Introduction to BCS system of classification, Basic concepts of Clinical Trials, ANDA, NDA, New Drug development, New Drugs and Clinical Trials Rules, 2019. Brand v/s Generic, Trade name concept, Introduction to Patent Law and Intellectual Property Rights, Emergency Use Authorization

Introduction to the BCS system of classification

The Biopharmaceutical Classification System (BCS) is a scientific framework to classify API into four basic groups based on its aqueous solubility, intestinal permeability (GIT mucosa permeability), and dissolution rate. These three factors govern the rate and extent of oral drug absorption from Immediate Release (IR) solid oral dosage forms. The solubility classification of a drug in the BCS is based on the highest dose strength in an IR product. A drug substance is considered highly soluble when the highest strength is soluble in 250 mL or less of aqueous media over the pH range of 1.0–7.5. Otherwise, the API is considered poorly soluble. The volume of 250 mL is considered because of the administration of a drug product to fasting human volunteers with a glass (about 8 ounces) of water. The permeability classification is based directly on the extent of intestinal absorption of a drug substance in humans or indirectly on the measurements of the rate of mass transfer across the human intestinal membrane. A drug is considered highly permeable when the extent of intestinal absorption is 90% or higher. Otherwise, the drug substance is considered to be poor permeability GIT mucosa.

An IR drug product dissolution is not less than 85% of the labeled amount of the drug substance dissolves within 30 minutes using USP Apparatus I at 100 rpm or USP Apparatus II at 50 rpm in a volume of 900 mL or less of each of the following media: 1) 0.1 N HCl or USP simulated gastric fluid without enzymes; 2) a pH 4.5 buffer; and 3) a pH 6.8 buffer or USP simulated intestinal fluid without enzymes. Otherwise, the drug product is considered to be a slow-dissolution product.

PRINCIPLE: The BCS Principle is that if two drug products yield the same concentration profile along the gastrointestinal (GI) tract, they will result in the same plasma profile after oral administration. In terms of bioequivalence, it is assumed that highly permeable, highly soluble drugs in rapidly dissolving drug products will be bioequivalent unless major changes are made.

Classification: The BCS categorizes drug substances into one of four BCS classes as follows:

• 1. Class I: high solubility, high permeability

• 2. Class II: low solubility, high permeability

• 3. Class III: high solubility, low permeability

• 4. Class IV: low solubility, low permeability

CHARACTERISTICS OF API OF VARIOUS BCS CLASSES

• Class I drugs (APIs): High Solubility, High Permeability (High Absorption and High Dissolution). The bioavailability of these APIs is very rapid. These APIs are highly suitable for the SR and CR formulations. Examples are Ketoprofen, Naproxen, Carbamazepine, Propanolol, Metoprolol, Diltiazem, Verapamil, etc.

• Class II drugs (APIs): Low Solubility, High Permeability (Low Dissolution and High Absorption). These drugs exhibit variable bioavailability. They require the enhancement in dissolution to increase the bioavailability. These drugs are suitable for the SR and CR formulations. Examples are Phenytoin, Danazol, Ketoconazole, Mefenamic acid, Nifedinpine, Felodipine, Nicardipine, Nisoldipine etc.

• Class III drugs (APIs): high Solubility, Low permeability (High Dissolution and Low Absorption). These drugs exhibit a high variation in their rate and extent of GIT absorption. Since the dissolution is rapid, the variation is due to alteration of physiology and membrane permeability. Their variable rate of absorption is not due to the dosage form factors. These drugs are not suitable for controlled release (CR) dosage form. These drugs have low bioavailability. Examples are Acyclovir, Alendronate, Captopril, Enalaprilat Neomycin B, etc.

• Class IV drugs (APIs): Low Solubility, Low Permeability (Low Dissolution and Low Absorption). They exhibit poor and variable bioavailability. These are not suitable for controlled release (CR) dosage forms. Examples are Chlothaizude, Furosemide, Tobramycine, Cefuroxime, etc.

Alok Bains

Basic Concepts of Clinical Trials, ANDA, NDA, New Drug Development

“The Medical research to assess the safety and efficacy of new treatments, interventions, or medical devices using human participants is called the clinical trial”. People/patients participating in clinical trials to answer specific health questions for research studies are called volunteers. Clinical trials are the safest and fastest way to find new treatments and improve health. The plan to conduct a clinical trial is called a protocol. Protocol describes:

• The types of people/patients for clinical trial

• The schedules of tests and procedures

• The drugs involved

• The dosages, or amount of the drug

• The length of the study

• Aim to learn from the study.

Volunteers must agree to the rules and terms outlined in the protocol. Similarly, researchers, doctors, and other health professionals managing clinical trials must follow the rules set by the FDA.

Clinical trials are conducted for many reasons:

• To determine whether a new drug or device is safe and effective.

• To study different ways to use standard treatments or approved treatments to make them more effective, easier to use, or decrease side effects.

• To learn the safe use of a treatment in a population.

Eligibility Criteria for Volunteers

It is a must to test drugs and medical products in the population they are meant to help. It is also important to conduct clinical trials on a variety of people. People of different ages, races, ethnic groups, genders, types and stages of disease, previous treatment history, and other medical conditions are included in clinical trials. Participants in clinical trials should represent the patients that will use the medical products. This helps to reduce the variation within the study. It also ensures that the researchers will get answers to the questions they plan to study.

Some people participate in clinical trials because none of the standard (approved) treatment options have worked, or they are unable to tolerate certain side effects. Clinical trials provide another option when standard therapy has failed. Others participate in trials because they want to contribute to the advancement of medical knowledge.

Clinical trials also include placebos. Neither patients nor their doctors know who is receiving the placebo and how is being treated with the experimental drug. Clinical trials for many cancers, and other serious and life-threatening conditions do not include placebo control groups. In these cases, all participants receive the experimental drug.

Clinical trials organizers: Clinical trials can be sponsored by organizations (such as pharmaceutical companies), academic institutions, etc. The sponsor determines the location(s) of the trials, which are usually conducted at medical centers, clinics, hospitals, and other industry-funded research sites.

Clinical trial safety: It is the responsibility of the FDA to protect participants in clinical trials and to ensure that people have reliable information. Efforts are made to control the risks to participants. However, it may be unavoidable because clinical trials are learning more about the medical treatments in the study.

Volunteers will be given an informed consent document that describes the rights of a participant and details about the study, including potential risks. The informed consent is part of the process that makes sure volunteers understand the known risks associated with the study.

Phases of Clinical Trials; Clinical trials are conducted in several phases to test the safety, efficacy, and dosage of a new drug. These phases are to assess the treatment's effectiveness and safety profile of the drug. The following are the phases of clinical trials:

• 1. Phase 0: It involves a small number of people, usually fewer than 15. The aim is to gather initial data about pharmacokinetics and Pharmacodynamics.

• 2. Phase I: Phase I trials involve a small group of healthy volunteers and aim to determine the safety profile of the drug, its dosage range, and any potential side effects. These trials typically enroll fewer than 100 participants.

• 3. Phase II: Phase II trials involve a larger group of patients (usually several hundred). The main objectives are to further assess safety, evaluate the drug's efficacy in treating the disease, and determine the optimal dosage and regimen.

• 4. Phase III: Phase III trials are large-scale studies involving thousands of patients. These trials are designed to confirm the effectiveness of the drug, monitor side effects, compare it to standard treatments or a placebo, and collect additional information about its safety. Phase III trials are crucial for obtaining regulatory approval for the drug.

• Phase IV (Also known as post-marketing surveillance trials): Phase IV trials take place after the drug has been approved and made available to the public. These trials continue to monitor the drug's safety and effectiveness in real-world settings, often on a larger scale and for a longer duration than earlier phases.

Basic concepts of ANDA

The ANDA process facilitates the approval of generic drugs. An Abbreviated New Drug Application (ANDA) is an application to the FDA for the approval of generic drugs. It demonstrates that the proposed drug is equivalent in safety, efficacy, and quality to a previously approved listed drug. The ANDA includes information on the drug’s active ingredients, usage, administration, dosage form, potency, labeling, and bioavailability to prove its bioequivalence to the approved listed drugs.

ANDA is designed to boost competition and lower prescription drug costs by allowing generic drug makers to bypass some costly clinical trials. This has led to the entry of affordable generic drugs and enhanced accessibility.

The basics of ANDAs: The ANDAs can be divided into two categories:

• 1. ANDA Application: This is approved by the FDA for a drug that is identical to a previously approved drug. It relies on the FDA’s prior approval of the approved listed drugs, affirming its safety and effectiveness.

• 2. Petitioned ANDA: This applies to a drug that varies in dosage form, administration route, strength, or active ingredient from the approved listed drugs. Approval is granted when the FDA confirms that no additional studies are needed to verify the proposed drug's safety and effectiveness. The drug is expected to offer the same therapeutic benefits as the approved listed drugs.

The ANDA Process: The following steps are involved in submitting an ANDA for FDA approval.

• 1. Pre-ANDA Preparation: Collection of detailed information about the approved listed drugs. It includes its chemical composition, pharmacological properties, formulation, labeling, and regulatory history. This step ensures the generic drug's equivalence to the approved listed drugs

• 2. ANDA Preparation: Compilation of the ANDA data that underlines the generic drug's chemical, pharmacological, and clinical similarities to the approved listed drugs. It also states the manufacturing process, quality control measures, and proposed labeling.

• 3. ANDA Submission: The ANDA is submitted to the FDA.

• 4. FDA Review: The FDA assesses the ANDA to verify and satisfy the regulatory criteria for approval. This phase generally requires about 30 months but can be fast-tracked for drugs addressing severe conditions or unmet medical needs.

• 5. FDA Decision: The FDA either sanctions or rejects the ANDA after review. Approval gallows to market the generic drug.

Alok Bains

Brand v/s Generic, Trade name concept,

Brand Name: A brand name is the product name given seller that markets it. The brand name distinguishes one seller's product or service from those of others in the market. For example, Crocin is a brand name of paracetamol.

Generic Name: A generic name is often a shorthand version of the chemical name, structure, or formula.

Brands are often associated with a certain level of quality, reputation, and trust.

In the Pharmaceutical field, new active ingredient is developed. it is patented and sold under a brand name. After the patent expires, others are allowed to develop a dosage form using this active ingredient. It is sold in the chemical name of the active ingredients. It is a generic version of the drug.

Generic products may differ in minor ways from branded products, but both have similar efficacy.

Brand v/s Generic: The following points are considered while comparing generic medicines and branded medicines

• 1. A generic medicine usually costs less but has the same effect as the brand-medicine. This is because the manufacturer has not spent money on research and development, buying the rights to sell it, influencing prescribers to prescribe, etc.

• 2. A generic name is often a shorthand version of the chemical name, structure, or formula. Thus not catchy and difficult to remember. Brand names are usually catchy and easy to remember.

• 3. Brands are often associated with a certain level of quality, reputation, and trust. Although generic drugs have the same effect.

• 4. Brand medicine is selected to avoid confusion, especially in polypharmacy.

• 5. Many medicines contain fillers, binding agents, flavors, or other ingredients. They may trigger an allergic reaction in some people. If there is a known allergy then stick with brand medicines not containing allergic compounds for that particular patient.

Trade Name: A trade name is a name used by a company to identify its business or operation. It is often used interchangeably with the term "business name" or "company name." Trade names are important for identification and differentiation in the business world. For example, "Coca-Cola" is both a brand name and a trade name. As a brand name, it identifies a specific product (a carbonated beverage). As a trade name, it identifies the company that produces the product (The Coca-Cola Company).

Introduction to Patent Law and Intellectual Property Rights,

Intellectual Property Rights (IPR) is the legal protection of the creations of the human mind. It encourages innovation and fosters economic growth. It creates an environment for innovation, recognition, reward, and protection of creativity. Among the various facets of intellectual property, Patent Law stands to safeguard inventive concepts and technological advancement. It is a comprehensive legal framework that governs Intellectual Property Rights, providing inventors and creators with the necessary protection and incentives for their contributions.

Patent Law in India: Patent law is a crucial component of Intellectual Property Rights to protect inventions by granting inventors exclusive rights for a specified duration. The Patents Act of 1970, along with subsequent amendments, constitutes the legislative foundation for patents in India. The law is designed to encourage scientific and technological advancements by securing innovations of inventors.

The following are the main Features of Indian Patent Law:

• 1. Eligibility Criteria: An invention must be novel, involve an inventive step, and be capable of industrial application to qualify for patent protection. It includes processes, manufacturers, machines, and compositions of matter that are new, involve an inventive step, and have industrial applicability.

• 2. Duration of Protection: Patents in India typically have a duration of 20 years from the filing date, during which the inventor holds exclusive rights to exploit the invention.

• 3. Patent Office: The Indian Patent Office, headed by the Controller General of Patents, Designs & Trade Marks, is responsible for the administration and regulation of patents in the country. There are several regional offices across the country to facilitate the patent application process. It recognizes and protects other forms of intellectual property, including trademarks, copyrights, industrial designs, and geographical indications.