Hospital Based Research Pharmacy Services

Introduction to Research Pharmacy

Investigational Drug Control and Patient Safety

CUMC RPRobert B. MacArthur, Pharm.D.

Why does it take so long and cost so much for me to get my study pills ?

TopicsWhat, Why, and How about CUMCRPLabelingSome FDA and ISMP Standards and RequirementsCPOERevenue and Expenses

What Do We Do ?Investigational Drug Management and DispensingCompoundingClinical Trial KitsPharmacokinetic Study Design and SupportInteractive Voice Response System (IVRS)Multicenter clinical trial drug distribution

CUMC Research Pharmacy Locations

CUMC/NYPH CampusIrving Pavilion IP-749Black Building, Basement B-30, New Jersey 17 Smith Street, Englewood NJ Website: www.researchpharmacy.orgEmail:researchpharmacy@columbia.edu

CUMC Research Pharmacy ProductionActive Studies - 200 - 280New projects/month 10 - 15Dispensed products/month 300Destroyed products/month 125 Kits/month 360 Shipments/month 160

Why?Adds value to the clinical research capabilities offered by the medical centerGives Investigators the ability to adhere to GCPs in a simple, cost-effective mannerAdds an additional level of quality control to drug storage and dispensingResearch Early DaysI combed the Eastman Chemical Company Catalog and other price lists for suitable phenyl compoundsThey wrote back to me that they had on hand 19 different compounds analogous to Phenobarbital, and that I was welcome to them1937 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 therapywithout a doubt considerably more toxic than bromides and barbituric compounds 1938 Merritt and Putnam

Multiple Regulatory Agencies Involved

Regulatory Issues21 CFR 312.57 A sponsor shall maintain adequate records showing receipt, shipment, or other disposition of investigational drug21 CFR 312.59sponsor shall assure the return of all unused drug supplies from each investigator and maintain written records21 CFR 312.62An investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjectsinvestigator shall return the unused drug supplies to the sponsorRoutine FDA Inspection Findings1977 - 1990, 2308 inspectionsMost Common Deficienciesconsent form problems54%protocol non-adherence26%drug accountability problems25%

J Clin Pharmacol 1990;30:296-302FDA Inspection FindingsDrug AccountabilityOn-going accountability does not match CRFMedication started before IRB approvalPoorly maintained on-going drug accountabilityMaintained only in CRF, not independentlyTest drug not dispensed in sequential orderDiversion of drug to animal studies without PI or sponsor approval

13Microsoft Visual Basic for Applications (VBA) is used to create screens.Microsoft Access database management system is used to store data.Client / Server based system with database backend residing on departmental server. Application front-end installed on each PC workstation. No Web-based access to the system.Record of system logins are maintained. Record of user creating each kit is recorded.

Investigational Drug Accountability Report

Product Expiration ReportLabelingPrescription 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 GLYCOLmarkets 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 neurotoxicityWithdrawan 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 SignedManufacturers 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 recordsFDA-IND Labeling RegulationsSec. 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 Noticesand Requirements" (Preservation, Packaging, Storage, and Labeling) section of the USP.

Labeling Investigational DrugsNo patient instructions

No expiration date, retest date only

What does one do with a retest date?Labeling Investigational Drugs

Detailed instructionsabout how to pushtablets throughblister packin 11languages

Font too small to readNot Childproof

Minimal product labeling

Beautiful syringe labeling in French

StoringInvestigational Drugs

One Study of 2 Active Drugs5 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 TitrationMaintenanceConversionAdjustment

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

Senator J D. KleinWhat pharmacists need to focus on25About 1 in 184 Dispensing Errors Reported by Outpatient Pharmacies in Hospitals Caused Harm to Patients1 in 184 errors are harmful

E= temporary harm to the patient and required interventionF= temporary harm to the patient and required prolonged hospitalizationG= permanent patient harmH= required intervention necessary to sustain lifeI= contributed to or resulted in a patient's death

26ISMP 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 instructionsISMP 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 LabelingAgent dispensed to study subjects should be clearly labeled as an investigation drug.Caution: Drug Limited by Federal Law to Investigational Use OnlyWarning Labels

Subject Name / Hospital MRNSubject Study NumberHospital or Clinic NameAdministration instructionsAccepted name of drug and doseNumber of units or total volume Date agent prepared and expiration dateIRB numberOrdering physician name and pharmacist nameName, address and phone number of dispensing pharmacy

Sample Kit Box LabelSample Tube/Vial LabelBlinded Inv Drug Kit Labels31CPOE 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 ManagementNov. 17, 2008 Westin Tyson's Corner Falls Church, VA

Computerized Physician Order EntryRPH Assigned, 1st DraftDraft completedRPh, ReviewedSent to nursing for reviewReturned to RPh for editsSent to Eclypsis ITReceived back from Eclypsis ITScreen Shot in Review by RPhScreen Shot sent to nursingScreen Shot sent to Eclypsis ITOrder set not finalized by PIOrder set approved by PIAll signatures

CPOE Example

CUMC and NYPH Investigational Drug PoliciesJCAHO RequirementDistribution of investigational drugs administered to patients cared for within a health care organization be under the central control of the hospital pharmacy department

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.

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.

NYPH PolicyCUMC Policy39CUMC and NYPH Investigational Drug PoliciesJCAHO RequirementDistribution of investigational drugs administered to patients cared for within a health care organization be under the central control of the hospital pharmacy department.

Orders in Hospital medication profiling systemOrders must be written and made available in the patients medical record and pharmacy medication profiling system.

NYPH PolicyCUMC Policy40CUMC and NYPH Investigational Drug PoliciesJCAHO RequirementDistribution of investigational drugs administered to patients cared for within a health care organization be under the central control of the hospital pharmacy department.

Pharmacy Dept will order, store, inventory, dispense, destroy/return all investigational drug.The RP will order, store, inventory, dispense and destroy/ return all investigational drug. NYPH PolicyCUMC Policy41CUMC and NYPH Investigational Drug PoliciesJCAHO RequirementDistribution of investigational drugs administered to patients cared for within a health care organization be under the central control of the hospital pharmacy department.

Pharmacy Department will only dispense with a valid order.The RP will only dispense an investigational drug subsequent to a valid order by an authorized investigator.

NYPH PolicyCUMC Policy42Net Revenue per Project over 9 YearsPer project revenue by research groupOnly group 1 has all values above $0.00Groups 3 and 4 are all served without revenueGroup 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!

USP Outpatient Medication ErrorError Severity CodeNumberPercentage of Overall ErrorsA40,59520.3%B101,12250.6%C52,63426.3%D4,3072.2%E1,0800.5%F2530.1%G210.01%H140.01%I60.003%Total Errors200,032Total Harmful Errors1,3740.69%KeyA= Circumstances or events that have the capacity to cause errors (potential error)B= An error occurred but the error did not reach the patientC= An error occurred that reached the patient but did not cause patient harmD= An error occurred that reached the patient and required monitoring to confirm that it resulted in no harm to the patient and/or required intervention to prevent harmE= An error occurred that may have contributed to or resulted in temporary harm to the patient and required interventionF= An error that may have contributed to or resulted in temporary harm to the patient and required initial or prolonged hospitalizationG= An error occurred that may have contributed to or resulted in permanent patient harmH= An error occurred that required intervention necessary to sustain lifeI= An error occurred that may have contributed to or resulted in a patient's death

200,0320.69%1,374

USP Type of Medication ErrorsError TypeTotal Number% of Total ErrorsImproper Dose/Quantity10,64235%Unauthorized/Wrong Drug7,30424%Wrong Patient3,97613%Drug Prepared Incorrectly2,7079%Wrong Dosage Form2,5138%

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USP Outpatient Medication ErrorError Severity CodeNumberPercentage of Overall ErrorsA00%B1581153%C1349445%D5361.79%E1300.43%F300.1%G20.007%H00%I10.003%Total Errors30004Total Harmful Errors1630.54%KeyA= Circumstances or events that have the capacity to cause errors (potential error)B= An error occurred but the error did not reach the patientC= An error occurred that reached the patient but did not cause patient harmD= An error occurred that reached the patient and required monitoring to confirm that it resulted in no harm to the patient and/or required intervention to prevent harmE= An error occurred that may have contributed to or resulted in temporary harm to the patient and required interventionF= An error that may have contributed to or resulted in temporary harm to the patient and required initial or prolonged hospitalizationG= An error occurred that may have contributed to or resulted in permanent patient harmH= An error occurred that required intervention necessary to sustain lifeI= An error occurred that may have contributed to or resulted in a patient's death

300040.54%163

USP Type of Medication ErrorsError TypeTotal Number% of Total ErrorsImproper Dose/Quantity10,64235%Unauthorized/Wrong Drug7,30424%Wrong Patient3,97613%Drug Prepared Incorrectly2,7079%Wrong Dosage Form2,5138%

Sheet3