phase clinical trails 1,2,3&4

1. Phase 1 clinical trial
M.RAMESH BABU,M.PHARM
ASSISTANT PROFESSOR
Dept. of Pharmaceutical Analysis
SRPS-BESTAVARIPETA

2. What is a clinical trial?
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General definition: A clinical trial is any research study that
prospectively assigns human participants or groups of humans to one
or more health-related interventions to evaluate the effects on health
outcomes.
1. Interventions include but are not restricted to drugs,
2. cells and other biological products
3. surgical procedures
4. radiological procedures, devices
5. behavioral treatments
6. process-of-care changes
7. preventive care (WHO)
Clinical trial of drugs: a systematic study of pharmaceutical
products on human subjects in order to determine or verify the
clinical, pharmacological and adverse effects with the objective of
determining their safety and efficacy.

3. History of clinical trials
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Earliest documented clinical trial:
found in old testament (605-562 BC)
1537: clinical trial to prevent infection of
battlefield wounds
1747 Landmark scurvy trial : done
on British sailors to prevent scurvy
conducted by sir James Lind.
1948: first properly conducted RCT
( randomized controlled trial)
1945 onwards ethical impact on clinical
trials became increasingly important.

4. Phases of clinical trial of
new drug
 Phase I: determines whether drug is safe to check for
efficacy
 Phase II: determines whether drug can have any efficacy
 Phase III: determines a drug's therapeutic effect
 Post marketing surveillance or Phase IV: watch
drug's long term effects

5. Phases of drug development

7. PHASE-1
 studies designed mainly to investigate the safety/tolerability , identify
maximum tolerated dose ( MTD), pharmacokinetics and
pharmacodynamics of an investigational drug in humans
 PK: what the body does to the drug (Absorption, Distribution,
Metabolism, Excretion)
 PD: what the drug does to the body
 The development of new and better medicines is vital for public health.
 A key step in taking potential new medicines from the laboratory to
humans is the phase 1 clinical trial.
 Phase 1 is the gateway between scientific research and clinical
practice.

8. Few terms associated with
 Potential new medicines are called investigational medicinal products
(IMPs)
 Clinical trials of an IMP that do not benefit subjects are called phase
1 or nontherapeutic trials
 The premises where trials are done are called phase 1 units, or
simply units
 People who take part in clinical trials are called subjects
 The discipline that underpins phase 1 trials is called clinical or human
pharmacology

9. Investigational Medicinal
Products (IMPs)
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chemical entities
biotechnology products
cell therapy products
gene therapy products
plasma-derived products
Immunological products
herbal, homeopathic and
radiopharmaceutical products

10. High risk IMPs
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any agent that might cause severe disturbance of vital body systems
agents with agonistic or stimulatory action
novel agents or mechanisms of action for which there is no prior
experience
species-specificity, making pre-clinical risk assessment difficult or
impossible
high potency, e.g. compared with a natural ligand
multifunctional agents, e.g. bivalent antibodies
cell-associated targets
targets that bypass normal control mechanisms
immune system targets
targets in systems with potential for large biological amplification in vivo

11. Objectives
1. To assess a safe & tolerated dose
2. To see if pharmacokinetics differ much from animal to man
3. To see if kinetics show proper absorption, bioavailability
4. To detect effects unrelated to the expected action
5. To detect any toxicity

12. Method of First In Man study
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Done in small number of healthy volunteers or in certain cases
patients
First in a small group of 20 to 25
Start with a dose adjusted from animal data
Slowly increase the dose to find a safe tolerated dose
If safe  in a larger group of up to about 50 –75
Randomized , placebo controlled studies.
Performed by clinical pharmacologists
Performed after receiving ethics committee clearance and proper
regulatory approval.
Centre has emergency care & facility for kinetics study
Performed in a single centre
Takes 3 – 6 months [ 70% success rate]

13. Stages of FIH study
 Single ascending dose (Phase Ia): In single ascending
dose studies, small groups of subjects are given a single dose of the
drug while they are observed and tested for a period of time to confirm
safety
 Multiple ascending dose (Phase Ib): Multiple ascending
dose studies investigate the pharmacokinetics and pharmacodynamics
of multiple doses of the drug, looking at safety and tolerability.

14. Preclinical assessments of
safety
 Pre clinical safety evaluation is essential for a safe starting dose for FIH
studies and identification of potential adverse effects that may occur
 Studies include: 1. single dose toxicity studies
2. repeat dose toxicity studies
3. safety pharmacology studies
4. pharmacokinetic and toxicology studies
5. local tolerance studies
6. genotoxicity and carcinogenecity studies
7. reproductive toxicity studies

15. Study Designs Applied
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Parallel group design
Crossover study design
a. standard sequential dosing
b. interlocking cohort design
(Crossover studies are more favored over parallel designs
because they allow more efficient use of subjects who
serves as their own control with respect to safety and PK,
PD, there by reducing variability.)

16. Execution of phase 1-Subject
selection
Inclusion criteria
 Healthy volunteers ,
Uniformity of subjects
about age, sex,
nutritional status
[Informed consent a
must]
Exception:
 Patients only for toxic
drugs Eg AntiHIV,
Anticancer
Exclusion criteria
 Women of child bearing
age, children

17. Execution of phase 1-
Informed consent
Informed consent :
 subjects who enter phase 1 trial need to be fully informed that these
studies usually the initial clinical experiments in human
 Expected side effects as noted in preclinical studies are presented and
the possibility of other unpredictable side effects can occur must be
stated.
 Preferably be explained by clinical staff at the study site rather than the
sponsor and must contain rationale for the start dose and maximum
dose in lay language.

18. Execution of phase 1- starting
dose selection
 No observed adverse effect level (NOAEL) approach: most
commonly used approach. includes the following steps
1.determination of NOAELs in animal species.
2.conversion of NOAELs into human equivalent dose. Done by the
following equation:
HED (mg/Kg) = animal NOAEL x (weight animal/ weight
human) (1- b )
3.selection of the most appropriate animal species.
4.the application of a safety factor to determine the maximum
recommended starting dose (MRSD) for human studies.
 Minimum anticipated biological effect level (MABEL)
approach: usually done in case of high risk IMPs. Start with lowest dose
anticipated to be active rather than highest dose evaluated to be safe.
there is no definite protocol yet

19. Execution of phase 1- study
site
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Regulatory agency
Appropriate medical governance
Drug specific biomarker
assessment facilities are present
Experienced with clinical trials of
IMPs at various levels of risk
standard protocols for carrying
out detailed safety monitoring is
present
Has a strategy for and
experience with dose escalation
decisions
Facilities and personnel for
acute emergency are present
coupled with intensive care unit
facilities

20. Execution of phase 1-
formulation applied
 Intravenous : most flexible as
1.doses can be adjusted easily
2.administration can be stopped
immediately if
any adverse event occurs. (intravenous
infusion using a controllable infusion
pump is preferable to bolus
administration)
 Oral:
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oral powder reconstituted as
suspension or solution is administered
to the subject.
tablet formulations may be used as
well.

21. Execution of phase 1-
Required testing
 Regular monitoring of vitals- BP, pulse, respiration,
intake-output
 Routine investigations of hematological,
biochemical parameters, ECG, X-Ray, urine
analysis etc.
 Special investigations if needed
 blood and other laboratory tests are performed at
frequent intervals, measure the blood level of the
agent to monitor PK and PD profile of the drug

22. Execution of phase 1- data
collected about IND
 Pharmacokinetic data:
plasma level of drug and its metabolites are measured. Properties
include: Cmax
Tmax
AUC
plasma T1/2
Clearance
Volume of distribution
Early pharmacodynamics: target molecule binding etc
 PK Modeling: dose responserelationship

23. Benefits
 Safety, tolerability , pharmacokinetic profile of the drug are interpreted.
 A dose for phase 2 studies is decided based on MTD
 Usually phase 2 dose is about 80% of MTD
 While phase 1 studies are primarily directed toward establishing a
dose for further study there is always possibility of therapeutic benefit
in these studies when patients are taken as study subjects.

24. Subsequent Studies Done
1. ADME (i.e. Mass Balance) Study :
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Objective: To understand the full clearance mechanisms of the drug and
its metabolites in humans
Information gained:
Primary mechanism(s) of elimination and excretion from the body
Proportion of parent drug converted to metabolite(s)
2.Bioavailability/Bioequivalence (BA/BE )Studies :
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Objective: To evaluate the rate and extent of absorption of drug from a
test formulation (vs. reference formulation)
Information gained: Relative BA, Absolute BA of drug from a formulation
BE (no significant difference in BA) of test vs.
reference

25. Subsequent Studies Done
3.Food Effect Study :
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Objective: To evaluate the effect of food on rate and extent of drug
absorption from a given formulation
Information gained: effect of food on the BA of oral drugs and
whether to administer drug on empty stomach or without regard to
meals
4.Renal Impairment Study :
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Effect of renal impairment on drug clearance; dosage recommendations
for various stages of renal impairment
Effect of hemodialysis (HD) on drug exposure; info on whether dialysis
could be used as treatment for drug overdosage

26. Subsequent Studies Done
5.Hepatic Impairment Study
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Effect of hepatic impairment on PK of parent drug and metabolites
Dosage recommendations for various stages of hepatic impairment
6.Drug Interaction Studies :
 Exposure-response information on the drug is important in assessing the
clinical significance of the change in AUC of substrate by inhibitor/inducer.
7.Thorough QT Study (TQT):
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In vivo safety study required for all IMPs
identify drugs that prolong QT and need a more thorough ECG monitoring
in pivotal trials

27. Desirable Clinical Pharmacology
Properties of a Drug
ABSORPTION:
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High absolute bioavailability with low variability
Exhibits linear PK over therapeutic dose range
AUC, Cmax not significantly affected by concomitant food, pH-
altering medications, grapefruit, alcohol, etc.
DISTRIBUTION:
 Reaches the target site(s) of action immediately and at
effective/nontoxic concentrations; doesn’t accumulate in non-
target organs.
 Not significantly (>80 to 95%) bound to plasma proteins; extent of
protein binding not concentration- and time-dependent

28. Desirable Clinical Pharmacology
Properties of a Drug
METABOLISM/EXCRETION:
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Not extensively metabolized or not exclusively metabolized by a
CYP450 enzyme.
Not metabolized by polymorphic enzymes (e.g., CYPs 2D6, 2C19, 2C9,
NAT2).
CL not highly variable.
CL not time-dependent
OTHERS:
Not a Narrow Therapeutic Index Drug
Does not prolong the QT interval
Not a significant inhibitor or inducer of CYP3A, P-gp, etc.
Does not trigger formation of neutralizing anti-drug antibodies or organ-
damaging immune complexes

29. Phase 1 Studies: Impact on
Labeling

30. Conclusion
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Conducting FIH studies of new drug involves many complex issues that
require a multidisciplinary approach involving close collaboration
between pharmacologists
toxicologists
statisticians
pharmacists
pharmaceutical chemists and
clinicians
The primary concern at study site must be the safety of study
participants.
The selection of study subjects, design, initial dose selection and dose
escalation strategies are largely dictated by character of the IMP.
Implementation is done after strictly maintaining scientific, regulatory
and ethical obligations.

31. Renal Impairment
Example:
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doripenem powder for
IV use:
Because doripenem is primarily
eliminated by the kidneys, a Full PK
study in patients with renal impairment
was conducted.
 In Phase 2/3 trials, dosage was adjusted
based on creatinine clearance (CrCL).
 The label recommends dosage reduction
for patients with moderate or severe
renal impairment and hemodialysis as a
treatment for overdosage.

32. Food Effect Example:
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atazanavir oral capsules:
Administration of a single dose of atazanavir
(800 mg) with a light meal increased Cmax by
57% and AUC by 70%; a high-fat meal
increased AUC by 35% with no change in Cmax.
Clinical trials were conducted under fed
conditions
 Label directs administration with a meal or snack

33. Drug Interaction Example:
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bosutinib oral tablets:
Bosutinib a CYP3A substrate is extensively
metabolized; only 3% of the dose is
excreted unchanged in the urine.
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In vivo, bosutinib AUC ↑ 9x with
ketoconazole (a strong CYP3A inhibitor), ↓
by 93% with rifampin (strong CYP3A
inducer).
Avoid concomitant use with all strong or
moderate CYP3A inducers or inhibitors.

34. Thank you