14. INTRODUCTION TO BCS SYSTEM OF CLASSIFICATION, BASIC CONCEPTS OF CLINICAL TRIALS, ANDA, NDA, NEW DRUG DEVELOPMENT, NEW DRUGS AND CLINICAL TRIALS RULES, 2019

BCS SYSTEM OF CLASSIFICATION

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.

BCS Drug Classification

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

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 FDA for review and potential approval of a generic drug product. Generic drug applications are called “abbreviated” because they don’t require preclinical (animal) and clinical (human) data to establish safety and effectiveness.

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.
5. Reduce the time development.
6. Increase bioavailability compared to reference listed drug.

Patent Certifications (Orange Book)

• 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 FDA approve a new pharmaceutical for sale and marketing in the U.S.

NDA Content (CTD Format)

• 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.
• Phase II: Investigates procedures on wider population to watch for adverse effects.
• Phase III: Carried out on bigger populations in various locations just before drug approval.
• Phase IV: Conducted after national approval; more extensive testing over longer period.

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.

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)