Summary Drugs: From Discovery to Approval 3rd
Edition.
Ziekte & Medicijnen GEO2-2215
Summary includes chapter: 1, 2, 3, 4, 7, 8, 10, 11
Chapter 1. Introduction
FDA (Food & Drug administration) definition of a drug:
● A substance recognized by an official pharmacopoeia of formulary
● A substance intended for use in the diagnosis, cure, mitigation, treatment, or
prevention of disease
● A substance (other than food) intended to affect the structure of any function of
the body
● A substance intended for use as a component of a medicine but not a device or a
component, part or accessory of a device
● Biological products are included within this definition and are generally covered
by the same laws and regulations, but differences exist regarding their
manufacturing processes (chemical process vs. biological process)
3 names associated with a drug: trade/proprietary name, generic/nonproprietary name,
and the specific chemical name for the active ingredient.
Generic name → INN (International Nonproprietary Names) of the WHO (World Health
Organization).
Ethical drugs are prescription drugs that require prescriptions by physicians , whereas
OTC (over-the-counter) drugs can be purchased from pharmacies without prescriptions.
There is a further differentiation of ethical drugs into new drugs (those covered by
patents) and generics (copies of drugs that have expired patents).
An overview of the drug discovery to approval process
Personnel with different disciplines and expertise are needed to contribute to discover
and develop drug targeting diseases at the cellular and molecular levels. On average, a
drug takes 1-12 years to progress from initial research to the commercialization stage,
with costs of 1 billion US dollars (in the early 2000s). These are both costs for successful
and failed drugs. Stages from drug discovery to approval process:
1. Drug discovery: discovering the target that causes or leads to the disease →
chemical or biological compounds are screened using specific assays and tested
against these targets to find leading candidates for further development.
2. Preclinical drug development: tests are performed with the lead compounds in
test tubes (laboratory, in vitro) and on animals (in vivo) to check how they affect
the biological systems. → toxicology, pharmacodynamics,, pharmacokinetics, and
optimization of drug delivery systems. At the end of this process, an optimized
compound is found and it becomes a potential drug ready for clinical trials in
humans. The development work has to follow GLP (Good Laboratory Process) to
ensure that proper quality system and ethical considerations are established.
3. Clinical development: Clinical trials using the drug dosage form intended for
marketing are conducted on human subjects. The pertinent parameters for clinical
trials are protocols (methods about how trials are to be conducted), safety and
respect for human subjects, responsibilities of investigators, institutional review
board, informed consent, trial monitoring, and adverse event reporting. These
parameters form the basis of Good Clinical Practice (GCP). Clinical trials must
follow regulations and guidelines from the US FDA, the European Medicines
Agency (EMA) of the European Union (EU) or European Member States, Japan’s
Pharmaceuticals and Medical Devices Agency (PMDA), or regulatory authorities in
, other prospective countries where the drug is intended to be registered and
commercialized.
4. Manufacturing: the drug designated for clinical trials has to be manufactured in
compliance with current Good Manufacturing Practice (cGMP), following US FDA
requirements, EU regulations or directives or ICH (International Conference of
Harmonization) guidelines. → Inspections, quality systems, and audit trails.
5. Marketing application, approval and postapproval: A drug is not permitted
for sale until the marketing application for the new drug has been reviewed and
approved by regulatory authorities such as the US FDA, the EU EMA, or Japan’s
PMDA → demonstrate safety, potency, efficacy. and purity of the drug. After the
drug has been approved and marketed, the safety and performance of the drug is
continually monitored to ensure that it is prescribed correctly, and adverse events
(side effects) are reported and investigated.
The pharmaceutical industry
Drug discovery and development are primarily carried out by pharmaceutical companies,
universities, and government research agencies, although there are increasing activities
in smaller companies and start-ups that specialize in particular fields of research. →
licensed to multinational pharmaceutical companies that have the resources for clinical
trials, manufacturing, marketing, and distribution. Alternatively, alliances are formed with
the multinational pharmaceutical companies to develop or market the drugs. A primary
reason for these business relationships is the huge cost involved in drug discovery,
development, and commercialization. US + EU + Japan = 70% of worldwide
pharmaceutical market. Blockbuster drugs → exceeds 1 billion US dollars.
While the majority of drugs have been based on small molecules for many years,
biopharmaceuticals have become increasingly important in the past three decades since
the first one was introduced.
● Seretide/Advair - treatment of asthma and COPD
● Humira - treatment of rheumatoid arthritis and autoimmune diseases
According to reports by the Pharmaceutical Research and Manufacturers of America
(PhRMA), US pharmaceutical companies have almost doubled their R&D spending every
5 years since 1980. Out of every five dollars earned in sales, one dollar is put back into
R&D.
Economics of drug discovery and development
The pharmaceutical market is very competitive. Up until the clinical stage, the
investment is substantial in the discovery and development processes. The largest cash
demand is in the clinical trial stages where hundreds to thousands of human subjects are
recruited to test the drug. The overall profitability of a drug is the difference between the
positive returns and the negative expenses within the patent period of 20 years. After
patent expiry, generic drugs from other companies are unencumbered by patent rights
infringement and can encroach into the profitability of the company that developed the
original patented drug. It is thus crucial that drugs are marketed as quickly as possible to
,maximize the length of patent coverage period and to be “first to market,” to establish a
premium position.
A patent is a right granted by a government for
any device, substance, method, or process that is
new, inventive, and useful. The patent discloses all
information pertaining to the invention. There are
two ways to register patents: either through
applying in individual countries (which means
multiple applications for different countries) or
through designating the desired countries in a
single application using the Patent Cooperation
Treaty (PCT) mechanism (national and
international phase). Another important aspect of a
patent is the priority date. The priority date is established when a patent application is
filed for the first time. If the invention is known before this date, then the patent is not
granted. Most countries are first-to-file countries, meaning that the patent is awarded to
the person with the earliest filing date.
Trends in drug discovery and development
● Irrational approach → the historical method of discovering and developing
drugs.
● Rational approach → requires three-dimensional knowledge of the target
structure involved in the disease.
● Antisense approach → is a relatively new approach and it requires the
modifications to oligonucleotides that can bind to RNA and DNA
● RNAi approach → uses short interfering RNA (siRNA, sometimes called small
interfering or silencing RNA) to interfere with the expression of a particular gene.
● Biopharmaceuticals/biologics → mainly protein-based drugs in the form of
antibodies, vaccines, and cytokines.
● Gene therapy → This therapy is based on remedying a diseased gene by
inserting a missing gene or modified gene in the cells.
● Stem cell therapy (somatic- & germ cell) → The aim of stem cell therapy is to
grow body parts to replace defective human organs and nerves.
Regardless of the approach used for discovering new drugs, pharmaceutical and
biotechnology companies are now using a full suite of technologies to discover new
drugs. These enabling technologies are as follows:
● Microarray for disease target identification
● High-throughput screening
● Combinatorial chemistry
● Structure–activity relationships: X-ray crystallography, nuclear magnetic
resonance, computational chemistry
● Genomics and proteomics
● Metabolomics
● Systems biology
● Nanotechnology
● Bioinformatics: data mining
● rDNA technologies.
Case study → Roche, Pfizer, and Novartis → Read for better understanding of the
literature
Other important points
● Regulatory supervision is an integral part of the pharmaceutical industry to
ensure safety, efficacy, purity, and consistency of drugs for human use.
● The global pharmaceutical market in 2012 was US$962 billion.
Biopharmaceuticals account for more than 10% of the market, with higher growth
rate compared to conventional pharmaceuticals.
, ● The top selling drug in 2012 was Seretide/Advair from GlaxoSmithKline, and the
top biopharmaceutical was Humira from Abbott.
● The pharmaceutical R&D expenditure, at more than 15% of revenue, is higher
than many other technology-based industries.
● Pharmaceutical companies draw on traditional as well as advances in new
technologies to identify and develop new drugs.
