Phase 1 clinical trial

Dr Banhisikha Adhikari

What is a clinical trial? 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, devices5. behavioral treatments6. 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.

History of clinical trials

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.

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

Phases of drug development

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.

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

Investigational Medicinal Products (IMPs)

chemical entities biotechnology products cell therapy products gene therapy products plasma-derived products Immunological products herbal, homeopathic and radiopharmaceutical products

High risk IMPs

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

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

Method of First In Man study

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]

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.

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

Study Designs Applied

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.)

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

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.

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

Execution of phase 1- study site

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

Execution of phase 1- formulation applied

Intravenous : most flexible as 1.doses can be adjusted easily2.administration can be stopped

immediately if any adverse event occurs. (intravenous

infusion using a controllable infusion pump is preferable to bolus

administration) Oral: • oral powder reconstituted as suspension

or solution is administered to the subject.• tablet formulations may be used as well.

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

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 response relationship

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.

Subsequent Studies Done

1. ADME (i.e. Mass Balance) Study : 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 : 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

Subsequent Studies Done

3.Food Effect Study : 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 : 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

Subsequent Studies Done

5.Hepatic Impairment Study 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): In vivo safety study required for all IMPs identify drugs that prolong QT and need a more thorough ECG monitoring

in pivotal trials

Desirable Clinical Pharmacology Properties of a Drug

ABSORPTION: 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

Desirable Clinical Pharmacology Properties of a Drug

METABOLISM/EXCRETION: 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

Phase 1 Studies: Impact on Labeling

Conclusion 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.

Renal Impairment Example:

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.

Food Effect Example:

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

Drug Interaction Example:

bosutinib oral tablets: Bosutinib a CYP3A substrate is extensively

metabolized; only 3% of the dose is excreted unchanged in the 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.

Thank you