The Federal Food, Drug and Cosmetics act regulated through Title 21 of U.S Code of federal Regulations, requires a new drug to be approved by FDA before legally getting introduced into the market. In India, a new drug may be approved as regulated by Schedule Y to the Rules of Drugs and Cosmetics Act, 1940 and Rules 1945.
INVESTIGATIONAL NEW DRUG (IND):- It is defined under 21 CFR 312.3(b) as ‘a new drug or biological drug that is used in clinical investigation’. The term also includes a biological product used in vitro for diagnostic purposes. After pre-clinical investigations when the new molecule has been screened for pharmacological activity and acute toxicity potential in animals the sponsor requires permission from FDA for its clinical trials in humans. The sponsor submits the application for conduct of human clinical trials called Investigational N ew Drug (IND) application to FDA or DCGI. Once IND application is submitted, the sponsor must wait for 30 days before initiating any clinical trial. Clinical trials in humans can begin only after IND is reviewed by the FDA and a local institutional review board (IRB). IRBs approve clinical trial protocol, informed consent of all participants and appropriate steps to prevent subjects from harm. If the FDA accepts the IND request within 30 days of submission, clinical testing of the new molecule on human may begin by the investigator. At this point, the molecule under the legal status of FDA becomes a new drug subject to specific requirements of drug regulatory system. If at any time during clinical testing, the data furnished to FDA indicate the IP to be toxic under the criterion of FDA’s Benefit/Risk ratio, FDA can terminate clinical trial and its actions are not subject to any judicial review.

  • COMMERCIAL INDs: – These are applications that are submitted primarily by the companies to obtain marketing approval for a new product.
  • NONCOMMERCIAL (Research) INDs:- These INDs are filed for noncommercial research. These are: Investigator’s IND- It is submitted by a physician who both initiates and conducts an investigation and who also administers and dispenses the IP. A physician might submit a research IND to propose studying an unapproved drug or an approved drug for new indications or in new patient population.
  • Emergency Use IND: – This IND allows FDA to allow the use of an experimental drug in an emergency situation that does not allow submission of an IND in accordance with 21 CFR Sec312.23 or Sec 312.34. It can also be used for patients who do not meet the criteria of an existing study protocol or if an approved study protocol does not exist.
  • Treatment IND:- Also called Expanded Access IND this IND may be submitted for experimental drugs showing promise in clinical testing of serious and immediately life threatening conditions while the final clinical work is conducted and the FDA review takes place (21 CFR 312.34).

The IND application must contain information in 3 broad areas:

  • Animal Pharmacology and toxicology studies:- Preclinical data to assess if the product is reasonably safe for initial testing in humans. Also, included are any previous with drug in humans.
  • Manufacturing information:- Information pertaining to composition, manufacturer, stability and controls used for manufacturing drug product to ensure that the company can adequately produce and supply consistent batches of the drug.
  • Clinical Protocol and Investigator information:- Detailed protocols for proposed clinical studies to make sure subjects are not exposed to undue risks. Also, information on the qualifications of the investigators (chiefly physicians) if they fulfill their clinical duties. Finally, commitments to obtain informed consent from all research subjects, to obtain review of the study by an IRB and to adhere to the investigational new drug regulations. An IND must also include The Investigator’s brochure.

Format and content of IND:- Format and content of ind Cover sheet ( Form FDA 1571).

  • A table of contents.
  • Introductory statement and General Investigational Plan.
  • Investigator’s Brochure.
  • Chemistry, Manufacturing and Control information.
  • Pharmacology and Toxicology Information.
  • Previous human experience with IP.
  • Additional Information.

WITHDRAWAL OF AN IND:- At any time a sponsor can withdraw an effective IND . In such a case, FDA and IRB shall be so notified with reasons for withdrawal, all clinical studies ended, all current investigators and subjects notified, all stocks of drug returned to the sponsor or otherwise disposed off on request of sponsor in accordance with 312.59.
IND PROCESS IN INDIA:- IND process in India has been defined under Rule 122-DA (3) of Drugs and Cosmetics Rules 1945 as a chemical entity having therapeutic indication but which have never been earlier tested on humans. No clinical trial for new drug for any purpose be conducted without permission , in writing, of the Licensing Authority (DCGI). Application for conducting clinical trials in India require submission by the sponsor on Form 44 along with requisite fee ( Rs 50k) and documents as provided under Schedule Y to Drugs and Cosmetics Act 1940. Data to be submitted along with the application on Form44 to conduct clinical trials (2 hard copies and 2 soft copies i.e., CDs in PDF format) Application on Form 44 Introduction of the drug Fee Rs 50K through challan form Chemical and Pharmaceutical information as per Appendix I of Schedule Y Animal Pharmacology as per Appendix IV Animal Toxicology as per Appendix III Human/Clinical Pharmacology data as per Appendix I Regulatory status in other countries as per Appendix I. It takes 4-6 months for the approval but it is not documented. The Ethical Committee also requires 1-3 months’ time. Thus, it almost takes 7-9 months for approval of INDA from DCGI. For international applicants, import license to import IP samples and permission from Director General Foreign Trade to export blood samples is also needed.
NEW DRUG APPLICATION (NDA):- The New Drug Application is the vehicle through which the drug sponsors formally propose FDA or DCGI to approve a new investigational drug for sale and marketing after Phase IIIA Pivot trials. The official definition of New Drug is in Sec 201(p) of Federal Drug, Food and Cosmetics Act as; Any new drug , the composition of which is such that it is not recognized among experts qualified by scientific training as safe and effective for use under prescribed, recommended or suggested conditions OR Any drug the composition of which is such that it as a result of investigations to determine safety and efficacy for use has become recognized, but which has not, otherwise in such investigations been used to a material extent . The following letter codes describe the review priority of the drug;

  • S-Standard review:- For drugs similar to currently available drugs.
  • P-Priority review:- For drugs that represent significant advances over existing treatments.

Classification of drugs in NDA:- CDER classifies new drug applications according to the type of drug being submitted and its intended use:

  • New molecular entity
  • New salt of previously approved drug
  • New formulation of previously approved drug
  • 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 previous approved NDA)

In US following 4 types of applications are submitted for approval of drug for marketing depending upon the type and nature of the drug:

  • New Drug Application (NDA)
  • Biological License Application (BLA) Application u/s 505(b)(2)-Paper NDA
  • Supplemental New Drug Application (SNDA)

Format and content of NDA:- The application is required to be submitted in common technical document format with the following different sections:

  • FDA Form 356h
  • User Fee Cover Sheet (FDA Form 3397)
  • Cover letter (Comprehensive table of contents for Modules 1to 5)
  • Summary Chemistry,
  • Manufacturing and Control Samples,
  • Method
  • Validation Package and Labeling
  • Nonclinical Pharmacology and Toxicology
  • Human Pharmacokinetics and Bioavailability
  • Microbiology ( F or anti-microbial drugs only)
  • Statistical methods and analysis of Clinical Data Safety Update Report (typically submitted 120 days after NDA submission)
  • Statement regarding compliance to IRB and Informed Consent Requirements Case report
  • Tabulations Case Report Forms
  • Patent information and certification
  • Other information.

General requirements for filing NDA:- General requirements for filing NDA The new NDA regulations require the application to be submitted in 2 copies:

  • An Archival Copy:- It is a complete copy of application submission that serves as its permanent record.
  • A Review Copy:- It is divided into 6 technical sections:
  1. Chemistry,
  2. Manufacturing
  • Controls (CMC)
  1. Nonclinical Pharmacology and Toxicology
  2. Human Pharmacokinetics
  3. Bioavailability

Clinical data Statistical:- On receipt of NDA, the CDER stamps with a receipt date to enable FDA to forward action within 180 days called ‘Review Clock’ under Review Time Frames (21CFR 314.1OO). The FDA assigns the application for review. The FDA has to intimate the applicant if it is incomplete within 60 days according to Filing Time Frames (21CFR 314.101). FDA notifies the sponsor of its completion/ incompletion and if complete sends it for secondary review process. FDA inspects the manufacturing facilities for the drug, It may also inspect sample of clinical trial locations to verify the accuracy of data submitted. iv. Microbiology (if required)
NDA PROCESS IN INDIA:- In India, New Drug is defined under Rule 122-E of Drugs and Cosmetics Act as: A drug which has not been used in the country to any significant extent under various conditions A drug already approved by DCGI for certain claims which is now proposed to be marketed with new claims like indications, dosage, dosage form etc. A fixed dose combination of two individually approved drug being combined for the first time in a fixed ratio or new ratio in already marketed combination.
All vaccines are considered as new drugs. A new drug continues to be considered as new drug for a period of 4 years from its approval or its inclusion in Indian Pharmacopoeia. After successful finishing of clinical trials, the applicant seeking for approval to manufacture a new drug requires to submit application on Form 44 along with data as given in Appendix I to Schedule Y of Rules 1945 to DCGI who grants its approval in Form 46 or 46-A. Further, the applicant is required to submit evidence that the drug for manufacturing approval has already been approved by DCGI in his name while applying to manufacture a new drug to State Licensing Authority. Thus, the applicant is required to obtain necessary approval from DCGI as well as SLA for manufacturing a new drug for sale purposes in India. The approval issued is ‘manufacture for sale’ rather than ‘marketing approval’ as per the practice world over.

  • Brief introduction of the new drug
  • Chemical and pharmacological information
  • Animal pharmacology and Toxicology Human/ Clinical Pharmacology (Phase I)
  • Exploratory Clinical Trials (Phase II)
  • Confirmatory Clinical Trial s(Phase III)
  • Bio-availability,
  • dissolution and stability study data
  • Regulatory status in other countries
  • Application for test license Marketing information.

ABBREVIATED NEW DRUG APPLICATION (ANDA):- Generic drug applications are referred to Abbreviated New Drug Application. Pharmaceutical companies must admit ANDAs and receive FDA’s approval before marketing new generic drugs according to 21CFR 314.105(d). Once ANDA is approved, an applicant can manufacture and market generic drug to provide safe, effective and low-cost alternative of innovator drug product to the public. Generic drugs are termed ‘abbreviated’ as they are not required to include preclinical and clinical data to establish safety and efficacy. They must scientifically demonstrate Bioequivalence to Innovator ( brand name) drug. A generic drug is comparable to Innovator drug I dosage form, strength, route of administration, quality, performance and intended use. One of the ways to demonstrate bioequivalence is to measure the time taken by generic drug to reach bloodstream in 24-36 healthy volunteers. The time and amount of active ingredients in the bloodstream should be comparable to those of Innovator drug. Use of bioequivalence as base for approving generic drug products was established in 1984, also known as WAXMAN-HATCH ACT. It is because of this act that generic drugs are cheaper without conducting costly and duplicative clinical trials.
CODE OF FEDERAL REGULATIONS:- The following regulations apply to ANDA process:

  • 21 CFR 314- Applications for FDA approval to market a New Drug or Antibiotic Drug
  • 21 CFR 320- Bioavailability and Bioequivalence requirements
  • 21 CFR 310- New Drugs.

Office of Generic Drug(OGD) strongly encourages submission of bioequivalence, chemistry and labeling portions of the application in electronic format.
FORMAT AND CONTENT OF ANDA:- 3 copies of the Abbreviated application are required to be submitted; an archival copy, a review copy and a field copy. An Archival copy shall contain the following:-

  • Application form
  • Table of Contents
  • Basis for ANDA submission
  • Conditions of use Active Ingredients
  • Route of Administration Dosage form and Strength.
  • Bioequivalence and Bioavailability
  • Labeling Chemistry,
  • Manufacturing and Controls Samples
  • Patent Certification
  • Financial Certification or disclosure statement.
  • Other Information.

Under Sec 314.94 (a) (12), the patent certification includes one of the following:-

  • Paragraph I Certification:- That the patent information has not been submitted to FDA.
  • Paragraph II Certification:- That the patent has expired.
  • Paragraph III Certification:– That the patent will expire (on date of marketing) Paragraph IV Certification- That the patent is invalid, unenforceable, or will not be infringed by manufacture, use or sale of generic drug.


  • NDA requires submission of: – Well-controlled clinical studies to demonstrate effectiveness. Preclinical and clinical data to show safety. Details of Manufacturing and Packaging. Proposed annotated Labeling.
  • In contrast ANDA requires submission of: – Detailed description of components, Manufacturing, Controls, Packaging, data to assure bioequivalence and bioavailability and Labeling. Labeling should be prepared in accordance with DESI (Drug efficacy study implementation).

EXCLUSIVITY:- Exclusivity is a statutory provision designed to promote a balance between an Innovator and Generic drug competitor. As long as a drug patent lasts, a reference listed drug company enjoys a period of market exclusivity or monopoly. Expiration of patent removes the monopoly of the patent holder.

  • Orphan drugs- 7 years
  • New Chemical Entity-5 years
  • Pediatric Exclusivity-6 months
  • Additional Patent Challenge-180 days.

HATCH-WAXMAN AMENDMENTS AND 180 DAYS EXCLUSIVITY:- Hatch- waxman amendments and 180 days exclusivity. Before Hatch Waxman Amendment, generic manufacturer could file ANDA only after innovator’s patent expiry or cancellation. But under Sec 505(j)(5)(B) of Hatch Waxman amendment it permits preparation and filing of ANDA before patent expiration, so that the effective approval date of generic drug would be on expiration date of the patent of Innovator Original drug. The Act also establishes another procedure in which the generic company can challenge patent of the Innovator. For generic companies, the amendment provides an inventive 180-day exclusivity period in which no other ANDA for that drug can be approved. This 180-day period is to encourage generic companies to challenge validity of Orange book listed patents or to design around these patents to bring more quickly a generic drug to market. For Innovator company, filing of an ANDA is an act of patent infringement. So, if innovator company brings suit within 45 days, the approval of generic company’s ANDA is delayed for upto 30 months.
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One Comment

  • PharmaState Academy

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