The document discusses the process of drug discovery and development. It has 5 main stages: drug discovery, pre-clinical testing, clinical trials (phases I-III), regulatory approval, and post-marketing surveillance. Drug discovery involves screening compounds for pharmacological activity through random testing, serendipitous findings, or rational drug design. Pre-clinical testing involves extensive animal studies to evaluate safety, efficacy, and adverse effects. Clinical trials in humans have 3 phases to further assess these factors before regulatory approval and marketing of the drug. Post-approval monitoring continues to study long-term safety and efficacy.

1. DRUG DISCOVERY AND
DEVELOPMENT
Moderator: Prof ( Dr) Meghali Chaliha Presenter : Dr Reuben.P. Syiem
HOD of Pharmacology PGT 1st year
JMCH Department of Pharmacology

2. WHAT IS A DRUG?
 WHO defines it as any substance or a product that is used or intended to be used
to modify or explore the physiological system or pathological states for the
benefit of the recipient.
 New drug is a substance of chemical or biological origin for which adequate data
is not available for the regulatory authorities to judge its efficacy and safety of
the proposed claim.
 New drug development is done as per the guidelines laid down by Schedule Y of
DRUGS AND COSMECTIC ACT (10th amendment),2001 which were
amended later in 2005.

3. STAGES IN NEW DRUG DEVELOPMENT
1. DRUG DISCOVERY 2-5 years
2. PRE-CLINICAL PHASE 1.5-2 years
3. CLINICAL TRAIL PHASE 5-7 years
 PHASE I
 PHASE II
 PHASE III
4. REGULATORY APPROVAL 1.5 years
5. RESTRICTED MARKETING Upto 4 years
 Post Marketing Surveillance phase

4. “OLD METHODS OF DRUG
DISCOVERY”
 Crude plants, animal products, minerals were used to treat disease in India, China
and Egypt.
 No study before using them. Agents were selected on the basis of their symbolic
qualities and astrological signs.
 Greek physicians used Iron against Weakness.
 Horn of Rhinoceros as a potent aphrodisiac.

5. DRUG DEVELOPMENT
Drug development process can be divided into 3 many phases, namely :
1. Drug Discovery Phase : Candidate Molecules are chosen on basis of
Pharmacological properties.
2. Preclinical Phase : Wide range of animal studies are performed.
3. Clinical trial phase : Lead compound is evaluated for efficacy, safety and
adverse effects.

6. DRUG DISCOVERY

7. DRUG DISCOVERY PHASE
“RANDOM SCREENING”
 Blind hitting procedure where new chemicals are subjected to various
Pharmacological screening procedure.
 Test include studies on Animal behaviour, Animal models of the disease and on
isolated tissues.
 Drugs like Morphine, Atropine & Digitalis were discovered this way.

8. SERENDIPITY
 Sometimes, a new use is discovered for an old drug or its side effects find a new
therapeutic application.
Example:
 Lignocaine and Phenytoin were later used as antiarrhythmics
 Methotrexate used for Psoriasis
 Penicillin was also discovered this way.
 Cyclophosphamide and Azathioprine used to prevent tissue rejection in kidney
transplant.

9. RATIONALE DRUG DESIGNING
Two basic strategies are used :
Compound centred approach Target centered approach
In Compound Centered approach,
 Promising agents can be obtained from natural products.
E.g., Penicillin from Mold penicillum
Paclitaxel derived from Pacific Yew tree.
Cyclosporine obtained from fungus.

10.  Lead Optimisation becomes difficult as these natural sources are complex
molecules and are difficult to synthesised.
 Compound Centered Drug Designing can be followed for synthetic drug also,
Drug this way can be obtained from structure activity of an already established
drug.
Example:
a) ß-adrenoceptor blocking drugs are based on propranolol structure.
b) Many triptans are based on structure of sumatriptan.

11. TARGET CENTERED APPROACH
Valid Biochemical Molecular Targets
 Inhibition of ACE blocks conversion of Angiotensin I to Angiotensin II and
hence lowers Blood pressure.
 Hence ACE Inhibitors (Lisinopril, Ramipril) and Angiotensin II receptor
antagonist (Losartan, Telmisartan) are useful antihypertensive.

12. DESIGNING OF A PRODRUG OR ACTIVE METABOLITE
 Prodrug – agent that is administered as a precursor of a drug and converted
into active metabolite in the body.
e.g., Levodopa used as a prodrug of Dopamine in the treatment of
parkinsonism.
 Active metabolites of certain drugs have also been found to have therapeutic
effect.
e.g., Paracetamol an active metabolite of Phenacetin was introduced as a safe
analgesic this way.

13.  After Synthesis or isolation of compounds, purity is ascertained by physico-chemical and
analytical studies.
Stage of LEAD OPTIMISATION
Aim is to identify one or two drug candidates for further investigation
(3-5 years may be spent to come to this stage)
Promising LEAD COMPOUND
Subjected to preclinical evaluation.
 Clinical trails follow only when the results of Preclinical evaluations are encouraging.

14. PRECLINICAL EVALUATION PHASE
(ANIMAL STUDIES)
 After identifying a Prospective Compound, it is tested on
animals to expose the Pharmacological profile.
 Experiments are performed on rodents and then on larger
animal.
 As evaluation progresses, only a few out of thousands reach
the stage when administration to humans is considered.

15. OBJECTIVES OF ANIMAL STUDY:
 Activity
 Toxicity
 Selectivity and Specificity
 Mechanism Of Action
 Drug Metabolism

16. The following types of studies are performed:
 PHARMACODYNAMIC STUDIES
 Here actions relevant to the proposed therapeutic use are studied.
 For e.g., Study of Antihypertensive activity of lead compound.
 TEST ON ISOLATED ORGANS,BACTERIAL CULTURES
 Performed to detect specific activity such as Antisecretory, Antibacterial.
 TEST ON ANIMAL MODELS OF HUMAN DISEASES

17.  GENERAL OBSERVATION TEST
Drugs injected in tripling doses to small groups of mice and observed for overt effects.
 CONFIRMATORY TEST AND ANALOGOUS ACTIVITIES
Active compounds are taken for detailed study and also tested for other related
activities.
 MECHANISM OF ACTION
Attempts are made to find out mechanism of action.
 SYSTEMIC PHARMACOLOGY
 QUANTIATIVE TESTS

18.  TOXICOLOGICAL STUDIES:
Aim : To determine safety of compound in atleast two Animal species by oral and
Parenteral route.
Types :
1) ACUTE TOXICITY
 Aim is to find out the acute dose that is lethal to 50% of animals (LD 50)
 Organ toxicity is examined by histopathology on all animals.

19. 2) SUBACUTE TOXICITY:
 Aim : Identify target organs susceptible to drug toxicity.
 Animals maintained at Maximum tolerated doses for 1-3 months to allow development of
pathological changes.
 Finally animals are killed and subjected to histopathological examination.
3) CHRONIC TOXICITY:
 Important if the drug is intended for chronic use in humans.
 Duration of study ranges from one to two years.

20.  PHARMACOKINETIC STUDIES
 Done after toxicological studies.
 Information is obtained about its Pharmacokinetic parameters.
 SPECIAL LONG TERM TOXICITY
 Test performed only on drugs which cross phase 1 clinical trials.
 REPRODUCTION AND TERATOGENICITY
 Effects on Spermatogenesis, Ovulation, Fertility and developing foetus are studied.

21.  MUTAGENECITY
 Ability of the drug to induce genetic damage is assessed in bacteria, Mammalian
cell cultures and intact rodents.
 CARCINOGENECITY
 Drug is given for long term and observed for development of tumours.
 Standardized procedures under “GOOD LABORATORY PRACTICES” (GLP)
are laid down for conduct of animal experiments, especially toxicity studies.
 This ensures reliability and reproducibility of laboratory data and minimise
human errors.

22. ASSESSMENT OF SAFETY INDEX
 Therapeutic Index.
 Maximum tolerated dose.
 No observable adverse effects level (NOAEL)
 No observable Effects level (NOEL )
 Human Equivalent dose (HED) are determined in species similar to humans(like
monkeys) to calculate FIRST IN HUMAN DOSE (FIH) which will be used in phase 1
clinical trials.
 FIH is 1/5 or 1/10th of HED.

23. “CLINICAL TRAIL PHASE ( HUMAN TRAILS)”
 A Systematic study of a New Drug in human subjects to generate data for
verifying the Pharmacological and adverse effects with an aim to determine the
Safety and Efficacy of the drug in question.
 The clinical trails are done under the guideline of Good Clinical Practice
(GCP) laid down by International Conference on Harmonization (ICH) and
Declaration of Helsinki.
 Good clinical practice include:
• Protection of human rights as subject in clinical trial.
• Provides assurance of the safety and efficacy of newly developed compounds.

24.  The Declaration of Helsinki is a set of ethical
principles regarding human experimentation developed
for the medical community by the World Medical
Association
 The Declaration was originally adopted in June 1964 in
Helsinki, Finland, and has since undergone seven
revisions (the most recent at the General Assembly in
October 2013)

25. HISTORY OF CLINICAL TRIAL
World’s First Clinical Trial was recorded in the
BOOK of DANIEL in the BIBLE.
James Lind is Considered the first physician to
have conducted a controlled clinical trial of the
Modern era In 1747

26. WHY CLINICAL TRIALS?
To Discover or Verify:
 Pharmacodynamics ( how it works )
 Pharmacokinetics ( What happens to it )
 Therapeutic effects ( Efficacy)
 Adverse Reactions ( Safety )

27. PRECLINICAL NEW DRUG OR
INVESTIGATIONAL NEW DRUG
 After the New Compound passes the Pharmacological Screening
The Manufacturer may file a Preclinical New Drug or Investigational New Drug
Application to an authorised Drug Control body of respective country.
 In India it is submitted to the Drugs Controller General, Govt of India, New
Delhi.

28. The IND Application must contain the following information about the test drug:
1. Chemical structure, source, its manufacturing data with details of purity.
2. Preclinical data about Pharmacodynamics, pharmacokinetics and toxicology studies
with ED50 and LD50 data.
3. Specification of dosage forms.
4. Detailed description of the investigational protocol to be undertaken.
5. Names and qualifications of each investigator and facilities available to them.

29. 7. Agreement from the sponsors to submit annual progress report regularly.
8. Certificate of Informed consent from human volunteers and that ethics of research
in human beings will be followed.
9. Sponsors has to ensure that copies of all information material has been supplied to
each investigator.
10. Only when approval is given by the regulatory body, the drug can be
administered to the men for clinical trail.

30. ETHICS COMMITTEE AND ITS
RESPONSIBILITIES
 The Institutional Ethics Committee (IEC ) ensure
the rights and welfare of the participants in clinical
trails.
 Responsibilities:
a) Review and accord its approval to a clinical trail
according to protocol.
b) Safeguard the rights, safety and well being of the
trail subjects.
c) Make a periodical review of the trail and ensure
standard operation procedures (SOPs) and protocols are
followed.

31. INFORMED CONSENT
 Law requires that the investigator should obtain the written informed consent from
every human volunteer.
 The investigator must provide information about the study verbally as well as by
providing a Patient Information Sheet(PIS) in a language that is understandable by
subjects participating in the trail.
 Both the Patient Information Sheet as well as the Informed Consent from should
be approved by the IEC before submitting to the licensing authority.

32. BASIC ELEMENTS OF INFORMED CONSENT
 Statement that the study involves research and
purpose of research.
 Description of any risks or discomforts.
 Description of any benefits to the subjects.
 Disclosure of appropriate alternative procedures
or treatment that may be available.

33.  Statement describing the extent to which confidentiality of records will be
maintained.
 Explanation as to whether any compensation or any medical treatment are
available if injury occurs.
 Explanation of whom to contact for answers related to research.
 Statement that participation is voluntary.

34. “UNETHICAL TRIAL”
The Tuskegee Syphilis Study was an infamous and unethical
clinical study conducted between 1932 and 1972 by the U.S.
Public Health Service, to observe the natural progression of
Untreated Syphilis in African-American men in Alabama under
the guise of receiving free health care.

35. “CLINICAL TRAIL : PHASES”
PHASE 1
 Performed on a small number of healthy volunteers (25-100).
 OBJECTIVES:
1)To check for safety and its tolerability.
2) Determine whether humans and animals shows significant Pharmacokinetic
differences.
3)Determine a safe clinical dosage range in humans.
4) Determine the pharmacokinetics of the drug in humans.
5) Detect any predictable toxicity.
 These trails are NON BLIND or OPEN LABEL.

36. “PHASE II”
 Purpose: Gather evidence that the drug has the effects as suggested by Preclinical trials.
 Trials divided into EARLY and LATE PHASES.
EARLY PHASE II
 A small number of Patients ( up to 200 ) are studied in detail to observe the potential
therapeutic benefits and side effects.
 SINGLE BLIND.
LATE PHASE II
 Trials are conducted on large number of patients (200-400).
 DOUBLE BLIND.

37. “PHASE III”
 Large scale Multicentred randomized Double blind trail.
 Conducted in 1000-5000 plus patients.
 Done to establish safety and efficacy.
 Trails are made using DOUBLE – BLIND CROSS OVER Designs.

38. “NEW DRUG APPLICATION”
 Once the Phase III trials are completed.
 Sponsors can file a “NEW DRUG APPLICATION” with the Drug Control Authorities
of respective country.
 New drug application usually contains thousands of pages and includes complete
detailed monograph of the product, results of the trials, proposed registered name of
product and package insert.
 Data is reviewed by Drug Control Authorities and even by outside consultant.
 If documentation is in compliance with the regulations, the drug control authorities can
allow the drug to enter the market with NEW DRUG STATUS.

39. “PHASE IV”
 It is Post Licensing Phase.
 No fixed duration as it is Surveillance phase & Performance of the drug is
monitored for several years.
 During the New Drug Status period, the manufacturer is expected to report any
information about the drug concerning its safety.
 Such periodic safety update report is to be submitted every 6 months to first 2
years and then annually for the next 2 years.
 Drug remain in “New Drug Status” for several years until Drug Control
Authorities are confident about its release to unrestricted marketing.

40. “PHARMACOVIGILANCE”
 Greek : Pharmakon = a drug, Vigilare = to be observant means to remain vigilant and observe the adverse
effects of drugs.
 Continuous monitoring for unwanted effects and other safety related aspects of marketed drugs.
 WHO defines it as the science and activities relating to the Detection, Assessment, Understanding and
Prevention (DAUP) of adverse affects or any drug related problems.
 WHO prepared a document on “SAFETY MONITORING OF MEDICINAL PRODUCTS” and suggested
guidelines for setting up and running a pharmacovigilance centre in every country.
 ADR data of a new drug ( even of an old drug ) can be shared with global health care community through WHO
Uppsala Monitoring centre located in Sweden.

41. PHARMACOVIGILANCE
PROGRAMME OF INDIA (PvPI)
In the year 2010,the Ministry of Health and Family welfare started a nationwide
Pharmacovigilance Programme by the name Pharmacovigilance Programme of India.
Objectives:
• Monitor ADRs in Indian Population.
• Create awareness about the importance of ADR reporting.
• Monitor benefit risk profile of Medicines approved.
• Generate evidence based recommendations on medicine safety.
• Support CDSCO in formulating safety related regulatory decisions.
• Create a national centre excellence at par with global drug safety
monitoring standards.

42. “EXAMPLES OF DRUG WITHDRAWAL”
 Antihistamine :Terfenadine, Astemizole producing “Torsa de
Pointes”
 Selective COX-II inhibitor : Rofecoxib and Celecoxib for
producing Cardiotoxicity.
 NSAIDs : Nimesulide is banned for all age groups in Western
Countries and for Paediatric age group in India.
 Aspirin Liquid Formulation due to possibilities of producing
Reye’s Syndrome in Children.

43. “CLINICAL TRIALS: Recent Developments”
Celltrion is set to launch global Phase 3
clinical trial for its Bevacizumab
biosimilar ‘CT-P16' for the treatment of
cancer.
In July, 2018, I-Mab Biopharma (I-Mab)
announced that it received clinical trial approval
from China National Drug Administration
(CNDA) for TJ103 INJECTION: an
innovative, humanized, long-acting recombinant
glucagon-like peptide-1 (hGLP-1) fused with a
hybrid Fc for TYPE 2 DIABETIS
TREATMENT

44. As per reports of clinicaltrials.gov,
The Number of Clinical Trials in
India is expected to grow by 2018-19
as a result of regulations for clinical
trials in India becoming more stable
and predictable, according to Dr Chirag
Trivedi, President, Indian Society for
Clinical Research (ISCR).

45. “CLINICAL TRIAL DEATHS”
• An RTI response received by NGO
Swasthya Adhikar Manch, reveals that a
Total of 24,117 cases of deaths and SAEs
due to Clinical trials occurred between
January 2005 and September 2016.
• According to the RTI response, 341 cases
of SAEs resulting in death were
reported in 2015, out of which only four
cases were compensated.

46. “DRUG DEVELOPMENT TIMELINE”

47. CONCLUSION
 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.
 Advances in understanding human biology and disease are opening up exciting new
possibilities for breakthrough medicine.
 At the same time researchers face great challenges in understanding and applying these
advances to the treatment of disease.
 Each Success is built on many, many prior failures.