Phases of Clinical Trials

preclinical Drug Development

Before clinical drug development can begin, many years of preclinical development occur.

Basic research teams consisting of chemists. pharmacologists, biologists, and biochemists.

This team identify promising therapeutic categories and classes of compounds.

Animal Testing

Compounds are selected for secondary pharmacology evaluations and toxicology testing in animal models.

Compound that is pharmacologically active and safe in at least two nonhuman species may then be selected for study in humans.

Investigational New Drug (IND):

Before the drug can be tested in humans, an Investigational New Drug (IND) application must be filed with an appropriate regulatory agency.

IND  contains supporting preclinical information and the

proposed clinical study designs.

Phases of clinical trials

Development of a new drug in humans is divided into four phases.

Different phases refer to different types of studies rather than a specific time course of studies.

The generalized sequence of studies may be tailored to each new drug during development.

Pre-approval segments (Phases 1 through 3).

Post-approval segment (Phase 4).

Phase 1

Studies that involve normal subjects, are included in Phase 1.

Phase 1 of the clinical program begins After the regulatory agency has approved the drug for testing in humans.

Goal:

To demonstrate safety in humans.

To collect sufficient pharmacokinetic/pharmacological information for determination of the dose strength and regimen for Phase 2 studies.

Study Subjects:

Typically conducted in healthy adult subjects.

Other Evidences obtained:

Metabolic profile.

Adverse events associated with increasing dosages.

Evidence of efficacy.

Pharmacokinetic profile…includes information

about absorption (initial studies has an oral formulation).

Drug-drug interactions.

Assessment of bioequivalence of various formulations.

Dose range and route of administration.

Dosing/Sampling (Phase 1)

The initial dose may be based on animal pharmacology or toxicology data.

Doses are increased gradually until an adverse event is observed.

Sampling is done by collecting Blood and urine.

First Study (single dosing)

Second Study (Multiple dosing).

Study Design (Phase 1)

Placebo controlled, double-blind(so that the drug effects, such as drug induced can be distinguished from the nondrug effects)

Escalating single-dose study is initiated.

Healthy  volunteers are recruited.

Sometimes  patients are used (e.g testing anticancer drug that may be too toxic to administer to healthy volunteers).

Include two or three cohorts, with six or eight subjects receiving the active drug and two subjects receiving placebo.

The groups may receive alternating dose levels which allow assessment of dose response (i.e., adverse events) relationship.

Study Setting (Phase 1)

Participants in the first study are usually hospitalized or enrolled in a clinic.

Why???

Clinical measurements can be performed under controlled conditions.

Any medical emergency can be handled in the most expeditious manner.

Maximum Tolerated Dose(MTD)

The first study in humans is usually not considered successfully completed until an MTD has been reached.

Relationship between a clinical event (e.g., emesis) and a particular dose level observed under controlled conditions can provide information that will be extremely useful when designing future trials.

Multiple-dose safety

A multiple-dose safety study typically is initiated once the first study in humans is completed.

Goal:

To define an MTD with multiple dosing before to initiating well-controlled efficacy testing.

Study Design:

Should simulate actual clinical conditions in as many ways as possible.

The inclusion of a placebo group is essential to allow the determination of drug-related versus nondrug-related events.

Dosages, frequency, dose escalations, and dose tapering, should simulate the regimen to be followed in efficacy testing.

Study Duration:

dosing in the second study lasts for 2 weeks.

length of the study may be increased depending on the pharmacokinetics of the drug.

if the drug is to be used to treat a chronic condition, a 4-week study duration may be appropriate.

Study Subjects:

minimum enrollment of 24 subjects should be anticipated.

subjects would be hospitalized for the duration of the study.

Samples:

Blood and urine.

Pharmacokinetic data

To determine:

whether the pk parameters obtained in the 1st study accurately predicted the multiple dose pharmacokinetic behavior of the drug.

verification of pharmacokinetic linearity (i.e., dose proportionality of C,,, and AUC)observed in the  1st study.

whether the drug is subject to autoinduction of clearance upon multidosing.

Existence and accumulation of metabolites that could not be detected in the previous single-dose study

Demerits of ADR clinical Trials

Pre-marketing trials cannot detect important reactions that occur at rates of 1 in 10,000.

Only pharmacologically predictable ADRs may be identified in clinical trials.

ADRs are only assessed by the clinicians who run them so rare/potentially serious ADRs often remain undetected.

ADR’s and Clinical Trials

Evidence of safety must be demonstrated for regulatory authorities to permit marketing.

The degree of exposure of the drug is an important factor in understanding the toxicologic results of the study.

However, it is not possible to discover the complete safety profile of a new drug prior to its launch.

These involves on average 2500 patients.

Patient selected for ADR detection should be without the multiple disease states or complex drug histories.

Phase 2

Focus on efficacy.

Pharmacokinetic information obtained in Phase 1 studies is used to optimize the dosage regimen.

Not as closely monitored as Phase 1 studies.

Conducted in patients.

Information Obtained:

These studies are designed to obtain information

On:

Efficacy.

Pharmacologic effects.

Pharmacokinetics.

Efficacy trials (Phase 2)

Efficacy trials should not to be initiated until the MTD has been defined.

Therapeutic window:

On completion of the efficacy trial, a therapeutic

window for plasma drug concentrations can be defined by reviewing the correlation between plasma drug concentrations and key safety and efficacy parameters.

Goal:

To improve efficacy and safety of the drug. 

By individualizing the dosage based upon previous plasma drug concentration profiles in the same patient.

Study Design (Phase 2)

Pharmacokinetic information obtained in healthy volunteers (during phase 1) is key to the design of successful efficacy trials.

During the planning stage of an efficacy trial, the focus is on the dosage regimen and its relationship to efficacy measurements.

Dosage regimen:

Following information obtained earlier must be considered when choosing an optimal dosage regimen for the study.

Disease or physiological states of the test patients 

(e.g., organ dysfunction as a function of age).

concurrent medications (e.g., enzyme inducers or inhibitors).

Safety data

Phase 3

Phase 3 clinical trials will be initiated if:

earlier clinical studies establishes: 

Drug’s therapeutic properties.

Cinical pharmacologic properties.

Toxicologic properties.

and if it is still considered to be a promising drug.

Study Subjects:

Phase 3 studies enroll many more patients.

Study Site:

conducted both in a hospital or controlled setting and in general practice settings.

Goals:

to confirm the therapeutic effects.

to establish dosage range and interval.

to assess long-term safety and toxicity.

to identify less common side effects and AEs that develop latently.

to evaluate/quantify specific effects of the drug, such as drowsiness.

to establish a place for the drug in its therapeutic class.

to identify the most appropriate population or subpopulation for the study drug.

Relative safety profiles:

to establish better safety profile of the investigative

compound as compared to its already available/existing alternative.

Drug Interactions (Phase 3)

Polytherapy ….high risk of drug-drug interactions,both from pK and pD perspectives.

Closer inspection of drug interactions is warranted in Phase 3 clinical trials.

The likelihood of drug interactions and may be predicted from in vitro data.

Evaluation of Drug Interactions :

The potential for interactions needs to be evaluated from two perspectives:

potential that the new drug may affect the pharmacokinetics of other drugs

(depends on the ability of the new drug to affect various enzyme and carrier-mediated clearance processes).

the potential that other drugs may affect the pharmacokinetics of the new drug.

(requires knowledge of the components of clearance 

General practitioners (phase 3)

Early clinical trials are conducted at university medical centers with specialized physicians.

General physicians are exposed to study drugs during this phase because they will be the one writing most of the prescriptions post marketing.

Phase 4

Phase 1, 2, and 3 studies depends on strict inclusion and exclusion criteria.

Phase 4 emphasizes on collection of safety information.

Phase 4 studies employ mainly observational study designs.

Post marketing surveillance and any additional studies requested by the regulatory agency are conducted during Phase 4.

Data collection (Phase 4)

Is an extensive, scientific exercise.

Involves:

Detailed blood work.

Special laboratory tests.

Careful physiologic monitoring.

Patient Population:

Post marketing studies, however, are often targeted for much larger patient populations (5000- 10,000 or more).

Groups in Clinical Trials

Comparative groups to assess the efficacy and safety of the investigational drug relative to other drugs currently marketed. 

Control group

The control groups take either placebo or active medication.
Sometimes more than one control group is used in a study.

Cohort group
group taking the investigational drug.

Placebo & Active Medication
Placebo Should be as similar as possible to the drug being investigated.(e.g., same color. taste. and shape).

Active medication taken by the control group also should be as similar as possible to the drug being investigated (e.g.. same color, taste, and shape).
To  maintain the blind:
If the formulations cannot be made with similar appearances a placebo of each formulation could be made.
So subjects would take one active formulation and the placebo of the other formulation.