The drug development process is a complex journey that begins with identifying specific diseases and biological targets, followed by drug discovery, optimization, and rigorous testing. Preclinical studies assess safety and efficacy before moving on to clinical trials, which are conducted in phases to ensure thorough evaluation of new drugs. Ultimately, an application for a New Drug Application (NDA) is submitted for regulatory approval, and ongoing monitoring continues post-approval.

1. The Drug development
process
By: Nasim Arshadi
In the name of God

3. Pharmaceutical discovery—like all kinds of discovery—favors those who
search in the right places.
The drug-discovery process begin by focusing on specific diseases and
patient needs.
scientists search for biological targets within the body that play a role in a
given disease. Targets can be part of the body (such as a protein, receptor,
or gene) or foreign (such as a virus or bacteria).
Researchers work to:
validate these targets,
discover the right molecule (potential drug) to interact with the target
chosen,
test the new compound in the lab and clinic for safety and efficacy
gain approval and get the new drug into the hands of doctors and patients.
Discovery of biopharmaceuticals

4. Pre-discovery
Understand the disease
Target Identification
Choose a molecule to target with a drug
Target Validation
Test the target and confirm its role in the disease
Drug Discovery
Find a promising molecule (a “lead compound”)
that could become a drug
The Discovery Process
PUBLIC AND PRIVATE Collaborations

5. Nature:
Until recently, scientists usually turned to nature to find interesting compounds for
fighting disease. Bacteria found in soil and moldy plants both led to important new
treatments
De novo:
to advances in chemistry, scientists can also create molecules from scratch. They
can use sophisticated computer modeling to predict what type of molecule may work.
High-throughput Screening:
This process is the most common way that leads are usually found. Advances in
robotics and computational power allow researchers to test hundreds of thousands of
compounds against the target to identify any that might be promising.
Biotechnology:
Scientists can also genetically engineer living systems to produce disease-fighting
biological molecules.
There are a few ways to find a lead
compound:

6. The assignment of function to the products of
sequenced genes can be pursued via various approaches
,including:
sequence homology studies; degree of similarity between sequences
phylogenetic profiling: predict functional relationships.
Rosetta stone method;
gene neighbourhood method;
knockout animal studies;
DNA microarray technology (gene chips);
proteomics approach;
structural genomics approach.

7. Pharmacogenetics
Pharmacogenetics relates to studying the pattern of expression of
gene products involved in a drug response.
The range and severity of adverse effects induced by a drug can
also vary significantly within a patient population base .
While the basis of such differential responses can sometimes be
non-genetic (e.g. general state of health, etc.), genetic variation
amongst individuals remains the predominant factor.
single nucleotide polymorphisms(SNPs) :
interplay of multiple gene products.
‘Environmental’ factors such as patient age, sex and general
health also play a prominent Role .

8. Lead Optimization
Alter the structure of lead candidates to improve properties
Lead compounds that survive the initial screening are then
“optimized,” or altered to make them more effective and safer.
By changing the structure of a compound, scientists can give it
different properties.
For example, they can make it less likely to interact with other
chemical pathways in the body, thus reducing the potential for side
effects.
Hundreds of different variations or “analogues” of the initial
leads are made and tested

9. Teams of biologists and chemists work together closely:
The biologists test the effects of analogues on biological systems.
chemists take this information to make additional alterations that are then
retested by the biologists.
The resulting compound is the candidate drug.
Even at this early stage researchers begin to think about:
how the drug will be made,
considering formulation (the recipe for making a drug, including inactive
ingredients used to hold it together and allow it to dissolve at the right time),
delivery mechanism (the way the drug is taken – by mouth, injection, inhaler)
and large-scale manufacturing (how you make the drug in large quantities).

10. Lead Optimization
at the molecular level
New techniques have revolutionized the ability of researchers
to optimize potential drug molecules.
technologies such as magnetic resonance imaging and X-ray
crystallography, along with powerful computer modeling
capabilities, chemists can actually “see” the target in 3D and
design potential drugs to more powerfully bind to the parts of
the target where they can be most effective.
In addition, new chemistry techniques help scientists to
synthesize the new compounds quickly.

11. Preclinical studies
Lab and animal testing to determine if the drug is safe enough
for human testing ,
In order to gain approval for general medical use, the quality,
safety and efficacy of any product must be demonstrated.
Regulatory authority approval to commence clinical trials is
based largely upon preclinical pharmacological and toxicological
assessment of the potential new drug in animals.
Such preclinical studies can take up to 3 years to complete,

12. Scientists carry out in vitro and in vivo tests.
The U.S. Food and Drug Administration (FDA) requires extremely
thorough testing before the candidate drug can be studied in
humans.
During this stage researchers also must work out how to make
large enough quantities of the drug for clinical trials. Techniques
for making a drug in the lab on a small scale do not translate
easily to larger production.
This is the first scale up. The drug will need to be scaled up even
more if it is approved for use in the general patient population.
scientists now have winnowed the group down to between one and
five molecules, “candidate drugs,” which will be studied in
clinical trials.

14. The range of major tests undertaken on a potential new drug during
preclinical trials.
Pharmacokinetic profile
Pharmacodynamic profle
Bioequivalence and bioavailability
Acute toxicity
Chronic toxicity
Reproductive toxicity and teratogenicity
Mutagenicity
Carcinogenicity
Immunotoxicity

15. Pharmacokinetics
&
pharmacodynamics
Pharmacology may be described as the study of the
properties of drugs and how they interact with/affect the body.
Within this broad discipline exist subdisciplines, including
pharmacokinetics and pharmacodynamics.
bioavailability relates to the proportion of a drug that
actually reaches its site of action after administration
Bioequivalence studies come into play if any change in
product reduction/delivery systems was being contemplated.

16. Pharmacokinetics
What does the body to the drug ?
relates to the fate of a drug in the body, particularly its ADME, i.e.
its absorption into the body, its distribution within the body, its
metabolism by the body, and its excretion from the body.
Generally, ADME studies are undertaken in two species, usually
rats and dogs,
repeated at various different dosage levels. Males & females.
If initial clinical trials reveal differences in human versus animal
model pharmacokinetic profiles, additional pharmacokinetic
studies may be necessary using primates.

17. pharmacodynamics
What does the drug to the body ?
studies deal more specifically with how the drug brings
about its characteristic effects. Emphasis in such studies
is often placed:
Physiological effects
Drug action
Relationship between drug concentration and effect

18. Toxicity studies
Toxicity studies are carried out on all putative new drugs, largely via testing
in animals, in order to ascertain whether the product exhibits any short-term
or long-term toxicity.
Acute toxicity is usually assessed by administration of a single high dose of the
test drug to rodents. Both rats and mice (male and female) are usually
employed.
Chronic toxicity studies also require large numbers of animals and, in some
instances, can last for up to 2 years.
Earlier studies demanded calculation of an LD50 value (i.e. the quantity of the
drug required to cause death of 50 per cent of the test animals). Such studies
required large quantities of animals,were expensive, and attracted much
attention from animal welfare groups.
Nowadays, in most world regions, calculation of the approximate lethal dose
is sufficient.

19. administration of the drug at three different dosage levels.
The highest level should ideally induce a mild but
observable toxic effect, whereas the lowest level should not
induce any ill effects.
The studies are normally carried out in two different
species, usually rats and dogs, and using both males and
females.
The duration of such toxicity tests varies. In the USA, the
FDA usually recommends a period of up to 2 years,
whereas in Europe the recommended duration is usually
much shorter.

20. Reproductive toxicity and teratogenicity
All reproductive at three different dosage levels (ranging from non-toxic to
slightly toxic) to different groups of the chosen target species (usually
rodents).
Fertility studies aim to assess the nature of any effect of the substance on
male or female reproductive function.
The drug is administered to males for at least 60 days (one full
spermatogenesis cycle).
Females are dosed for at least 14 days before they are mated.
These reproductive toxicity studies complement teratogenicity studies,
which aim to assess whether the drug promotes any developmental
abnormalities in the foetus. (usually rats and rabbits)

21. Mutagenicity, carcinogenicity and other tests
Mutagenicity tests aim to determine whether the proposed drug is capable of
inducing DNA damage, either by inducing alterations in chromosomal
structure or by promoting changes in nucleotide base sequence.
Mutagenicity tests are usually carried out in vitro and in vivo, often using
both prokaryotic and eukaryotic organisms.
Longer-term carcinogenicity tests are undertaken, particularly if
(a) the product’s likely therapeutic indication will necessitate its
administration over prolonged periods few weeks or more .
(b) if there is any reason to suspect that the active ingredient or other
constituents could be carcinogenic.
for many biopharmaceuticals, immunotoxicity tests (i.e. the product’s ability
to induce an allergic or hypersensitive response, or even a clinically relevant
antibody response) are often impractical.

22. Patenting
The discovery and Lead Optimization of any substance of
potential pharmaceutical application is followed by its patenting.
a method of synthesis and its biological effects, the better the
chances of successfully securing a patent.
Thus, patenting may not take place until preclinical trials and
phase I clinical trials are completed.
Patenting, once successfully completed:
1. it must be proven safe and effective in subsequent clinical trials,
2. be approved for general medical use by the relevant regulatory
authorities.

23. What is a patent and what is
patentable?
A patent may be described as a monopoly granted by a government
to an inventor, such that only the inventor may exploit the
invention/innovation for a fixed period of time (up to 20 years).
In order to be considered patentable, an invention/innovation must
satisfy several criteria:
novelty
non-obviousness
sufficiency of disclosure
utility

24. Investigational New Drug (IND) Application and Safety
File IND with the FDA before clinical testing can begin;ensure safety for
clinical trial volunteers through an Institutional Review Board(IRB)
Before any clinical trial can begin, the researchers must file an
Investigational New Drug (IND) application with the FDA.
The application includes :
the results of preclinical work,
candidate drug’s chemical structure
how it is thought to work in the body, a
listing of any side effects ,
method of product manufacture and
proposed protocol for initial clinical trials

25. The IND also provides a detailed clinical trial plan that outlines how, where and
by whom the studies will be performed.
The FDA reviews the application to make sure people participating in the
clinical trials will not be exposed to unreasonable risks.
all clinical trials must be reviewed and approved by the Institutional Review
Board (IRB) at the institutions where the trials will take place.
This process includes the development of appropriate informed consent, which
will be required of all clinical trial participants.
Statisticians and others are constantly monitoring the data as it becomes
available.

26. The FDA or the sponsor company can stop the trial at any time if
problems arise.
In some cases a study may be stopped because the candidate drug
is performing so well that it would be unethical to withhold it from
the patients receiving a placebo or another drug.
Finally, the company sponsoring the research must provide
comprehensive regular reports to the FDA and the IRB on the
progress of clinical trials.
,

27. Clinical trials
assess the safety and efficacy of any potential new therapeutic ,
Safe’ generally refers to a favourable risk :benefit ratio, i.e. the
benefits should outweigh any associated risk .
efficacy’ could be defined as prevention of death/prolonging of life
by a specific time-frame .
Clinical trials may be divided into three consecutive phases.
The aims of these studies are largely to establish:
the pharmacological properties of the drug in humans
the toxicological properties of the drug in humans
the appropriate route and frequency of administration of the drug
to humans.

28. Average duration
(years)
Evaluation undertaken
(and usual number of patients)
Trial
phase
1Safety testing in healthy human volunteers (20–80)I
2Efficacy and safety testing in small number of
patients
(100–300)
II
3Large-scale efficacy and safety testing in
substantial numbers of patients (1000–3000)
III
SeveralPost-marketing safety surveillance undertaken for
some drugs that are administered over particularly
long periods of time number of patients varies)
IV
‘

29. Phase 1 Clinical Trial
• The main goal of a Phase 1 trial is to discover if the drug
is safe in humans.
Researchers look at the pharmacokinetics of a drug:
How is it absorbed?
How is it metabolized & eliminated from the body?
They also study the drug’s pharmacodynamics:
Does it cause side effects?
Does it produce desired effects?

30. Phase 2 Clinical Trial
In Phase 2 trials researchers evaluate the candidate
drug’s effectiveness, and examine the possible short-term
side effects. They also strive to answer these questions:
Is the drug working by the expected mechanism?
Does it improve the condition in question?
Researchers also analyze optimal dose strength and
schedules for using the drug.

31. Phase 3 Clinical Trial
This phase of research is key in determining whether the drug is safe and
effective. It also provides the basis for labeling instructions to help ensure
proper use of the drug (e.g.,information on potential interactions with other
medicines).
Phase 3 trials are both the costliest and longest trials.
Hundreds of sites around the United States and the world participate
in the study to get a large and diverse group of patients.

32. The material used for preclinical and clinical trials should be produced using the same process.
Whereas a comprehensive phase III trial would normally require at least
several hundred patients, smaller trials would suffice if, for example:
the target disease is very serious/fatal;
there are no existing acceptable alternative treatments;
the target disease population is quite small;
the new drug is clearly effective and exhibits little toxicity.

33. Clinical trials design
An incredible amount of thought goes into the design of each
clinical trial.
To provide the highest level of confidence in the validity of results,
many drug trials are :
Placebo-controlled: Some subjects will receive the new drug
candidate and others will receive a placebo. (In some instances,
the drug candidate may be tested against another treatment rather
than a placebo.)
Randomized: Each of the study subjects in the trial is assigned
randomly to one of the treatments.

34. Double-blinded:
Neither the researchers nor the subjects know which treatment is being
delivered until the study is over.
This method of testing provides the best evidence of any direct relationship
between the test compound and its effect on disease because it minimizes
human error.
However, in many instances, alternative trial designs are chosen based on
ethical or other grounds.
In most cases, two groups are considered: control and test. However, these
designs can be adapted to facilitate more complex subgrouping. Clinical trial
design is a subject whose scope is too broad to be undertaken in this text.

35. New Drug Application (NDA) and Approval
Submit application for approval to FDA
Once all three phases of the clinical trials are complete, the sponsoring
company analyzes all of the data.
If the findings demonstrate that the experimental medicine is both safe and
effective, the company files a New Drug Application (NDA) — which can run
100,000 pages or more — with the FDA requesting approval to market the
drug.
The NDA includes all of the information from the previous years of work, as
well as the proposals for manufacturing and labeling of the new medicine.
FDA experts review all the information included in the NDA to determine if it
demonstrates that the medicine is safe and effective enough to be approved.

36. Following rigorous review, the FDA can either
1) approve the medicine,
2) send the company an “approvable” letter requesting more
information or studies before approval can be given, or
3) deny approval.
Review of an NDA may include an evaluation by an advisory
committee,an independent panel of FDA-appointed experts who
consider data presented by company representatives and FDA
reviewers.
Committees then vote on whether the FDA should approve an
application, and under what conditions.
The FDA is not required to follow the recommendations of the
advisory committees, but often does.

38. Ongoing Studies and Phase 4 Trials
Research on a new medicine continues even after approval.
As a much larger number of patients begin to use the drug,
companies must continue to monitor it carefully and submit
periodic reports, including cases of adverse events, to the
FDA.
In addition, the FDA sometimes requires a company to
conduct additional studies on an approved drug in “Phase 4”
studies.
These trials can be set up to evaluate long-term safety or how
the new medicine affects a specific subgroup of patients.

39. The role and remit of regulatory
authorities
The Food and Drug Administration
The investigational new drug application
The new drug application
European regulations
National regulatory authorities
The European Medicines Agency and the new EU drug approval
systems
The centralized procedure
Mutual recognition
Drug registration in Japan
World harmonization of drug approvals

40. Drug registration in Japan
The Japanese are the greatest consumers of pharmaceutical
products per capita in the world.
Within the department is the Pharmaceutical Affairs Bureau (PAB),
which exercises this authority.
There are three basic steps in the Japanese regulatory process:
approval must be obtained to manufacture or import a drug;
a licence must also be obtained;
an official price for the drug must be set.
The PAB undertakes drug dossier evaluations, a process that
normally takes 18 months.

41. World harmonization of drug approvals
The International Conference on harmonization of
technical requirement for registration of pharmaceuticals
for human use .
A collaboration between regulator from US / EU / JAPAN.
Produce guidelines on drug development and clinical trial
that are accepted across countries.
Good starting place for summaries of clinical tria l issues.

42. The average cost to research and develop each successful drug is
estimated to be $800 million to $1 billion.

43. Conclusion
The drug discovery and development process is a long and complicated
process.
Before any newly discovered drug is placed on the market, it must undergo
extensive testing,
The discovery and development of new medicines is a long, expensive and
complicated process.
Each success is built on many, many prior failures.
Advances in understanding human biology and disease are opening up
exciting new possibilities for breakthrough medicines.
At the same time, researchers face great challenges in understanding and
applying these advances to the treatment of disease. These possibilities will
grow as our scientific knowledge expands and becomes increasingly
complex.
Research-based pharmaceutical companies are committed to advancing

44. References
G.Walsh , Pharmaceutical Biotechnology Concepts and Applications book, University of
Limerick, Republic of Ireland,2007.
J.A. DiMasi, “New Drug Development in the United States from 1963-1999,” Clinical
Pharmacology and Therapeutics 69, no. 5 (2001): 286-296.
J.A. DiMasi, R.W. Hansen and H.G. Grabowski, “The Price of Innovation: New Estimates of
Drug Development Costs,” Journal of Health Economics 22 (2003): 151-185.
Pharmaceutical Research and Manufacturers of America, based on data from Tufts
University, Tufts Center for the Study of Drug Development (1995).
Meadows, M. (2002) The FDA’s Drug Review Process: Ensuring Drugs are Safe and
Effective. FDA Consumer 36: (revised September 2002,
http://www.fda.gov/fdac/features/2002/402_drug.html)
Pharmaceutical Research and Manufacturers of America, Pharmaceutical Industry Profile
2006,(Washington, DC: PhRMA, March 2006).
Tufts Center for the Study of Drug Development, "Average Cost to Develop a New
Biotechnology Product Is $1.2 Billion, According to the Tufts Center for the Study of Drug
Development," 9 November 2006,
http://csdd.tufts.edu/NewsEvents/NewsArticle.asp?newsid=69 (accessed 18 December