This document provides an overview of paper NDAs (new drug applications), which allowed generic drug companies to rely on published literature to demonstrate the safety and efficacy of reference drugs whose patents had expired. It discusses the history and implementation of paper NDAs, how they worked, and how they were replaced by the 505(b)(2) application pathway established by the Hatch-Waxman Act of 1984 to streamline the approval of generic drugs.

1. PAPER NDA
(NEW DRUG APPLICATION)
MSC IN CLINICAL RESEARCH
BY –PRADEEP GUSAIN

2. CONTENT
HISTORY OF NDA
HATCH-WAXMAN ACT
ANDA
SECTION 505(b)(2) APPLICATION OR PAPER NDA
1962 DRUG AMENDMENT ACT IMPLEMENTATION
HISTORY OF PAPER NDA
INTRODUCTION TO PAPER NDA
FDA APPROACH TO PAPER NDA
WORKING OF 505(b)(2) APPLICATION
CONCLUSION

3. INTRODUCTION
Once the sponsor has completed all non clinical and clinical testing which is necessary to
demonstrate the safety and effectiveness of the drug , the test results must be compiled in an NDA
for submission to FDA.
The information of drug’s safety and efficacy collected during IND process becomes part of NDA
application.
NDA is a regulatory mechanism that is designed to give FDA sufficient information to make
meaningful evaluation of new drug.

4. HISTORY OF NDA(NEW DRUG APPLICATION)
When the Federal Food, Drug and Cosmetic act of 1938 was passed ,a new era of drug product
development began.
The act required the assurance of safety.
It provided only 60 days for review by FDA for distribution of new drug product.
The 1962 Kefauver-Harris Amendment to the act required greatly increased information concerning
safety, effectiveness, quality, and control of drug products.

5. HATCH-WAXMAN ACT 1984
It is also known as “Drug Price Competition and Patent Term Restoration Act 1984”.
The act dealing with the approval of generic drugs.
Created two statutory pathways :-
1. ANDA(Abbreviated New Drug Application)
2. 505(b)(2)application or Paper NDA
OBJECTIVE- 1.) To reduce the cost associated with approval of a generic drug.
2.) Allow Early-Experimental use.
3.) Motivating the generic drug manufacturers.

6. ANDA(Abbreviated New Drug Application)
Under an ANDA , a generic drug company must establish that the generic drug is effectively a
duplicate of the branded, NDA drug, which is referred to as Reference Listed Drug.
It is Abbreviated because they generally not required to include preclinical(animal) and
clinical(human) data to establish safety and effectiveness.
Its main objective
1. To reduce the price of drug
2. To reduce the time development
3. To increase the bioavailability

7. SECTION 505(B)(2) APPLICATION OR PAPER NDA
If a Proposed generic drug may differ in significant ways from RLD(Reference Listed Drug).
Under these circumstances ,the proposed generic drug must be approved through the section
505(b)(2) paper NDA application process, which is a hybrid of full NDA and an ANDA.
Like an NDA, 505(b)(2) Application contains a full report of investigations of safety and
effectiveness of the proposed product.
In contrast to NDA ,however 505(b)(2) application relies upon published literature providing
pre-clinical or clinical data.

8. ANDA NDA
An Abbreviated New Drug Application is an
application for a U.S. generic dug approval for
an existing licensed medication or approved
drug.
Takes less time (1-2 yrs.)
Cost of drug is less.
Only bioequivalence study is essential.
New Drug Application applicable for approval
of New drug .
Takes longer time (12-15 yrs.)
Cost of drug is more.
Bioavailability and Bioequivalence studies are
essential.

9. WHAT LED TO 1962 DRUG AMENDMENT ACT IMPLEMENTATION
Elixir sulfanilamide crisis which led to changes in U.S. drug regulation in 1938, a similar crisis in 1961
in Europe spurred more disaster where hypnotic drug known as thalidomide was found to cause
severe birth defects and even death in babies, when their mother took the drug early in pregnancy.
As a result , countries around the world including US updated their drug regulatory system.
A worldwide thalidomide drug disaster in 1961 resulted in enactment of 1962 Drug Amendment,
which explicitly stated that FDA would rely on scientific testing and that new drug approval would
be based not only upon proof of safety alone but also on “ substantial evidence” of a drug’s
efficacy{i.e. the impact of drug in a clinical trial setting}.

10. HISTORY OF PAPER NDA CONCEPT
For many years generic companies attempted to convince the FDA –
That once the patent of an innovator's product had expired, there was no reason why they
should have to duplicate research programs for drugs that had already been proven to be
safe and effective since they were approved by FDA after 1962 or after the Kefauver –
Harris Amendment Act.
FDA agreed with this logic and developed Paper NDA concept.

11. Therefore adopted a program that permitted the generic companies to file a Paper NDA
which contains full manufacturing and controls data , a bioequivalence study and the
summary of literature supporting the safety and efficacy of drug product being submitted as
Paper NDA.

12. PAPER NDA
The term ‘paper’ obviously refers to medical and scientific literature sources for both pre
clinical and clinical data that support the safety and effectiveness of drug.
Before 1984, there was no specific regulatory mechanism to allow introduction of generic
version of pioneer products introduced after 1962.
A partial mechanism to allow this opportunity was created via the “paper NDA” , in which
in vivo evidence of bioequivalence to a reference product could be allied with literature
documentation of safety and efficacy.
This mechanism permitted introduction of a small number of generic formulations for drug
products approved between 1962 and 1984 .

13. Nineteen original products served as reference drug for 47 paper NDA’s approved by FDA between
January 1979 and June 1983.
Based upon published studies to support safety and efficacy that the generic applicant submitted in
an NDA.
Bioequivalence studies were required in some cases.
Many drugs started getting approval as generic drugs for the drugs that had already been proved
safe and effective.

14. FDA APPROACH TO PAPER NDA
The FDA had administratively created the concept of an abbreviated NDA to handle generic
version of pre -1962 pioneer new drugs, but there was no similar mechanism for approval of
generic version of post -1962 new drugs.
As time went by ,more and more post-1962 pioneer new drugs lost patent protection, but
retained an equivalent protection under the Food Drug and Cosmetic Act because FDA had no
authority to approve any form of abbreviated NDA for generic version of these drugs.
FDA therefore began to search for a solution to this problem.
In 1978,FDA announced it would approve a “Paper NDA” for generic copies of a post-1962
pioneer new drugs based on the published scientific data for the drug.

15. SECTION 505(b)(2)APPLICATION
(PAPER NDA)
An application that contains full reports of investigations of safety and effectiveness but some of
the information required for the approval comes from studies which are not conducted by the
applicant or for which the applicant has not obtained a right of reference.
Changing a drug from a prescription indication to an over-the-counter indication would also
require a 505(b)(2)NDA.
Innovations that may qualify for this application include modifications to the dosage form,
formulation, strength, route of administration, dosing regimen, indication for use, active
ingredients and others.
{so these are actually changes to approved drugs that would require a 505(b)(2) application}.
Goal of a 505(b)(2) application is to present a complete body of evidence to demonstrate that
the drug is safe and effective.

16. WORKING OF 505(B)(2) APPLICATION
The standard for approval of a 505(b)(2) application is the same as traditional NDA.
Both applications require inclusion of data demonstrating substantial evidence of safety and
effectiveness.
In a traditional NDA ,you own all the data. In a 505(b)(2) application, you rely upon data that you
don’t own or have a right of reference to, including published literature or the FDA’s previous finding
of safety and effectiveness.
NOTE: Enactment of the generic drug approval provision of Hatch –Waxman Amendments ended the
need for approval of duplicate drugs through paper NDA process by permitting approval under
505(j) application which is based on the basis of chemistry and bioequivalence data , without the
need for evidence from literature of effectiveness and safety.

17. WHAT SHOULD BE INCLUDED IN 505(b)(2)APPLICATION
Identification of those portions of the application that rely on information the applicant does not own
or to which the applicant does not have a right of reference .
Identification of all listed drugs by established name, proprietary name (If any), dosage form,
strength, route of administration, name of the listed drug's sponsor, and the application number.
Even if the 505(b)(2) application is based solely upon literature and does not rely on an Agency’s
finding of safety and effectiveness for a listed drug, the applicant must identify the listed drug(s) on
which the studies were conducted, if there are any.
A patent certification required under section 505(b)(2) of the Act with respect to any relevant
patents that claim the listed drug and that claim any other drugs on which the investigations relied
on for approval of the application.

18. If an application is for approval of a new indication, and not for the indications approved for the
listed drug, a certification so stating .
A Bioavailability/Bioequivalence (BA/BE) study comparing the proposed product to the listed
drug (if any)
Studies necessary to support the change or modification from the listed drug.
NOTE - Complete studies of safety and effectiveness may not be necessary if appropriate
bridging studies are found to provide an adequate basis for reliance upon FDA’s finding of safety
and effectiveness of the listed drug(s).

19. CONCLUSION
The 505(b)(2) NDA provides a potentially streamlined path for sponsors that have developed
improvements to drug products that have previously received FDA approval.
The 505(b)(2) and 505(j) pathways are intended to provide an efficient means for approving non
innovator drug products by harnessing existing information to support the approval package.
Section 505(b)(2) and (j) together replaced FDA’s paper NDA policy, which had permitted an
applicant to rely on studies published in the scientific literature to demonstrate the safety and
effectiveness of duplicates of certain post -1962 pioneer drug products.