Clinical trials pres

Ernest Mario School of Pharmacy

Clinical Research Overview

William Jackson, PharmD, RPh

Introduction to Pharmaceutical Industry 1/28/2014


Objectives

•Explain the historical evolution of clinical trials

•Define the various phases of clinical trial development

•Describe some of the operations and logistics of clinical trial development seen in the pharmaceutical industry

•Apply understanding of clinical trial development by reviewing a case study


The big WHY?

• What do I want you to get out of this lecture?

• Be comfortable explaining to patients how we determine a drug’s safety and efficacy

• Describe opportunities within the industry in clinical trial development for pharmacists


Early medicine

• Imhotep – 2850 BC; diagnosed breast cancer

• Sushruta – 600BC; counted human bones

• Ibn Sina – 973-1037; Wrote the Canon of Medicine

– 7 conditions of experimentation from Canon of Medicine

– Drug must be pure

– Drug must be tested for only 1 condition

– Drug must be tested in humans before judgment

Galin JI, 2007, p. 1-10.


Early modern clinical trials and Scurvy

• Although citrus fruit was known to treat scurvy, some believed it was due to the acid in the fruit

• 1747 - James Lind evaluated this theory in 12 sailors

afflicted with scurvy

• He created six groups of two each

• Each group was given an identical diet except for the “experimental treatment”

– Sulfuric acid, cider, seawater, nutmeg mixture, physician follow-up, and citrus fruit

• The only sailors cured were the two in the citrus fruit group

Galin JI, 2007, p. 1-10.


Modern clinical trials

Sacks FM, et al. N Eng J Med. 1996(14):1001-1009.


What are we doing in clinical trials?

• Question: Does Drug A work?

• Hypothesis: Yes

• Experimental Design: Clinical trials!!!

Question

Hypothesis

Experimental Design

Patient Pop

Data

Analysis

Conclusions

• Samples: People

• Data, analysis, and conclusions are what lead to approval and use in clinical settings and society


Phase 1

• Goal: Understand the drug

– Safety and tolerability

– Pharmacokinetics

• Study Participants:

– Healthy volunteers (sometimes disease state individuals)

– 20-100 healthy volunteers

• Design

– Weeks to months

– Dose escalation

– Exploratory biomarker studies

1. Lipsky MS and Sharp LK. From idea to market: the drug approval process. J Am Board Fam Med. 2001;14(5):e1-8.

2. Clinicaltrials.gov Accessed Jan 14, 2013


Phase 2

• Goal: Preliminary efficacy data in disease state group

– Understand drug effect in population of interest

– Determine optimal dose


– Patients in disease state of interest

– 100-400 patients (depends on disease state)

• Design:

– Months to years

– Randomized, placebo-controlled

– Dose ranging study

– Comparative efficacy




Phase 3

• Goal: Large efficacy trials, usually registrational trials

– Show long term safety and efficacy


– Patients in disease state of interest

– 500-1000 or more patients depending on disease state

• Design:

– Long time lines (years)

– Randomized, double-blind, placebo controlled

– Well-powered, strong clinically relevant primary endpoints

– Used for labeling purposes




Phase 4

• Goal: Additional information about drug’s safety, efficacy, and optimal use

– Long-term analysis of adverse event profile

– Quality of life


– Patients

• Design:

– Post-marketing/FDA approval

– Investigator sponsored research

– Observational




Clinical research in labeling

• Can be found in section 14 of package insert

Pravastatin sodium [package insert]. Baltimore, MD: Lupin Pharmaceuticals, Inc; 2013.


IND Submitted

NDA Submitted

Review Decision

Sponsor answers anyquestions from review


How is it actually done

• Components

– Budget

– Regulations

– Protocol development

– Investigator/site initiation

– Investigational Review Board (IRB)

– Trial/study participant enrollment/data maintenance

– Study closure/statistical analysis/reporting

Initiation of trial

Maintenance of trial/data

Reporting of data


Clinical trial research matrix

Clinical trial

manager

Staticians

Clinical investigators

Medical oversight

Clinical site monitors

Drug supply

Labs (Vendors)

Advocacy groups

Data mgtspecialists

IT specialists

Regulatory agencies

(FDA)


Budget

• Drug companies spend $2.8-6.3 billion per new drug

• Where does this cost come from?

• How do you budget for all costs?

1. Herper. Forbes. 2013. www.forbes.com2. Figure from: Faye AC and Mattison DR. Blickpunkt DER MANN. 2008.


Protocol development

• Medical and clinical operations work in concert to develop protocol

– Clinical scientists (MDs, PhDs) develop clinical framework for study design (clinical endpoints, inclusion criteria, study design)

– Clinical operations serves as project manager for ensuring budget, time horizon, and external vendors are in place for protocol


Regulations

• Good clinical practices (GCP)

– International ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of humans

– 1964 Declaration of Helsinki

• International Committee on Harmonisation

– Unified standard for EU, Japan, USA, Australia, Canada, Nordic countries, and WHO

• Title 21 of the Code for Federal Regulations (CFR)

– Includes: electronic records, protection of human subjects, financial disclosures by clinical investigators, IRB, investigational new drug applications (IND), applications for FDA approval to market a new drug

1. Zoon et al, 2007, p. 97-107.2. Guidelines for good clinical practice – ICH Topic E6(R1)


Investigational Review Board

• Any clinical research must be approved by institution’s IRB • Reviews risk/benefit to patients, ethical practice, informed

consent• Academic and hospitals have their own IRB. Thousands

exist in US• At least 5 members

– Must include diverse areas with some with non-scientific background


Investigator/site initiation

• Single site versus multi-center

• Case report forms and trial database

• Vendors and/or contractors

• Drug supply


Data and reporting

• Track patient recruitment

• Ensure protocol is followed

• Trouble shoot

• Database management

• Ensure timelines are being met

• Case report forms

• Data queries


Study closure/Follow-up

• Collect and combine data for analysis

• Prepare clinical study report (CSR)

• Ensure all invoices are accounted for

• Archive all data

• Main goal: prepare for NDA submission and/or publications


Put this all in perspective…

Accurate as of Jan 13, 2014Figure is from clinicaltrials.gov


Case study

• Drug company Scarlet Knight has found a promising biological agent in the fight against scarlet fever.

• Pre-clinical data has been finished, and the company has filed for a IND

• They plan on starting clinical trials in the next quarter

• As the clinical trial manager, you are helping with the clinical operations of the study


Case study continued

• List your main goals for phases 3 clinical trials.

• What regulations help protect participants from unethical behavior?

• In addition to the clinical trial manager, who are some of the key players within the matrix that work to ensure successful launch and closure of study?


References

Clinicaltrials.gov. Accessed January 19, 2014.

Principles and practices of clinical research 2nd ed. 2007. Elsevier Inc.

Lipsky MS and Sharp LK. From idea to market: the drug approval process. J Am Board Fam Med. 2001;14(5):e1-8.

Guideline for Good Clinical Practice – ICH Topic E6(R1) http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf

Related FDA and ICH guidances. http://www.fda.gov/RegulatoryInformation/Guidances/default.htm

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf







Questions?

Clinical trials pres

Documents

Transcript of Clinical trials pres