Introduction to Research Pharmacy
Investigational Drug Control and
Patient Safety
CUMC RP
Robert B. MacArthur, Pharm.D.
“ Why does it take so long
and cost so much for me to
get my study pills ? “
Topics
What, Why, and How about CUMCRP
Labeling
Some FDA and ISMP Standards and
Requirements
CPOE
Revenue and Expenses
What Do We Do ?
• Investigational
Drug Management and
Dispensing
• Compounding
• Clinical Trial Kits
• Pharmacokinetic Study Design and Support
• Interactive Voice Response System (IVRS)
• Multicenter clinical trial drug distribution
CUMC Research Pharmacy – Locations
• CUMC/NYPH Campus
– Irving Pavilion IP-749
– Black Building, Basement B-30,
• New Jersey
– 17 Smith Street, Englewood NJ
• Website: www.researchpharmacy.org
• Email:
researchpharmacy@columbia.edu
CUMC Research Pharmacy – Production
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Active Studies - ≈ 200 - 280
New projects/month ≈ 10 - 15
Dispensed products/month ≈ 300
Destroyed products/month ≈ 125
Kits/month ≈ 360
Shipments/month ≈ 160
Why?
• Adds value to the clinical research capabilities
offered by the medical center
• Gives Investigators the ability to adhere to
GCPs in a simple, cost-effective manner
• Adds an additional level of quality control to
drug storage and dispensing
Research – Early Days
“…I combed the Eastman Chemical Company Catalog and other
price lists for suitable phenyl compounds…They wrote back to
me that they had on hand 19 different compounds analogous
to Phenobarbital, and that I was welcome to them…”
1937 Putnam
“…142 patients received dilantin therapy for two to 11 months…
was effective in controlling convulsive seizures in a great
majority of a select group of patients who were not helped by
other methods or therapy…without a doubt considerably
more toxic than bromides and barbituric compounds…”
1938 Merritt and Putnam
Multiple Regulatory Agencies Involved
Regulatory Issues
• 21 CFR 312.57
– A sponsor shall maintain adequate records showing
receipt, shipment, or other disposition of
investigational drug…
• 21 CFR 312.59
– …sponsor shall assure the return of all unused drug
supplies from each investigator… and maintain written
records…
• 21 CFR 312.62
– An investigator is required to maintain adequate
records of the disposition of the drug, including dates,
quantity, and use by subjects…investigator shall return
the unused drug supplies to the sponsor
Routine FDA Inspection Findings
1977 - 1990, 2308 inspections
• Most Common Deficiencies
– consent form problems
– protocol non-adherence
– drug accountability problems
54%
26%
25%
» J Clin Pharmacol 1990;30:296-302
FDA Inspection Findings
Drug Accountability
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On-going accountability does not match CRF
Medication started before IRB approval
Poorly maintained on-going drug accountability
Maintained only in CRF, not independently
Test drug not dispensed in sequential order
Diversion of drug to animal studies without PI or
sponsor approval
Investigational Drug Accountability Report
Product Expiration Report
Labeling
Prescription Product
Patent Medicines
1906 Legislation Food and Drug Act
Prohibited interstate commerce of adulterated or misbranded food and drugs, unlawful to add ingredients that would
represent a health hazard, Food and drug labeling cannot be misleading
1937 Tragedy S.E. Massengill Company DIETHYLENE GLYCOL
markets an oral liquid sulfanilamide preparation using diethylene glycol as a solvent. Several deaths result
1938 Legislation Federal Food, Drug and Cosmetic Act includes FDA authority to
inspect sponsors, CROs, Investigators, IRBs 1941 Legislation Agency batch approval of insulin and antibiotics. Brought
medical devices and cosmetics under FDA perview. Prohibited false therapeutic claims on labeling, drugs had to be
labeled with adequate instructions, FDA inspections of factories were authorized, drug manufacturing and controls, drugs
had to be shown to be safe before they could be marketed, birth of the NDA [505(b)(1)]
1955 Tragedy Cutter Laboratories polio vaccine causes 260 cases of polio,
including 192 cases of paralytic polio 1965 Legislation Drug Abuse and Control Amendments
1960 Tragedy Thalidomide British Medical Journal publishes about
neurotoxicity
Withdrawan in Germany for causing congenital abnormalities. Complete US drug recall, 25000 doses unaccounted for, 17
cases of thalidomide-induced phocomelia identified
1962 Legislation Kefauver, Kelsey Amendments Signed
Manufacturers had to prove that drugs were effective, as well as safe, going back to 1938. Experimental subjects to be
given informed consent, FDA regulation of clinical investigations, GMP requirements, new drugs could only be marketed
with FDA assent, with no limitation on approval time. FDA inspectors have access to establishment records
FDA-IND Labeling Regulations
Sec. 312.6 Labeling of an investigational new drug
• (a) On the immediate package… "Caution: New Drug--Limited by Federal
(or United States) law to investigational use.“
• (b) The label or labeling of an investigational new drug shall not bear any
statement that is false or misleading in any particular and shall not
represent that the investigational new drug is safe or effective for the
purposes for which it is being investigated.
• (c) The appropriate FDA Center Director, according to the procedures set
forth in 201.26 or 610.68 of this chapter, may grant an exception or
alternative to the provision in paragraph…. (a) of this section, to the extent
that this provision is not explicitly required by statute, for specified lots,
batches, or other units of a human drug product that is or will be included
in the Strategic National Stockpile.
FDA-NDA Labeling Regulations
The United States Pharmacopeial Convention has
established requirements for containers which are
described in many of the drug product monographs
in The United States Pharmacopeia/National
Formulary (USP/NF)…..
These requirements are defined in the "General Notices
and Requirements" (Preservation, Packaging, Storage,
and Labeling) section of the USP.
Labeling
Investigational Drugs
No patient instructions
No expiration date, retest
date only
What does one do with a
retest date?
Labeling
Investigational Drugs
Detailed instructions
about how to push
tablets through
blister pack…
in 11
languages
Font too small to read
Not Childproof
Minimal product labeling
Beautiful syringe labeling in
French
Storing
Investigational Drugs
One Study of 2 Active Drugs
5 Dosage Forms
Drug A, Drug A Placebo
Drug B, Drug B Placebo
Drug A or B (blinded active)
4 Dosing Phases each with a
Separate Drug Supply
Titration
Maintenance
Conversion
Adjustment
2 shelves per study
Over 30,000 Dispensing Errors Have Been Voluntarily Reported In The Last 3
Years From Outpatient Pharmacies in Hospitals To U.S. Pharmacopeia
5 Most Frequent Types of
Prescription Drug Dispensing Errors
(As Voluntarily Reported to U.S. Pharmacopeia by Outpatient Pharmacies at
Hospitals from 2004-2006)
Error Type
Improper Dose/Quantity
Unauthorized/Wrong Drug
Wrong Patient
Drug Prepared Incorrectly
Wrong Dosage Form
Total Number % of Total Errors
10,642
35%
7,304
24%
3,976
13%
2,707
9%
2,513
8%
What pharmacists need to focus on
Senator J D. Klein
About 1 in 184 Dispensing Errors Reported by Outpatient
Pharmacies in Hospitals Caused Harm to Patients
Nationwide Prescription Drug Dispensing Errors
By Level of Severity
(As Voluntarily Reported to U.S. Pharmacopeia by Outpatient Pharmacies
at Hospitals from 2004-2006)
Error Severity Code
A
B
C
D
E
F
G
H
I
Total Errors
Total Harmful Errors
Number
0
15811
13494
536
130
30
2
0
1
30004
163
Percentage of Overall Errors
0%
53%
45%
1.79%
0.43%
0.1%
0.007%
0%
0.003%
1 in 184
errors are
harmful
0.54%
E= temporary harm to the patient and required intervention
F= temporary harm to the patient and required prolonged hospitalization
G= permanent patient harm
H= required intervention necessary to sustain life
I= contributed to or resulted in a patient's death
ISMP errors with investigational drugs
“…syringes are labeled with an identification number [only].
“Once the syringes are removed from the box, the carton
label containing important information is lost….”
“…license plate-type code name changes name to generic
name. The code name remains on the product label, but the
research team refers to and orders the drug by its new generic
name. ..”
Pharmaceutical Industry estimates of in hospital
investigational drug dispensing error rates are
typically 4 – 6 %
Pharmacist training programs are improving, via
pharmacy manuals, on-line training,
pictogram drug preparation instructions
ISMP error potential investigational drugs
“…Many investigational drugs are labeled using a
very small font size;… drug packages for active
and placebo look remarkably similar…”
“…drugs are not supplied in
unit-dose packages. Additionally,
vial sizes of parenteral drugs
are sometimes inappropriate…”
5 ml dose, 50 ml vial
Standard Labeling
• Agent dispensed to study subjects should be clearly
labeled as an investigation drug.
• Caution: Drug Limited by Federal Law to Investigational
Use Only
• Warning Labels
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Subject Name / Hospital MRN
Subject Study Number
Hospital or Clinic Name
Administration instructions
Accepted name of drug and dose
Number of units or total volume
Date agent prepared and expiration date
IRB number
Ordering physician name and pharmacist name
Name, address and phone number of dispensing
pharmacy
Blinded Inv Drug Kit Labels
Sample Kit Box
Label
Sample
Tube/Vial
Label
CPOE and EPRESCRIBING
The first national e-prescribing conference following
the release of new rules and regulations borne from the
Medicare Improvements for Patients and
Providers Act of 2008 (MIPPA)
The World Health Care Congress Leadership Summit on –
ePrescribing & Medication Management
Nov. 17, 2008 Westin Tyson's Corner – Falls Church, VA
Computerized Physician Order Entry
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RPH Assigned, 1st Draft
Draft completed
RPh, Reviewed
Sent to nursing for review
Returned to RPh for edits
Sent to Eclypsis IT
Received back from Eclypsis IT
Screen Shot in Review by RPh
Screen Shot sent to nursing
Screen Shot sent to Eclypsis IT
Order set not finalized by PI
Order set approved by PI
All signatures
CPOE Example
CUMC and NYPH Investigational Drug Policies
JCAHO Requirement
Distribution of investigational drugs administered to patients cared for within a health care organization be under the
central control of the hospital pharmacy department
NYPH Policy
CUMC Policy
• Any use of an investigational drug
must be approved by the
Columbia University Institutional
Review Board
• Any use of an investigational drug
must be approved by the
Columbia University Institutional
Review Board
• All research protocols using
investigational drugs must
contain the investigational drug
information required to be
provided in a Columbia University
IRB submission.
• All research protocols using
investigational drugs must
contain the investigational drug
information required to be
provided in a Columbia University
IRB submission.
CUMC and NYPH Investigational Drug Policies
JCAHO Requirement
Distribution of investigational drugs administered to patients cared for within a health care organization be under the
central control of the hospital pharmacy department.
NYPH Policy
• Orders in Hospital
medication profiling
system
CUMC Policy
• Orders must be written
and made available in
the patient’s medical
record and pharmacy
medication profiling
system.
CUMC and NYPH Investigational Drug Policies
JCAHO Requirement
Distribution of investigational drugs administered to patients cared for within a health care organization be under the central
control of the hospital pharmacy department.
NYPH Policy
• Pharmacy Dept will
order, store, inventory,
dispense,
destroy/return all
investigational drug.
CUMC Policy
• The RP will order, store,
inventory, dispense and
destroy/ return all
investigational drug.
CUMC and NYPH Investigational Drug Policies
JCAHO Requirement
Distribution of investigational drugs administered to patients cared for within a health care organization be under the central
control of the hospital pharmacy department.
NYPH Policy
• Pharmacy Department
will only dispense with
a valid order.
CUMC Policy
• The RP will only
dispense an
investigational drug
subsequent to a valid
order by an authorized
investigator.
Net Revenue per Project over 9 Years
Per project revenue by research group
Only group 1 has all values above $0.00
Groups 3 and 4 are all served without revenue
Group 0 and 1 are used to supplement losses in all other groups
Revenue:Expense Ratios
over 9 years
Close to 1.0
“That Research Pharmacy
sure does a great job ! “
Thanks for listening,
and
for supporting
safe dispensing practices!