How do Drugs Come How do Drugs Come

into Market? into Market?

Dr. Huma Fahim
Most of today's major pharmaceutical Most of today's major pharmaceutical
companies were founded in the late 19th companies were founded in the late 19th
and early 20th centuries. and early 20th centuries.
Key discoveries of the 1920s and 1930s, Key discoveries of the 1920s and 1930s,
such as such as insulin insulin and and penicillin penicillin, became , became
mass mass- -manufactured and distributed. manufactured and distributed.
Switzerland, Germany and taly had Switzerland, Germany and taly had
particularly strong industries, with the UK particularly strong industries, with the UK
and US following suit. and US following suit.
umerous new drugs were developed umerous new drugs were developed
during the 1950s and mass during the 1950s and mass- -produced and produced and
marketed through the 1960s. marketed through the 1960s.
o o This included the first oral contraceptive, "The This included the first oral contraceptive, "The
Pill, Cortisone, blood Pill, Cortisone, blood- -pressure drugs and pressure drugs and
other heart medications. MAO nhibitors, other heart medications. MAO nhibitors,
chlorpromazine (Thorazine), Haldol chlorpromazine (Thorazine), Haldol
(Haloperidol) and the tranquilizers ushered in (Haloperidol) and the tranquilizers ushered in
the age of psychiatric medication. the age of psychiatric medication.
o o Valium (diazepam), discovered in 1960, was Valium (diazepam), discovered in 1960, was
marketed from 1963 and rapidly became the marketed from 1963 and rapidly became the
most prescribed drug in history, prior to most prescribed drug in history, prior to
controversy over dependency and habituation controversy over dependency and habituation
Drug Discovery Drug Discovery
Drug discovery Drug discovery is the process by which is the process by which
potential drugs are discovered or potential drugs are discovered or
designed. designed.
n the past most drugs have been discovered n the past most drugs have been discovered
either by isolating the active ingredient from either by isolating the active ingredient from
traditional remedies or by serendipitous traditional remedies or by serendipitous
discovery. discovery.
A great deal of early A great deal of early- -stage drug discovery has stage drug discovery has
traditionally been carried out by universities traditionally been carried out by universities
and research institutions. and research institutions.
Objectives of Drug Development Objectives of Drug Development
Drug deveIopment Drug deveIopment refers to activities undertaken after a refers to activities undertaken after a
compound is identified as a potential drug in order to compound is identified as a potential drug in order to
establish its suitability as a medication. establish its suitability as a medication.
Objectives of drug development are to determine appropriate Objectives of drug development are to determine appropriate
Formulation Formulation and and Dosing, Dosing, as well as to establish as well as to establish safety. safety.
Research in these areas generally includes a combination of Research in these areas generally includes a combination of in vitro in vitro
studies, studies, in vivo in vivo studies, and clinical trials. studies, and clinical trials.
Often, large multinational corporations exhibit vertical integration, Often, large multinational corporations exhibit vertical integration,
participating in a broad range of drug discovery and development, participating in a broad range of drug discovery and development,
manufacturing and quality control, marketing, sales, and distribution. manufacturing and quality control, marketing, sales, and distribution.
Smaller organizations, on the other hand, often focus on a specific Smaller organizations, on the other hand, often focus on a specific
aspect such as discovering drug candidates or developing formulations. aspect such as discovering drug candidates or developing formulations.
Often, collaborative agreements between research organizations and Often, collaborative agreements between research organizations and
large pharmaceutical companies are formed to explore the potential of large pharmaceutical companies are formed to explore the potential of
new drug substances. new drug substances.
o o Attempts were made to increase regulation and to limit Attempts were made to increase regulation and to limit
financial links between pharmaceutical companies and financial links between pharmaceutical companies and
prescribing physicians, including by the relatively new prescribing physicians, including by the relatively new
US US FDA FDA. .
o o Such calls increased in the 1960s after the Such calls increased in the 1960s after the
thalidomide thalidomide tragedy came to light, in which the use of a tragedy came to light, in which the use of a
new tranquilizer in pregnant women caused severe birth new tranquilizer in pregnant women caused severe birth
defects. defects.
o o n 1964, the World Medical Association issued its n 1964, the World Medical Association issued its
Declaration of Helsinki, which set standards for clinical Declaration of Helsinki, which set standards for clinical
research and demanded that subjects give their informed research and demanded that subjects give their informed
consent before enrolling in an experiment. consent before enrolling in an experiment.
o o Phamaceutical companies became required to prove Phamaceutical companies became required to prove
efficacy efficacy in clinical trials before marketing drugs. in clinical trials before marketing drugs.
Aspects of clinical development Aspects of clinical development
Scientific medical aspect Scientific medical aspect
How to prove efficacy and safety of the new How to prove efficacy and safety of the new
substance substance
Regulatory aspect Regulatory aspect
How to fulfill all relevant regulatory requirements How to fulfill all relevant regulatory requirements
Organizational aspect Organizational aspect
How to develop cost and time effective development How to develop cost and time effective development
What is GCP? What is GCP?
An international ethical and quality An international ethical and quality
standard for the designing, conducting, standard for the designing, conducting,
recording and reporting trials that involve recording and reporting trials that involve
the participation of human subjects the participation of human subjects
(CH definition) (CH definition)
Four columns of GCP Four columns of GCP
Protection of the rights and of the welfare of the subjects Protection of the rights and of the welfare of the subjects
and ensurance of high degree of ethical standards and ensurance of high degree of ethical standards
(ethics comm.) (ethics comm.)
High scientific and performance quality in planning, High scientific and performance quality in planning,
conduct and evaluation of clinical trials (ethical basis conduct and evaluation of clinical trials (ethical basis
includes scientific rationale: statistics/sufficiently high includes scientific rationale: statistics/sufficiently high
patient numbers/comparisons) patient numbers/comparisons)
Comprehensive and verifiable documentation of the trial Comprehensive and verifiable documentation of the trial
performance (CRFs, monitoring, SDV source data performance (CRFs, monitoring, SDV source data
verification) verification)
Definition of responsibilities and functions f the parties Definition of responsibilities and functions f the parties
involved in clinical trials. involved in clinical trials.
(legal considerations: For all interventional studies, (legal considerations: For all interventional studies,
regardless of the phase, GCP is applicable regardless of the phase, GCP is applicable
Drug development Drug development
Preclinical toxicology
D investigational new drug application
Phase safety and dosage
Phase evaluate effect side effect
Phase Verify effect, monitor side effects
DA new drug application
Approval
Years 0
20
10
PMS, SS, Phase V
Phase 0 Phase 0
Phase 0 is a recent designation for Phase 0 is a recent designation for
exploratory exploratory
Conducted in accordance with FDA Conducted in accordance with FDA
guidelines guidelines
Sub therapeutic dose of the study drug is Sub therapeutic dose of the study drug is
administered in small number of subjects administered in small number of subjects
to gather preliminary data on PK & PD to gather preliminary data on PK & PD
Phase Phase
To get the sufficient information about the drug in order to justify the first To get the sufficient information about the drug in order to justify the first
application in patients application in patients
First application to First application to
humans humans
Usually healthy male Usually healthy male
volunteers volunteers
PK: absorption, PK: absorption,
distribution, distribution,
metabolism, excretion metabolism, excretion
PD: effects on human PD: effects on human
body body
Bioavailability Bioavailability
Dose finding Dose finding
(tolerability, safety) (tolerability, safety)
Food interaction Food interaction
Comparison of Comparison of
formulations, choice formulations, choice
of route application of route application
Total number of Total number of
subjects: 20 subjects: 20- -100 100
Phase Phase
To show effect on the disease or even prove efficacy and relative safety in To show effect on the disease or even prove efficacy and relative safety in
highly selected patients highly selected patients
First application to First application to
patients suffering patients suffering
from the disease from the disease
Limited number of Limited number of
patients and trial sites patients and trial sites
Limited duration Limited duration
Many inclusion Many inclusion
exclusion criteria exclusion criteria
Efficacy and short Efficacy and short
term safety term safety
Placebo controlled Placebo controlled
trial when possible trial when possible
Total number of Total number of
patients: 150 patients: 150- -400 400
Phase a, to assess Phase a, to assess
dosing requirements dosing requirements
Phase b, to study Phase b, to study
efficacy efficacy
Phase Phase
To get To get sufficient efficacy and safety data for marketing approval sufficient efficacy and safety data for marketing approval
Treatment under real life Treatment under real life
conditions: conditions:
Fewer exclusion criteria Fewer exclusion criteria
Confirmation of Confirmation of
therapeutic benefit on a therapeutic benefit on a
broad level broad level
Preferably randomized Preferably randomized
standard therapy standard therapy
controlled, double blind, controlled, double blind,
multicenter and multicenter and
multinational trials multinational trials
Clarification of crucial Clarification of crucial
questions: questions:
Short and long term Short and long term
efficacy and safety efficacy and safety
Efficacy and safety in Efficacy and safety in
special populations special populations
dentification of dentification of
contraindications contraindications
dentification of drug dentification of drug
interactions interactions
Total o. : 600 Total o. : 600- -3000 3000
Phase V Phase V
To obtain extended knowledge about the new compound To obtain extended knowledge about the new compound
Trials after market approval with in the Trials after market approval with in the
approved indication approved indication
Collection of additional safety data Collection of additional safety data
Detection of non frequent side effects Detection of non frequent side effects
Comparisons with new drugs introduced to Comparisons with new drugs introduced to
the market the market
Research on questions not yet answered Research on questions not yet answered
by Phase by Phase - -
Total number of subjects 1000 Total number of subjects 1000- -10,000 10,000
Post Marketing Surveillance PMS Post Marketing Surveillance PMS
To enlarge safety and tolerance data base and confirm trial data in To enlarge safety and tolerance data base and confirm trial data in
clinical practice clinical practice
on interventional trial on interventional trial
Pure observation Pure observation
Does not interfere with clinical practice Does not interfere with clinical practice
o trial related risks for patients o trial related risks for patients
Large patient number Large patient number
Trends in ew Drug Development Trends in ew Drug Development
Pipelines* by Therapeutic Class Pipelines* by Therapeutic Class
Trends in ew Drug Development Trends in ew Drug Development
Pipelines* by Therapeutic Class Pipelines* by Therapeutic Class
.8%
20.5%
.3%
21.9%
1.3%
13.7%
6.5%
27.2%
8.3%
19.6%
9.1%
11.6%
9.1%
20.2%
10.7%
20.6%
8.7%
7.9%
0% 30%
Respiratory
Oncology/Immunologic
GI/Metabolism
CNS
Cardiovascular
Antiinfective
!ercent of !hase I !ipeIine
1993-97 1998-02 2003-05
Source: Tufts CSDD Impact Report, 8(3): May/June 2006
` Ten largest pharmaceutical firms
Approval Success Rates for Approval Success Rates for
CEs Also Vary by Therapeutic CEs Also Vary by Therapeutic
Class Class
Approval Success Rates for Approval Success Rates for
CEs Also Vary by Therapeutic CEs Also Vary by Therapeutic
Class Class
0.9%
.%
.2%
9.9%
27.2%
0.%
0 5
Approval Success Rate
GI/Metabolism
CNS
Cardiovascular
Respiratory
Oncology/Immunology
Antiinfective
Source: Tufts CSDD Impact Report, 8(3): May/June 2006
Clinical and Approval Times Vary Clinical and Approval Times Vary
Across Therapeutic Classes, Across Therapeutic Classes,
2002 2002- -04 04
Clinical and Approval Times Vary Clinical and Approval Times Vary
Across Therapeutic Classes, Across Therapeutic Classes,
2002 2002- -04 04
.8 .
.2 2.8
.6 .9
6.3 0.6
6.3 .3
6.6 .9
9.0 0.8
0. .7
0 1
ears
Cardiovascular
Anesthetic/Analgesic
Gastrointestinal
AIDS Antivirals
Endocrine
Antiinfectives
Antineoplastic
Neuropharmacologic
Clinical Phase Approval Phase
2.
7.6
8.
7.
8.0
6.3
9.8
Source: Tufts CSDD, 2006
6.9
"uestions? "uestions?
Drug deveIopment Drug deveIopment
Drug deveIopment Drug deveIopment or or precIinicaI deveIopment precIinicaI deveIopment is defined in many pharmaceutical is defined in many pharmaceutical
companies as the process of taking a new chemical lead through the stages companies as the process of taking a new chemical lead through the stages
necessary to allow it to be tested in human necessary to allow it to be tested in human clinical trials clinical trials, although a broader definition , although a broader definition
would encompass the entire process of drug discovery and clinical testing of novel would encompass the entire process of drug discovery and clinical testing of novel
drug candidates. drug candidates.
ontents ontents
hide] hide]
edit edit] New chemicaI entity (N deveIopment ] New chemicaI entity (N deveIopment
ew chemical entities ew chemical entities ( (Ns Ns) are compounds which emerge from the process of ) are compounds which emerge from the process of
drug discovery drug discovery. These will have promising activity against a particular biological target . These will have promising activity against a particular biological target
thought to be important in disease, however little will be known about the safety, thought to be important in disease, however little will be known about the safety,
toxicity toxicity, , pharmacokinetics pharmacokinetics and and metabolism metabolism of this CE in humans. t is the function of of this CE in humans. t is the function of
drug development to assess all of these parameters prior to human clinical trials. A drug development to assess all of these parameters prior to human clinical trials. A
further major objective of drug development is to make a recommendation of the further major objective of drug development is to make a recommendation of the
dose and schedule to be used the first time an CE is used in a human clinical trial dose and schedule to be used the first time an CE is used in a human clinical trial
(" ("first first- -in in- -man man", FM). ", FM).
n addition, drug development is required to establish the physicochemical properties n addition, drug development is required to establish the physicochemical properties
of the CE: its chemical makeup, stability, solubility. The process by which the of the CE: its chemical makeup, stability, solubility. The process by which the
chemical is made will be optimized so that from being made at the bench on a chemical is made will be optimized so that from being made at the bench on a
milligram milligram scale by a scale by a synthetic chemist synthetic chemist, it can be manufactured on the , it can be manufactured on the kilogram kilogram and and
then on the then on the ton ton scale. t will be further examined for its suitability to be made into scale. t will be further examined for its suitability to be made into
capsules capsules, , tablets tablets, aeresol, intramuscular injectable, subcuteneous injectable, or , aeresol, intramuscular injectable, subcuteneous injectable, or
intravenous intravenous formulations formulations. Together these processes are known in preclinical . Together these processes are known in preclinical
development as development as : Chemistry, Manufacturing and Control. : Chemistry, Manufacturing and Control.
Many aspects of drug development are focused on satisfying the Many aspects of drug development are focused on satisfying the regulatory regulatory