DRUG DEVELOPMENT & REGULATORY PROCESS

- Which countries do drugs come from?

o In 1998 to 2007, there are 272 new molecules and they
came from the following countries:
 USA (118)  France (12)
 Japan (low  Other EU
20s) countries(29)
 UK (low 20s)  Canada (7)
 Germany (low  Australia (7)
20s)  Israel (6.5)
 Switzerland  China (6.5)
(low 20s)  India (6.5)
o Innovative versus “me too” drug producers
 Innovative drugs come from the following countries:
 United States of America
 United Kingdom
 Innovative drugs also come from these countries to
a lesser extent:
 Switzerland
 Canada
 Australia
 “me too” usually come from:
 Germany
 Japan

- The university in drug discovery

o 58% from pharmaceutical companies
o 18% from biotechnology companies
o 16% from universities then transferred to biotechnology
companies
o 8% from universities then transferred pharmaceutical
companies

- Non-industry drug discovery and development

o Small molecule discovery center at University of
California, San Francisco
o Drug discovery facility at Imperial College, London
o Dundee drug discovery unit at Scotland, United Kingdom
o CRUK center for cancer, Institute of cancer research at
London

- In the Philippines, there are numerous studies being done in the

universities but it remains in there. Nobody cares to pursue
what was previously discovered so the scenario is that Filipino
discoveries do not get past pre-clinical trials and drug discovery
remains a mere academic requirement

- The gap in Philippine drug development

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- Unexplored sources of drug candidates
o In marine environments there may be 3.7 x 10 30
microorganisms, many of which may produce fascinating
natural products as drug candidates
o Fewer than 15% of higher plant species have been
examined for bioactivity
o Concept of metagenomics was proposed to look at genes
and their function in samples obtained directly from the
environment
o At present most pharmaceutical firms do not appear to be
undertaking efforts in this direction for drug discovery

- Department of Science and Technology (DOST) has been

supporting promising projects like the Pharmaseas and those of
the Marine Science Institute at University of the Philippines
Diliman

- Challenge for the Filipino scientists:

o We end up with drug-like compounds; we don’t pursue
them further
o Researchers taking on “new projects” all the time
o Lead optimization is an iterative process and we do not
have medicinal chemists!!!

- TKS1225
o Synthetic version of GI peptide oxyntomodulin (for
treatment of medical obesity by appetite suppression)
o Discovered at the Imperial College of London and went for
a virtual company named Thiakis with only 3 people
o After phase I, it was bought by Wyeth in 2008 with upfront
payment of 30 million dollars. Future milestone payments
is worth 120 million dollars

- Other examples of university partnership

o Institute of Cancer, University of London partners for drug
development of the following products
 Carboplastin (Bristol Myers Squibb)
 A chemotherapy drug used against some forms
of cancer (mainly ovarian carcinoma, lung,
head and neck cancers)
 Tomudex (AstraZeneca)

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  An antimetabolite drug used in cancer
chemotherapy that works by inhibiting
thymidylate synthase
 Busulfan (GlaxoSmithKline)
 Used to treat chronic myelogenous leukemia
 Chlorambucil (GlaxoSmithKline)
 A chemotherapy drug that has been mainly
used in the treatment of chronic lymphocytic
leukemia
o The University of Chicago partners for drug development
of Epoiten alfa (Epogen) with Amgen. Epogen is used to
treat anemia.
o The Memorial Sloan-Kettering Cancer Research Center
partners for drug development of Neupogen with Amgen.
Neupogen is used to treat neutropenia
o Stanford University partners for drug development of
Rituxan with Genentech. Rituxan is indicated for the
treatment of non-hodgkins lymphoma (NHL) which is a
cancer that develops in the lymphatic system
o University of California San Francisco partners for drug
development of Humulin N with Genentech. Humulin N is
biosynthetic human insulin products for diabetes

- Important understanding on the following topics are needed in

the modern generation of new drug compounds
o Drug-receptor modeling
o High-throughput screening
o Candidate selection

- Some inputs on drug discovery:

o Diversify or scale-up, example is to study more than one
plant
o Identify at least drug-like candidates
o Strategize drug discovery approach, we have limited
resources
o Partner to share the risks
o Cash-in! Extract value from your early-stage assets
o Change mindset, dream big!

New Therapeutic Molecule

- Although drug therapy has natural and humble origins, it is the

application of scientific principles which has given rise to the
clinical safety and efficacy of modern medicines

- The drug product development and approval process in the USA

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 - Early medicines where of botanical and zoological origin but in
the 19th to 20th century, it marked the increase in the use of
synthetic organic chemicals. In the 21st century, there is likely to
have increasing use of the products derived using data from the
Human Genome Project (HGP)

- The need for new drugs can easily be seen from the leading
cause of disease and disability worldwide:

Rank 1990 2020

1 Ischemic heart disease Ischemic heart disease
2 Cerebrovascular disease Unipolar major depression
3 Lower respiratory infections Road traffic accidents
4 Diarrheal diseases Cerebrovascular disease
5 Perinatal disorders Chronic obstructive
pulmonary disease
6 Chronic obstructive Lower respiratory infections
pulmonary disease
7 Tuberculosis (HIV excluded) Tuberculosis
8 Measles War injuries
9 Road traffic accidents Diarrheal diseases
10 Lung, trachea and bronchial HIV
cancer

- Examples of benefits of drugs for the treatment of disease can

be seen in antimicrobial chemotherapy which revolutionized the
chances of patients surviving severe infections such as lobar
pneumonia, the mortality from which was 27% in the pre-
antimicrobial era but fell to 8% (and subsequently less)
following the introduction of sulphonamides and penicillins
(although antibiotic resistance has been a global problem lately)

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- Overview to pre-clinical testing
o A typical drug development process starts with target
identification. Then, a lead candidate is identified using
molecular modeling, combinatorial chemistry, or high
throughput screening
o The lead candidates are next synthesized or produced,
screened by in vitro assays for biological or
pharmacological activity. And further optimized to attain
the desired level of activity
o Then the New Molecular Entity (NME) is tested in animal
models for activity, which is followed by pharmacokinetic
and toxicological studies
o The simplest formulations, such as solutions or
suspensions, are used in preclinical testing

- Identification of new therapeutic molecule

o The process of identifying new molecules with the
potential to produce a desired therapeutic effect may
require:
 Research on the fundamental mechanisms of the
disease or biological process
 Research on the action of known therapeutic agents
 Random selection and broad biologic screening
o Sources of drug molecules
 Animal
 Use of animals in the production of various
biologic products
o Hormonal substances, such as thyroid
extract, insulin (from pig and cow), and
pituitary hormones obtained from the
endocrine glands of cattle, sheep, and
swine are life-saving drugs used daily as
replacement therapy
o Growth hormone from human itself are
also a source of drug through
biotechnology
o New vaccines for diseases such as AIDS
and cancer are being developed through
the use of cell and tissue cultures
 Plant
 A major advance in the safety of plant-derived
medicines was the isolation, purification and
chemical characterization of the active
component. This has three advantages:
o The administration of controlled
amounts of the purified active compound
removed biological variability in potency
of the crude plant preparation
o The administration of the purified active
compound removed the unwanted and
potentially toxic effects of contaminating
substances in the crude preparations
o The identification and isolation of the
active component allowed the
mechanism of action to be defined,
leading to the synthesis and
development of drugs based on the
structure of the active component with
the same action but with greater
potency, greater selectivity, fewer

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 unwanted effects, altered duration of
action, better absorption, etc.
 Some drugs of plant origin
o Digoxin from digitalis
o Morphine
o Vinblastine and Vincristine (anticancer
drugs) from Vinca rosea plant
o Paclitaxel (Taxol) which is used in the
treatment of ovarian cancer is from
Pacific yew
 Inorganic
 Arsenic
 Mercury
 Lithium
 Synthetic
 Organic synthesis
o After the isolation and structural
identification of active plant
constituents, organic chemists may
create these constituents by total
synthesis in the laboratory or use the
natural chemical of the starting material
to create new compounds through
molecular manipulations
o Propanolol is an example of drug from
organic synthesis
 Genetic engineering
o Two basic technologies that drive the
genetic field of drug development:
 Recombinant DNA
 Involve protein production
within cells of lower animals
 Produce wide variety of
proteins, examples are
o Human insulin
o Human growth
hormone
o Hepatitis B vaccine
o Interferon
 Monoclonal antibody production
 Conducted mainly in cells of
higher animals, as well as
patients
 Gene therapy
o The process of correction or
replacement of defective genes and has
the potential to be used to prevent,
treat, cure, diagnose or mitigate human
disease caused by genetic disorders
o Oligonucleotides and siRNA are used to
inhibit aberrant protein production,
whereas gene therapy aims at
expressing therapeutic proteins inside
the body

- Approaches to drug discovery

o Synthesis and screening of new chemical entities
 Simplest method
 Subject new chemical entities (novel chemicals not
previously synthesized) to a battery of screening

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 tests that are designed to detect different types of
biological activity
 Includes:
 in vitro studies on isolated tissues
 in vivo studies of complex and integrated
systems, such as animal behavior
 Novel chemicals for screening may be
produced by direct chemical synthesis or may
be isolated from biological sources such as
plants, and then purified and characterized
 This approach has been revolutionized in
recent years by developments in high-
throughput screening, which takes advantage
of laboratory robotics combined with in vitro
cell lines that express cloned human receptors
or enzymes
 Solid-phase peptide synthesis combined with
knowledge from the human genome project
allows the rapid synthesis of large libraries of
potential candidate molecules
o Testing of analogues of existing medicines
 Generally, the products of this research show only
minor advances in adsorbtion, potency or a more
selective action. However, unexpected additional
properties may become evident when the compound
is tried in humans
 Examples
 Minor modifications of the sulphanilamide
antimicrobial molecule gave rise to the
thiazide diuretics and the sulphonylurea
hypoglycemic
 Reversing the positions of proline and lysine in
human insulin to create insulin lispro (cool!)

o Design of compounds for a particular biological function

 More recent
 Design of substances to fulfill a particular biological
role, which may entail the synthesis of a naturally

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 occurring substance (or a structural analogue), its
precursor or an antagonist.
 Logical drug development of this type depends on a
detailed understanding of human physiology both in
health and disease. High-throughput screening is
particularly useful in such a focused approach
 Example:
 Levodopa used in the treatment of Parkinson’s
disease
 Omeprazole, the first proton pump inhibitor

Pre-formulation & Formulation

- Formulation development
o Inappropriate dosage forms or invalidated manufacturing
processes can result in disastrous consequences during
clinical trials
o Factors such as the target population (children or adults),
the amount of drug to be given in each dose, storage
stability of the drug product, and the design and
cleanliness of the process

- Pre-formulation studies
o Initiated to define the physical and chemical properties of
the agent

- Formulation
o Develop the initial features of the proposed
pharmaceutical product or dosage forms
o Excepients
 Added in the final formulation in addition to the
active ingredients

Clinical Studies

- All drugs and formulations have to pass a rigorous evaluation of

safety, quality and efficacy
o In the USA, drug development costs $802 million
o In the UK, drug development costs 500 million pounds

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- Establishing safety and efficacy
o Preclinical studies
 To establish the basic pharmacology,
pharmacokinetics and toxicological profile of the
drug and its metabolites, using animals and in vitro
systems
 These studies investigate 3 areas:
 Pharmacological effects
o in vitro effects using isolated
cells/organs
o Receptor binding characteristics
o in vivo effects in animals and/or animal
models of human disease
o Prediction of potential therapeutic use
 Pharmacokinetics
o Identification of metabolites (since these
may be the active form of the compound)
o Evidence of bioavailability (to assist with
the design of both clinical trials and in
vivo animal toxicity studies)
o Establishment of principal route and
rate of elimination
 Toxicological effects
o A battery of in vitro and in vivo studies
undertaken with the aim of identifying
toxicity as early as possible, and before
there is extensive in vivo exposure of
animals or, subsequently, of humans
o Toxicity testing
 Has two primary goals:
 Identification of hazards
 Prediction of the likely risk
of that hazard occurring in
humans receiving
therapeutic doses of the new
medicine
 Toxicity tests include the following
 Mutagenicity
 Acute toxicity
 Subacute toxicity
 Chronic toxicity
 Carcinogenicity
 Reproductive toxicity
 Nonclinical studies
 Nonhuman studies that may continue at any
stage of research to obtain additional
information concerning the pharmacology and
toxicology of the drug
o Pre-marketing clinical studies
 Purpose of pre-marketing clinical studies:
 To establish that the drug has a useful action
in humans
 To define any toxicity at therapeutic doses in
humans
 To establish the nature of common (type A)
unwanted effects
 Phase I clinical studies
 Term used to describe the first few
administrations of a new drug to humans

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  Purpose is to establish the human
pharmacology and pharmacokinetics, together
with a simple safety profile
 Phase I summarized:
o Healthy volunteers (20-80)
 Recruited in a n open
advertisement
o Safety profiles
o Drug tolerance
 The first few administrations are usually by
mouth in a dose that may be as low as one-
fiftieth of the minimum required to produce a
pharmacological effect in animals
 Depending upon what is found, the dose may
be then built up, either in small increments or
by doubling, until a pharmacological effect is
observed or an unwanted action occurs
 During these studies, toxic effects are looked
for by means of routine hematology and
biochemical investigations of liver and renal
function; other tests, including an
electrocardiogram, will be performed as
appropriate
 It is also usual to study the disposition,
metabolism and main pathways of elimination
of the proposed new drug in humans at this
stage. Such studies help to identify the most
suitable dose and route of administration for
future clinical studies
 TGN 1412
o A new immodulatory compound, caused
significant toxicity in its first human
phase I trial in March 2006
o The severe toxicity occurred at a dose
500 times lower than the dose found to
be safe in animals
 Phase II clinical studies
 Purpose is to establish the dose-response and
to develop the dosage protocol for clinical use,
together with more extensive safety data
 Phase II summarized:
o Patients (100-300)
o Controlled, randomized trials
o Double-blinded
o Short-term side effects
o Decision on final dosage form
 A limited number of patients with the disease
or condition for which the drug was developed
are treated under close supervision
 Detailed clinical pharmacology of the new
compound is determined in groups of
individuals of the new compound is
determined in groups of individuals with the
intended clinical condition
 A principal aim of these studies is to define the
relationship between dose and
pharmacological and/or therapeutic response
in humans
 Evidence of a beneficial effect will normally
emerge during phase II studies

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  The optimum dosage regimen should be
defined in the phase II studies, and this is then
used in large clinical trials, which aim to
demonstrate the efficacy and safety of the
drug (determines therapeutic index, ratio of
toxic dose to effective dose)
 At this stage, a drug formulation having good
physico-chemical stability is developed
 Phase III clinical studies
 Purpose is to establish the efficacy and safety
profile of the drug in people with the proposed
disease for which the drug will be indicated
 Phase III summarized:
o Patients (1000-3000)
o Expanded and uncontrolled trials
o Monitor adverse reactions
o Confirm effectiveness
o Decision on physician labeling
 The main clinical trials and usually involve
comparison with a placebo that looks (and
tastes) similar to the active compound
 Large-scale, multicenter clinical studies are
performed with the final dosage form
developed in phase III

 Two main types

o Within subject
 An individual is randomly allocated
to commence treatment with
either the new compound or its
comparator (or placebo) before
“crossing over” to the alternative
therapy

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 o Between subject
 Involve randomization to receive
one of two (or more) treatments
for the duration of the study

o Phase IV
 Not a part of the pre-marketing clinical studies
 Approval to market the product is obtained from the
FDA, manufacturing scale-up activities occur
 Scale-up
 The increase in the batch size from the clinical
batch, submission batch, or both to the full-
scale production batch size, using the finished,
marketed products
 The drug product may be improved as a result of
equipment, regulatory, supply, or market demands
 Additional clinical studies may be performed in
special populations, such as the elderly, pediatric,
and renal-impaired, to obtain information on the
efficacy of the drug in these subjects
 Additional clinical studies may be performed to
determine if the drug can be used for a new or
additional labeling indications
o Phase V
 Also called Post-Marketing Surveillance (PMS)
 Not a part of the pre-marketing clinical studies
 After the FDA grants market approval of the drug,
product development may continue
 The drug formulation may be modified slightly as a
result of data obtained during the manufacturing
scale-up and validation process

Regulatory Issues

- Regulation and control of new drugs in the Philippines have

been based on New Drug Applications (NDA) to the FDA

- FDA Philippines is divided into various centers, that accepts a

corresponding NDA:
o Center for Drug Regulation and Research (CDRR)
o Center for Device Regulation, Radiation Health and
Research (CDRRHR)
o Center for Cosmetic Regulation and Research (CCRR)
o Center for Food Regulation and Research (CFRR)

- New pharmaceutical product in the US requires the following

o Preclinical laboratory tests and in vivo preclinical studies
o Submission of an Investigational New Drug (IND)
application for the FDA for clinical testing
o Clinical trials for establishing product safety and efficacy
o Submission of an NDA to the FDA for a biologics license
application (BLA)
o FDA approval of the NDA or BLA before any commercial
sale

- Abbreviated New Drug Application (ANDA)

o Submitted to gain approval for a generic product whose
active ingredient has already been approved and is being
marketed by the pioneer or original sponsor of the drug

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Pharmacovigilance

- The pharmacological science relating to the detection,

assessment, understanding and prevention of adverse effects,
particularly long term and short term side effects of medicines

- The purpose of pharmacovigilance is to monitor adverse events

following approval and the more widespread use of drugs

- The pharmacovigilance flow of global adverse event reporting:

- Functions of pharmacovigilance
o Detection and study of adverse reactions
o Measurement of risk
o Measurement of effectiveness
o Benefit & harm evaluation
o Dissemination of information, education
 Early warning
 Rational and safe use of medicines

- Done because the full spectrum of benefits and risks of

medicines may not become clear until after marketing. Reasons
for this include:
o The low frequency of certain adverse drug reactions
o The tendency to avoid the inclusion of children
o The elderly and women of childbearing age in pre-
marketing clinical studies
o Widespread use of produce an unexpected interaction
with the new drug

- Recent developments in information about the beneficial and

adverse effects of drug has been the use of systematic meta-
analyses of clinical trials’ data

- Pharmacovigilance in different countries

o United Kingdom
 Two main systems of pharmacovigilance, or post-
marketing surveillance that are used in the UK:
 The yellow card system
o The most important
o The doctor reporting suspected serious
adverse reactions directly to the
authorities using postage prepaid cards

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 (available in the British National
Formulary) and the Monthly Index of
Medical Specialties (MIMS)
 Systematic post-marketing surveillance of
recently marketed medicines
o Organized by the pharmaceutical
company responsible for the
manufacture of the new drug
o United States of America
 MedWatch
 The FDA’s reporting system for an adverse
event or sentinel event
 Ways of reporting:
 Online
 Phone 1-800-FDA-1088, or
 Submitting the MedWatch 3500 form by mail
or fax 1-800-FDA-0178
o Philippines
 National Policy and Program on Pharmacovigilance
is a new policy administrative order approved last
2011
 Suspected adverse reaction form is being used
replacing the MedSurveillance form
 A training on Pharmacovigilance for Qualified
Person in Regulatory Affairs (QPIRA) is done
regularly by the FDA academy
 Reports from the Philippines are submitted to the
regional headquarters finally, to Uppsala drug
monitoring center in Sweden where the reports are
studied

New Drugs

- New formulations

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- New indication

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- New combination products

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