The document discusses the process of clinical drug design and development. It begins by defining drugs and their targets in the body. It then outlines the various phases of clinical trials that drugs must undergo to test their safety and efficacy before regulatory approval. These phases progress from small healthy volunteer groups to large patient populations. The document also discusses strategies for drug design such as targeting specific sites in the body and computer-aided approaches. Quality by design principles are highlighted as important to developing products that meet clinical performance standards.

1. Clinical Drug Design
Prof. Dr. Basavaraj K. Nanjwade M. Pharm., PhD
Department of Pharmacy Practice,
The Oxford College of Pharmacy,
Bengaluru-560068, Karnataka, India.
E-mail: nanjwadebk@gmail.com
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2. What is Drug
• Drugs are chemical or biological substances that have some kind
of physiological or biochemical effect on our bodies.
• They may be single compounds or a mixture of different
compounds.
• Their effects are intended to be beneficial but can cause harmful side
effects in some people.
• All drugs interact with specific ‘targets’ in the body, with the aim of
modifying their activity and often resulting in a therapeutic effect.
• Drug targets are usually proteins but are in some cases small regions
of DNAor RNA.
• Drugs work either by stimulating or blocking the activity of their
targets.
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3. The Ultimate Goal
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4. Drug Design
• Drug design is the approach of finding drugs by
design, based on their biological targets.
• Typically a drug target is a key molecule involved in
a particular metabolic or signaling pathway
• Other approaches may be to enhance the normal
pathway by promoting specific molecules in the
normal pathways that may have been affected in the
diseases state.
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6. Drug Design
• Enzymatic physicochemical-based (e.g., brain-
targeting) CDSs: exploit site-specific traffic
properties by sequential metabolic conversions that
result in considerably altered properties
• Site-specific enzyme-activated (e.g., eye-targeting)
CDSs: exploit specific enzymes found primarily,
exclusively, or at higher activity at the site of action
• Receptor-based transient anchor-type (e.g., lung-
targeting) CDSs: provide enhanced selectivity and
activity through transient, reversible binding at the
receptor
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8. Advances in Drug Design
• Computer aided based drug design
• Chemistry based drug design (Property-based drug
design)
• Ligand based drug design
• Bioinformatics based drug design
• In Silica based drug design
• Structured based drug design
• Pharmaceutics/Biopharmaceutics based drug design
• Clinical Based Drug Design
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9. Pharmacokinetics
• Drug design strategies used to optimise binding site
interactions of modified lead compounds were described
earlier.
• A compound with good binding site interactions may not be
able to overcome the obstacles interfering with the
compound’s ability to reach the target.
• A compound with optimised binding site interactions may be
susceptible to enzymatic degradation.
• Most drugs in clinical use are orally administered.
• Methods used to improve drug absorption, distribution, site-
specificity, and metabolic stability must be used alongside
strategies used to improve binding site interactions.
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10. Pharmacokinetics
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11. Drug Design for Oral Route
• Log P is less than +5
• Molecular mass is less than 500 Da
• Hydrogen bond acceptors must not be greater than
10
• Hydrogen bond donors must not be greater than 5
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12. Design and Development
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13. Phase I Clinical Trial
(INITIAL SAFETY TESTING IN A SMALL GROUP OF HEALTHY VOLUNTEERS )
• In Phase I trials the candidate drug is tested in people for the first
time.
• These studies are usually conducted with a small number of healthy
volunteers, generally 100 or less.
• The main goal of a Phase I trial is to assess the safety of the
medicine when used in humans.
• Researchers look at the pharmacokinetics of a drug: How is it
absorbed?
• How is it metabolized and eliminated from the body?
• They also study the drug’s pharmacodynamics: Does it cause side
effects?
• These closely monitored trials are designed to help researchers
determine what the safe dosing range is and if the candidate
medicine should move on to the next stage of development.
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14. Phase I
• Patients: 20 to 100 healthy volunteers or people with
the disease/condition.
• Length of Study: Several months
• Purpose: Safety and dosage
• Percentage of Drugs that Move to the next Phase
70%
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15. Study Types Included
• Safety & Tolerability studies (Single/ multiple dose in
patients or healthy volunteers)
• Oncology studies in patients with tolerability / MTD
as primary endpoint (efficacy might be a secondary
endpoint)
• Drug-Drug interaction & Food Effect
• PK in renal or hepatic impaired patients
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16. Phase II Clinical Trial
(ASSESS SAFETY AND EFFICACY IN A SMALL GROUP OF PATIENTS)
• In Phase II trials researchers evaluate the candidate
drug’s effectiveness in 100 to 500 patient volunteers
with the disease or condition under study.
• Researchers also analyze optimal dose strength and
schedules for using the drug and examine the possible
short-term side effects (adverse events) and risks
associated with the drug.
• If the drug continues to show promise, they prepare
for the much larger Phase III trials.
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17. Phase II
• Phase IIA: Exploratory (non-pivotal) study that has
clinical efficacy, Pharmacodynamics or biological
activity as primary endpoint, conducted in patients or
healthy volunteers.
• Phase IIB: Definite dose range finding study in
patients with efficacy as primary endpoint.
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18. Phase II
• Patients: Up to several hundred people with the
disease/condition.
• Length of Study: Several months to 2 years
• Purpose: Efficacy and side effects
• Percentage of Drugs that Move to the Next Phase
33%
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19. Study Type Included
• Proof of concept, efficacy, or mechanism
• Mechanistic studies
• Dose range exploration
• Pilot studies
• Definite dose finding studies
• Extension studies of Phase IIB studies
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20. Phase III Clinical Trial
(DEMONSTRATE SAFETY AND EFFICACY IN A LARGE GROUP OF PATIENTS)
• Phase III trials generate statistically significant data about
the safety, efficacy and the overall benefit-risk
relationship of the investigational medicine.
• Phase III trials may enroll 1,000 to 5,000 patients or more
across numerous clinical trials sites around the world.
• This phase of research is essential 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, specific
dosing instructions, etc.)
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21. Phase III
• Patients: 100 to 5000 volunteers who have the
disease or condition
• Length of Study: 1 to 4 years
• Purpose: Efficacy and monitoring of adverse
reactions
• Percentage of Drugs that Move to the Next Phase
25-30%
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22. Phase III
• Phase IIIA: A Pivotal study that is a trial designed &
executed to get statistically significant evidence of
efficacy and safety as required NDA/ sNDA approval. 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, specific
dosing instructions, etc.)
• Phase IIIB: A study started prior to approval and whose
primary intention is support of publications rather than
registration or label changes. The results are not intended
to be included in the submission dossier.
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23. Study Time Included
• Pivotal studies (vs placebo/comparator)
• Long term safety studies for registration
• Local registration studies
• Post marketing study commitments
• Phase IIIA extension studies
• Studies intended to support publication, claims or
to prepare launch, which start before approval but
are not intended for Regulatory submissions
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24. Phase IV
• Phase IV: A study started after approval with primary
intention to support publications rather than
registration or label changes.
• The results are not intended to be included in a
submission dossier.
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25. Phase IV Clinical Trial
• Patients: Several thousand volunteers who have the
disease/condition
• Purpose: Safety and efficacy
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26. Steps in Pharmaceutical Products
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27. Quality by Design (QbD)
• QbD became the answer to assisting both the industry
and FDA to move toward a more scientific, risk-
based, holistic and proactive approach to
pharmaceutical development.
• In the QbD paradigm, a product is designed so that it
will meet its desired clinical performance.
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28. Medicines research
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29. Clinical Design Space
• The concept of clinical design space can be used to
quantify the clinical experience with a product.
• The size of the clinical design space for a given
product will depend on the number of manufactured
lots put in the clinic.
• The clinical design space should be given
consideration, patient safety should not be
jeopardized.
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31. REFERENCES
• http://www.yourgenome.org/facts/how-are-drugs-
designed-and-developed.
• http://cenblog.org/the-haystack/2012/02/drug_design/
• Anurag S Rathore & Helen Winkle Quality by design
for biopharmaceuticals. Nature Biotechnology 27, 26
- 34 (2009), doi:10.1038/nbt0109-26.
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32. THANK YOUE-mail: nanjwadebk @gmail.com
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