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Ernest Mario School of Pharmacy
Clinical Research Overview
William Jackson, PharmD, RPh
Introduction to Pharmaceutical Industry 1/28/2014
Ernest Mario School of Pharmacy
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
Ernest Mario School of Pharmacy
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
Ernest Mario School of Pharmacy
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.
Ernest Mario School of Pharmacy
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.
Ernest Mario School of Pharmacy
Modern clinical trials
Sacks FM, et al. N Eng J Med. 1996(14):1001-1009.
Ernest Mario School of Pharmacy
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
Ernest Mario School of Pharmacy
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
Ernest Mario School of Pharmacy
Phase 2
• Goal: Preliminary efficacy data in disease state group
– Understand drug effect in population of interest
– Determine optimal dose
• Study Participants:
– 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
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
Ernest Mario School of Pharmacy
Phase 3
• Goal: Large efficacy trials, usually registrational trials
– Show long term safety and efficacy
• Study Participants:
– 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
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
Ernest Mario School of Pharmacy
Phase 4
• Goal: Additional information about drug’s safety, efficacy, and optimal use
– Long-term analysis of adverse event profile
– Quality of life
• Study Participants:
– Patients
• Design:
– Post-marketing/FDA approval
– Investigator sponsored research
– Observational
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
Ernest Mario School of Pharmacy
Clinical research in labeling
• Can be found in section 14 of package insert
Pravastatin sodium [package insert]. Baltimore, MD: Lupin Pharmaceuticals, Inc; 2013.
Ernest Mario School of Pharmacy
IND Submitted
NDA Submitted
Review Decision
Sponsor answers anyquestions from review
Ernest Mario School of Pharmacy
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
Ernest Mario School of Pharmacy
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)
Ernest Mario School of Pharmacy
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.
Ernest Mario School of Pharmacy
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
Ernest Mario School of Pharmacy
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)
Ernest Mario School of Pharmacy
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
Ernest Mario School of Pharmacy
Investigator/site initiation
• Single site versus multi-center
• Case report forms and trial database
• Vendors and/or contractors
• Drug supply
Ernest Mario School of Pharmacy
Data and reporting
• Track patient recruitment
• Ensure protocol is followed
• Trouble shoot
• Database management
• Ensure timelines are being met
• Case report forms
• Data queries
Ernest Mario School of Pharmacy
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
Ernest Mario School of Pharmacy
Put this all in perspective…
Accurate as of Jan 13, 2014Figure is from clinicaltrials.gov
Ernest Mario School of Pharmacy
Put this all in perspective…
Accurate as of Jan 13, 2014Figure is from clinicaltrials.gov
Ernest Mario School of Pharmacy
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
Ernest Mario School of Pharmacy
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?
Ernest Mario School of Pharmacy
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