Federal Food, Drug & Cosmetics Act

Kefauver's-Harris Amendments

ABDUL MUHEEM
M.PHARMA 2ND SEM.
(PHARMACEUTICS)
JAMIA HAMADARD
muheem.abdul985@gmail.com
 OBJECTIVES OF FFDCA
In United States Federal Food, Drug, and Cosmetic
Act (FFDCA, FDCA, or FD&C), is a set of laws passed by Congress in 1938 giving
authority to the U.S. Food and Drug Administration (FDA) to oversee the safety
of food, drugs, and cosmetics.
 It replaced the earlier Pure Food and Drug Act of 1906 due to Elixir
Sulphanilamide disaster.
 1938 Act continued the information provision requirements of
the 1906 Act. The classification “misbranded” was expanded
example, and now included any drug whose label failed to
identify and quantify the precise ingredients, to list effects
and possible side effects, and to give directions and
cautionary information.
 1938 Act also expanded the FDA’s powers over medical
devices .
Reason for implemented new act
 1937 – sulfanilamide crisis

November 16, 1937:

A Senate resolution directs the U.S.
Department of Agriculture to give a
full accounting of the "Elixir
Sulfanilamide" tragedy. The
drug, containing a poisonous
solvent(ethylene glycol / propylene
glycol mix-up), was not safety tested
and has killed 107 persons, many of
them children. The incident made
Congress to pass the Federal
Food, Drug, and Cosmetic Act, which
includes stronger drug safety
requirements
 OTHER TRAGEDIES
Koremlu Cream
Contained Thallium acetate
Serious hazardous side effects due to thallium
Radiothor
"Radium containing water“
Consumers died of radiation exposure
Label true and no therapeutic claims
 Lack of standards for food products
 Developments in Science and technology
Canning / Chemical analysis
 Expansion of cosmetics industry
GOALS OF FDCA(1938)
 The FDCA mandates the safety, purity, and in some cases the
"effectiveness" of the products within its scope.
 FDA ensures safety through inspections of products already on
the market, controls the manufacturing practices of
companies, and possesses recall and seizure authority.
 The FDCA's Goal is to disclose information- requires
truthfulness and completeness in product labeling and other
marketing communications.
 The act forbids "misbranding," and provides a range of civil and
criminal enforcement mechanisms against inaccurate product
labeling.
 Section contains both civil law and criminal law clauses.
 The FDCA in 1958 with the Food Additives Amendment (also
called the "Delaney Clause" after its House sponsor), precluding
FDA approval of any food additive found to cause cancer in
humans or animals.
Food & drug act
 Prohibited the sales of adulterated &misbranded drugs.
 Drug could be marketed as long as the label did not present
false information regarding the strength & purity.
 no requirement to disclose ingredients.
 A largely unregulated industry was causing numerous public
health problems.
 CHAPTER WISE DESCRIPTION:
Chapter I. Short Titles
Chapter II – Definitions.
 201(f) is the definition for a food, which explicitly includes chewing
gum
 201(g) is the definition for a drug
 201(h) is the definition for a medical device
 201(s) is the definition of a food additive
 201(ff) is the definition of a dietary supplement
CHAPTER III. Prohibited Acts and Penalties

301. Prohibited Acts

302. Injunction proceedings
303. Penalties
304. Seizures
305. Hearing before report of criminal violation
306. Report of minor violations
307. Proceedings in name of United States; provision as to
subpoenas .
CHAPTER IV. Food
401. Definitions and standards for food
402. Adulterated food
403. Misbranded food
404. Emergency permit control
405. Regulations making exemptions
406. Tolerances for poisonous ingredients in food
407. Oleomargarine or margarine
408. Tolerances for pesticide chemicals in or
on raw agricultural commodities
409. Food additives
410. Bottled drinking water
411. Vitamins and minerals
412. Requirements for Infant Formulas .
CHAPTER V. Drugs and Devices

 505 is the description of the drug approval process

 510(k) is the section that allows for clearance of medical devices
 515 is the description of the device approval process.
 DRUG AND DEVICES
Sections in FDCA gives following information-
 505 is the description of the drug approval process
 510(k) is the section that allows for clearance of class II medical
devices
 515 is the description of the (class III) device approval process.
Section 510(k) of the Federal Food, Drug, and Cosmetic Act requires
those device manufacturers who must register to notify FDA, at least
90 days in advance, of their intent to market a medical device. This is
known as Premarket Notification.
Class I: Devices that do not require premarket approval or clearance but
must follow general controls. Dental floss is a class I device.
Class II: Devices that are cleared using the 510(k) process. Diagnostic
tests, cardiac catheters, and amalgam alloys used to fill cavities are
all class II devices.
Class III: Devices that are approved by the Premarket Approval (PMA)
process, analogous to a New Drug Application. These tend to be
devices that are permanently implanted into a human body or may be
necessary to sustain life
CHAPTER VII :

GENERAL ADMINISTRATIVE PROVISIONS

701. Regulations and hearings

702. Examinations and investigations
702a. Seafood inspection
703. Records of interstate shipment
704. Factory inspection
705. Publicity
706. Listing and certification of color additives for foods, drugs, and
cosmetics.
CHAPTER VIII :
801.Imports And Exports 8

CHAPTER IX :
901. Miscellaneous
LIMITATIONS OF 1938,FOOD DRUG
AND COSMETIC ACT INCLUDES
 It did not included drugs which were previously
marketed.
 Drugs had to be proven safe but not proven
effective.
 The federal govt. had little authority to enact
penalties, if the information on the labels was not
written clearly.
 Drugs manufacturer were given the responsibility for
determining whether a drug would be sold as a
prescription or over the counter drug.
 Drug manufacturers conducted their own test to
determine drugs effectiveness.
Introduction
 The Food and Drug Administration (FDA),
established in 1938 as a part of the US Department
of Health and Human Services (HHS), regulates
products accounting for roughly 25% of the US gross
national product.
 Major concerns arose with the scandal of birth
defects in European nations caused by
Thalidomide, a drug to be introduced into the US.
 The drug was already in use by the pregnant women
in Africa and Europe from 1956-1962 and caused an
estimated 10,000 children born with congenital
deformitiesPhocomelia.).
IMPORTANT ACT &
AMENDMENTS
 News & Implementation Of
Amendments
Week In FDA History - July
15,1962
Thalidomide, a newly developed
sleeping pill, is found to have
caused birth defects in
thousands of babies born in
Western Europe. News reports
on the role of FDA medical
officer Dr. Frances O. Kelsey in
keeping the drug off the
American market arouse public
support for stronger drug
regulation
 Week In FDA History - Oct. 10,1962
 October 10, 1962:
The Kefauver-Harris
Drug Amendments are
passed, prompted in part
by public concern over
birth defects caused by
the drug thalidomide.
Among the new
requirements: proof of
drug effectiveness as
well as safety, controls
over clinical trials, and
better quality assurance
practices in drug
manufacturing
 Dr. Francis Kathleen Oldham Kelsey, working for the US FDA
did not want to approve thalidomide into the American drug
market because it was not properly tested as a result of what
was going on in those years.
 The KEFAUVER HARRIS AMENDMENT was a response to the
thalidomide tragedy. It was signed by President John F.
Kennedy on October 10, 1962.
 US senator Estes Kefauver of the state of Tennessee and
Arkansas state representative Oren Harris required the
American drug manufacturers to present proof of the safety and
effectiveness of their drugs before any endorsements.
 Hence, this amendment is also referred to as the DRUG
EFFICACY AMENDMENT.
KEFAUVER HARRIS
AMENDMENT

I
N
T
Concerne Controls
R over clinical
O d with
trials and
D proof of
Passed in better QA
U drug
1962 practices in
C effectiven drug
T ess and manufacturi
I safety ng
O
N
Objectives Of Amendments
 Efficacy was to be established for all drugs since
1938.
 Required FDA to assess the efficacy as well as
safety for all drugs products.
 First time manufactures were required to prove
effectiveness of drug products prior to marketing.
 Gave FDA stricter control over clinical drug trials.
 Set GMP to be followed by drug industry.
 Regulated advertising.
 Kefauver-Harris imposed the efficacy requirement
prior to NDA approval by FDA.
APPROVAL OF NEW DRUGS AFTER
IMPLEMENTED OF AMENDMENTS

 New drug:
1) safe and effective.
2) approved under NDA procedure a/c
to act at section 505.
 IND: for filing IND, form FD-1571,FD-
1572 and FD-1573 are filled.
 NDA: Form FD-356.
DRUG EFFICACY STUDy
IMPLEMENTATION (DESI)

COLLABORATION
WITH NATIONAL ESTABLISHME
ACADEMY OF NT OF THE
SCIENCE- DESI
NATIONAL PROGRAM IN
RESEARCH 1968
COUNCIL (NAS-
NRC)

It was a retrospective efficacy assessment of drugs

approved prior to 1962.
 DRUG EFFICACY STUDIES
Early development
In 1966, FDA commissioner approached NAS-NRC to review
already marketed drugs under NDAs approved from 1938-1962.
There were about 300 different medicinal agents.

This was carried out by establishing review committees and a

Policy Advisory Committee whose members were well
acquainted with medical, legal and industrial problems of drugs.

27 and more panels were developed concerning with drugs used

in allergy, anti histaminics, dermatology, anti neoplastics, etc.
Guidelines were established by the advisory committee to review
work of the panels.

By October 1969, the review program was formerly organized and

in operation. The types of products reviewed included single drug
entities or products with two or more entities.
 DRUG EFFICACY STUDIES
Early development

The panels sought evidence of drug efficacy

from four main sources:

1) Briefs submitted by the sponsor of the drug

2)Additional evidence directly solicited from the
sponsor
3)The files of the FDA
4)Pertinent medical literature brought in by the
panelists.
DRUG EFFICACY STUDIES
Effectiveness
categories

EFFECTIVE
Substantial
evidence of
efficacy

INEFFECTI
VE
Insufficient
data
supporting
efficacy
PROBABLY POSSIBLY
EFFECTIVE EFFECTIVE
Needed Research
extra info, needed, max
max time 12 time 6
months months
DRUG EFFICACY STUDIES
The conclusions

IMMEDIATE REMOVAL OF PRODUCTS

CURRENTLY MARKETED

RECOGNITION OF CLINICAL STUDIES TO

VERIFY OR ESTABLISH EFFECTIVENESS
UNDER THE NEW LAW

RECOGNITION THAT DIRECTION OR

LABELLING OF CERTAIN PRODUCTS WERE
POORLY ORGANIZED, OUTDATED AND
ORIENTED TO PROMOTION OF PRODUCT
PACKAGE INSERTS NEEDED TO BE
BROUGHT UP TO MODERN STANDARDS
OF ACCURATE AND OBJECTIVE DRUG
INFORMATION.
 DRUG EFFICACY STUDY
RECORDS
The records of the Drug Efficacy
Study contains:

 Correspondence

 reports

 meeting minutes

 press clippings

 other records documenting the

activities of the DES.
 DRUG EFFICACY STUDIES
abbreviated new drug applications
 One of the early effects of DESI study was the
development of ANDA.
 An Abbreviated New Drug Application (ANDA) is an
application for a U.S. generic drug approval for an existing
licensed medication or approved drug.
 The ANDA is submitted to FDA's Center for Drug
Evaluation and Research, Office of Generic Drugs, which
provides for the review and ultimate approval of a generic
drug product. Once approved, an applicant may
manufacture and market the generic drug product to
provide a safe, effective, low cost alternative to the
American public.
 A generic drug product is one that is comparable to an
innovator drug product in dosage form, strength, route of
administration, quality, performance characteristics and
intended use. All approved products, both innovator and
generic, are listed in FDA's Approved Drug Products
with Therapeutic Equivalence Evaluations.
 DRUG EFFICACY STUDIES
abbreviated new drug applications
 Generic drug applications are termed "abbreviated"
because they are generally not required to include
preclinical (animal) and clinical (human) data to establish
safety and effectiveness. Instead, generic applicants must
scientifically demonstrate that their product is
bioequivalent (i.e., performs in the same manner as the
innovator drug).
 The generic version must deliver the same amount of
active ingredients into a patient's bloodstream in the same
amount of time as the innovator drug.
 Using bioequivalence as the basis for approving generic
copies of drug products was established by the Drug Price
Competition and Patent Term Restoration Act of
1984, also known as the HATCH-WAXMAN ACT.
 This Act expedites the availability of less costly generic
drugs by permitting FDA to approve applications to market
generic versions of brand-name drugs without conducting
costly and duplicative clinical trials.
FLUOROQU
INOLONE
THE BLACK BOX
Tendonitis
(8 july,
REGULATION
2008)  On 12 Feb. 1972 FDA promulgated this regulation which
required that the “less than effective” products should be
AVANDIA notified to the practitioner’s by including a statement
(anti prominently in the labeling & surrounding it with an
diabetic) appropriate border.
Heart attack
14
Nov, 2007
 It is a type of warning that appears on the package insert
DEPO for prescription drugs that may cause serious adverse
PROVERA effects. It is so named for the black border that usually
Loss of bone surrounds the text of the warning.
density
17 Nov,
2004  It is the strongest warning that the FDA requires.
CELEBREX
(celecoxib)
CV & GI
risk
2002
THE BLACK BOX
REGULATION
Other FDA REASSESSMENT
PROJECTS
 The GRAS List Review of 1969
(review of the safety of all the
food ingredients that had been
included on the Generally
Recognized As Safe List of the late
1950s);
 The OTC Drug Review of 1972
(review of the safety and efficacy
of all OTC drugs; and
 The Biologics Review of 1972
(review the safety and efficacy of
all biologicals)
Other related
legislations
The Medical Device
Amendments of 1976
followed a U.S. Senate
finding that faulty
medical devices had
caused 10,000 injuries,
including 731 deaths. The
law applied safety and
effectiveness safeguards
to new devices.
Other related
legislations

2005
Formation of the Drug Safety
Board consisting of FDA staff
and representatives from the
National Institutes of Health and
the Veterans Administration.
The Board will advise the
Director, Center for Drug
Evaluation and Research, FDA,
on drug safety issues.
Contd…
DRUG SAFETY AND DRUG EFFICACY:
TWO SIDES OF THE SAME COIN

In 2007, a committee of academic

scientists, research advocates and
representatives of patient community
was convened to recommend ways in
which the Congress and the FDA could
further strengthen product evaluation for
it’s efficacy.
A similar article was also published in the
AACR, in the same year.
 SAFETY AND EFFICACY
MONITORING
Current scenario

FDA’s
MedWatch
program can
Serious & also be
unexpected approached
side effects for this
NDA sponsors should write to purpose.
submit reports the FDA within
quarterly for 15 days of
first 3 yrs and receipt of info.
annually
afterwards.
Impacts of Kefauver Harris
Amendment(1962)
• The Kefauver Harris Amendment strengthened the U.S.
Food and Drug Administration's control of
experimentation on humans.
• It changed the way new drugs are approved and
regulated.
• It introduced a "proof-of-efficacy" requirement, that
was not present before.
• The Amendment required drug advertising to disclose
accurate information about side effects and efficacy of
treatments.
• Cheap generic drugs could no longer be marketed as
expensive drugs under new trade names as new
"breakthrough" medications, as they were prior to the
amendment
DRUG EFFICACY STUDY IMPLEMENTATION

The amendment made onerous to evaluate each

product, also to evaluate the active ingredients in
the products. The active ingredients were placed
into one of the three categories.
Category I drugs: those determined to be safe ,
effective, and properly labeled.
Category II drugs: those not generally
recognized as safe and effective, or recognized as
mislabeled; must be removed from medications
within 6 months after the FDA issues its final
regulations.
Category III drugs: those for which data is
insufficient to determine general recognition of
safety and effectiveness.
 CONCLUSION
Today, the FDA regulates $1 trillion worth
of products a year. It ensures the safety of
all food except for meat, poultry and some
egg products; ensures the safety and
effectiveness of all drugs, biological
products (including blood, vaccines and
tissues for transplantation), medical
devices, and animal drugs and feed; and
makes sure that cosmetics and medical
and consumer products that emit radiation
do no harm.
 ConClusions …

By 1984, final action had been completed on 3,443

products; - 2,225 were found to be effective, 1,051
were found not effective, and 167 were pending.
 References
 http://www.absoluteastronomy.com/discussion/Drug_Efficacy_Stu
dy_Implementation
 http://en.wikipedia.org/wiki/Talk:Drug_Efficacy_Study_Implement
ation
 http://www.ssa.gov/OP_Home/comp2/B-CFR-42.html
 http://www.nationalacademies.org/ The Drug Efficacy Study of the
National Research Council’s Division of Medical Sciences, 1966-
1969,
 W.M. WARDELL, The US Drug Efficacy Study and its Implication
(DESI), Associate Professor, Pharmacology and Toxicology,
University of Rochester, and Director, Center for the Study of Drug
Development, USA
 http://edocket.access.gpo.gov/cfr_2008/aprqtr/pdf/21cfr207.20.p
df
 W.E. GILBERTSON, The OCT Drug Review - FDA's Viewpoint,
Director Division of OTC Drug Evaluation, Food and Drug
Administration, Rockville, Maryland, USA
 Julie B. Esmay, B.S., and Albert I. Wertheimer, Ph.D., A REVIEW OF
OVER-THE-COUNTER DRUG THERAPY, Journal of Community Health
Vol. 5, No. 1, Fall 1979,
 References
 Http://www.Personalcarecouncil.Org/
 Http://www.Fda.Gov/drugs/informationondrugs/default.Htm
 Http://www.Fda.Gov/drugs/guidancecomplianceregulatoryin
formation/drugregistrationandlisting/default.Htm
 Center for veterinary medicine program policy and
procedures manual, guide 1240.3560, General review and
enforcement policies, responsible office: hfv-210,
registration of producers of drugs and listing of drugs in
commercial distribution.
 Guidance for industry , providing regulatory submissions in
electronic format – drug establishment registration and drug
listing
 Alan h. Kaplan, esq., Fifty years of drug amendments
revisited: in easy-to-swallow capsule form