1. A Story of Drug Development: from Conception of the Molecule till Market Approval
Dr. Bhaswat S. Chakraborty
Sr. Vice President, Research & Development,
Cadila Pharmaceuticals Ltd., Ahmedabad
Human life expectancy has doubled in last 100 years in both developed and developing economies. And
one of the main reasons for this unprecedented improvement in life span is due to better medicines
than before. In some cases, such medicines (synonymously drugs or pharmaceuticals) have contributed
to a better quality of life as well. The backbone of these effective and safe medicine is, of course,
research in the areas drug discovery, preclinical, formulation development and clinical studies. In last
two decades, the high cost of pharmaceutical research and development (R&D) has almost become
prohibitive (of the order of a couple of billion UD dollars). Despite this intimidating expense and the
patents‐warfare, good medicines are reaching the patients of all walks of life.
In this article, we take the readers through a bird’s eye view of drug development. We will briefly
review the discovery part of the R&D, and then focus on the development of a lead molecule to its
approval for marketing. Selection and characterization of the target disease are important in any drug
discovery program, for when a disease is well understood and characterized, the protein (usually)
associated with the disease can be targeted by a molecule of choice (viz. a lead compound) which has
Figure 1: The basic schema of drug discovery; LTS = low throughput systems; HTS = high throughput
systems (adapted from Ref 1).
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2. desirable properties (Figure 1). Such targeting can be aimed for either curing the disease or to control it.
Using high throughput system (HTS) robotics, data processing and control softwares, liquid handling
devices, and sensitive detectors, a researcher can now conduct millions of chemical, genetic or
pharmacological tests in few days. The advantage of such in silico molecular modeling is actually a
tremendous acceleration of the drug discovery process. For example, using traditional drug
development techniques it took nearly 40 years to understand the cholesterol biosynthesis pathway to
develop the statin drugs – those that inhibit the enzyme HMG‐CoA reductase, the rate limiting step in
cholesterol biosynthesis. On the other hand, a molecular‐level understanding of the role of the HER‐2
receptor in breast cancer led to the development of the chemotherapeutic agent Herceptin® within only
three years.1
Development process following the identification of the lead compounds
Only a few lead compounds emerge after in silico simulations and chemistry experiments (say, 3‐4 lead
compounds per 2000 structures examined). These precious few molecules are then subjected to
preclinical efficacy and safety testing which is a stamp of the suitability of one or more candidate to be
experimented in humans. The first set of experiments in humans, called Phase I studies, look at the
human toxicity, maximum tolerated dose and pharmacokinetics (ADME – absorption, distribution,
metabolism and elimination) of the administered drug. At this stage, there may also be a slight hint of
human efficacy of the lead drug in some cases. If the toxicity profile and tolerability of the drug (at this
stage you may be left with only one lead compound) are considered acceptable, the drug is tested in
limited number of patients first (a Phase II study) and then finally in a substantial number of patients in
epidemiologic setup (Phase III study) as shown in Figure 2.
Figure 2: The lead compounds are screened in animals and then select lead compounds, only a few, are
taken to the subsequent clinical studies.
Results from clinical trials are fed back to enhance the next round of target selection and lead
identification and optimization. Although each step in the process involves specific information tools,
the tools are related and in some cases overlap. For example, much of today’s animal model work
involves comparative genomics including tools for multiple sequence homology and pattern matching.
Many of these tools are also used to help find genes that code for target proteins. Similarly, both target
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3. validation and lead optimization are enhanced by the use of programs that facilitate predicting 3D
structures of proteins and protein–ligand complexes.
Super‐ordinate goals of Drug Discovery and Development (DD)
The highest goal of drug DD is to evidence that the drug is safe and effective in its proposed use(s), and
whether the benefits of the drug outweigh the risks. It is also aimed at evidencing that the methods
used in manufacturing the drug and the controls used to maintain the drug's quality are adequate to
preserve the drug's identity, strength, quality, and purity. Proposed labeling (package insert) of the drug
must be appropriate, complete and well communicated.
Preclinical Research
Preclinical research includes pharmacokinetic, pharmacodynamic and toxicology studies involving in vivo
and in vitro models in animals. Ideally, preclinical and clinical scientists work together to maximize the
assessment of safety and efficacy of lead candidates in the discovery process. All preclinical safety
studies are required to comply with the international good laboratory practices (GLP) standards these
days. The preclinical research organizations dedicatedly stick to the international norms of GLP. They
also maintain an excellent husbandry of rodent and non‐rodent animals, and special cell lines such as
mouse, human or spontaneous transgenic, mutant tumors. They can develop and conduct Proof of
Concept experiments and follow all regulatory protocols with proper report preparations.
For carrying out preclinical research work, there are a few competent CROs (contract research
organizations) in India. While they deliver the rodent experiments very efficiently, non‐rodent animal
studies have an issue. Studies in large mammals such as dogs and monkeys are a big problem in India.
The government and regulators should take a close look at this issue so that these experiments can be
conducted in India without much hassle.2
Clinical Research
Phase I studies are usually conducted in healthy volunteers, the exception being the highly toxic drugs
(such as cytotoxic anticancer agents), which are tested in relevant patients. The goal in Phase I
experiments is to determine what the drug's most frequent side effects are and, how the drug is
metabolized and excreted. The number of subjects typically ranges from 20 to 100.
Phase II studies begin if Phase I studies don't reveal unacceptable toxicity. While the emphasis in Phase
1 is on safety, the emphasis in Phase II is on effectiveness. This phase aims to obtain preliminary data on
whether the drug works in people who have a certain disease or condition at selected doses.
For controlled trials, patients receiving the drug are compared with similar patients receiving a different
treatment‐‐usually an inactive substance (placebo), or a different drug. Safety continues to be
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4. evaluated, and short‐term side effects are studied. Typically, the number of patients in Phase II studies
ranges from a few dozen to about 300.
At the end of Phase II, the FDA and sponsors try to come to an agreement on how the large‐scale studies
in Phase 3 should be done. How often the FDA meets with a sponsor varies, but this is one of two most
common meeting points prior to submission of a new drug application (NDA). The other most common
time is pre‐NDA, right before an NDA is submitted. Phase III studies begin if evidence of effectiveness is
shown in Phase II. These studies gather more information about safety and effectiveness, studying
different populations and different dosages and using the drug in combination with other drugs. The
number of patients usually ranges from several hundred to about 3,000 people. Results of Phase III
studies provide the main evince of efficacy and safety in a Regulatory application.
Following the Regulatory approval by the authorized agency of a given country, the drug can be
marketed in that country. Post‐marketing study commitments are called Phase IV commitments. Studies
required of or agreed to by sponsors that are conducted after the FDA has approved a drug for
marketing. The FDA uses post‐marketing study commitments to gather additional information about a
drug's safety, efficacy, or optimal use. All clinical phases of drug development and post‐marketing
information have been schematically presented in Figure 3.
Figure 3: The clinical phases of drug development and their dependence on preclinical research,
meetings with FDA, filing of a New Drug Application and regulatory approval for marketing the drug.
A few words need to be said on the clinical research environment in India. It is just about the same as
the global scenario. Large, multinational clinical trials are preferred over smaller, locally‐sponsored
trials. This is due to the pressures on pharmaceutical and biotechnology companies to accelerate
development timelines under tighter budgets and resource constraints. The goal behind initiating these
multinational trials is to increase access to treatment of naïve subjects by enlisting sites outside of major
markets, and to drive cost savings through economies of scale.2
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5. Following a steep learning curve in the 1990’s, most of the pharmaceutical giants and CROs now have
systems in place to capture the benefits of large, multinational studies while minimizing the problems.
These include Hardware and IT infrastructure harmony, support in multiple languages and responding to
regulators’ queries from several countries arriving at the same time.
Some aspects of successful management of large, multinational clinical studies have become mature
through repetition and experience, such as training and support, while others, often critical processes,
require constant oversight to avoid serious mistakes.3
Concluding Remarks
We have not dealt with the important issue of the cost of new drug development in this article.
However, this is a relevant topic which we shall deal with at some length in another article. This article
gives the reader a basic understanding of modern new drug development in order to bring it to the
marketplace.
The discovery or isolation of the drug, whether it is a small or large molecule is an exciting but a complex
process of studying its structure (along with several hundred or thousand of structures of related
compounds), mechanism of action, and physicochemical properties. In an NDA, however, the chemistry
of the drug and aspects of its batch manufacturing with a promised purity profile is elaborated to the
finest details. The preclinical phase actually decides which few candidates will go further to be tested
clinically in humans – healthy and patients. Such clinical studies test the drug to see whether it should
be approved for wider use in the relevant patient population. The outcome measures in clinical trials
describe and quantitate the benefits (and risks) of the drug.
Other than a chemical drug of a relatively small molecular weight, a medical device, or biologic, such as
a vaccine, blood product, or gene therapy go through the same route of development and approval. All
preclinical studies in animals and all clinical studies in humans are carried out following highest
standards of ethics.
References
1. Augen J. (2002). Drug Discovery Today, 7, 315‐323.
2. Chakraborty B. (2011). Ingredients South Asia, October 16‐31, 34‐36.
3. Edwards B. (2008). Indian Journal of Pharmacology, 40, S24–S27.
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