pharmacopoeia, National Formulary. B. Articles intended for use in diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals. C. Articles (other than food) intended to affect the structure or any function of the body of man or other animals. Definitions: According to 21 CFR 310.3, a drug is defined as "Product used to diagnose, cure, mitigate, treat or prevent a disease or affecting structure or function of the body." •

Generic Biologics and Biosimilars

Biosimilar (used as substitute to new biologic) •A biosimilar is biological product that may have minor differences in the inactive components of reference product and must have no difference in safety and effectiveness. •Reference product is FDA-approved biological product that is already in the US market. •In 2010 Patient Protection and Affordable Care Act amended the PHS act to create Abbreviated License Pathway for Biosimilars OR "Interchangeable" biological products under Biologics Price Competition and Innovation Act (BPCIA act). •The BPCIA is conceptually the same as Hatch-Waxman Act which was established for abbreviated new drug applications. •Biosimilars are not required to be exact copies of reference Product. •A biosimilar must undergo extensive safety and efficacy testing due to complex nature of the product.

Examples of combination Products

Components packaged together: Surgical tray and instruments and lidocaine or alcohol swabs. Components packaged individually but labeled for use together: Photosensitizing drug and activating laser (or light). Iontophoretic drug delivery system.

Drug discovery and characterization of NCE

Computational and modeling tools are used to create molecular structure and Lead compounds. •Naturally occurring compounds such as antibiotics. •NCE is discovered as potential drug, it is subjected to full characterization (elucidation of chemical structure, impurity profiling, molecular weight, and other physicochemical attributes).

Combinations of Device

Congress enacted the Safety Medical Devices Act (SMDA, 1990). Law requires FDA to designate the center (CDER, CBER, or CDRH) based on mode of action. Thereafter, congress established office of combination products (OCP) within FDA office of commissioner for prompt assignment to the appropriate FDA center. •Request for designation may be made by the company to ask the agency to determine mode of action and the lead center for premarket review. •The 21st Century Cures Act (CCA) [December 2016] amended FD&C Act section 503 (g) for enhancement of coordination between different premarket review centers/offices [Draft Guidance for Industry & FDA staff (February 2019)].

New drug development process

Key questions in Drug Development •Characterize safety (risk profile)... the purpose is to minimize risk. • •Characterize efficacy....benefits of the drug to treat the disease (maximize benefit). Sequence to Develop a New Drug •Evaluation is taken place in the following order: 1.In vitro studies. 2.In vivo studies using smaller species first. 3.Adult humans (healthy subjects)... dose tolerability studies/safety/pharmacokinetic profile. 4.Patient population to demonstrate efficacy. 5.Special population (geriatrics, patients with liver or kidney disease). 6.Pediatric studies (if label claims for pediatric administration).

What is New Drug?

New use of active ingredient, excipient, carrier, coating. New use of a combination of approved drugs. A new indication for use. Change in dosage form, route of administration. Change in proportions of ingredients in an approved drug.

Branded & Authorized Generics

•Branded: ANDA applicant gives a proprietary brand name to distinguish their product from other generics. The innovator companies can offer branded generics. • •Authorized: Innovator company is licensing a manufacturer to market their RLD as generic so that they continue to market RLD.

Combination Products

•Combinations may be composed of: •Drug-Device. •Drug-Biologic. •Device-Biologic. •Drug-Device-Biologic.

Non-clinical drug development and Good Laboratory Practice Regulations (GLP)

•In vitro studies. •In vivo studies to establish: •Maximum tolerable dose and duration of exposure. •Proposed dose, route, and duration for phase I human clinical trials. •Genotoxicity: Drug potential to induce cancer and DNA damage. •Teratogenicity and reproductive toxicology.

What is combination product?

•It may be two or more separate products co-packaged in single package comprised of drug-device, device-biologic, or drug-biologic. •It could be investigational drug, device, or biological product packaged separately, and according to proposed labeling, it is used only with another individually specified investigational drug, device, or biological product. Both are required to achieve the intended use or indication.

Examples of combination Products

•Single entity combination products: Physically, chemically, or otherwise combined: •Monoclonal antibody combined with a therapeutic drug. •Device coated with a drug. •Catheter with antimicrobial coating. •Prefilled syringes, insulin injector pens, metered dose inhalers, transdermal batches.

Paper NDA (New Drug Application)

•Submitted under 505(b)(2). •Relies on approved application (for which safety and effectiveness are established). •Offer patent & marketing exclusivity provisions [unlike 505 (j) ANDA for generics]

Bridging and expansion issues and approaches [505(b)(2) pathway]

•The 505(b)(2) pathway used for: A NCE (new chemical entity) with studies conduced by other sponsors (e.g. pro drug, active metabolite of previously approved drug). New indication not approved for active moiety. Bridging and expansion issues and approaches [505(b)(2) pathway] •Change in dosage form, route of administration, formulation, strength [i.e. any change not accepted by FDA in suitability petition to office of generic drugs (OGD)]. A suitability petition to the FDA under section 505(j)(2)(C) of the FD&C Act is requesting permission to submit an ANDA for a generic drug product that differs from a reference listed drug (RLD) in its route of administration, dosage form, or strength or that has one different active ingredient in a fixed-combination drug product (i.e., a drug product with multiple active ingredients). In the suitability petition, the petitioner shall include information to show that: The active ingredients (AI) have the same pharmacological or therapeutic class as those of the RLD. The drug product is expected to have the same therapeutic effect as the RLD (for condition listed in the RLD labeling). For a combination product with one different AI (including a different ester or salt, from the RLD), the different AI shall have previously been approved in a listed drug or is a drug that does not meet the definition of "new drug" according to the FD&C Act. Change in active ingredient (different salt, ester, chelate, etc....). Change in impurity profile of the active ingredient. New combination product with previously approved active ingredient. •Change from prescription indication to Over-the-counter (OTC). •Change of OTC monograph drug (new dosage form or new indication). •Changes in either drug substance or drug product or both needs additional toxicological, mutagenicity, and genotoxicity studies. •The 505(b)(2) application may be granted three years of exclusivity if clinical investigation is conducted. •The 505(b)(2) application for NME or NCE not previously approved can be granted 5 years exclusivity. •An IND is required if the 505(b)(2) application requires clinical studies be conducted. Important point: If any of the preceding is submitted by NDA holder, they became supplements to existing 505(b)(1) application).

Abbreviated NDA for 505(J) [Generics]

•The application contains information to demonstrate equivalence to the RLD in terms of: •Pharmaceutical equivalence: same active ingredient, dosage form, strength, route of administration, labeling, quality, performance characteristics, intended use, etc.... •Bioequivalence. •The Hatch-Waxman act expedited availability of less-costly generics. •Give FDA authority to review & approve ANDA after expiration of patent & exclusivity. •Characteristics: •No animal safety and clinical data are needed to establish safety and effectiveness. •For oral dosage forms, generics should be bioequivalent to Reference Listed Drug (RLD). •For sterile injections, otic products & ophthalmic products with high solubility and high permeability. These products may receive waiver of bioequivalence studies. •Characteristics: The ANDA labeling will have the same RLD labeling except for few changes. Orange book contains a list of drug products with therapeutic Equivalence Evaluations. It contains information about RLD, Reference Listed Strength (RLS), and patents and exclusivities expiration date Abbreviated NDA for 505(J) [Generics] •Primary components of ANDA application: •Chemistry, Manufacturing, and Controls (CMC) information. •Manufacture of drug development under cGMP •Bioequivalence data. Bioavailability studies are conducted under •Fasted state (two-way cross over studies). •Fed state (if there is food effect) using standardized high fat meal. •A generic is deemed bioequivalent •If 90% CI for population geometric means between two measurement is contained in 80-125% for Area under curve (AUC) & peak serum concentration (Cmax). •This does not represent the difference of active ingredient between generic & RLD (there is statistical calculations that derives this number).

New Drug Application (NDA)

•Under 21 CFR 314. •§ 505(b)(1) pathway: New Drug Application to market a drug after establishing safety and efficacy. •§ 505(b)(2) pathway: Paper NDA, by reference to safety & effectiveness for previously approved product (certain molecular entity or indication).

Pathways for drug marketing approval

•Under Food, Drug & Cosmetic Act (FD&C Act) •§ 505(b)(1) pathway for New Drug Applications (NDA) to develop Reference Listed Drug (RLD). •§ 505(b)(2) pathway for drugs that reference NDA but with different strength, dosage form, etc... •§ 505(j) pathway for Generics that are identical to RLD.