REGULATORY REQUIREMENTS OF DRUGS AND PHARMACEUTICALS

BY:-Abhinab GoswamiM.Pharm 1st sem

DRUGS REGULATIONDrug regulation is the control of drug use by international agreement and/or by regulatory authorities such as the US Food and Drug Administration (FDA), the European Medicinal Agency (EMA) and the Japanese Pharmaceutical and Medical Devices Agency (PMDA). This includes regulations concerned with the development, approval, manufacturing and marketing of drugs.

FDA Role and Organization• FDA is organized into a number of offices and centers headed

by a commissioner who is appointed by the President with consent of the senate

• These offices and centers are assigned with different responsibilities to accomplish the objective of FDA

1. Center for Drug Evaluation and Research (CDER)2. Center for Biologic Evaluation and Research (CBER)3. Center for Devices and Radiological Health (CDRH)4. Center for Food Safety and Applied Nutrition (CFSAN)5. Center for Veterinary medicine (CVM)

TYPES OF APPLICATIONS

• Investigational New Drug Application

• New Drug Application

• Abbreviated New Drug Application

• Biologic License Application

• Over-the-counter (OTC) drug application

Clinical Hold

IND Filing

IND Approval

Drug Discovery and

Lead Compound Selection

Biologic Activity testing

(in vivo)

Formulation development and

stability

Chemical Synthesis and Scale up testing

Safety Testing in Animals

IND Application

Phase I Clinical trials Phase II Clinical trials Phase III Clinical trials

NDA Filing

FDA Disapproval FDA Conditional Approval

FDA Approval

MARKETPost-Approval Safety report to FDA

PRE-CLINICAL TESTING (4+ YEARS)

CLINICAL TESTING (6+ YEARS)

Fig: the new drug approval process

Revision

Revision

Investigational New Drug (IND)• It deals with a new chemical entity, which will be tested for

obtaining evidence of safety and effectiveness in accordance with the regulation. It is the vehicle through a new drug advances into next stage of drug development i.e. Clinical trials

Types of INDs1. Investigator IND:- It is submitted by a physician who initiates

and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. A physician might submit a research IND to proposed studying an unapproved drug, or an approved product for a new indication or in a new patient population.

2. Emergency Use IND:-This allow the FDA to authorize an experimental drug in an emergency situation that does not allow for submission of an IND in accordance with 21CFR, Sec. 312.23 0r Sec.312.20. It is also used for patient who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist.

3. Treatment IND:- It is submitted for experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions while the final work is conducted and the FDA review takes place.

Investigational New Drug Application

Criteria for application• A clinical study is required for an IND if it is intended to

support a: – New Indication. – Change in the approved route of administration or dosage

level.– Change in the approved patient population or a population

at greater or increased of risk . – Significant change in the promotion of an approved drug

Application Content

• Animal Pharmacology and Toxicology studies.• Chemistry and Manufacturing Information.• Clinical Protocols and Investigator Information.

NEW DRUG APPLICATION (NDA)

• The New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. NDA is responsible for are providing enough information to permit FDA reviewers to establish the following: – Whether the drug safe and effective in its proposed use(s) when used

as directed, and do the benefits of the drug outweigh the risks. – Whether the drug’s proposed labeling (package insert) appropriate,

and what should it contain.– Whether the methods used in manufacturing (Good Manufacturing

Practice, GMP) the drug and the controls used to maintain the drug’s quality adequate to preserve the drug’s identity, strength, quality, and purity.

Fundamentals of NDA Submission • As outlined in Form FDA-356h, Application to Market a New

Drug for Human Use Or As An Antibiotic Drug For Human Use, NDAs can consist of as many as 15 different sections: – Index – Summary – Chemistry, Manufacturing, and Control; – Samples, Method Validation Package, and Labeling – Nonclinical Pharmacology and Toxicology – Human Pharmacokinetics and Bioavailability – Microbiology (for anti-microbial drugs only);

– Clinical Data; – Safety Update Report (typically submitted 120 days after

the NDA's submission); – Statistical; – Case Report Tabulations; – Case Report Forms; – Patent Information; – Patent Certification; and – Other Information

Classification of drugs in NDACDER classifies new drug applications with a code that reflects both the type of drug being submitted and its intended uses. – New Molecular Entity – New Salt of Previously Approved Drug (not a new molecular entity) – New Formulation of Previously Approved Drug (not a new salt OR a

new molecular entity) – New Combination of Two or More Drugs – 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 Previously Approved NDA

GENERAL REQUIREMENTS for filing an NDA

• The new (present) NDA regulations require that an application be submitted in two copies :

(A) an archival copy that serves as a permanent record of the submission, and

(B) a review copy. – The review copy is made up of a number of separate technical volumes,

each tailored to the needs of the disciplines involved in the review. – Both the archival and review copies are submitted in hard copy, the

regulations permit an application to submit the archival copy as microfiche.

– The NDA application form (FORM FDA 356h ) consists of: Twelve items (including index) deals with the safety and efficacy features of drug product, two are concerned with patent information

• The archival copy is a complete copy of an application submission and must be bound in a blue cover jacket.

• The archival copy should include a blue cover letter to:– Confirm any agreement or understanding between the FDA

and the agreement;– Identify the contact person regarding the application– Identify the reviewing division of the FDA and include HFD

number; – Convey any other important information about the

application.

REVIEW SECTION COLOUR CODE

(i) Chemistry, Manufacturing and Controls (CMC) RED

(ii) Nonclinical Pharmacology and Toxicology YELLOW

(iii) Human Pharmacokinetics and Bioavailability ORANGE

(iv) Microbiology (if required) WHITE

(v) Clinical Data LIGHT BROWN

(vi) Statistical GREEN

The review copy is divided into six technical sections (“review sections”) and should be submitted with each review section separately bound in a specific color:

• Each review section should contain the following:

(i) a copy of the cover letter attached to the archival copy;

(ii) a completed application form FDA 356h; (iii) a copy of the summary (defined below); (iv) a copy of the general index of the entire application;(v) an index specific to that particular review section; (vi) letters of reference or authorization, if appropriate; (vii) patent information

ABBREVIATED NEW DRUG APPLICATION

• In addition to approving new drug products , the FDA is charged with the approval of generic products (21 CFR 314), which is accomplished through CDER’s Office of Generic Drugs.

• An Abbreviated New Drug Application (ANDA) contains data submitted to FDA's Center for Drug Evaluation and Research, Office of Generic Drugs, for review and ultimate approval of a generic drug product.

• The reviewing process for generic drug is focused on bioequivalence testing rather than safety and efficacy.

• To be considered bioequivalent, both rate and extend of drug absorption must be within established parameter in comparison to the reference drug.

• Use of bioequivalence as the base for approving generic drug products was established by the "Drug Price Competition and Patent Term Restoration Act of 1984," also known as the WAXMAN-HATCH ACT.

Guidelines available for ANDA:

• Various guidelines have been developed to assist applicants in preparing and filing ANDAs

• Format & content for the following sections: a. Application summary b. Chemistry, Manufacturing and controls section c. Non clinical pharmacology and toxicology section d. Human pharmacokinetics & bioavailability section e. Clinical and statically section f. Microbiology section

ANDA requires the submission of : • Detailed descriptions of the components • Manufacturing, controls, packaging, and labeling

(which can be in final, printed form), data sufficient to assure the bioavailability or bioequivalence of the drug to be marketed.

• The labeling should be prepared in accordance with that specified in DESI (Drug efficacy study implementation) Notice or other Federal Register

NDA ANDAApplicable for new drug Applicable for generic drugTake longer time ( 12-15 years) Compare to NDA less time

taken(1-2 years)More expenditure of money Comparatively lessCost of drugs are more Cost of drugs are lessNonclinical studies and clinical investigations are essential

Nonclinical studies and clinical investigations are nonessential except bioavailability and bioequivalence

COMPARISON

REFERENCES

1. The theory and practice of Industrial Pharmacy ,Leon Lachman and Herbert A. Lieberman Indian Edition 2009,page no. 856-871

2. The Science and Practice of Pharmacy, Remington 21st Edition, Volume 1 . Page no 965-975.

3. http://www.fda.gov/AboutFDA/Transparency/Basics/ucm194879.htm

Thank You