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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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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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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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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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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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A story of drug development

  • 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).  1   
  • 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  2   
  • 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  3   
  • 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   4   
  • 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.     5