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
2001;14(5):e1-8.

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
2001;14(5):e1-8.

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
2001;14(5):e1-8.

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 any
questions 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 mgt
specialists
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.com
2. 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, 2014
Figure 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/Guideli
nes/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf
Related FDA and ICH guidances.
http://www.fda.gov/RegulatoryInformation/Guidances/default.htm

Questions?

Clinical trials pres

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