This document discusses various approaches to drug discovery and development. It begins by outlining historical approaches such as studying plants used in traditional medicine. It then describes modern approaches like studying disease processes and biological pathways. The document also discusses key events in the development of drugs like aspirin and quinine. It provides an overview of the drug development process, noting the high costs and failure rates. Various phases of clinical trials are defined. Pre-clinical development and requirements for an Investigational New Drug application to enter human trials are also summarized.

1. Drug
Development
Value Added
Chain

2. Approaches to drug discovery
 Historical; Cinchona (Quinine) & willow barks (aspirin); chinese medicine
currently.
 Study disease process; Breast cancer (Tamoxifen); Parkinson’s disease (L-
dopa)
 Study biochem/physiological pathway; Renin/ angiotensin
 Develop SAR to natural compound; Beta-adrenoceptors (propranolol),
H2-receptors (cimetidine)
 Design to fit known structurally identified biological site;Angiotensin-
Converting enzyme inhibitors
 By side profile of other drug- Sildenafil in erectile dysfunction, Thalidomide
use in mutilple myeloma
 By chance (serendipidy); random screening Penicillin;
dimenhydramate; pethidine
 Genomics; identification of receptors; gene therapy; recombinant materials;

3. Willow bark & Salicylic Acid
 The Rev Edward Stone (1760s) searched along a riverbank (i.e. a cold
and wet place) for a plant-based cure for the fevers associated with
influenza. Found that the bark of the willow was effective in reducing
fever.
 Native American Cherokees used willow bark for such purposes for
centuries.
 * willow bark contains salicin → * metabolized in vivo to the active agent
salicylic acid → * salicylic acid and more tolerable “prodrug” aspirin
made in late 19century → * mechanism of action not discovered until the
1970s.

4. Quinine
 Powdered dried bark of the cinchona tree, a native of South
America, was made into a drink and used by the Quechua
Indians of Peru to treat fevers.
 Discovered by Jesuit priests in the 1620s, Barnabé de Cobo
takes cinchona bark to Europe in 1632 to treat malaria.
 Quinine isolated in 1820 by Pierre Joseph Pelletier and Joseph
Caventou
 First Total Synthesis (1943) by RB Woodward and WE von
Doering
 Kills parasites causing malaria. Mode of action complex and still
not 100% worked out

5. Drug development
18th century
All ancient civilizations made
discoveries in this field
Natural sources; limited
possibilities; Prepared
by individuals; Small
scale; not purified,
standardized or test -
ed; limited adminis
tration; no controls; no
idea of mechanisms.
20th century
 synthetic source; unlimited
possibilities; prepared by
companies massive scale;
highly purified,
standardized and tested;
world-wide administration;
tight legislative control;
mechanisms partly
understood

6. Drug development in today’s
world
 Development of new medicines is complex, time consuming and
very expensive (800$ million for a completely new drug)
 Success rate in getting from an initial compound to an approved
and commercially available product is very low.
 < 2% of new compounds investigated may show suitable biological
activity
 Modification of an existing drug can yield as little as 1% suitable
compounds
 < 10% of these compounds result in successful human clinical
trials and reaches the market place

7. Attrition due to different Factors
Current ADME approaches have reduced drug failure due to PK but not
overall attrition
From Nature Reviews/Drug Discovery vol. 3 (2004) p. 711

8. What led us to invest so heavily
on drug development??
 Unmet medical need-
New diseases (Swine Flu; AIDS, Alzheimer’s;
Side effects (antidepressants, antipsychotics)
Low efficacy (dementia, cancer);
 Health costs; (Alzheimer’s; spinal injury)
 costs to individual/country; (depression in
developed country)
 sustain industrial activity; pharmaceutical industry
employs thousands and makes a massive
contribution to overseas earnings; Personal
interest; competitive Market; patent expiry

9. The Drug Development Lifecycle

10. Steps in Drug discovery
 Deciding Disease/ Area of Research
 Target identification
 Target validation
 Lead identification
 Lead optimization
 Pre clinical development
 IND/CTA application
 Phase 1-3 Clinical trail
 NDA/MAA
 Phase 4

11. Deciding an Disease
/area of research
Selection of a disease target:
 – In the ‘early days’ there were many therapeutic
opportunities: Infectious diseases, cardiovascular….etc
 – whereas acceptable therapies are available today for
many conditions, e.g. Antibiotics for bacterial diseases etc,
paracetamol / ibuprofen etc. for moderate pain relief
 Now a days acceptable therapies are available for many
conditions.New agents must have statistically proven clear
advantages over existing therapy (not just that it is
clinically effective).
 In 1962, US FDA amended to approve the drug on the
basis of evidence of efficacy as comparison to safety
alone before that.

12. Consideration before deciding
area of research
A) The medical need
 – life threatening or self-limiting condition?
B) Availability of current therapy
 – is level of satisfaction high or low? A new drug may
have advantages as it provides a new dosage
 form which results in a particular advantage to the
patient (e.g. oral formulation vs. creams) or which
requires less frequent dosing (once a day tablet).
C) Competitor activity. Will the proposed new drug:
–show increased selectivity for a particular biological
mechanism?

13. Cont..
 Permit a novel approach to the management of the
disease?
 Optimum agents of a particular class may have been
identified next therapeutic advance requires an alternative
pharmacological approach. Must choose whether to seek
improvements within an existing drug class or follow a novel
approach.
D) commercial opportunity
 potential market (patient numbers)? duration of the
proposed therapy? is the condition acute or chronic?
The bottom line is company do invest in diseases which afflict
“first world” countries: (e.g. cancer, cardiovascular
diseases, depression, diabetes, flu, migraine, obesity)
rather than diseases of third world countries.

14. Target identification
 Drug targets are most often proteins, but nucleic acids
may also be attractive targets for some diseases.
 TARGET MECHANISM
Enzyme Inhibitor - reversible or irreversible
Receptor Agonist or antagonist
Nucleic acid Binder, modifier or substrate mimic.
Ion channels Blockers or openers
Transporters Uptake inhibitors

15. Drug Target validation
A bio(macro)molecule may be involved in a disease process, but to be
a drug target it has to be validated. In other words shown to be critical
in the disease process.
Useful techniques available are to validate a target are:
 Gene knockout: does removal of the gene that encodes the target
protein result in, for example, the death of a pathogen (disease
causing microorganism)
 RNA interference (RNAi): Involves double-stranded ribonucleic acid
(dsRNA) interfering with the expression of genes with sequences
complementary to the dsRNA. Results in a reduction of the production
of the protein (target) in question.

16. Lead identification
 Molecule that has potential to treat disease is a lead molecule
 A lead compound is: – “a compound from a series of related
compounds that has some of a desired biological activity. This
molecule can be characterised, and modified to produce another
molecule with a better profile of wanted properties to unwanted
side effects”
 –A lead compound is a first foothold on the drug discovery
ladder – It takes much more effort to make a lead compound
into a drug candidate

17. Lead optimization/ Screening
 Lead molecules are assessed to select the
compound with safety and efficacy.
 “The testing of a (series of) molecule(s) against a
known biological target that correlates with a cellular
or pharmacological activity is known as screening -
e.g. enzyme inhibition or receptor binding”

18. Drug Development Phases and
Decision Checkpoints
Early development Late develop. Post reg.
Pre clinical
developme
nt
Phase
1
Phase
2a
Phase
2B
Phase
3
Phase
4
Human
trail began
and file
IND
Healthy
human
safety
Patient
efficacy/
safety
MAA/
NDA file

19. Clinical research &
Clinical trails
Clinical research involves methodical and systemic
study of drugs, devices, biological vaccines used in
the diagnosis, prevention or treatment of disease
 Clinical trail is defined as a systemic and prospective
study aimed to compare the effect and values of
intervention against a control group in subjects.
 Its also defined as controlled experiment having a
clinical outcome measure and done in clinical setting
and involving persons with specific disease or health
condition

20. History of clinical trail
 Clinical trials were first introduced in Avicenna's The
Canon of Medicine in 1025 AD, in which he laid down
rules for the experimental use and testing of drugs.
 In the 16th century trail of egg yolk+ rose oil+turpentine
 James lind called the father of clinical trail.
 Mint water in rheumatic heart disease in 1865.
 First clinical trail where the sample size was statistically
determined is use of streptomycin in TB in year 1944

21. Global scenario
 Around 24,000 drugs are in various phase of
development of which cancer is leading one with 25%
drugs are for cancer disease.
 Still more than 60% are performed in the US because
of having market of US $ 350 billion out of global
pharmaceutical market of US $ 500

22. Possibilities in Clinical trail
 Assess the safety and effectiveness of a new medication or
device on a specific kind of patient (e.g., patients who have
been diagnosed with Kala azar
 Assess the safety and effectiveness of a different dose of a
medication than is commonly used (e.g., 10 mg dose instead of
5 mg dose)
 Assess the safety and effectiveness of an already marketed
medication or device for a new indication, i.e. a disease for
which the drug is not specifically approved.
 Assess whether the new medication or device is more effective
for the patient's condition than the already used, standard
medication or device ("the gold standard" or "standard therapy")

23. 23
Multidisciplinary Teams In Clinical Trials
1. Clinical Investigator
2. Site coordinator
3. Pharmacologist
4. Trialist/Methodologist
5. Biostatistician
6. Lab Coordinator
7. Reference lab
8. Project manager
9. Clinical Research
Manager/Associate
10. Monitor
11. Regulatory affairs
12. Clinical Data Management
13. Clinical Safety Surveillance
Associate (SSA)
14. IT
15. IT/IS personnel
16. Trial pharmacist
17. Clinical supply
18. Auditor/Compliance

24. Types of clinical trails
Classification of clinical trials on the basis of the way
the researchers behave-
 Observational study- The investigators observe the subjects
and measure their outcomes. The researchers do not actively
manage the experiment. This is also called a natural
experiment.
 Interventional study- The investigators give the research
subjects a particular medicine or other intervention. Usually,
they compare the treated subjects to subjects who receive no
treatment or standard treatment. Then the researchers measure
how the subjects' health changes and other parameter

25. Cont …
Classification of clinical trail by their purpose.
 Treatment
 Prevention
 Screening and early detection
 Diagnostic
 Genetics
 Quality-of-life / supportive care

26. Treatment Trails
 Test safety and effectiveness of new agents
or interventions in people
 Possible benefit:
» Early access to new treatments
 Possible risk:
» Occurrence of unknown side effects

27. Prevention Trials
 Evaluate the effectiveness of ways to reduce the risk
of a particular disease
 Enroll healthy people at high risk for developing that
disease
 Better ways to prevent disease in people who have
never had the disease or to prevent a disease from
returning
These approaches may include medicines, vitamins,
vaccines, minerals, or lifestyle changes.

28. Cont….
 Screening trials: Test the best way to detect certain
diseases or health conditions.
 Diagnostic trials: conducted to find better tests or
procedures for diagnosing a particular disease or
condition.
 Quality of life trials: explore ways to improve comfort
and the quality of life for individuals with a chronic
illness (Supportive Care trials) eg- FACT, EORTC.

29. Clinical testing

30. Cont….
Phase II Phase III
Phase I
Discovery
Research
Clinical
Development
Approval
Phase
Preclinical
Research
File
IND
File
NDA
$ 802 M
2 years
4.70%
of R&D
Budget
1.5 years
7.41%
of R&D
Budget
5 years
42.35%
of R&D Budget
33.37%
of R&D Budget
3.5 years

31. Pre clinical development
1.Acute toxicology -
 Usually in rat & mice using the same route as intended for
humans.
 Mortality should be looked for up to 72 hours after parentral
administration and up to 7 days after oral administration.
 LD 50 should be reported preferably with 95% confidence limit.
2. Long term toxicity:-
 Must be carried out in 2 mammalian species, of which one
should be non rodent.
 Drug should be administered 7 days a week by the route
intended for clinical use in humans.
 Control group of animals with 3 other groups which are given
graded dose.

32. Cont….
3. Reproductive studies-
(a) Fertility studies
(b) Teratogenicity studies (during organogenesis)
(c) Perinatal studies (last 3 months)
4. Local toxicity
5. Mutagenicity & carcinogenicity
Animal Pharmacology
 Pharmacological action
 Dose- response relationship

33. Phase 0
 First-in-human trials conducted in accordance with
the U.S. Food and Drug Administration’s (FDA) 2006
 Phase 0 trials are also known as human Micro-dosing
study studies and are designed to speed up the
development of promising drugs
 By establishing very early on whether the drug or
agent behaves in human subjects as was expected
from preclinical studies
 Study of Pharmacokinetic & Pharmacodynamic
behavior in humans

34. Phase I
• Small group of healthy volunteer (20-80)
• Informed consent
• Evaluate its safety; common side effects:
• Fatigue, nausea, hair loss, vomiting
• Determine MTD, effect of route; bioavailability
• 6-9 months
• Determining Pharmacokinetics
 How drug is:
» Absorbed
» Metabolized
» Excreted
» Duration of action

35. Phase II
• Larger group of people (100-300)
• People with disease
• 6 months- 2 year
• Phase IIA is specifically designed to assess dosing
requirements (how much drug should be given),
whereas Phase IIB is specifically designed to study
efficacy (how well the drug works at the prescribed
dose(s).

36. Cont….
OBJECTIVES:
o Indication for use; type of patient; severity of
disease;
o Dose range, schedule and increment;
o Pharmacokinetic studies in ill people;
o Nature of side effects and severity;
o Effects in special groups

37. Phase III
• Large groups of people (1,000-3,000)
• To confirm its effectiveness
• Monitor side effects
• Compare it to commonly used treatments
• Interactions (with other meds)
• Multicenter trial – many docs; many hospitals

38. Phase IV
• After the drug or treatment has been marketed
• Collect information about their effect in various
populations
• Side effects associated with long-term use.
• New indications: important for company to extend its
patent protection.

39. IND application
 IND is a request for food and drug administration
authorization to administer an investigational drug to humans
 IND application is the Gate-way for entering into human
clinical trail from animal study .
Types of IND applications-
1. Investigator IND- Physician file IND for unapproved drug,
or an approved product for a new indication or in new patient
population.
2. Emergency use IND- for an emergency situation
3. Treatment IND- Drugs showing promise in Clinical testing
for serious condition

40. Sponsor/FDA Meetings ( Pre-IND)
 Prior to clinical studies, the sponsor needs evidence that the
compound is biologically active, and both sponsor and the FDA
need data showing that the drug is reasonably safe for initial
administration to humans.
 Meeting at such an early stage in the process are useful
opportunities for open discussion about testing phases, data,
requirements, and any scientific issues that may need to be
resolved prior to IND submission
 At these meeting, the sponsor and FDA discuss and agree upon
the design of the animal studies needed to initiate human testing

41. Cont ….
 IND’s can also be classified as
1.Commercial
2. Non- Commercial
The IND application must contain information in 3 broad
areas
 Animal and Pharmacological studies
 Manufacturing information
 Clinical protocols and investigator information

42. Cont…
The important forms for use in submitting IND’s include:
 FDA 1571,Investigational new drug application
Sponsors file the relevant data for consideration by
CDER for permission
 FDA 1572, Statement of investigator
Helps the regulators to assess the investigators, their
facility and the IRB with the view to ascertain the
safety .
21 CFR part 312 is for investigational new drug
application

43. IND Review process

44. NDA REVIEW

45. IRB’s / IEC
The Institutional Review Board (IRB):
 Operates under federal regulations.
 Charged with protecting the rights and welfare of
people involved in research.
 Keeps pace with the ever changing environment of
human subjects research.
 Facilitates and strengthens human subjects
research conducted by investigators at the institution.

46. Who can be Members of IRB
 The IRB must have at least five members
 At least one member whose primary are is of
Non-scientific area.
 At least one member who is independent of
the institution trial/site.
Only those IRB/IEC member who are
independent of the investigator and the
sponsor of the trial should vote/provide
opinion on trail related matter.

47. What does the IRB do?
 Oversees all research that involves human
subjects.
 Mandated by:
» FDA: 21 CFR 50 & 56
 Ethical Guidance:
» Nuremburg Code
» Declaration of Helsinki
» Belmont Report

48. What’ s in INDIA
 There are ethics committees in various
hospital/ medical institute which are
constituted as per the ICMR “Ethical
guidelines for biomedical research on human
subjects” and ICH- GCP guidelines.

49. Where an IRB review required??
 IRB review is required for all human subjects
research
 Definition of HUMAN SUBJECT according to 45 CFR 46:
“living individual (s) about whom an investigator (whether
professional or student) conducting research obtains…
(1) data through INTERVENTION or INTERACTION with
the individual OR
(2) identifiable PRIVATE INFORMATION obtained for this
research in a form associable with the individual (that is,
the identity of the subject is or may readily be
ascertained or associated with information)

50. Documents required
Cover Letter
IRB Submission Application
Protocol Summary
Full Protocol
Informed Consent
HIPAA Authorization
Human Subjects protection training for PIs and study staff (CITI)
Recruitment materials: ads, radio announcements, brochures
Study questionnaires and surveys
IND/IDE information
Investigational brochure or product labeling (drug/device studies)
Conflict of interest documentation
For federally funded research: grant application

51. What does the IRB look for in a
research project?
 Risks minimized (coercion?)
 Risk vs. Benefits ratio
 Equitable participant selection
 Informed Consent process appropriate
 Privacy, confidentiality, safety - maximized
 Safeguards for vulnerable subjects
 Research design - scientifically sound

52. Who should submit????
o Responsibility of principal investigator
(PI), prior to implementation
o previously collected data must be
submitted to the IRB

53. What else u do??
You must contact the IRB whenever there
are any changes in:
Methods/objectives
Population used
Unanticipated problem - adverse event

54. Protections Built into Biomedical Research
Informed
Consent
IRB
Examination of
Research
Data
Security
Biomedical Research