14. BCS Classification, Clinical Trials, ANDA, NDA, and New Drug Development: A Complete Guide

BCS CLASSIFICATION, CLINICAL TRIALS, ANDA, NDA, NEW DRUG DEVELOPMENT, AND NEW DRUGS AND CLINICAL TRIALS RULES, 2019: A TEACHER’S COMPREHENSIVE GUIDE

Welcome, future pharmacists and pharmaceutical scientists!

As a pharmaceutical sciences educator with years of experience teaching drug development and regulatory affairs, I have observed that understanding the drug development process, regulatory pathways, and classification systems is essential for anyone entering the pharmaceutical industry. The Biopharmaceutics Classification System (BCS) is a fundamental guideline for determining the conditions under which In-Vitro In-Vivo Correlations (IVIVC) are expected. BCS is also used as a tool for developing in-vitro dissolution specifications.

In this comprehensive guide, I will take you through the BCS system of classification, new drug development stages, Abbreviated New Drug Application (ANDA), New Drug Application (NDA), clinical trials, New Drugs and Clinical Trials Rules, 2019, Intellectual Property Rights, patents, and Emergency Use Authorisation (EUA). By the end of this article, you will have a thorough understanding of the drug development and regulatory landscape. Let us begin.

BCS DRUG CLASSIFICATION

The Biopharmaceutics Classification System (BCS) is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability. It is a fundamental guideline for determining the conditions under which In-Vitro In-Vivo Correlations (IVIVC) are expected. BCS is also used as a tool for developing in-vitro dissolution specifications and for requesting biowaivers for certain drug products.

Class	Solubility	Permeability	Rate Limiting Step	Bioavailability
Class I	High	High	Dissolution & absorption very fast	High; BE/BC unnecessary
Class II	Low	High	Dissolution rate	Variable; can be improved by enhancing dissolution
Class III	High	Low	Intestinal membrane permeation	Low; permeability needs enhancement
Class IV	Low	Low	Poor and variable bioavailability; not suitable for oral delivery without special technologies (nanosuspensions)

NEW DRUG DEVELOPMENT – STAGES

The process of developing a new drug is complex, time-consuming, and expensive. It typically takes 10-15 years and costs over $2 billion to bring a new drug to market. The development process involves several stages:

1. Discovery and Development: Screening hits, medicinal chemistry, optimisation of hits, improving potency, in-vivo stability, and oral bioavailability.
2. Pre-clinical Studies: Performed on non-human subjects (efficacy, toxicity, pharmacokinetics – ADME, side effects, dosage, route of administration).
3. Clinical Studies: Clinical trials and volunteer studies to discover drug for human use.
4. FDA Drug Review: Non-clinical activities including FDA review and post-marketing monitoring.
5. Post-marketing Drug Safety Monitoring: Monitoring safety using FAERS database.

ABBREVIATED NEW DRUG APPLICATION (ANDA)

ANDA includes data submitted to the FDA for review and potential approval of a generic drug product. Generic drug applications are called “abbreviated” because they do not require preclinical (animal) and clinical (human) data to establish safety and effectiveness. Instead, generic manufacturers must demonstrate that their product is bioequivalent to the reference listed drug (RLD).

Objectives of ANDA

1. Check whether benefits outweigh risks; drug is safe and effective in proposed use.
2. Check whether proposed labelling (package insert) is appropriate.
3. Check whether controls used to preserve drug’s quality and methods are adequate.
4. Reduce the price of the drug by introducing generic competition.
5. Reduce the time development compared to a full NDA.
6. Increase bioavailability compared to reference listed drug.

Patent Certifications (Orange Book)

When submitting an ANDA, the applicant must certify the patent status of the reference listed drug. The four patent certifications are:

• Para I: No patent listed for the drug.
• Para II: The listed patent has expired.
• Para III: Patent is valid; generic wants permission after patent expires.
• Para IV: Generic manufacturer declares patent invalid or does not infringe patent claims.

NEW DRUG APPLICATION (NDA)

NDA is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U.S. An NDA contains all the data collected during drug development, including preclinical and clinical trial results, manufacturing information, and proposed labelling.

NDA Content (CTD Format)

The NDA is submitted in the Common Technical Document (CTD) format and includes:

• FDA Form 356h, User Fee Cover Sheet, Cover letter
• Summary, Chemistry, manufacturing and control
• Samples, method validation package and labelling
• Non-clinical pharmacology and toxicology
• Human pharmacokinetics and bioavailability
• Microbiology (for antimicrobial drugs)
• Statistical methods and analysis of clinical data
• Safety update report (120 days after NDA submission)
• Statement regarding IRB and Informed Consent compliance
• Case report tabulations and forms
• Patent information and certification

CLINICAL TRIALS

Types of Clinical Trials

• Interventional Trials: Participants assigned to different treatment groups (computer-based) to gather information about a particular intervention.
• Observational Studies: Research team observes what happens to people in different situations without influencing treatments.

Phases of Clinical Trials

• Phase I: Determines safe dose range and adverse effects on limited volunteers (20-80 healthy volunteers).
• Phase II: Investigates procedures on wider population (100-300 patients) to watch for adverse effects and preliminary efficacy.
• Phase III: Carried out on bigger populations (300-3,000 patients) in various locations just before drug approval; confirms efficacy and monitors adverse reactions.
• Phase IV: Conducted after national approval; more extensive testing over longer period (post-marketing surveillance).

NEW DRUGS AND CLINICAL TRIALS RULES, 2019

The New Drugs and Clinical Trials Rules, 2019 were released by India’s Ministry of Health and Family Welfare (MoHFW). The new rules include provisions for orphan drugs, post-trial access, and pre- and post-submission meetings. The rules aim to streamline the clinical trial approval process and promote research and development in India.

New Definitions

• Academic Clinical Trial: Clinical trial of approved drug for new indication/route/dose/dosage form for academic/research purposes (not for regulatory approval).
• Biomedical and Health Research: Research designed to increase scientific knowledge about diseases and conditions (excluding clinical trials).
• Orphan Drug: Drug intended to treat condition affecting not more than 5 lakh persons in India.
• Post-trial Access: Making a new drug available to trial subject after trial completion if found beneficial.

BRAND NAME VS GENERIC DRUGS

Feature	Generic Drugs	Brand Name Drugs
Definition	Off-patent product manufactured after patent expiry	Product developed and marketed under patent or registered trademark
Patent	Off patent	Patent protected
Trade Name	Marketed under generic name	Unique proprietary name
Application	ANDA required for USFDA approval	NDA required for USFDA approval
Animal & Clinical Trial	Not required	Essential to perform
Price	Cheaper	Costly
Appearance	Different from brand drug	Unique design

INTELLECTUAL PROPERTY RIGHTS (IPRs)

Forms of IPRs

• Patents: Exclusive right to prevent others from using inventions without permission.
• Trademarks: Distinctive signs (logos, names, symbols) identifying source of goods/services.
• Copyrights: Right for original works (literature, art, music, drama).
• Trade Secrets: Concealed practice, formula, method, or data giving competitive edge.
• Franchising: Agreement where franchisor grants right to franchisee to use trade name/brand and business processes.
• Licensing: Accomplishes business expansion, quality enhancement, and market position improvement.

Importance of IPRs in Pharmaceutical Company

1. Protects invention (patent rights best option in India as trade secrets law not codified)
2. Accelerates economic growth and competitiveness
3. Protects consumers and families (safety and quality assurance)
4. Protects against potential infringement of drug discovery and development

PATENTS

Conditions of Patentability

1. Novelty: Invention must not be already in the market or part of existing knowledge.
2. Non-Obvious: Not obvious to individuals expert in the field.
3. Useful and Industrially Applicable: Beneficial to society and industrially applicable.

Process for Obtaining Patent

1. Filing Application (application number provided)
2. Publication of Application (after 18 months in official gazette)
3. First Examination Report (comply within 6 months + 3 months extension)
4. Grant (if objections answered successfully)
5. Post-grant Opposition (within 1 year of grant)

Term of Patent

Validity of patent is 20 years from the date on which patent application is filed.

Importance of Patents

1. Right to restrict others from manufacturing the product
2. Market product without competition for considerable period
3. Legally sue anyone who attempts to make or sell without permission
4. Generate money by selling or licensing
5. Provides ‘a negative right’ to prevent others from making, selling, or importing
6. Encourages incremental changes and innovation (‘evolution’ rather than ‘revolution’)
7. Rights are territorial (registered in India limited to India only)
8. Promotes technological innovations

EMERGENCY USE AUTHORISATION (EUA)

EUA is an authorisation issued for unregistered drugs and vaccines in a public health emergency. The FDA may issue EUA to make a treatment or test available if known and potential benefits outweigh known and potential risks.

Conditions for Issuing EUA

• Agent may result in serious/life-threatening illness
• Product may be useful in diagnosing/treating/preventing the disease
• Known and potential benefits outweigh risks
• Product is the only suitable, authorised, and accessible option

COVID-19 Vaccines Authorised by FDA

• Pfizer-BioNTech/Comirnaty COVID-19 mRNA Vaccine
• ChAdOx1-S [recombinant] VAXZEVRIA (AstraZeneca)
• SARS-CoV-2 Vaccine (Vero Cell) Inactivated [Coronavac]
• Sputnik V / Sputnik Light COVID-19 Vaccine
• Janssen COVID-19 Vaccine (Ad26.COV2-S)
• Whole Virion Inactivated Corona Virus Vaccine [Covaxin]
• COVID-19 mRNA Vaccine Moderna
• COVID-19 Vaccine Sinopharm
• SARS-CoV-2 rS Protein Nanoparticle Vaccine [Covovax]

COVID-19 Drugs Authorised by FDA

• Casirivimab + Imdevimab
• Molnupiravir
• Nirmatrelvir + Ritonavir (Paxlovid)

A TEACHER’S CLINICAL INSIGHTS

Over my years of teaching drug development and regulatory affairs, I have developed a few key insights that I always share with my students:

• The BCS classification system is a powerful tool for predicting drug absorption and guiding formulation development. Understanding a drug’s BCS class helps in designing appropriate dissolution tests and predicting in-vivo performance.
• Generic drugs play a vital role in improving patient access to medicines and reducing healthcare costs. The ANDA pathway ensures that generic drugs are safe, effective, and bioequivalent to brand-name drugs.
• Intellectual Property Rights are essential for fostering innovation in the pharmaceutical industry. Patents provide the incentive for companies to invest in drug discovery and development.
• The New Drugs and Clinical Trials Rules, 2019, have streamlined the clinical trial approval process in India, promoting research and development while ensuring patient safety.

FREQUENTLY ASKED QUESTIONS (FAQs)

1. What is the Biopharmaceutics Classification System?

The BCS is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability. It is used to predict in-vivo drug absorption and guide formulation development.

2. What is the difference between ANDA and NDA?

ANDA is used for generic drugs and does not require preclinical and clinical data to establish safety and effectiveness. NDA is used for new drugs and requires comprehensive data from preclinical and clinical studies.

3. What are the phases of clinical trials?

The phases are Phase I (safety and dosing), Phase II (efficacy and side effects), Phase III (confirmation of efficacy in larger populations), and Phase IV (post-marketing surveillance).

4. What is an orphan drug?

An orphan drug is intended to treat a condition affecting not more than 5 lakh persons in India. The New Drugs and Clinical Trials Rules, 2019, include provisions for orphan drugs.

5. What is Emergency Use Authorisation?

EUA is an authorisation issued for unregistered drugs and vaccines in a public health emergency when the benefits outweigh the risks.

6. What are the conditions for patentability?

The conditions are novelty, non-obviousness, and usefulness/industrial applicability.

7. What is the term of a patent?

The validity of a patent is 20 years from the date on which the patent application is filed.

SUMMARY

The BCS system of classification, new drug development stages, ANDA, NDA, clinical trials, New Drugs and Clinical Trials Rules, 2019, IPRs, patents, and EUA are essential concepts in pharmaceutical sciences and regulatory affairs. The BCS system guides drug formulation and biowaiver requests. New drug development involves five stages from discovery to post-marketing surveillance. ANDA is the pathway for generic drug approval, while NDA is for new drugs. Clinical trials are conducted in four phases to establish safety and efficacy. The New Drugs and Clinical Trials Rules, 2019, streamline clinical trial approvals in India. IPRs, particularly patents, protect pharmaceutical innovations and incentivize research and development. EUA provides emergency access to unregistered drugs and vaccines during public health crises.

As I always tell my students: “Understanding the drug development and regulatory landscape is essential for anyone entering the pharmaceutical industry. These concepts form the foundation of safe and effective drug delivery to patients.”

REFERENCES AND FURTHER READING

• Amidon, G. L., Lennernäs, H., Shah, V. P., & Crison, J. R. (1995). A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharmaceutical Research, 12(3), 413-420.
• U.S. Food and Drug Administration (FDA). (2022). Abbreviated New Drug Application (ANDA) and New Drug Application (NDA) Guidelines. Retrieved from https://www.fda.gov.
• Ministry of Health and Family Welfare. (2019). New Drugs and Clinical Trials Rules, 2019. Government of India.
• World Intellectual Property Organization (WIPO). (2022). Intellectual Property Rights in Pharmaceuticals. Retrieved from https://www.wipo.int.
• U.S. Food and Drug Administration (FDA). (2022). Emergency Use Authorization (EUA) Guidelines. Retrieved from https://www.fda.gov.

Disclaimer: This article is for educational purposes only and does not constitute medical or legal advice. Always refer to the latest regulatory guidelines for drug development and clinical trial approvals.