Clinical Trials (Phases and Design of Clinical Trials)

Question 1

What is clinical trials in short?

Answer 1

research of new drugs or treatment on human patients (not to be confused with preclinical trials where they test on animals)

Question 2

What are the stages of drug discovery?

Answer 2

1. Target identification and validation

2. Lead identification and optimization

Question 3

What are the stages of Drug development?

Answer 3

1. Preclinical studies
2. IND (investigational new drug)
3. Clinical trial: Phase 1,2,3
4. NDA (new drug application)
5. Large scale Manufacturing/ Phase IV

Question 4

What occurs in the target identification and validation?

Answer 4

Target identification -identify the cause of the disease

Target validation -functional role of the target in a disease

Question 5

Define the term UMN:

Answer 5

UMN identification of unmet medical needs – therapeutic areas that are required for drug development

Question 6

What is hit identification?

Answer 6

Hit identification-the chemicals that have bioactivity against the drug target

Question 7

What is the difference between lead generation and lead optimisation?

Answer 7

Lead generation- leads selected from hits, is the compound promised to treat the disease

Lead optimisation- optimise the compound that demonstrate the potential of the new drug and modify the chemical structure of a lead compound

Difference, lead generation is the compound to treat the disease but lead optimisation is a better version of it , where it is essentially “optimized” “fine tuning”, improve the properties to make it less toxic and more effective

Question 8

Why is preclinical studies important?

Answer 8

We cannot start clinical studies until a reasonable amount of pre-clinical work has been completed and there is enough evidence that the compound is potentially safe for use in humans

Question 9

What does the IND involve and what is its significance?

Answer 9

Before the clinical trials, the sponsor must file an IND with the FDA

IND must include:
results from pre clinical studies
must be updated annually

Sponsor must wait 30 days after filing the IND before starting studies in humans

Question 10

What occurs during the Phase 1 clinical trials?

Answer 10

FIH (first in human) study

During this phase, the investigational drug (IP-investigational product, Study drug) or biologic (compound derived from living organism (e.g enzyme, protein, vaccine) is given to humans for the first time

Frequently referred as safety studies

Question 11

What are the objectives of the first Phase study?

Answer 11

1. Determine the metabolic, pharmacokinetic (ADME) and pharmacologic action (drug characteristics/properties) of the drug in humans
2. To asses the adverse effects (side effects) associated with different doses (dose-finding)
3. Indication of whether there is evidence of efficacy

Main concern: Subject safety (how well it works) not drug efficacy

Question 12

What does ADME stand for?

Answer 12

Absorption- bioavailability of the drug (amount of drug that is available that will reach the target site after passing through gastric and liver metabolism)

Distribution- how much of the drug is being distributed to the tissue/ targeted site

Metabolism- How it will be metabolized (how will it break down?)

Excretion- how it will pass out the body

Question 13

Dose-finding:

Answer 13

Finding the minimum and maximum effective doses, looking for safe dose range

Question 14

What are the characteristics of the Phase 1 Clinical Trials?

Answer 14

Short duration (few weeks-months)

On a small group of healthy volunteers (no targeted disease)
-20 to 100

Very closely monitored

Not randomized
-everybody receives active compound

Often done in special testing facilities designed for phase 1 studies

Phase 1a: Healthy subjects
Phase 1b: Patient with targeted disease

Question 15

Explain the term randomization:

Answer 15

The process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias

Question 16

Randomization process:

Answer 16

1 control group which takes another drug in the market to compare with the IP and the other is the treatment group which takes the IP

Question 17

What is the need for Stratification?

Answer 17

Stratification- categorizing subjects into subgroups by specific characteristics
(e.g age, gender, etc)

Enables researchers to look into separate subgroups to see whether differences exist

Question 18

What are the characteristics of the Phase 2 of Clinical Trials?

Answer 18

• rigid, well controlled studies (all variables are kept constant, can be replicated to generate similar or same results)
• small patient population
• less that few 100s

Subjects have the target disease but no other illnesses (don’t want to complicate the response or contribute to side effects)

Usually consists of double blind studies using a placebo (“fake drug”, inert substance) or comparator drug (marketed drug)

Question 19

Define the term Blinding:

Answer 19

Also known as “masking”
-A procedure in which one or more parties to the trial are kept unaware of the treatment assignments

Single blinding
-Subject(s) being unaware of the treatment assignment(s) but investigators and sponsors are aware

Double blinding
-Subject(s), investigator(s), monitor/CRA are unaware of the treatment assignment(s) to remove bias and fair assessment

Question 20

Define the term control in Clinical trials:

Answer 20

Used as reference

Also known as comparator (compare the drug to another drug)

Can be either
-active compound
another marketed drug
different dose of drug under study

-Placebo

Question 21

Define the term placebo:

Answer 21

A preparation which is pharmacologically inert but do not have any therapeutic effect

Often referred as dummy drug or inactive compound to patients

Question 22

What is the purpose of Phase 2?

Answer 22

Determine whether or not the investigational drug (IP) demonstrates efficacy for the indication within the safe dose range established in phase 1
(drug efficacy within safe dose ranges)

Short term adverse effects (side effects) and risks are also assessed

Determine the toxicity of the drug maybe not seen in phase 1 because we are working with larger population and different people may have different responses due to their genetic makeup.

Safety will still be of the primary concern

Question 23

What is the difference between phase 2A and Phase 2B?

Answer 23

Phase 2A: specifically designed to assess dosing requirements (how much drug should be given)

Phase 2B: is specifically designed to study the efficacy (how well the drug works at the prescribed dose(s)

Question 24

During Phase 2 we also carry out

Dose ranging finding:

Answer 24

• Establishing a minimum and maximum effective dose

- PK(ADME) data correlating blood levels of the drug with pharmacological effect

Question 25

When will Phase 3 of the clinical trial be carried out?

Answer 25

Only be initiated if the data generated in phase 1 and phase 2 show a satisfactory safety profile and there is sufficient evidence of efficacy

Question 26

What is the purpose of Phase 3 of the clinical trial?

Answer 26

-To demonstrate the long-term safety and efficacy needed to assess the risk/benefit relationship of the drug and to provide adequate data for the product package insert

-compare new treatment against standard treatment
(or placebo)

Question 27

What are the characteristics of Phase 3?

Answer 27

Expanded, randomized, controlled studies

Large patient populations
-Multi-centered

Patient population represent the types of patients the compound is intended to treat after it is marketed

May extend to several years

Question 28

When is Phase 3A conducted and why?

Answer 28

Conducted after efficacy of the drug is demonstrated but prior to regulatory submission

(before NDA submission)

• conducted in patients with targeted disease
• generate additional safety and efficacy of data

[] May conduct in special patient groups such as the elderly, renal impaired (people with co existing diseases)

-provide information needed for the package insert and labelling of the medicine

Question 29

When is Phase 3B conducted and why?

Answer 29

conducted after regulatory submission but before approval and launch of drugs

Purpose of this study:

• to gather additional safety data,
• to gather information on additional indications for the drug
• to assess its use in special patient populations such as pediatric or geriatric patients

Question 30

What is the importance of Phase 4 clinical trials? When is it done?

Answer 30

Done after the approval of NDA (Post-marketing trial)

Often to determine additional information about the safety or efficacy profile of the compound

Question 31

What are the characteristics of Phase 4?

Answer 31

-Studies required as a condition of approval by the FDA

-Long-term safety studies required by the FDA
[]epidemiologic or post-marketing surveillance studies

• Studies conducted to look at the compound in comparison with other marketed products
• Studies designed to familiarize physician with the compound
• May discover new indications or drug interaction

Question 32

Summary:

Answer 32

Phase 1 studies are small safety studies, usually done in healthy volunteers

Phase 2 studies are usually the first studies in patients with the disease or condition of interest

Phase 3 studies are large, comprehensive safety and efficacy trials

Phase 3B studies are those being done during the time the compound is in the FDA review cycle

Phase 4 studies are done after approval of the compound

Question 33

Designs of clinical trial-What are randomized control trials?

Answer 33

Are comparative studies with an intervention (new treatment) group and a control group

The assignment of the participant to a group is determined by randomization

Question 34

Why are randomized control trials effective?

Answer 34

-most rigorous way of determining
[] whether a cause-effect relation exists
[] the cost effectiveness of a treatment (pharmacoeconomics)

Question 35

What are the advantages of the randomized control studies design?

Answer 35

• Randomization removes the potential of bias in the allocation of participants to the intervention group or control group
• Variables and other characteristics of the participants will be evenly balanced between the intervention and control group
• Validity of statistical tests of significance is guaranteed

Question 36

What are the important features of RCT?

Answer 36

1. Random allocation to intervention groups (using a computer to generate groups by chance)
2. Patient and trialists should remain unaware of which treatment was given until the study is complete
3. All intervention groups are treated identically except for the experimental treatment (treated the same but the only difference is the type of drugs)
4. Patients are normally analyzed within the group to which they were allocated, irrespective of whether they experienced the intended intervention
5. The analysis is focused on estimating the size of the difference in predefined outcomes between intervention groups (look for difference base on a fixed outcome)

Question 37

What are the attributes of a proper randomization scheme?

Answer 37

1. Assignment remains unknown to the patient, doctor and the clinic staff until it is needed for treatment initiation
2. Future assignment cannot be predicted from past assignment
   (you can’t predict the next assignment based on current trend of allocation)
3. Order of allocation is reproducible (can replicate)
4. Method of generation of allocation is documented
5. Method of generation of allocations has known statistical properties
6. Method of generation provides clear audit tracking
   (allows you to fully track any changes affecting your system)
7. Departures from the established order of allocation can be detected (detect any protocol division, deviate away)

Question 38

What are the limitations of RCT?

Answer 38

The use of RCT is limited by ethical and practical concerns

Exposing patients to an intervention believed to be inferior to current treatment is often thought unethical

In other circumstances a randomized controlled trial may be ethical but infeasible (not possible to do easily or conveniently; impracticable)

Randomized controlled trials are generally more costly and time consuming than others