1. Clinical Trials: HISTORY
Dr Urmila M. Aswar
Department of Pharmacology, SIOP, Narhe

2. • Clinical trials are sets of tests in medical,
medical research and drug development that
generate safety and efficacy data (information
about adverse drug reactions and adverse
effects of other treatments) for health
interventions (e.g., drugs, diagnostics, devices,
therapy protocols).

3. History of CT before yr 1750
• Persian physician and philosopher, Avicenna
• In The Canon of Medicine, he laid down rules
for the experimental use and testing of
drugs and wrote a precise guide for practical
experimentation in the process of discovering
and proving the effectiveness of
medical drugs and substances. He laid out the
following rules and principles for testing the
effectiveness of new drugs and medications.

4. Earlier rules
1. The drug must be free from any extraneous accidental quality.
2. It must be used on a simple, not a composite, disease.
3. The drug must be tested with two contrary types of diseases,
because sometimes a drug cures one disease by its essential
qualities and another by its accidental ones.
4. The quality of the drug must correspond to the strength of the
disease.
5. The time of action must be observed, so that effect and
accident are not confused.
6. The effect of the drug must be seen to occur constantly or in
many cases, for if this did not happen, it was an accidental
effect.
7. The experimentation must be done with the human body, for
testing a drug on a lion or a horse might not prove anything
about its effect on man.

5. History
Perhaps the first ever clinical trial was James Lind’s
demonstration in 1753 that citrus fruits cured scurvy. He
compared the effects of various different acidic
substances ranging from vinegar to cider, on groups of
sailors, and found that the group who were given
oranges and lemons had largely recovered from scurvy
after 6 days.

6. • Before one can initiate testing in human beings, they must
conduct extensive pre-clinical or laboratory research.
• Research usually involves years of experiments in animal and
human cells.
• If this stage of testing is successful, the sponsor then provides
this data to the FDA requesting approval to being testing in
humans. This is called an Investigational New Drug Application
(IND)
• If approved by the FDA, testing in humans begins. This is done
through a formally written and approved protocol.

7. What is a Protocol?
• A study plan on which all clinical trials are based.
• Carefully designed to protect the health of participants
• Describes what types of people may participate in the trial
(inclusion and exclusion criteria)
• Gives detailed schedule of tests, procedures, medications,
dosages, and length of the study.
• Principal Investigator is responsible for assuring that the
protocol is strictly followed for each participant

8. Randomization of trials
• Researchers assign patients by chance to either a group taking
the new diagnostic or treatment agent. Similar to “flipping a
coin”.
• Randomization helps avoid bias.
• The assigned groups are often referred to as “arms”.
Example: Patient #1 is assigned to Arm A of the trial,
which involves the new modality or treatment.
Patient #2 is assigned to Arm B, which is the standard
modality or treatment.

9. What is a Blinded Study?
• In a single blinded study, the patient does not know which arm
of the protocol they have been assigned to.
• This approach avoids bias because when people know what
they are taking, it might change the way they react.
Example: Patients who know that they are assigned to the
“new treatment” group might expect it to work better and
report hopeful signs because they want to believe they
are getting well. This could bias the study by making
results look better than they are.

10. CONT…
• Double blinded studies are those studies where neither the
patient or the research physician know whether the patient is
receiving the actual study drug or standard drug.
• When no standard is available, some studies compare new
drugs with placebo drugs.
• All patients are informed of the possibility of being assigned to
the placebo arm of a study
• Patients are “unblinded” only if it becomes medically
necessary prior to the end of the study.

11. Who Sponsors Clinical Trials?
• Physicians
• Medical Institutions
• Foundations
• Voluntary Groups
• Pharmaceutical Companies
• Federal Agencies (cooperative group
research)
– NIH

12. TYPES of CT
The most commonly performed clinical
trials evaluate new drugs, medical
devices, biologics, or other interventions
on patients in strictly scientifically
controlled settings, and are required for
regulatory authority approval of new
therapies.

13. Types of CT
• One way of classifying clinical trials is by the way the
researchers behave.
• In an observational study, the investigators observe the
subjects and measure their outcomes. The researchers
do not actively manage the study.
• In an 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.

14. Types of CT
• NIH organizes trials into 5 different categories.
• Treatment Trials- test experimental treatments, new
combinations of drugs, or new approaches to
surgery or radiology/radiation therapy.
• Prevention Trials- look for better ways to prevent
disease in people who have never had them or
prevent them from returning.
• Diagnostic Trials- conducted to find better tests or
procedures for diagnosing a particular disease or
condition.
• Screening Trials- test the best way to detect certain
diseases or health conditions.
• Quality of Life- explore ways to improve comfort and
the quality of life for individuals with chronic illness

15. Phases of Clinical trials
• Pre-clinical
• Phase 0 (First in human trials)
• Phase 1 (volunteers)
• Phase 2 (patients)
• Phase 3 (large scale multi-centre)
• Phase 4 (post registration
monitoring)

16. Preclinical evaluation
1. Toxicity Testing
2. PKPD
3. Pharmacological effects
Time required: 1.5-3yrs
IAEC approval

17. Toxicological studies
• Acute toxicity (Graded dose and 1 or 2 animal species)
• Subacute toxicity (3 dose and 2 animal species)
• Chronic toxicity (3 dose and 2 animal (1 rodent and
other non rodent)
• Special toxicity:
i. Effect on reproductive performance
ii. Teratogenicity
iii. Carcinogenicity (Same dose for 2 yrs)
iv. Mutagenicity : AMES Test (S.Typhi, Histidine medium)
v. Local toxicity: dermal, ocular, vaginal etc

18. Pharmacokinetic studies
• Rats, dogs, monkeys
• ADME
• BA
• T1/2

19. Pharmacological studies
• TI, ED50, LD50 estimation

20. Human Clinical Trial
• Human ethical committee: 2+5
• 2: 1 member secretary, 1 chairman from
outside Institute.
• 5: 1 medical doctor, 1 Pharmacologist, 1
socially aware member, 1 lawyer, 1 lay person
from society.
• Informed consent: verbal as well as written
Time period: 5-7 yrs

22. Phase 0
• Conducted in accordance with the United
States Food and Drug Administration's (FDA)
2006.
• Microdosing studies
• Administration of single sub therapeutic doses
• Small number of subjects (10 to 15)
• Provides agent's pharmacodynamics
and pharmacokinetics
• Companies: go/ no-go decisions

23. Phase I
• Pharmacologists & employees (25-100 in number)
ethical approval
• healthy
• informed consent
• Medical backup
• Monitor
• Three different kinds of Phase I trials include:
– SAD-single ascending dose studies
– MAD-multiple ascending dose studies
– Food Effect-investigates differences in absorption
caused by eating pre-dose

24. Objectives
• To check whether animal and human show
any differences
• Tolerated dose range (Pharmacovigilance),
• Pharmacokinetics, Variability between
individuals; effect of route; bioavailability
• Indication of therapeutic effects
• Indication of side effects
The trial is open labelled and non blind

25. Single ascending dose studies (SAD)
• SAD those in which small groups (3) of subjects
are given a single dose of the drug while they are
observed and tested for a period of time.
• If no adverse effects, dose is escalated with 3 new
healthy subjects
• If toxicity is obs. then 3 more subjects are given
the same dose and if found toxic, the dose is
considered as max. tolerated dose (MTD).

26. Multiple ascending dose (MAD)
• MAD are conducted to understand the
pharmacokinetics and pharmacodynamics of
multiple doses of the drug.
• A group of patients receives multiple low
doses of the drug
• Samples (of blood, and other fluids) are
collected at various time points
• Analyzed: How the drug is processed within
the body.

27. Food effects
• A short trial designed to investigate any
differences in absorption of the drug by the
body, caused by eating before the drug is
given.

28. Phase II
• 150-350 ill people; informed
consent
• End point is decided
• Maximum monitoring
• Often patients where other
treatment failed
• Early phase : 200 patients, single
blind
• Late Phase: 200-400, controlled
double blind
Once a drug has shown to be safe, then it must be tested for efficacy.
This phase may last from several months to two years.
Most of these trials are randomized trials

29. Objectives
Indication for use; type of patient;
severity of disease; dose range,
schedule and increment; pharmacokinetic studies in ill people;
Nature of side effects and severity; Effects in special groups.

30. Phase III
• 1500-3500 ill patients
• Multicentre
• Randomized
• Double blind
• More certain data from the objectives of phase 2
studies
• Interactions between drugs start to become
measurable in the larger population
• Sub-groups start to be established
• Special features and problems show up

31. Single arm trial
• Simplest CT
• Only one treatment
When drug is studied for the first time
When population is homologous
When there is no other therapy available
When placebo is not recommended
Eg TD1 to only one group of patient

32. Parallel group study
• When each of the grp receives a single
therapy simultaneously.
• Eg Grp I: tment A
• Grp II: tment B or control

33. Population Sample
Randomly
assigned
Experimental
group
Control
group
Independent variable
Treatment A Treatment B
Randomly
selected
Two-group simple randomized experimental
design
9/17/2013 33

34. Double blind cross over design of
Phase III trial
Patient group Week 1 Week 2 Week 3
I SD TD ND
II TD ND SD
III ND SD TD

35. Factorial design study
• Used when combination of drugs are to be given
• Eg in HIV
• Eg 3 gps
• A: TD1
• B:TD2
• C:TD1+TD2
• D: No tment
• Results are difficult to interpret

36. • Sponsorer can file the application for NDA
• Complete Monograph, insert etc

37. Phase IV
• After approval for marketing
• Post Licensing phase
• No fixed duration
• To find the rare side effects, congenital
effects,drug-drug interactions, safety studies,
mortality studies, epidemiological studies.
• PERIODIC SAFETY UPDATE REPORTS
• To be submitted by the manufacturer every 6
months for 2 yrs and then annually for next 2 yrs.

38. The refocoxib story
• Rofecoxib , anti-inflammatory drug (NSAID) that has now been
withdrawn over safety concerns. It was marketed by Merck &
Co. to treat osteoarthritis, acute pain conditions,
and dysmenorrhoea.
• Rofecoxib – FDA-on May 20, 1999, brand names Vioxx, Ceoxx,
and Ceeoxx.
• Rofecoxib used widely for arthritis and other conditions causing
chronic or acute pain. Worldwide, over 80 million people were
prescribed rofecoxib at some time.
• On September 30, 2004, Merck withdrew rofecoxib from the
market
• Increased risk of heart attack and stroke associated with long-term,
high-dosage use.
• Merck withdrew but the drug resulted in between 88,000 and
140,000 cases of serious heart disease
• US$2.5 billion in 5 yrs

39. Time required
S.no Phases Time period {yrs}
1 Drug discovery 2-5
2 Preclinical 1.5-2
3 Clinical 5-7
4 Regulatory 1.5
5 Phase IV 4
Total Approx 20 yrs

40. Costs Involved
• Omeprazole (anti-gastric acid) £3.5m
• Simvastatin (cholesterol lowering) £2.4m
• Beclomethasone (asthma) £1.8m
• Fluoxetine (antidepressant) £1.5m
• Lansoprazole (anti-gastric acid) £1.4m
• Ranitidine (anti-gastric acid) £1.3m
• Paroxetine (antidepressant) £1.2m
• TOP 7 TOTAL >£13m

41. Investigational New Drug Application
• Current Federal law requires that a drug be
approved for marketing application before it is
transported or distributed across state lines.
• But in case of investigational drug, it is
required by clinical investigators in many
states.
• IND is an exemption.

42. • FDA's role in the development of a new drug
begins when the drug's sponsor (usually the
manufacturer or potential marketer) having
screened the new molecule for
pharmacological activity and acute toxicity
potential in animals, wants to test its
diagnostic or therapeutic potential in
humans. At that point, the molecule changes
in legal status under the Federal Food, Drug,
and Cosmetic Act and becomes a new drug
subject to specific requirements of the drug
regulatory system.

43. Animal Pharmacology and Toxicology
Studies

44. Manufacturing Information
Composition, manufacturer, stability, and
controls used for manufacturing the drug
substance and the drug product.
This information is assessed to ensure that the
company can adequately produce and supply
consistent batches of the drug.
Lic form-29 is taken for mfg of new drug

45. Clinical Protocols and Investigator
Information
• Detailed protocols for proposed clinical studies to
assess whether the initial-phase trials will expose
subjects to unnecessary risks.
• Information on the qualifications of clinical trial
team.
• Informed consent from the research subjects,
• to obtain review of the study by an institutional
review board (IRB),
• Adherence to the investigational new drug
regulations.

46. Review by FDA
• Once the IND is submitted, the sponsor must
wait 30 calendar days before initiating any
clinical trials. During this time, FDA
(DCGI/CDSCO) has an opportunity to review
the IND for safety to assure that research
subjects will not be subjected to unreasonable
risk.

47. Summary
• An application to conduct clinical trials in India
should be submitted along with the data of
chemistry, manufacturing, control and animal
studies to DCGI. The date regarding the trial
protocol, investigator's brochures, and informed
consent documents should also be attached. A
copy of the application must be submitted to the
ethical committee and the clinical trials are
conducted only after approval of DCGI and ethical
committee. To determine the maximum tolerated
dose in humans, adverse reactions, etc.

48. New Drug Application
• The new drug registration (using form no. 44 along with full
pre-clinical and clinical testing information) is applied after
the completion of clinical trials.
• The comprehensive information on the marketing status of
the drug in other countries is also required other than the
information on safety and efficacy.
• The information regarding the prescription, samples and
testing protocols, product monograph, labels,
and cartons must also be submitted.
• Schedule Y of D&C act, provides the guidelines and
requirements for clinical trials.
• The application can be reviewed in a range of about 12- 18
months
• Then the permission is granted.

49. Regulatory bodies in World
• USA: FDA, Dept of health and human services
• Canada: Health Canada
• UK: Medicines and Healthcare products
regulatory agency (MHRA)
• EU: European Medicines Agency (EMEA)
• Japan: Pharmaceutical and Medical Devices
agencies (PMDA)
• India:

50. Regulating bodies in India
• The Drug and Cosmetic Act 1940 and Rules
1945 were passed by the India's parliament to
regulate the import, manufacture, distribution
and sale of drugs and cosmetics.
• The Central Drugs Standard Control
Organization (CDSCO),
• The Drugs Controller General (India) [DCGI]
was established.

51. NDA

52. Regulatory requirements for clinical
trials
Before starting trial
• Consent of investigator
• Approval by IRB..approval of protocol, site,
• Approval from ICMR in case of new molecules
developed in India
• Informed consent
• Insurance cover for trial related injury

53. During the conduct
• Compliance with the trial protocol
• Reporting protocol violations to EC
• Seek approval for protocol amendments
• Adherence to GCP
• Record all adverse effects
• Record of all serious adverse effects to sponsor in
24 hr
• Notification of fatal adv effect to RB
• Review the progress of results of study
• Send periodic status of study.

54. Post trial requirement
• Site close out
• Check investigational product utilization
• Analyze the data using statistical softwares
• Forward the report from investigator to EC
• Seek new drug approval.
• Prepare and submit the prescribing
information for ND to the authorities

55. Newly approved drugs
• Gilotrif (afatinib) Tablets: for lung cancer
Boehringer Ingelheim Pharmaceuticals
• Khedezla (desvenlafaxine): for depression
Osmotica Pharmaceutical Corp.