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Phases of clinical trials

Phases of clinical trials

Contents

• Introduction:Clinical research

• Drug development phases

• Pre-Phase 1 activities

• Phases of Clinical trial

• Regulatory approvals: IND & NDA

• Summary of Clinical trial phases

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INTRODUCTION

• Clinical trial is a systematic investigation in human subjects for evaluating the safety & efficacy of any new drug. • Clinical trials are a set of tests in medical research and drug development that generate safety and efficacy data for health interventions in human beings.

Clinical trials are conducted only when

  • Satisfactory information has been gathered on the quality of the nonclinical safety
  • Health authority/ethics committee approval is granted in the country where approval of the drug is sought.
  • Clinical Trial is the mainstay for bringing out New Drugs to the Market.

DRUG REVIEW STEPS

1. Pre-clinical (animal) testing.

2. An investigational new drug application (IND) : outlines what the sponsor of a new drug proposes for human testing in clinical trials.

3. Phase 1 studies

4. Phase 2 studies

5. Phase 3 studies

6. Submission of New Drug Application (NDA) is the formal step asking the FDA to consider a drug for marketing approval.

7. FDA reviewers will approve the application or find it either “approvable” or “not approvable.“

8. Phase 4 studies

DRUG REVIEW

  • Before one can initiate testing in human beings, extensive pre- clinical or laboratory research is required
  • Research usually involves years of experiments in animal and human cells.
  • If this stage of testing is successful, the sponsor then provides this data to the FDA requesting approval to begin testing in humans.This is called an Investigational New Drug (IND) Application
  • If approved by the FDA, testing in humans begins. This is done through a formally written and approved protocol.

 

PRECLINICAL EVALUATION PHASE (ANIMAL STUDIES)

Major areas are:

  • Pharmacodynamic studies in vivo in animals, In vitro preparation
  • Absorption, distribution , elimination studies (pharmacokinetics)
  • Acute ,sub acute, chronic toxicity studies (toxicity profile)
  • Therapeutic index (safety & efficacy evaluation)

 

IND APPLICATION FILING

 Once preclinical studies have indicated the safety and efficacy of a drug an IND application has to be filed with the regulatory authorities.

 For obtaining regulatory Approval for Phase I, phase II and Phase III clinical evaluation.

 Contents of IND application:

  • Preclinical Data (All data from animal studies)
  • Information on composition and source of drug • Chemical and manufacturing information • Proposed clinical plans and protocol
  • Ethical Committee Clearance

 

PHASE 0 STUDY/MICRO DOSING

  • Study of new drug in micro doseS to derive PK information in human before undertaking phase I studies is called PHASE O
  • 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: Sub acute toxicity study in one species by two routes of administration.

PHASE 0 STUDY/MICRO DOSING

• Advantages:

 Less chances of adverse effects

 Short duration

 Less no. of volunteers

 Reduced cost of development

 Reduced drug development time

• Limitations:

 Study mainly based on PK parameters – not efficacy and safety based

 Agents having different kinetic characteristics between micro dose and full dose are not evaluated by phase 0 trials  Of Limited use for agents having Non linear PKs

 The laboratory parameters are very limited and expensive, researchers have to depend on BA/BE labs

PHASE 1

• First stage of testing in human subjects.

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

• 20-25 healthy volunteers; Duration: 6-12 months.

• Patients: Anticancer drugs, AIDS therapy.

• The aim of a Phase I trial is to determine the maximum tolerated dose (MTD) of the new treatment.

Kinds of Phase I:

  • SAD: Single ascending dose studies.
  • MAD: Multiple ascending dose studies.
  • Food Effect: Investigates differences in absorption caused by food.

PHASE 1 SUBJECTS:

  • Healthy human volunteers: Commonly used.
  • Patient Volunteers: Cytotoxic drugs, AIDS therapy -Patients in advanced stage of disease.

LIMITATIONS:

  • Trial restricted to homogenous subjects.
  • Performance extrapolated to heterogeneous market place.

PHASE 2

• It is a Therapeutic Exploratory Trial consists of 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.

Optimum dose finding:

  • Dose efficacy relationship
  • Therapeutic dose regimen
  • Duration of therapy
  • Frequency of administration
  • Therapeutic window

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

Phase II Study Types:

  • Phase IIA: Designed to assess dosing requirements.
  • Phases IIB: Designed to study efficacy.

PHASE 3

  • It is a Therapeutic confirmatory trial.
  • Target population: several 100’s to 3000 patients.
  • Duration: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.
  • To assess overall and relative therapeutic value of the new drug Efficacy, Safety and Special Properties

PHASE 3 :Subtypes:

  • Phase IIIA: to get sufficient and significant data.
  • Phase IIIB: allows patients to continue the treatment, Label expansion, additional safety data.
  • Phase III B studies are known as “label expansion” to show the drug works for additional types of patients/diseases beyond the original use for which the drug was approved for marketing.

End Of Clinical Trial Activities

  • Sponsor: Expert Committee review of Efficacy, safety and potential sales (Profit).
  • Go-No Go decision to file new drug application with DCGI.
  • Expert review by DCGI’s Committee
  • DCGI approval.
  • NCE marketed Phase IV begins

NDA: New Drug Application

NDA Refers to New Drug Application.

 Formal proposal for the FDA/DCGI to approve a new drug for sale.

Sufficient evidences provided to FDA/DCGI to establish:

• Drug is safe and effective.

• Benefits outweigh the risks.

• Proposed labeling is appropriate.

NDA contains all of the information gathered during pre-clinical to phase III.

PHASE 4

 Post Marketing Surveillance (PMS).

 No fixed duration / patient population.

 Helps to detect rare ADRs, Drug interactions and also to explore new uses for drugs [Sometimes called Phase V].

PERIODIC SAFETY UPDATE REPORTS :

To be submitted by the manufacturer every 6 months for 2 yrs and then annually for next 2 yrs after marketing approval.

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

OBJECTIVES OF PHASE 4:

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

 Detect the unknown/rare adverse drug reaction/s.

 Evaluation of over-dosage.  Identifications of new indications.  Dose refinement: Evaluation of new formulations, dosages, durations of treatment.

REPORTING OF ADR:

 The ADR can be reported to a formal reporting system such as: WHO International System USFDA- Medwatch UK- Yellow card system INDIA- National Pharmacovigilance Programme (CDSCO)

CONCLUSION

 Clinical trial is a human experiment designed to study the efficacy and safety of a new drug/intervention.

 Involves Phase 1-4 with specific objectives and end results.

 Application to Regulatory authority:

• IND – Permission to conduct CT

• NDA – Permission to Market New drug.

 Well designed and effectively executed clinical trials form the base of therapeutic decisions.

 CT must follow guidelines & protocol to ensure well- being of participants.

 Ultimate Goal of Drug Development

REFERENCE • Clinical trials.gov • Wikipedia • WWW.nlm.nih.gov/services/ctphases.html • WWW.cancerresearchuk.org • WWW.centrewatch.com > home > clinical trials Images : Google Images 26 PHASES OF CLINICAL TRIALS 25PHARMACEUTICAL BIOTECHNOLOGY

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