Sep.

23th, 2024

Module 3 – Phase 0 and Phase 1 Clinical Trial

Phase 0 Clinical Trial

- Known as human micro- dosing studies designed to speed up development of promising

drugs

- Involves administration of “micro-doses” to a small number of subjects

- Does not give data on safety and efficacy

- The dose of the drug that is 1% (1/100th) of the pharmacologically active dose

determined from animal model and in vitro system, up to maximum of 100 mcg or 30

nanomole for protein products

- Sub-therapeutic doses of drugs to study their effects in humans, to gather preliminary

data on safety, pharmacokinetics, and potential therapeutic benefits without producing

significant physiological effects

Phase 0/Microdosing

- Because human micro dosing studies are performed prior to Phase 1 studies, hence are

termed as Phase 0 study

- Are also termed as Exploratory IND studies

- Sub-pharmacologically active dose of drug is administered, and samples (typically

plasma) are collected and analyzed for parent drug or metabolites with no therapeutic or

diagnostic intent

Phase 0 Clinical Trial

- The principle of human micro-dosing is that safely administering micro-doses of INDs to

human to get valuable information on human pharmacokinetics and pharmacodynamics

at a much earlier stage

- Why Phase 0?

 Nearly one third of INDs failed in Phase 1 trial, mainly due to abnormal PK/PD and

safety profiles
  If drug development were to be terminated at the Phase 1 stage, then human

volunteers would have been unnecessarily exposed to failed drugs and large number

of animals would have been saved

Feature of Phase 0 Trial

- First in human trial conducted prior to traditional Phase 1 study

- Conducted in limited number of Human participants (10-15)

- Have limited dosing duration (< 7 days)

- Involves a very small dose (1/100th of the dose required to yield a pharmacological effect

of the test substance with a maximal dose of < 100 mcg

- Are designed to evaluate PK and/or PD properties of selected investigational agent before

Phase 1 study

- Have no therapeutic or diagnostic intent

- Often take less than 6 months to complete

Purpose of Phase 0 Trial

- To assist the GO vs NO-GO decision-making process of drug’s fate in the development

process very earlier

Procedure

- After the drug candidate has been selected and animal PK data is achieved, possible

human therapeutic dose is determined

- A micro dosing clinical trial application (Exploratory IND) should be submitted

- Micro dose is calculated from human therapeutic dose

- Bio markers and Bio-analytical methods should be determined, standardized and

validated
Advantages

1. Reduces the clinical trial cost and time of drug development

2. Reduces unnecessary exposure of drug to large number of participants

3. It establishes if the agent is modulating its target or not, so further clinical development

can be decided at early stage

4. Risk of adverse events is negligible

5. Requirement of pre-clinical safety data for microdosing is less

Phase I Clinical Trials

Objectives of Phase I Trial

1. To assess safety of the drug

2. To assess tolerability of the drug

3. To calculate MTD (Maximum tolerated dose)

4. To elevate PK (Pharmacokinetic properties) and PD (Pharmacodynamics)

- These objectives provide firm basis for investigators to determine further testing of drug

on humans (to decided go-vs no-go)

Design and Conduct of Phase I Trials

- Types of Phase I trials

 Phase I trials include various types such as single ascending dose (SAD) studies,

multiple ascending dose (MAD) studies, and food effect studies, each designed to

evaluate different aspects of a drug's safety and pharmacokinetics

- Study population: healthy volunteers vs. patients

include patients, particularly when studying treatments for serious conditions or

diseases

- Dose-escalation methods and safety monitoring

 Dose-escalation methods, such as the 3+3 design, are used to identify the maximum

tolerated dose, while continuous safety monitoring ensures participant well-being

throughout the trial

Toxicology and Safety Pharmacology

- Preclinical toxicology studies required before Phase I

 Before Phase I trials, extensive preclinical toxicology studies are conducted to

evaluate the safety of a new drug

 These studies involve testing on animals to identify potential toxic effects and safe

dosage ranges

- Key toxicological endpoints

toxicity (long-term effects), and reproductive toxicity (effects on fertility and

offspring)

 These endpoints help in understanding the potential risks associated with the drug

- Safety pharmacology studies

 Safety pharmacology focuses on the potential adverse effects of the drug on vital

physiological functions, particularly cardiovascular, respiratory, and central nervous

system functions

 These studies ensure that the drug does not cause harmful side effects in critical

body systems

Ethical Considerations and Regulatory Requirements in Phase I Trial

- Ethical considerations in Phase I trials

 Ethical considerations include obtaining informed consent, ensuring patient safety,

and conducting trials with scientific validity

 Ethical oversight is provided by Institutional Review Boards (IRBs)

- Regulatory requirements for Phase I trials

 Regulatory requirements involve adherence to Good Clinical Practice (GCP)

guidelines, proper documentation, and compliance with national and international

regulations

- Role of IRBs and regulatory agencies

 IRBs review and approve trial protocols to protect participants, while regulatory

agencies such as the FDA oversee compliance and ensure that trials are conducted

ethically and scientifically

1. CMAX (Maximum Plasma Concentration Achieved)

2. TMAX (Time Required to Reach CMAX)

3. VMAX (Maximum Rate of Absorption of the Drug)

4. AUC (Area Under the Curve)

5. VD (Volume of Distribution of the Drug)

6. T HALF (Half-life of the Drug)

Pharmacodynamic Studies

- Blood samples are collected and stored

- Done to identify appropriate and validated biomarkers for determination of the drug

activity and efficacy

Stages of the 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

Single dose is given, and effects are observed

The assessment is mainly based on DLT (Dose limiting toxicity)

If PK data is in line with predicted safety value, then dose is increased in next group of

cohort

Dose escalation is continued till MTD (Maximum Tolerated Dose) is defined

Multiple Ascending Dose Design

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, thereby reducing variability)

- ICH Guidelines for Phase 0 and Phase 1

 For both phases, considerations include non-clinical safety studies (ICH M3(R2)),

pediatric populations (ICH E11(R1)), and good clinical practice (ICH E6(R2))

 SAFETY pharmacology and risk assessment are covered under ICH S7A and S7B

o Clinical safety management is guided by ICH norms ranging from E2A to E2F

- Role of the FDA and ICH

 FDA

o The FDA's role is primarily regulatory, ensuring that trials adhere to rigorous

guidelines protecting participant safety and ensuring data integrity

o It directly reviews and approves trial applications and oversees compliance with

regulations

 ICH

o The ICH provides a harmonized approach to help ensure that clinical trial data

are credible, optimizing the approval process and minimizing unnecessary

duplication of studies across regions

o It sets unified standards that are mutually recognized among regulatory

authorities in the US, EU, and other regions, facilitating drug registration

globally

o Both the FDA and ICH exert a significant influence on how clinical trials are

conducted, ensuring that the data arising from them are reliable, leading to safer

medicinal products
 o These organizations consistently work towards enhancing clinical trial

standards to protect public health and promote global cooperation in drug

development

Phase 1 Clinical Trial Information in Product Labels

Investigational New Drug Application

- An investigational New Drug (IND) program is how a pharmaceutical company obtains

permission to start human clinical trials and to ship an experimental drug across state

lines (usually to clinical investigators) before a marketing application for the drug has

been approved
Why IND is Needed

What is Required to Initiate IND Application?

- The results of previous experiments

- How, where, and by whom the new studies will be conducted

- Chemical structure of the compound: CMC info

- How the compound is manufactured

- Toxic effects in the animal studies

Types of IND Applications

- Investigator IND application

 Application is submitted by the investigator, who conducts a trial, and under whose

immediate direction the investigational drug is administered or dispensed

 An investigator submits a research IND application to propose studying of

o An unapproved drug

o An approved product for a new indication

o An approved product in a new patient population

 Application allows the FDA to authorize use of an experimental drug in an

emergency situation that does not allow time for submission of an IND application,

in accordance with 21CFR, Sec. 312.23 or Sec. 312.20

 It is also used for patients who do not meet the criteria of an existing study protocol,

or if an approved study protocol does not exist

 In such a case, FDA may authorize shipment of the drug for a specified use in

advance of submission of an IND application

- Treatment IND application

 Application is submitted for experimental drugs showing promise in clinical testing

for serious or immediately life-threatening conditions while the final clinical work is

conducted, and the FDA review takes place

 A drug that is not approved for marketing, may be under clinical investigation for a

serious or immediately life-threatening disease condition in patients for whom no

comparable or satisfactory alternative drug or other therapy is available

 In the case of a serious disease, a drug ordinarily may be made available for

treatment use during phase III investigations or after all clinical trials have been

completed

 In the case of an immediately life-threatening disease, a drug may be made available

for treatment use earlier than phase III, but ordinarily not earlier than phase II

- Screening IND application

 Filed for multiple, closely related compounds in order to screen for the preferred

compounds or formulations
  The preferred compound can then be developed under a separate IND

 Used for screening different salts, esters and other drug derivatives that are

chemically different, but pharmacodynamically similar

Resources for IND Applications

- The following resources include the legal requirements of an IND application, assistance

from CDER to help you meet those requirements, and internal IND review principles,

policies and procedures

i. Pre-IND Consultation Program

ii. Guidance Documents for INDs

iii. Laws, Regulations, Policies and Procedures

iv. Code of Federal Regulations (CFR)

v. Manual of Policies and Procedures (MaPPs)

Pre-IND Consultation Program

- CDER's Pre-Investigational New Drug Application (IND) Consultation Program fosters

early communications between sponsors and new drug review divisions to provide

guidance on the data necessary to warrant IND submission

- The review divisions are organized generally along therapeutic class and can each be

contacted using the designated Pre-IND Consultation List

After Submitting IND

- Once the IND application is submitted, the sponsor must wait 30 calendar days before

initiating any clinical trials

- If the sponsor hears nothing from CDER (Center for Drug Evaluation and Research), then

on Day 31 after submission of IND application, the study may proceed as submitted
 - The CDER is a division of the FDA that reviews New Drug Applications to ensure that

the drugs are safe and effective

Possible Reasons for Clinical Hold

- Human subjects are / would be exposed to an unreasonable and significant risk of illness

or injury

- Clinical Investigators named in IND application are not qualified

- Investigator Brochure is misleading, erroneous or materially incomplete

- IND does not contain sufficient information to assess risks

- Protocol is deficient to meet objective of trial

Following the Clinical Hold

- The sponsor may then respond to CDER by sending an “IND CLINICAL HOLD

RESPONSE” letter to the division

- To expedite processing, the letter must be clearly identified as an “IND CLINICAL

HOLD RESPONSE” letter

- The division then reviews the sponsor’s response and decides within 30 days as to

whether the hold should be lifted