Transcript Handling of Investigational Agents - Vanderbilt University Medical

Geri Foster, DPh
Compounding &
Investigational Drug Pharmacist
July 20, 2001, Friday
Johns Hopkins Death Brings
Halt To U.S.- Financed Human
Studies
Warning letter to Johns Hopkins
No IND submission
Didn’t mention all risks in consent
Failed to report adverse reactions
Failed to update consents following
adverse reactions.
Warning letter to Johns Hopkins
Failed to disclose experimental use of
drug.
Represented product as a medication and
failed to disclose it as chemical grade
intended only as lab use.
Failed to submit technical information,
such as, source and purity of the drug
substance.
Warning letter to Johns Hopkins
Poor documentation
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Undetermined amount of Sodium Bicarb
added to second solution, no records
Changed the dosing conditions in protocol
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delivery system
pH, osmolarity
rate of administration
Changed pre-medication
DEPARTMENT: INSTITUTIONAL REVIEW
BOARD POLICY NUMBER: XI.A SECTION:
Investigational Drugs, Biologics & Device
REVIEW RESPONSIBILITIES:
IRB Policy & Procedure Committee
ORIGINAL CREATION DATE: February 04, 2002
REVISION DATES October 17, 2003
Subject: Storage, Handling, and Dispensing of
Investigational Drugs, Agents, and/or
Biologics in Clinical Trials
Definitions:
1. Investigational Agents: A
pharmaceutical form of an active
ingredient or placebo being tested or used
as a reference in a clinical trial. This
includes products with a marketing
authorization when used or assembled
(formulated or packaged) in a way
different from the approved form, products
used for an unapproved indication, or
products used to gain further information
about an approved use.
2. Definitions:
Investigational Drugs/Investigational
Biologics (Test Articles): A new drug/agent or
biologic that is used in a clinical investigation.
The term investigational biologic also includes a
biological product that is used in vitro for
diagnostic purposes. Investigational drugs or
biologics may include:
a. Products that are not generally recognized as
being safe and effective for any use under the
conditions prescribed, recommended, or
suggested by the FDA; or
b. Products already approved by the FDA as safe
and effective for specific indications that are
being studied for new indications (or doses,
strengths, or frequency).
3 Definitions:
Investigational Drug Service (IDS):
A division of the VUMC Pharmacy
Department that provides support for
clinical drug studies including
Institutional Review Board
consultation and dispensing services
for investigational drugs, agents, or
biologics. This division actively
supports all Departments and
Investigators involved in research.
4. Definitions:
Joint Commission on Accreditation of
Healthcare Organizations (JCAHO): A
national accrediting body for hospitals and
other health care delivery organizations.
Policy
It is the policy of the Vanderbilt
University Institutional Review Board
that all investigational drugs, agents
and/or biologics used in human
subjects research be stored, handled,
and dispensed in accordance with
governing regulations and Institutional
policy.
Policy: Storage of Investigational
Drugs, Agents, or Biologics.
I.A. It is the responsibility of the
Investigator to comply with all
Institutional, State and Federal
regulations in regards to
storage of investigational
drugs, agents, or biologics.
Policy:
1. B. Investigational drugs,
agents, or biologics used in the
context of research, may be
stored in areas other than the
IDS under the direct
supervision of the Investigator
and is in accordance with the
sponsor, if applicable.
Policy:
I. C.
Controlled substances may
not be stored outside of the
pharmacy department.
Policy:
I. D. Investigational agent storage facilities
outside of the IDS must be in compliance
with Institutional, State, Federal [Food and
Drug Administration (FDA)], and Joint
Commission on Accreditation of Hospital
Organizations (JCAHO) requirements.
Pharmacy monitoring may be incorporated
into the IRB auditing process as needed to
assure compliance.
II. Dispensing of Investigational
Drugs, Agents, or Biologics.
II. A. All investigational drugs, agents,
or biologics administered to inpatients
should be dispensed through the IDS
pharmacy.
This includes all inpatient beds in the
Vanderbilt University Medical Center,
Clinical Research Center,
Stallworth Rehabilitation Hospital,
Psychiatric Hospital at Vanderbilt
II. B. If IDS is not utilized for the
dispensing of investigational
drugs, agents, or biologics, it is
the responsibility of the
Investigator to assure that
dispensing is in accordance
with all Institutional, State,
Federal, and JCAHO
requirements.
II. C. The Pharmacy must
prepare and dispense
controlled substances for all
inpatients and outpatients.
II. D. Compounding of oral and
intravenous drugs must be
handled by the Pharmacy. The
Pharmacy must prepare and
dispense such medications for
all inpatients and outpatients.
III. Investigations of issues
related to the potential
mishandling of investigational
drugs, agents, or biologics will
be conducted by the IDS and
promptly reported to the IRB.
Pharmacy IRB Ex-Offico Members
Phil Johnston: Asst. Director of
Pharmacy
David DiPersio: Clinical Pharmacist
Critical Care Pharmacy
Debbie Harrell: Geriatric Pharmacist
Specialist
Vanderbilt University Institutional
Review Board
Pharmacy Reviewer’s Comment Form
Name of Drug
Is it FDA Approved?
Is it being used for its approved
indication?
IND# for this protocol
Are the doses within acceptable dosing limits?
Is the route of administration noted in the
protocol?
Are the side effects of all agents listed
adequately in the protocol?
Are other clinical considerations (pregnancy,
dietary restrictions, or drug interaction potential)
clearly addressed in the consent document?
Are the Investigator’s descriptions of handling,
storage and dispensing adequate, if not using
the IDS?
What regulations govern
investigational drug policies?
Hospital policy (IRB)
ASHP (residency site)
JCAHO standards (Investigational
agents)
Department of Health and Human
Services through OHRP and FDA
USP/NF 795 & 797 (FDA enforced)
JCAHO Standards
MM.7.40 Investigational medications are
safely controlled and administered.
Specifying that when pharmacy services are
provided, the pharmacy controls the storage,
dispensing, labeling, and distribution of the
investigational medication
Why follow the USP/NF
Chapter 797 standards:
They may be adopted and
enforced by State Boards
Surveyed by accreditation
organizations (JCAHO).
Enforceable by the FDA
USP/NF Chapter 797
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Sterile Products
Training and Competence
Compounding Environment
Labeling and Expiration Dating
Aseptic Technique
Product and Environmental
Testing
QC procedures
What to do after the products
are made and distributed
Who must follow 797
The standards are applicable to health
care institutions, pharmacies, physician
practices and other facilities in which
compounded sterile products (CSP)
are prepared and stored.
 Not applicable to sterile products
prepared for immediate use.
Immediate Use means there is no
intermediary step such as laying it
down and waiting to give later- Daryl
Rich Pharm.D JCAHO Surveyor
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Practices that will fall under <797> using
this definition:
Drawing up flu vaccine or
immunizations into multiple syringes
for later use
Anesthesiologists’ practice of drawing
up all drugs into syringes at the
beginning of the day
Is this going to be your
office attire?
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Booties or
shoe covers
Occlusive hair
cover
Mask
Gown
Gloves
Why use the
Investigational Drug Service ?
Investigational Drug
Service Personnel
Phil Johnston, Pharm.D.
Assistant Director of Pharmacy
Hope Campbell, Pharm.D., BCPS,
Coordinator of IDS
Geri Foster, D.Ph.
Compounding Coordinator
Lori Choate, Certified Pharmacy Technician
Deborah Allen, Certified Pharmacy Technician
Advantages of the IDS
Investigators able to accommodate
more protocols
Ensure use is limited to authorized
prescribers
Ensures patient consent is obtained
Verification of protocol compliance
Available for monitoring visits and FDA
audits
Guaranteed compliance with all
applicable state, & federal regulations
Advantages of the IDS
Patient specific labeling
Consistency in labeling
Randomization and blinding available
Patient counseling (if needed)
Complete and maintain drug related
case report forms
Serve as the un-blinded participant
Order drugs and maintain proper
storage
Secured drug storage/space
Advantages of the IDS
Placebos identical in appearance to
product
Approved sources of products (C of A)
Formulas with
sources/documentation/logs
Drug accountability documentation
Quality service
Timely delivery
Inpatient Studies & The IDS
Study medication is printed on patient
MAR (medication administration record)
Drug interaction check specific to protocol
Drug exclusion check, specific to protocol
Protocol synopsis and nursing sheets on
the chart
Pharmacy
Supported
Study
Obtain a budget
Principal Investigator:
Sponsor
Protocol Number
Pretend, MD
Date:
Procter & Gamble
555999
Yearly Cost
Estimated Number of
Years
5/25/2006
$1,500.00
Yearly Fees
Investigator Initiated
$ 500.00
Yearly Fees Score 6-10
$ 750.00
Yearly Fees Score 1115
$1,000.00
Yearly Fees Score 1620
$1,500.00
1
Yearly Cost
Calculator
Scale
Study
Estimati
on
M-F, 7-5
1
1
M-Su, 7a-11p
2
365/24/7
3
Room Temperature
1
Refrigerated 2-8°C
2
Frozen -20°C
3
Frozen -70°C
4
When will enrollment
occur?
Drug Storage
Requirements?
Combination of
temperature ranges
5
2
How many drug
products will be
provided by
sponsor to be
stored?
1-2 drugs
1
3-4 drugs
2
Patient specific Kit
3
DEA Scheduled Drug
4
Blinded Envelopes/Sequential
Enrollment
2
IVRS database or automated
4
Open Label
1
schedule created by pharmacy
3
3
How will
randomization
occur?
4
Research occurs where?
Inpatient
4
Outpatient
2
Both
4
Sponsor
2
Investigator Initiated
1
4
Sponsored or
Nonsponsored
Research?
Total
Poin
ts
2
16
Additional services provided under yearly fee cost
Protocol Review
Computer Files Creation
Pharmacy Procedure Establishment
Site Initiation Meeting
Site Startup Meeting
Monitoring Visits
Drug Storage
Continous Temperature Monitoring
Drug Disposal
Long Distance fax/phone charges
Dispensing Fee
$
Estimated Number of Dispenses per
patient
50.00
1
Gene Therapy Preparations
$ 100.00
Oral Medication outpatient
dispensing/per medication
$
15.00
Compounded Prescription
Dispensing fees
$
10.00
Oral Medication inpatient
dispensing/dose
$
10.00
Preparation of Infusion single
bag/day
$
50.00
Preparation of Infusion multiple
bag/day
$
25.00
Preparation of HIV/Smallpox Vaccine
$
75.00
Preparation of SC or IM injections
for outpatient use/dispense
$
30.00
Quantity
Required
Compounding Fees
Placebo Capsule Compounding
Fee
Active Drug Capsule
Compounding Fee (0.15 + Cost
of drug)
Compounded Sterile IV
preparation per vial (15.00 +
Cost of drug)
Endotoxin (LAL) & Sterility Testing
per IV batch compounded
Total Compounding Costs
$
$
0.15
0
-
$
$
0.15
0
$
$
15.00
0
$
$
250.00
0
-
Number of estimated patients
25
Estimated Service Charges
$1,500.00
Estimated Dispensing Fees
$1,250.00
Estimated Compounding Fees
$
Estimated Total Charge for
study
$2,750.00
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Items needed from Principal
Investigator to setup Protocol
Protocol
Amendments
FDA 1572
IRB approval letter
Consent form copy
Drug Accountability forms (if sponsor provided)
Drug Label Pages (if sponsor provided)
Pharmacy Binder (if sponsor provided)
Investigator’s brochure (if sponsor provided)
Nursing Information Sheet
Pharmacy Commitments
Budget
Drug
Horizon Expert Orders (Wiz)
HMM (Horizon Meds Manager)
Outpatient Prescription
Maintain Protocol Specific Binder
Pharmacy Binder
Enrollment Log/Randomization Log
Drug Accountability Record
Patient Worksheet
RX How-to
Mixing Instructions
Copy of Current Consent
Copy of Protocol
Correspondence
Current IRB Approval Letter
Documentation and Inventory
Control Requirements
Date of dispensing
 Patients name and or study
number
 Manufacturer’s lot number
 Balance on hand
 Retest or expiration date
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Pharmaceutical dispensing
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Dispensing Pharmacy
The physician’s name, telephone, and address
The words “CAUTION: New Drug Limited by Federal
Law to Investigational Use”
Study title
Patient’s name or Study ID
Date
Drug name and strength & quantity dispensed
Complete directions for use
Storage Conditions/Expiration/Auxiliary Labels
Storage facilities
Locked
Restricted access
Investigational agents are kept
separate from non study medications
Appropriate temperature monitoring
Maintain temperature logs
Alarms notify of malfunctions 24/7
Investigational Drug Service
Department of Pharmaceutical Services
1161 21st Avenue South, VUH RM B-101 Nashville, TN 37232-7610
Phone: (615) 343-6537 Fax: (615) 322-6643
Investigational Drug Prescription
Ketamine Nasal Spray versus placebo to decrease narcotic usage
Principal Investigator:
Pretend, MD
Co-Investigators:
Geri Foster, DPh
Patient name:___________________ Date:________________
Rx :
Ketamine 25 mg/mL or Placebo
Treatment one:
Date: ____/____/____
Treatment two:
Date: ____/____/____
Deliver to GCRC S-3100 or E-507
____________________________________________________, M.D.
Patient meets study criteria and copy of informed consent signature page is
attached.
Department of Pharmaceutical Services
Investigational Drug Service
1161 21st Avenue South, VUH Rm B-101, Nashville, Tn 37232-7610
Fax: (615) 322-6643
Phone: (615) 343-6537
Investigational Drug Accountability Record
Name of Institution
Investigator of Record
Vanderbilt University Medical Center
Pretend, MD
IRB #
Pfizer
Drug Name/Strength/Dosage Form:
049996
Storage Location:
Ketamine Nasal Spray 25 mg/ml
Package Size:
Storage Temp/Form
30 ml vial
Sponsor:
Lot Number
IDS Ref Shelf
Expiration Date:
2-8° C
Quantity
Line
Date
Patient
Patient
Dispensed
Balance
Dispens
ed
#
mm/dd/yy
Initials
Number
or
6 x 30 mL
by:
Received
Balance
1
2
Comments
Department of Pharmaceutical Services
Investigational Drug Service
1161 21st Avenue South, VUH Rm B-101, Nashville, Tn 37232-7610
Phone: (615) 343-6537
Fax: (615) 322-6643
Pharmacy Enrollment Log
Protocol #
Sponsor
GCRC
Patient
Number
Ketamine
Placebo
Investigator
IRB # 032229
Patient Name
Pretend, MD
Date
Enrolled
Received
Consent
Order
by
:
Can either
1. Enroll Patient
2. View Information Sheet
Can Print Document
Return To Previous Screen
Prompted for Weight if not already in WizOrder
Known Values can be
automatically loaded on
page
Web Page enforces that all
relevant fields be completed
Web Page evaluates
information entered
Order for Investigational Agent
Study Authorization Order
Compounding Service
Why compound at VUMC?
Quality patient care
Serve needs of specialty patients
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Burn
Pediatrics
Trauma
Investigational Drug Service (30%)
Part of solution to healthcare problem
Compliance with regulations
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USP 795 & 797
Plan Ahead for Compounding
Determine compounding costs
21 day lead time minimum
Customize product for protocol
Plan one dose unit per patient visit
Project needs for 6 months
Compounding Team
Geri Foster, Compounding Pharmacist
Deborah Allen,
Lead Compounding Technician
Teresa Vo, Compounding Pharmacist
Josephine Guirguis, Eileen Cooper,
Van Nguyen, Linda Phaneuf, Technicians
“Compounding means the preparation, mixing,
assembling, packaging, or labeling of a drug or
device (i) as the result of a practioner’s
prescription drug order or initiative based on the
pharmacist/patient/prescriber relationship in the
course of professional practice, or (ii) for the
purpose of, as an incident to research, teaching,
or chemical analysis and not for sale or
dispensing. Compounding also includes the
preparation of drugs and devices in anticipation
of prescription drug orders based on routine,
regularly observed patients.”
Compounding
Pharmaceutical compounding is subject to
standards listed in United States
Pharmacopoeia (USP) or National
Formulary (NF), monograph if such
monograph exists
If monographs do not exist then drug
substance should be a component of
drugs approved by the Secretary or are
manufactured by an establishment
registered to do so and certificates of
analysis are available for each bulk
component
Types of Compounding
Oral liquids
Capsules
Topicals
Ophthalmics
Otics
Inhalations
Injections
Compounding Attire
Compounding Attire
Gown
Gloves
Quality Assurance
Print Weights
Log sheets
Calibration
Double Checks
Weight Variance
LEVAMISOLE 150 MG CAPSULES
SIZE #3 BLUE
#100
#25
Ingredients:
Levamisole Hydrochloride USP
17.7 gm
4.425gm
Red Dye, FD&C # 40
0.025 gm
0.013 gm
Lactose monohydrate, NF
3.825 gm
0.956 gm
Levamisole 1 mg = Levamisole Hydrochloride USP 1.18 mg
Yield
100 capsules
or 25 capsules
Starting Materials:
Capsule machine
mortar and pestle
large plastic bag and powder roller
Size #3 blue
Electronic balance with printer
capsule cleaning towels
Compounding:
1. Don appropriate attire for compounding.
2. Weigh powders and print weights. Add levamisole and red dye
to mortar and triturate with pestle.
3. Add lactose to mortar and mix well. Transfer to plastic bag and
mix powders together using powder roller until consistent color
is achieved.
4. Fill capsules, clean capsules, perform QA and label appropriately.
.
References :
Expiration Date:
Storage:
Auxiliary Labels:
Sample Labels:
VUMC Pharmacy experience, Charlie Armstrong, RPh , PCCA consultant 2/24/06
3 months
Room Temperature
Investigational Use Only
Vanderbilt Hospital Compounding Pharmacy
Levamisole 150 mg capsules # 100 or #25
(in Lactose, with red dye # 40)
NDC#
Lot# 022406M1 Exp:4 8/24/06
Prep by da/gef
Sterile Compounding
Compounding attire
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Hair cover
gloves
mask
gown
Quality assurance
measures
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Endotoxin testing
Sterility testing
Record keeping
Balance calibration
Chemo Prep Area
Morphine
Bupivacaine
Brilliant Green
Terbutaline
Cocaine Eye Drops
Clonidine
Hydromorphone HCl
Tyramine
Yohimbine
Methacholine
Bradykinin
Sterilization Techniques
Dry heat oven
Filtration
Gas
Steam Autoclave
Sterrad
Future - Radiation
Examples of Errors to Avoid
Order sent before consent received
Consenting volunteer to more than one study
Wrong consent form signed – out of date, or wrong
study
Administering meds not on consent form
Change practice before amendment approved
Dispense without appropriate labeling/container
Exceeding approved number of patients
Consent obtained by non-approved personnel
Inappropriate surrogate consent
Inappropriate destruction of study medications
IDS Pharmacy
VUH Room B101- 7610
Main Phone # 3-6537
Hope Campbell
Beeper 835-9066
Geri Foster
Beeper 835-1797
Lori Choate
Beeper 835-9067
Deborah Allen
Beeper 835-9068