phase1 clinical trial

1. PHASE 1 CLINICAL TRIAL

2. CLINICAL TRIAL
“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.”
o Interventions include drugs, biological products
• surgical procedures
• radiological procedures, devices
• behavioral treatments
• process-of-care changes
• preventive care
o Health outcomes include any biomedical or health-related measures obtained in patients or participants,
including pharmacokinetic measures and A/Es.

3. CLINICAL TRIAL OF DRUGS
systematic study of pharmaceutical products on human subjects in order
to determine or verify clinical, pharmacological and adverse effects with
objective of determining their safety and efficacy.

4. PHASES OF CLINICAL TRIAL
Phase 0 1 11 111 1V
PURPOSE Pk
Pd
Screening for Safety
Safe dosage
ADME
BA
S/Es
drug interaction
Short term s/es
efficacy
safety
efficacy
Monitor S/Es
basis for labelling
new formulations
Collect info
Compare to other
treatments
New indications
Qol surveillance
Risk benefit
Best use
subjects Healthy volunteers/
Sub w indication
Sub w
indication
Sub w indication Sub w
indication
Scope 20-80 Several 100 100-1000 100-1000
Length 0.5-1 1-2 2-3 1-5
70% 33% 25-30%

5. 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
safety
pharmacology
studies
pharmacokinetic
and toxicology
studies
reproductive
toxicity
studies
single dose
toxicity
studies
genotoxicity and
carcinogenecity
studies

6. OBJECTIVES
To assess a safe & tolerated dose
To see if Pk differ much from animal to man
To see if Pk show proper absorption, bioavailability
To detect any toxicity
To detect Pd including biomarkers

7. FIH-First In human study
gateway between
scientific research
and clinical practice
pharmacological
actions of new
drug, but also to find
dose level that has
acceptable S/Es.
provide early
evidence on
effectiveness.
serve as link to
advance new
promising drug
candidates and are
conducted primarily
to determine safe
dose range for
further clinical
development.
conducted in short
time, few centres,
depending on how
common disease is
and type of
intervention. Centre
has emergency care
& facility for
kinetics study
Performed after
receiving ethics
committee clearance
and submission of
regulatory filings to
health authorities
IND application in
US, IMPD in
Europe

8. PHASE 1 EXPLORATORY CLINICAL TRIAL
• small molecules; in rodents and non-rodent species; large molecules, a non-
rodent species, typically non-human primate.
• dose is determined by utilizing all relevant IND-enabling preclinical results from
pharmacology, toxicology,PK studies; any available human experience with other
therapies that share MOA.
• starting dose must mitigate risk of toxicity while balancing need to elicit
pharmacologic activity especially when dosing patients with more grievous
conditions, cancer.

9. STUDY POPULATION
• <30 individuals, upper end of age range for enrollment is typically capped between
45 and 60
• Healthy volunteers; Exception; toxic drugs Eg AntiHIV, Anticancer drug trials,
• Exclusion criteria ;Women of child bearing age, children
• If women of child bearing potential,studies short in duration (e.g., 2 weeks) with
intensive control of pregnancy risk.

10. STUDY DESIGNS
• Parallel group design
• Crossover study design

11. INFORMED CONSENT
• Expected side effects as noted in preclinical studies are presented and possibility of other unpredictable
side effects can occur must be stated.
• Preferably be explained by clinical staff at study site rather than sponsor and must contain rationale for
start dose and maximum dose in lay language.

12. STUDY SIZE
• blinded, placebo-controlled studies
• with 8-10 subjects per cohort randomized in 3:1 or 4:1 ratio such that 6-
8 subjects receive the active therapy and 2 subjects receive placebo.

13. WHICH DOSES?
• US FDA require evidence from at least two mammalian species, non-rodent
species.
• with anti-cancer drugs initial dose is usually 1/10 of dose that is associated
with 10% of rodents dying in lab studies.
• If non-rodent species indicates that this dose is too toxic then starting dose
could be 1/3 or 1/6 of lowest toxic dose in those species.

14. o FDA guidance aims at avoiding toxicity at initial doses by using accepted benchmark for
safety, NOAEL obtained from most sensitive toxicology test species as starting point for
determining reasonably safe starting dose in healthy volunteer
o EMA guidance gave 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.

16. HED
CALCULATION

17. MOST APPROPRIATE SPECIES SELECTION
• differences in ADME of therapeutic between species
• class experience that indicate a particular animal model is more
predictive of human toxicity

18. APPLICATION OF SAFETY FACTOR
to provide margin of safety for protection of human subjects receiving initial clinical dose. safety factor
allows for variability in extrapolating from animal toxicity studies to studies in humans resulting from:
• uncertainties due to enhanced sensitivity to pharmacologic activity in humans versus animals;
• difficulties in detecting certain toxicities in animals (e.g., headache, myalgias, mental disturbances);
• differences in receptor densities or affinities;
• unexpected toxicities;
• interspecies differences in ADME of the therapeutic.
differences can be accommodated by lowering human starting dose from HED of selected species NOAEL.

19. SAFETY FACTOR
• Steep dose response curve.
• Severe toxicities
• Non-monitorable toxicity.
• Toxicities without premonitory signs
• Variable bioavailability.
• Irreversible toxicity.
• Unexplained mortality.
• Large variability in doses or plasma drug
levels eliciting effect.
• Nonlinear pharmacokinetics.
• Inadequate dose-response data.
• Novel therapeutic targets.
• Animal models with limited utility.

20. SAFETY FACTOR
• smaller safety factor used when toxicities produced by therapeutic are easily monitored,
reversible, predictable, and exhibit moderate-to-shallow dose-response relationship with
toxicities
• that are consistent across tested species (both qualitatively and with respect to
appropriately scaled dose and exposure).

21. PAD
• Selection of PAD depends upon factors and differs among pharmacological drug classes
and clinical indications.
• once MRSD determined, it may be of value to compare it to the PAD derived from
appropriate pharmacodynamic models.
• If PAD from in vivo study, HED can be derived from PAD estimate. This HED value
should be compared directly to MRSD.

22. TRIAL DESIGNS
• 3+3, MBAD
• Other variations of this design have been
implemented including “2+4”, “3+3+3”,
and “3+1+1.”
• pharmacologically guided dose
escalation (PGDE) which escalates based
on prespecified systemic exposures that
correlate with pharmacologic activity
(e.g. significant tumor growth inhibition)
and/or toxicity .
• continual reassessment method (CRM)
• escalation with overdose control
(EWOC)
• modified CRM; utilizes time-to-event
endpoints for handling late-onset or
cumulative toxicities (TITE-CRM)
Rule based Adaptive Bayesian model-based

23. o several methods for determining subsequent doses; based on Fibonacci sequence,
o he range could be based on evidence from other studies or previous experience, or they could come from
logrithmic scale (if starting dose 5 mg, subsequent doses could be 10, 20 and 40 mg).
o researcher could decide dose range, increase could be greater earlier on. In example below, dose
increases by about 50% in three doses after starting dose of 100 mg, but at higher doses relative increases
are lower:
• Dose (mg) 100 150 225 350 450 550
• Relative increase − 50% 50% 55% 29% 22%

25. PRIMARY ENDPOINTS
• Primary goal is to identify appropriate dose and dosing interval for testing efficacy in phase 2 trials
• DLT should occur relatively soon after drug was administered. In phase I trials based on subjects
who are already ill, some adverse events are expected naturally, and so may not be classified as DLT.
trial protocol should provide clear definitions of toxicity.
• MTD
• MBAD

26. SAD studies MAD studies
Food effect
studies
ADME (Mass
Balance) studies
Studies in Specific
Populations

27. Renal Impairment Study
• 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
Hepatic Impairment Study
• Effect of hepatic impairment on PK of parent drug and metabolites
• Dosage recommendations for various stages of hepatic impairment

28. RENAL IMPAIRMENT: DORIPENEM
POWDER FOR IV USE
• Because doripenem is primarily eliminated by kidneys, Full PK study in
patients with renal impairment was conducted.
• In Phase 2/3 trials, dosage was adjusted based on Cr CL.
• label recommends dosage reduction for patients with moderate or severe
renal impairment and hemodialysis as treatment for overdosage.

29. DRUG INTERACTION STUDIES
• Exposure-response information on drug is important in assessing clinical
significance of change in AUC of substrate by inhibitor/inducer.
• Based on preclinical metabolism, drug transport, and DDI study results, if drug
candidate shows strong DDI potential in particular associated with key
metabolizing enzymes like cytochrome P450 3A4 (CYP3A4), prudent to include
DDI assessment

30. EXAMPLES :
DRUG INTERACTION: BOSUTINIB
ORAL TABLET
• Bosutinib, CYP3A substrate is extensively metabolized; only 3% of dose is excreted
unchanged in urine.
• 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.

31. FOOD EFFECT STUDY
• To evaluate effect of food on rate and extent of drug absorption from a
formulation
• effect of food on BA of oral drugs and to investigate any differences in absorption
of the drug by body, caused by eating before drug is given.
• crossover study, with volunteers being given two identical doses of drug while
fasted, and after being fed.

32. FOOD EFFECT: ATAZANAVIR ORAL
CAPSULES:
• Administration of single dose of atazanavir (800 mg) with light meal increased Cmax
by 57% and AUC by 70%; high-fat meal increased AUC by 35% with no change in
Cmax. Clinical trials were conducted under fed conditions
• Label directs administration with meal or snack

33. Bioavailability/Bioequivalence Studies

34. PHARMACOKINETICS

35. IMMUNOGENICITY ASSESSMENT
• animal studies are not predictive of immune responses in human,
• opportunity to gauge immunogenicity potential of new biologic
drug candidate
• carries implications for both clinical safety and efficacy.

36. SAFETY MONITORING
• assessment of CVS, CNS, and respiratory systems.
• Non-rodent species should be chosen that are most pharmacologically (e.g., target sequence
homology, relative binding affinity); for small molecules, metabolically relevant to human.
• Typically, canine and non-human primates are used for small and large molecule studies,
respectively
• Thorough QT Study
• more thorough ECG monitoring.

37. • anaphylaxis, Stevens Johnson syndrome or acute liver failure are almost always due to active
drug. new topical drug candidte , systematic collection of localized reactions.
• drugs that affect multiple signaling pathways or may cause amplification of immunologic or
coagulation cascades or risk release of cytokines warrant extra caution in monitoring and
dosing paradigms.

38. MONITORING OF A/Es
• to designate what toxicities are important. These can be laboratory tests (such as AST/ALT sr
creatinine) or set of symptoms such as severe diarrhea.
• over course of trial unanticipated DLT could emerge. duration of observation has to be defined
during which event has to occur in order to considered related to experimental therapy. it is
better to perform a study to determine MTD in population of patients for whom therapy will
be intended, because sometimes patients have different susceptibility to event compared to
healthy people .
• patients will more often have certain symptoms or findings that are part of their disease,
making interpretation difficult

39. MONITORING OF A/Es
• all cases, design safety monitoring plan prior. to set out how and what data will be collected,
how and when it will be reviewed, and what are the possible recommendations; in case where
toxicology studies suggest that particular type of medically serious toxicity likely to occur,
rules set out that require stopping dosing of study drug in individual subject or for stopping
study altogether
• independent DMC; FIH study in placebo controlled double blind manner; high level of
concern, new agent unduly toxic. privy to unblinded data so drug induced effects readily
identified.

40. BIOMARKER ASSESSEMENT
Disease Biomarker
DM RBS, FBS,HBIAC,RETINALASSESSMENTS
HTN BP.HR,PLASMA RENIN,ANGIOTENSIN 1, 11
ALDOSTERONE
HEART FAILURE PRO BNP
ASTHMA /COPD LEUKOTRIENENES
CARDIAC ISCHAEMIA TROP T , MYOGLOBIN
CANCER MARKERS PSA,HER2/NEU,EGFR
OXIDATIVE H2O2, ALPHA 1 ANTIPROTEINASE
ANTIOXIDANT SOD,GLUTATHIONE,CATALASE
BREAST CARCINOMA BRCA ½
PROSTRATE CANCER PSA
TRASTUZUMAB TREATMENT HER2

41. TWO PHASE 1, OPEN‐LABEL, MASS BALANCE STUDIES TO DETERMINE THE PHARMACOKINETICS OF
14C‐LABELED ISAVUCONAZONIUM SULFATE IN HEALTHY MALE VOLUNTEERS.
CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT. 2018 FEB 1;7(2):207-16
TOWNSEND R, KATO K, HALE C, KOWALSKI D, LADEMACHER C, YAMAZAKI T, AKHTAR S, DESAI A.
STUDY 1
• Isavuconazole
• High oral BA
• Profiling was carried out using orally
administered [cyano-14C]isavuconazonium
sulfate,labeled in isavuconazole component of
drug
• isavuconazole-derived radioactivity was
recovered approximately equally in urine and
feces (46.1% and 45.5%,).
STUDY 2
• BAL8728
• Low oral BA
• Profiling was achieved using IV-
administered [pyridinylmethyl14C]
isavuconazonium sulfate, labeled in
BAL8728 prodrug
• BAL8728-derived radioactivity was
predominantly recovered in urine
(96.0%).

42. Study feature Example
Target disease Parkinson’s disease
Drug being investigated BAY 63-9044, a new 5-HT1a-receptor agonist (has
neuroprotective and symptomatic effects)
Aim To determine the maximum tolerated dose
Design First-in-man trial of male healthy volunteers, aged 18–45 years
(randomised study)
Treatment doses investigated 0.25, 0.50, 1.20, 2.50, 5.00 mg and placebo
Definition of DLT
(i.e. treatment-related side-effects)
Any drug-related adverse event (graded mild, moderate, severe)
Number of subjects N = 45
Main result There were no serious adverse events
The number of mild or moderate events out of the number of
subjects in the cohort were:
Placebo n = 0/14
0.25 mg n = 2/7
0.50 n = 0/7
1.20 n = 0/6
2.50 n = 1/5
5.00 n = 5/6

43. SUMMARY
• Phase I studies are small and aim to provide first assessment of safety in human
subjects
• There are simple designs for determining dose of new drug that has acceptable no. of
serious S/Es
• Trials of new, safer therapies may need to have different biological endpoints as well
as toxicity
• Reports of phase I studies should provide clear information on pharmacological
properties of new drug, including plasma concentration curves over time, and details
of adverse events.

44. THANK YOU