Objectives Of Pre-clinical Studies

 Objectives Of Pre-clinical Studies

• The purpose of pre-clinical study is to develop adequate data to decide that it is reasonably safe to proceed with human trials of the drug.

• Means, a laboratory test of a new drug or a new medical device, usually done on animal subjects, to see if the treatment really works and if it is safe to test on humans.

• However the main objective is to collect the data to submit to the FDA for IND filing.



Phase 0- 

•Is the agent hitting its target ?

Phase 1- 

• How does the agent affect the human body.

• What doses are safe.

Phase 2-

• Does the agent or intervention have an effect on the disease

Phase 3-

• Is the new agent or intervention better than the standard?

• Participants have an equal chance to be assigned to one of two or more groups

Phase 4 - 

• Post Marketing Surveillance - Long Term Safety.

* Phase 0:- 

Advantages-

• Less chances of adverse effects.

• Less no. of volunteers.

• Short duration.

• Reduced cost of development.

• Reduced drug development time.

* * Study of new drug in micro doses to derive PK information in human before undertaking phase studies is called PHASE 0

• Micro dose:- 

- Less than 1/100 of the dose of a test substance calculated to produce pharmacological effect with a max dose ≤100 micrograms.

• Objective:-

- To obtain preliminary Pharmacokinetic data.

• Preclinical Data:-

- Subacute toxicity study in one species by two routes of administration.

* Phase 1:-

➤ First stage of testing in human subjects.

➤ Designed to assess the safety, tolerability, PK and PD of drug.

➤ 20-100 healthy volunteers.

➤ Patients: Anticancer drugs, AIDS therapy.

➤ Duration: 6-12 months No blinding/Open labelled.

➤ AIM: -

1. To determine the maximum tolerated dose (MTD) of the new treatment.

2. The MTD is found by escalating the treatment dose until the dose-limiting toxicity (DLT) is reached.

Objectives:-

• Primary:-

- Tolerability and Safety.

- Pharmacokinetics.

• Secondary:-

- Pharmacodynamics.

BASIC PRE-REQUISITES:-

• Preclinical data.

• IND application.

• Approval by the regulatory authority.

• Protocol approval by the Ethics Committee.

• Informed consent.

• Adherence to Declaration of Helsinki/ICH-GCP guidelines, at the start as well as from time to time, during the study.



* PHASE 2:-

• Therapeutic Exploratory Trial.

• 20-300 Subjects.

• To confirm effectiveness, monitor side effects, & further evaluate safety.

• First in patients (who have the disease that the drug is expected to treat).

• Duration: 6 months to several years.

* Phase II studies:- Pre-requisites

• Review of Phase I data.

•Innovator/Experts.

• IRB.

• DCGI.

• Prior approval by IRB and DCGI is Mandatory.

• For New Actions of a marketed drug, start with Phase II (Phase I exemption obtained)

* Phase II Types:-

• Phase IIA: Designed to assess dosing requirements.

• Phases IIB: Designed to study efficacy.

* PHASE 3:-

• Therapeutic confirmatory trials.

• Large scale, multicenter, Randomized, Controlled trials.

• Target population: several 300's to 3000 patients.

• Takes a long time: up to 5 years.

• To establish efficacy of the drug against existing therapy in larger number of patients, method of usage, & to collect safety data etc.

Objectives:-

•To assess overall and relative therapeutic value of the new drug Efficacy, Safety and Special Properties.

•To determine optimal dosage schedule for use in general.

•The dosage schedule in C.T.'s should be as close as possible to its anticipated clinical use.

Phase Illa:-

1. Prior to NDA.

2. Generates data on safety and efficacy.

Phase IllЬ:-

1. After the NDA but prior to the approval and launch.

2. These may supplement or complete the earlier trials or may be directed to Phase IV trials.

* PHASE 4:-

➤ Done after drug has been marketed.

➤ No fixed duration / patient population.

➤ Studies continue to collect data about effects in various populations & side effects from long term use.

➤ These are primarily observational or non- experimental in nature.

➤ Confirm the efficacy and safety profile in large populations during practice.

➤ Helps to detect rare ADRs, Drug interactions.

➤ Harmful effects discovered may result in a drug being no longer sold, or restricted to certain uses.


Example:- On September 30, 2004, Merck withdrew Rofecoxib from the market because of concerns about increased risk of heart attack and stroke associated with long-term, high-dosage use.


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