how misfortunes and tragedies has created the approval process

1. Historical Aspects
of
New Drug Approval Process
Prepared by:
Paresh K Bharodiya
Executive
Formulation Development
J.B Chemicals and Pharmaceuticals,
Panoli, Gujarat, India

2. New drug Approval.
• Today, the drug review process in the United States is
recognized worldwide as the gold standard. Drugs must
undergo a rigorous evaluation of safety, quality, and
effectiveness before they can be sold.
• The Center for Drug Evaluation and Research (CDER) is the
arm of the FDA that, as its name suggests, evaluates new
drugs before they are sold.
• This process requires multiple levels of research to make
sure that medications are safe and effective before they
are made available to the public. And that takes time and
money

3. Overview of the drug approval process
• Drug development can generally be divided
into phases.
1.The Preclinical phase
2.Clinical phases

4. subjects
Purpose
Time
corse
New
drugs
pass
Laboratory
&
Animal study
Access safety &
Biological activity
1-2 years
100 %
20-100
volunteers
Safety &
Dosage
3-4 years
70 % of IND
100-300
patients
Effectiveness.
Side effects
4-5years
33 %IND
1000-3000
patients
V
er
if
y
ef
fe
ct
iv
e
n
e
ss
.
lo
n
g
te
r
6-8 years
27 %
Fil
e
IN
D
File
N
D
A
Preclinical
Phase
Clinical
Phases
Phase 1 Phase 2 Phase 3

5. FDA Review and Approval
• After phase III, the pharmaceutical company
prepares reports on all studies conducted on
the drug and submits the reports to the FDA in
a New Drug Application (NDA).
• The FDA then reviews this information to
determine whether the drug is safe and
effective for its intended use. If the drug
passes this review, it is approved for use.

6. A Historical Perspective of drug
regulation and approval
• At the turn of the 20th century, there were no
federal regulations to protect the public from
dangerous drugs
• Misfortune, disaster, and tragedy have
triggered most of the advances in drug
regulation

7. The First Federal Drug Law
• The original Pure Food and Drugs Act was passed by
Congress in 1906 and signed by President Theodore
Roosevelt.
• concerns about worthless or even dangerous medicines
led to the enactment of the Food and Drug
Administration Act of 1906.
• This law
1. Required that drugs meet official standards of strength
and purity,
2. Defined the terms adulterated and misbranded, and
3. Prohibited the shipment for sale of misbranded and
adulterated foods, drinks, and drugs

8. • There was no requirement that any information be
submitted to the FDA before marketing
• the law required only that drugs meet standards of
strength and purity
• The burden of proof was on the government to show
that a drug's labeling was false and misleading before
it could be taken off the market.
Limitations of the first federal drug law

9. Sherley Amendment in 1912
• US v Johnson case
• The act did not prohibit false therapeutic claims,
only false claims about ingredients.
• Sherley Amendment - 1912
• specifically prohibits false claims

10. The Food, Drug, and Cosmetic Act 1938
• Revised legislation wasn't passed until 107 people
died from a poisonous ingredient in Elixir
Sulfanilamide. The S.E. Massengill Co. of Bristol,
Tenn.
• As a consequence of this event, Congress passed the
Federal Food, Drug, and Cosmetic (FD&C) Act of 1938
with new provisions

11. 1. manufacturers were required to show that a drug was
safe before it could be marketed.
2. Manufacturers had to submit an application to the FDA
before marketing a drug. If the FDA didn't act on the
application in a certain time period, the application
automatically became approved.
3. The 1938 act also eliminated the Sherley Amendment,
which called for adequate labeling for safe use
4. set safe tolerances for unavoidable poisonous
substances, and authorized factory inspections
• This mandate for premarket evidence of a drug's safety
represented the birth of the new drug application, or
NDA.

12. Durham-Humphrey Amendment, In 1951
• Following the 1938 Act, the FDA began to distribute
public notices (known as trade correspondences) to the
industry regarding the labeling and dispensing of drugs
• It was in these public notices that the FDA first
distinguished medications that should be available only
by prescription
• At this point the decision about which drugs should
receive a caution label was largely at the discretion of the
manufacturer.
• In 1951, the Durham-Humphrey Amendment set forth
the basis for distinguishing between prescription and
nonprescription drugs.

13. The DH amendments gave FDA the
responsibility to clarify which drugs are:
• Habit-forming,
• Not safe except under a practitioner’s supervision, and,
• Drugs limited to prescription sale as part of the approval
of a New Drug Application.
• Required “Caution: Federal Law Prohibits Dispensing
Without a Prescription.” (Today “Rx Only”.)
• Prescription exemption (for manufacturers)
• Pharmacists must label prior to dispensing.

14. The Kefauver-Harris Drug Amendments
• In 1961, an Australian obstetrician, William McBride, reported an
increase of fetal malformations in association with the hypnotic drug
thalidomide.
• Although thalidomide
was heavily marketed in
Western Europe, approval
of this drug was delayed
by the FDA in the United
States and never made it to
market
• In October 1962, Congress
passed the Kefauver-Harris
Drug Amendments to the
Federal FD&C Act

15. As per The Kefauver-Harris Drug Amendments
1. Before marketing a drug, firms now had to prove not
only safety, but also provide substantial evidence of
effectiveness for the product's intended use
2. Kefauver-Harris Drug Amendments also asked the
Secretary to establish rules of investigation of new drugs,
including a requirement for the informed consent of
study subjects.
3. The amendments also formalized good manufacturing
practices,
4. required that adverse events be reported,
5. and transferred the regulation of prescription drug
advertising from the Federal Trade Commission to the
FDA.

16. • In 1981,
1.formal standards for the Protection of
Human Subjects and
2. Institutional Review Boards (IRBs) were
strengthened.
• The IRBs are panels of scientists and non-
scientists in hospitals and research institutions
who ensure the safety and well-being of
human subjects involved in research

17. Anti-Tampering Regulations 1982
• After seven people in Chicago died from
swallowing Tylenol capsules laced with
cyanide, the FDA issued Tamper-Resistant
Packaging Requirements in 1982. The Federal
Anti-Tampering Act, passed in 1983, makes it
a crime to tamper with packaged consumer
products.

18. 1983 - “Orphan Drug Act
• the Orphan Drug Act (ODA) was passed in 1983
• It allowed the FDA to encourage research and
development of drugs needed to treat rare diseases
• The ODA created financial incentives, including tax
credits for the costs of clinical research and
• seven years of marketing exclusivity for the first
sponsor of an orphan product who receives FDA
approval for a particular indication
• Examples of rare diseases that can now be treated
with orphan medications include sickle cell anemia,
cystic fibrosis, and T-cell lymphoma.

19. Encouraging Generic Drugs
1984 - “Drug Price Competition
and Patent Term Restoration Act’’
• Expanded the number of drugs for which an
abbreviated new drug application (ANDA) could be
submitted.
• Generic drug companies don't have to repeat the
expensive clinical trials that brand companies have
already conducted to show safety and effectiveness
• But they must perform tests and show the FDA that
their drugs are equivalent to the brand name in terms
of therapeutic effect.

20. Drugs for Life-Threatening Illnesses
• In 1987, partially in response to the human
immunodeficiency virus (HIV) epidemic, new regulations
were developed to accelerate approval for high-priority
medications.
• Another example of improving access to treatment is
"accelerated approval," which was formalized in 1992
• This type of drug approval is based on an encouraging
effect such as tumor shrinkage, before there is actual
evidence of improved survival or other clinical benefit,
• The FDA approves a drug under accelerated approval on
the condition that the drug manufacturer verify the
actualclinicalbenefit.

21. The Prescription Drug User Fee Act
• The Prescription Drug User Fee Act (PDUFA)
was passed in 1992, and mandated that drug
companies pay user fees so the FDA could
add more resources and speed up drug review
times, without compromising standards.

22. The Food and Drug Modernization
Act of 1997
• In 1997, the PDUFA was renewed under the
Food and Drug Administration Modernization
Act and then renewed again in 2002 for five
more years
• In addition, the Food and Drug Modernization
Act (FDAMA) supported accelerated approval
and gave an extra period (six months) of
marketing exclusivity to manufacturers that
carried out studies in children.

23. Expanding Demographics
in Clinical Trials
• In the 1980s and 1990s, several FDA guidance's and
rules drew attention to the need to include
representative populations in clinical trials
• The inclusion of such populations has helped experts
analyze results for possible differences in drug
response among demographic subsets.
• Here are some key changes that have helped
expand demographic evaluation in drug research:

24. 1. In 1989, the FDA issued guidelines asking manufacturers to determine
whether a drug is likely to have significant use in older people, and to
include older patients in clinical studies.
2. In 1993, the FDA issued the Gender Guideline, which called for
assessments of medication responses in both genders
3. In 1998, the FDA required that a marketing application analyze data on
safety and effectiveness by age, gender, and race. This is known as the
Demographic Rule.
4. In 1998, the FDA promulgated the Pediatric Rule, a regulation that
required manufacturers of selected drugs to conduct studies to assess
their safety and efficacy in children.
5. In 2002, the Best Pharmaceuticals for Children Act was passed to improve
the safety and effectiveness of medicines for children.
6. In 2003, the FDA was given clear authority under the Pediatric Research
Equity Act to require drug sponsors to conduct clinical research into
pediatric applications for new drugs.

25. References
1. US Food and drug administration.“Histories
of Product Regulation” , available at http:/
www.fda.gov . Accessed 12 may 2010
2. Susan Berg,”From test tube to medicine
chest, the approval process for new drug”,
Asthma magazine, pg 24
3. Martin S. Lipsky, MD, and Lisa K. Sharp,
“From Idea to Market: The Drug Approval
Process”. JABFP September–October 2001
Vol. 14 No. 5, pg-362