ASHP Guidelines for the Management of Investigational Drug Products

ASHP Guidelines for the Management of

Investigational Drug Products

Purpose

The purpose of these guidelines is to describe a standard-

ized approach for the management of investigational drug

products by the clinical research pharmacy, pharmaceuti-

cal industry, and cooperative and research network groups.

The scope of these guidelines includes the receipt, account-

ability, storage, handling, preparation, dispensing, and fi-

nal disposition of investigational drug products to ensure

inspection readiness and compliance with regulations as

provided in the Code of Federal Regulations (CFR), 21

CFR, Part 312,

as well as International Conference on

Harmonisation of Technical Requirements for Registration

of Pharmaceuticals for Human Use (ICH) E6 Good Clinical

Practice

(GCP) (described in 21 CFR Part 312, section 120)

and Good Manufacturing Practice

(GMP) (described in 21

CFR Part 211), and the approved clinical study protocols.

These guidelines will facilitate the adoption of best practices

by new and established clinical research pharmacies (e.g.,

investigational drug service [IDS]) in collaboration with the

pharmaceutical industry for the optimal management of in-

vestigational drug products. The ultimate goals of standard-

izing the management of investigational drug products are

to improve patient safety, improve efficiency, and provide

robust clinical data that allow new and innovative medica-

tions to reach the patients who need them.

Value of a Clinical Research Pharmacy

Since 1962, the Kefauver-Harris Amendments

to the

Federal Food, Drug and Cosmetic Act have required drug

manufacturers to prove that new drugs are safe and effective.

This requirement is the foundation for clinical studies as

they are known today. The pharmaceutical industry spends

billions of dollars each year to test investigational drug prod-

ucts for safety and efficacy, and it may take a decade or more

for a drug product to obtain market approval.

Thousands

of subjects have been asked to consent and take part in the

clinical research study process.

The current practice of the biopharmaceutical indus-

try is to manufacture, distribute, and monitor investigational

drug products for clinical research use while utilizing the

expertise of healthcare providers, especially pharmacists,

who manage the products at clinical study sites. It is impera-

tive that pharmacists participating in these studies have the

expertise to manage investigational drug products appropri-

ately. The clinical research pharmacist is a critical member

of the clinical study site team and has the expertise to under-

stand the special handling requirements of investigational

drug products.

Clinical research pharmacists understand the

importance of managing and properly documenting inves-

tigational product receipt, storage, dispensing, returns, and

final disposition. Failure to accurately document investiga-

tional product accountability can undermine the validity of

clinical study data, which could spur sponsors to halt a site’s

participation in current or future studies and result in a loss

of local patients’ access to clinical studies.

Clinical research pharmacy is a specialized area of

pharmacy practice that has evolved to meet the needs of the

clinical study sites, help ensure research participants’ safety,

and protect the integrity of clinical study data. Clinical re-

search pharmacists possess an expert working knowledge of

the clinical research study process, human subject protec-

tion, and national and local regulations governing drug re-

search. They are responsible for providing information to the

appropriate healthcare team members, including pharmacy

staff, who may be unfamiliar with the investigational drug

product, enabling them to correctly dispense it as described

in the clinical protocol and ensure its safe use.

Clinical Research Pharmacy Models

A clinical research pharmacy may be as simple as a part-time

pharmacist or as complex as a team of dedicated clinical re-

search pharmacists, technicians, and coordinators. It most

commonly is part of the larger pharmacy organization (e.g.,

the hospital pharmacy). In rare cases, it may be a freestand-

ing entity. As the complexity and volume of clinical studies

at an institution increases, the decision to create a dedicated

clinical research pharmacy with highly trained and special-

ized personnel and management can be made.

When establishing a clinical research pharmacy, the

appropriate institutional metrics (e.g., staffing-to-order vol-

ume ratios)

6,7

should be used to determine the appropriate

staffing, facility, and storage requirements needed to manage

investigational drug products. A comprehensive approach

will allow institutional leadership to fully support the cre-

ation of a clinical research pharmacy and should include a

review of the types and therapeutic areas of studies that will

be handled.

Each institution must also establish a funding model

to support the clinical research pharmacy. This model may

include (1) direct cost recovery from the sponsor–investiga-

tor, (2) indirect funding (e.g., based on institutional over-

head such as grants to conduct research), (3) foundation

underwriting of the research, or (4) institutions absorbing

the cost of the clinical research. Clinical research pharmacy

fees should be included at an early stage during the nego-

tiation of each clinical study budget. Investigational drug

products provided by sponsors at no cost to the clinical

study

site for use in clinical studies must not be charged to

study participants.

Within the organization, pharmacy leadership, the clin-

ical research pharmacist, institutional research leadership,

and investigators should establish the locations where re-

search participants will receive their care with the appropri-

ate pharmacy support. A review of pharmacy activities and

workflow for investigational drug product handling should

be performed for the following locations, as appropriate: (1)

inpatient units, (2) clinical research unit, (3) ambulatory care

or outpatient clinic setting, and (4) a combination of inpa-

tient and outpatient areas. The organization should develop

a mechanism to handle participants being treated at multiple

locations and facilities.

Research–Guidelines 645

646 Research–Guidelines

A dedicated team should be identified as the clinical

research pharmacy staff. In institutions with a large volume

of clinical studies, the clinical research pharmacy staff may

form an IDS with the appropriate management structure

depending on the practice environment. Members of the

clinical research pharmacy staff must have knowledge and

documented training on ICH GCP,

the Health Insurance

Portability and Accountability Act,

institutional review

board (IRB) review and protection of human subjects,

the

Belmont Report,

and all other competencies and policies

required by the institution or the pharmacy.

Facilities, Security, and Limited

Staff Access

According to GCP guidelines, the investigational drug prod-

uct should be stored in a secure location as specified by the

sponsor and in accordance with all applicable regulatory

requirements.

Some institutions may have separate rooms

for the storage of investigational drug products; others may

have a separate storage area within the pharmacy depart-

ment. In either case, the area should be secured (e.g., by key

or electronic lock), with entry restricted to clinical research

pharmacy or delegated staff.

Each institution must evaluate its ability to provide

secure, limited access to investigational drug products. A

clinical research pharmacy that does not have continuous

(24-hour/365-day) support to provide access to investiga-

tional drug products may mitigate the need for access by

utilizing regular pharmacy staff and considering on-call sup-

port by the clinical research pharmacists to supplement this

staff.

Temperature Control and Monitoring

Control and monitoring of investigational drug product stor-

age conditions are important for maintaining the integrity of

the products and for the safety of the research participants.

Documentation that proper storage conditions in the phar-

macy have been maintained must be available. The sponsor

shall determine and communicate acceptable storage tem-

peratures, storage conditions (e.g., protection from light),

and storage times for the products.

The clinical research

pharmacist must be able to document the temperature stor-

age conditions of the investigational drug products at all

times while managed by the pharmacy. Each pharmacy loca-

tion where investigational drug products are stored must be

monitored to ensure that proper temperature storage condi-

tions have been maintained.

Clinical research pharmacy and the pharmaceutical in-

dustry shall follow United States Pharmacopeia standards

for controlled temperature storage.

Before the start of ac-

tivities at the clinical study site, the sponsor should estab-

lish and communicate known allowable out-of-range tem-

peratures and the maximum allowable deviation time (i.e.,

acceptable time out of range) for the investigational drug

product. This information will enable the clinical research

pharmacy to make independent decisions without quarantin-

ing the investigational drug product supply for acceptable

excursions. An investigational drug product that does not

meet the allowable excursion parameters must be quaran-

tined under the proper storage conditions by the clinical

research pharmacy, and the sponsor and principal investiga-

tor (PI) must be notified. Prompt direction from the sponsor

regarding how to handle the quarantined product must be

adequately documented and kept in the site study file.

If the investigational drug product is sensitive to hu-

midity, the sponsor must work directly with the clinical

research pharmacy regarding monitoring requirements for

relative humidity.

All locations, including refrigerator, freezer, and

room-temperature areas, storing the investigational drug

product must have a temperature monitoring device or sys-

tem. In addition, the temperature monitoring system should

be calibrated at least annually to meet National Institute of

Standards and Technology standards.

Documentation of

the calibration of each device must be maintained and avail-

able for inspection. If an electronic temperature monitoring

system is not available, a calibrated manual thermometer

with the ability to capture daily maximum and minimum

temperatures should be used. A daily record of the maximum

and minimum temperatures should be maintained.

Equipment used to store investigational drug product

should be connected to a backup power supply in the event

of power failure. All refrigerators and freezers shall have

preventive maintenance completed annually. All calibration

and maintenance records should be archived per institutional

policy.

Site Qualification

The site qualification by the sponsor determines whether the

site meets the potential protocol requirements.

A pharmacy

assessment should be part of the sponsor’s site qualification.

Ideally, the sponsor’s agent should review the site’s policies

and procedures and applicable sponsor site qualification re-

quirements with the clinical research pharmacy staff. If the

sponsor provides a written report of the site qualification to

the site PI, a copy should also be forwarded to the clinical

research pharmacy. This report serves as the minutes of the

visit and agreement of the scope and services the clinical

research pharmacy may provide. If a report is not provided,

informal notes or minutes may be taken by clinical research

pharmacy personnel and kept on file.

Clinical Research Pharmacy Staff

Responsibilities

The clinical research pharmacy should be included in the

pre-IRB review for new clinical protocols. During this pre-

IRB review, the clinical research pharmacy should determine

the safety and feasibility of conducting the clinical research

study at the institution with respect to its policies, pharmacy

services, and the fees that will be charged for the services

provided. For this review, the clinical research pharmacist

should compile the following documents and information

from the clinical study site team and sponsor:

•

Clinical trial protocol, including the following:

•

Research participant location (inpatient, outpa-

tient, or both)

•

Number of research participants expected to be

enrolled at the site and number of dispensing

visits

Research–Guidelines 647

•

Duration of the study, including recruitment and

treatment periods

•

Randomization method (i.e., how participants

are randomized in the clinical trial)

•

Blinding (e.g., open label, single blind, double

blind, third-party blinding by clinical research

pharmacy)

•

Investigator’s brochure (known investigational drug

product information including safety data, any rele-

vant animal and human data, and the doses previously

studied; provided by sponsor)

•

Investigational drug product handling manual (phar-

macy manual), if available, which should include the

following:

•

Interactive response technology (IRT) (e.g., in-

teractive voice or Web response systems [IVRS/

IWRS]) instructions, if applicable

•

Description of investigational drug product (e.g.,

dosage forms, strength, packaging)

•

Investigational drug product and ancillary sup-

ply sourcing (e.g., provided by sponsor, sourced

locally by clinical research pharmacy)

•

Ancillary supplies required (e.g., filters, bags,

tubing, bag covers)

•

Supply of concomitant medications required

(e.g., adjunctive therapies, premedications)

•

A discussion should be raised during the

study setup to determine which concomi-

tant medications will be reimbursed and

which will be considered standard of care

•

Investigational drug product storage conditions

(e.g., temperature, humidity)

•

Special handling precautions (e.g., protect from

light, hazardous handling precautions)

•

Investigational drug product preparation or

dispensing information (e.g., diluents, stability

of reconstituted vial and solution for admin-

istration, dispensing in original container or

repackaging)

•

Handling of containers used in preparing dose

•

Handling of participant investigational drug

product returns

•

Administration of investigational drug product (e.g.,

flushing of infusion line, order of investigational drug

product administration in relation to other drugs ad-

ministered at the same visit, drug and food interac-

tions)

Pharmacist Listing on

Statement of Investigator

The decision whether to list a pharmacist on the Statement

of Investigator (Form FDA 1572) depends on the contribu-

tion the individual makes to the study.

If the individual will

make a direct and significant contribution to the data or is

directly involved in the treatment or evaluation of partici-

pants, he or she should be listed. If the individual will pro-

vide ancillary or intermittent contributions, he or she should

not be listed. A pharmacist who prepares investigational

drug product doses and maintains drug accountability for

multiple clinical studies that are conducted at an institution

would not be making a direct and significant contribution to

the data for a particular study; therefore, it would not be nec-

essary to list the pharmacist as a subinvestigator. However,

the pharmacist should be listed in the investigator’s study

records as an individual to whom specific responsibilities

have been delegated.

Delegation of Authority to Technicians

and Pharmacy Support Staff

Many sites utilize individuals who are not pharmacists to

perform some of the functions of the clinical research phar-

macy under the direction of a licensed pharmacist. Certified

pharmacy technicians or pharmacy coordinators may be del-

egated tasks, according to institutional policy, that do not re-

quire a pharmacist license. The clinical research pharmacist

is responsible for ensuring compliance with laws, rules, and

regulations regarding technician responsibilities. In many

states, a technician may only perform certain duties under

the direct supervision of a pharmacist, and the pharmacist is

ultimately responsible for the work performed by the techni-

cian; therefore, only the clinical research pharmacist should

sign the sponsor’s Delegation of Authority log.

Clinical Research

Pharmacy Staff Training

The clinical research pharmacist must be a participant in

the sponsor’s site initiation visit or the internal site initia-

tion meeting (for sponsor–investigator or cooperative group

studies). The clinical research pharmacist must participate in

the pharmacy-specific training session and have the oppor-

tunity to discuss the investigational drug product dispens-

ing logistics with the sponsor and clinical site study team.

The clinical research pharmacist should provide the spon-

sor with key policies and procedures and standard operating

procedures (SOPs) for review and approval, if not provided

at the site qualification visit. These may include but are not

limited to SOPs on training and delegation of tasks assigned

to pharmacy personnel regarding investigational drug prod-

uct handling, temperature monitoring, onsite investigational

drug product destruction, essential document retention, and

monitoring visit guidelines. Occasionally, sponsors conduct

the site initiation remotely via telephone or Internet confer-

ence. The clinical research pharmacist must be invited and

should participate in the pharmacy-specific training session.

At the site initiation visit, the pharmacy responsibili-

ties are determined and the Delegation of Authority form is

completed and signed by the clinical research pharmacist

and PI. Specific tasks need to be determined at study initia-

tion by the clinical research pharmacy and the clinical study

site team (e.g., which team member is accessing the IRT for

randomization, kit/bottle assignment). The clinical research

pharmacist should determine which qualified pharmacy staff

member will perform the delegated roles. The clinical re-

search pharmacist should also determine which pharmacy

staff will require electronic signatures (user name and pass-

words) for protocol systems such as IRT and coordinate with

the sponsor to obtain them.

All pharmacy staff who may dispense investigational

drug products should be trained in the proper dispens-

ing process and in GCP

as it relates to PI-delegated roles.

Training should be completed upon hire, and the information

should be reviewed periodically. Records of training must be

648 Research–Guidelines

maintained and made available for inspection by regulatory

agencies and sponsors.

Clinical research pharmacists and staff are required to

follow all relevant pharmacy practice standards, institution

policies and procedures, state and federal laws, and Joint

Commission or other accreditation standards, as well as GCP

guidance.

Clinical research pharmacy staff should maintain

all certifications and competencies specified by the pharmacy

department and the institution related to this requirement.

Formal sponsor training for every pharmacy staff

member for each protocol and all protocol amendments

is often not practical. Pharmacy staff should be trained to

refer to the most recent version of the study-specific dis-

pensing guidelines every time a delegated responsibility is

performed. This practice ensures that the most recent proce-

dures are used each time the investigational drug product is

prepared and dispensed. Therefore, study-specific training

by the sponsor is not indicated for all pharmacy staff. A phar-

macy signature log with staff initials should be maintained

and archived centrally by the pharmacy department for the

purpose of verifying study-related records.

Sponsors frequently request the curriculum vitae (CV)

of all pharmacy staff handling investigational drug product.

However, since the institution maintains licensure and cre-

dentialing information, it is appropriate for clinical research

pharmacy staff to only provide CVs to the sponsor if the

pharmacist is listed on Form FDA 1571 (Investigational

New Drug Application) or Form FDA 1572 (Statement of

Investigator).

The clinical research pharmacist should determine

whether interested parties can confirm pharmacist licensing

information at the individual state licensing office and, if so,

provide the sponsor with access information. It is not neces-

sary to provide proof of pharmacy technician certification.

Clinical Research Pharmacy Study Setup

The process of opening a new clinical research study should

include preparing dispensing guidelines, a model physician

order (prescription template), and a template of the dispens-

ing label. The process should also include creating a proto-

col-specific study drug entry and order set in the electronic

medical record as well as setting up a clinical research phar-

macy study file.

Dispensing guidelines should be prepared by the clini-

cal research pharmacist using the clinical protocol and any

other relevant information provided to the clinical research

pharmacy by the sponsor (e.g., investigational drug product

handling manual, site initiation visit materials, investiga-

tor’s brochure). It is the responsibility of the PI to ensure

that the research pharmacy has the most up-to-date versions

of all study documents. Dispensing guidelines describe the

protocol-specific functions that the clinical research phar-

macy staff must perform in order to adhere to the protocol

and complete all responsibilities delegated to the pharmacy

by the PI.

The dispensing guidelines are intended to opera-

tionalize the management of investigational drug products

for a specific protocol within the institution and are used as

a training tool by the pharmacy staff involved in the prepara-

tion and dispensing of the investigational drug product. A

sample of dispensing guidelines has been previously pub-

lished.

A draft version of the dispensing guidelines should

be prepared before the site initiation visit to allow the clinical

research pharmacist to identify the information that needs to

be obtained at the meeting and to ensure that the clinical site

will have all of the information needed before enrolling the

first participant into the study.

Dispensing guidelines should be revised as appropriate

after IRB approval of protocol amendments or other changes

to study procedures. The clinical research pharmacist should

maintain a system to document version control. Dispensing

guidelines should be available (in print or electronic for-

mats) to any pharmacy staff responsible for participant care.

The physician order template for the investigational

drug product should be prepared by the clinical research

pharmacist using the clinical protocol and other relevant

information provided by the sponsor.

In institutions that

use computerized provider order entry, the clinical research

pharmacist should ensure that an order set is available in the

system.

The investigational drug product should be entered

into the pharmacy computer dispensing systems, if avail-

able. A dispensing label template should be created to ensure

that information required by the clinical protocol is included

on the label and that the administration instructions are con-

sistent with the clinical protocol.

The dispensing label for the investigational drug prod-

uct must comply with all state and federal rules and regu-

lations as well as protocol requirements. The information

on the label should be consistent with the information and

instructions on the physician’s order as well as the original

drug container. The institution’s contact information should

be included on the label to aid in coordination of the par-

ticipant’s care by an outside institution. Special instructions

should be included on the dispensing label or provided as

auxiliary labels (e.g., food intake recommendations, storage

conditions).

If the clinical research pharmacy repackages the in-

vestigational drug product, the Federal Investigational

Drug Caution Statement —“Caution: New Drug—Limited

by Federal (or United States) law to investigational use”—

should be on the clinical site pharmacy label.

All labeling

must also comply with applicable local and state regulations.

In addition, the clinical research pharmacist should ensure

that any required medication counseling (e.g., for psychiat-

ric or teratogenic medications) is to be provided by the clini-

cal research pharmacist or an appropriate member of the

clinical site study team.

Considerations for Blinded Studies

When preparing dispensing guidelines for blinded studies

in which the clinical research pharmacy staff are unblinded,

the clinical research pharmacist should be cognizant that

there are clinical site personnel with direct patient care re-

sponsibilities who are blinded to the research participant’s

treatment assignment, and the dispensing guidelines should

be designed accordingly. Ideally, unblinded clinical site

personnel should not be involved in direct patient care for

study participants. Interactions between blinded and un-

blinded personnel should be minimized, and care should

be taken to avoid communication that could inadvertently

reveal a participant’s treatment assignment. Any pharmacy

staff member who is unblinded must use extreme care when

communicating with blinded staff regarding any patient care

Research–Guidelines 649

information in order to avoid revealing the participant’s

blinded treatment assignment.

Active and placebo investigational drug products must

be identical in appearance, labeling, preparation time, expi-

ration date and time, and supplies used. Considerations when

preparing blinded investigational drug products include

•

Ensuring that the preparation times for the active drug

and the placebo dose are the same.

•

Providing the identical information on the active drug

and placebo labels, including the expiration date and

time; if the active drug and placebo products have dif-

ferent expiration dates and times, the shorter of the 2

times should be used.

•

Making the port on intravenous bags look the same

(i.e., if a commercial bag of diluent is used as the

placebo, insert a needle into the port using aseptic

technique to give the appearance that a drug has been

added; if additive port covers are used, ensure match-

ing covers).

•

Using the same type of needle and tubing for adminis-

tration of the active drug and the placebo dose.

An unblinding process must be established that allows the

blinded treatment assignment to be determined. Examples of

events that require unblinding include a research participant

experiencing a severe adverse reaction and an unauthorized

person ingesting or being administered the investigational

drug product. An unblinding process that allows for immedi-

ate determination of the participant’s treatment assignment

or access to the sponsor’s medical monitor should be devel-

oped. In order to allow continuous access to the unblinding

process in the event of an emergent need to determine a par-

ticipant’s treatment assignment, a clinical site-specific plan

should be developed that is not dependent solely on the PI.

When labeling a blinded study medication, the clinical

research pharmacy must label it such that the blinding is pro-

tected and that clinical site study staff are not able to deter-

mine the actual contents of the container. The product should

be labeled as “drug name or placebo.” The protocol acronym

should not be used solely in place of the product name; if a

research participant presents at an emergency department,

the treating physician should be able to identify the potential

contents of the container so that treatment is not delayed.

Barcoding of Investigational

Drug Products

Improved patient safety with barcoding has been well docu-

mented.

Although barcoding is desirable, the lack of a

standard system limits its ability to be implemented with

investigational drug products. Development of a standard-

ized barcode lexicon that will facilitate the implementation

of a global barcoding system is necessary. ASHP has urged

the Food and Drug Administration (FDA) and other regula-

tory agencies, standard-setting bodies, contracting entities,

health systems, and pharmaceutical manufacturers to de-

velop and implement a universal symbology (e.g., barcodes,

radio frequency identifiers) that are readily deciphered by

commonly used scanning equipment to code for the National

Drug Code, lot number, and expiration date on all unit dose,

unit-of-use, and injectable drug packaging.

Investigational Drug Product

Accountability and Documentation

Detailed records, required to be kept by the sponsor, must

identify the investigator to whom the investigational drug

product is shipped as well as the date, quantity, and batch or

code mark of such shipment.

The clinical site is required to

maintain records detailing the participant to whom the inves-

tigational drug product was dispensed, the date, the quantity,

and the batch or code mark dispensed. Incomplete or inac-

curate drug accountability is a deficiency frequently cited in

Form FDA 483 Inspectional Observations notices.

U.S. law

does not require the use of an expiration date, use-by date,

or retest date on product labels. In many cases, the date may

be found on the packing slip; however, the clinical research

pharmacy may reach out to the sponsor to request documen-

tation of the retest or expiration date.

Routine inventory counts (e.g., monthly) should be

performed for each investigational drug product in order to

ensure that the physical quantity on hand corresponds to the

quantities recorded on the drug accountability record form

(DARF) and to manage investigational drug product with

limited use dates. Any discrepancy should be reviewed and

resolved for each investigational drug product.

According to the CFR and GCP guidelines,

1,2

inves-

tigational drug product receipt, dispensing, participant re-

turns, and disposition are required transactions that must

be documented. Sponsors may provide investigational

drug product accountability records, or individual clinical

research pharmacies may have their own accountability re-

cords. Frequently, sponsor-provided DARFs do not contain

sections to document all of the required transactions. For

clinical research pharmacies with multiple ongoing clinical

studies, DARFs from different sponsors requiring inconsis-

tent information can cause confusion. Use of standardized

DARFs containing sections for the required transactions

would ensure consistency and compliance with applicable

regulations. Figure 1 displays a template for a DARF, which

can be customized for different clinical protocols and sites

but maintains a standard appearance that will allow clini-

cal research pharmacy personnel to complete the forms cor-

rectly and provide sponsors with the required documenta-

tion. The form allows the site to document the receipt and

dispensing of individual bottles, vials, or kits, and the header

of the form can be customized for the specific needs of the

protocol. If a hard copy of the DARF is required by sponsors

and an electronic dispensing/accountability system is used,

it must have the capability of printing a hard copy of the

DARF that shows the required transactions. At a minimum,

the items on the form should be adhered to, ensuring site and

sponsor compliance with regulatory agencies. The clinical

research pharmacy DARF may be customized to include ad-

ditional information requested by sponsors, such as the time

of dose preparation or investigational drug product container

numbers.

When the investigational drug product is transferred

from the clinical research pharmacy to a satellite pharmacy

or dispensing location, a separate DARF must be main-

tained with the investigational drug product. The DARF in

the clinical research pharmacy should reflect the transfer of

investigational drug product to the satellite location, and the

satellite location’s DARF should reflect receipt of the inves-

tigational drug product from the clinical research pharmacy.

650 Research–Guidelines

The satellite location’s DARF should reflect all dispensing

activity at that location. Any remaining investigational drug

product must be returned to the clinical research pharmacy

and documented in both DARFs accordingly.

TheDARFisanocialrecord,and,assuch,anycor-

rections that are made must be performed by making a

line through the

original entry, accompanied by the re-

corder’s initials and date. The original entry may not be

obscured.

Investigational Drug Product Receipt

The clinical protocol or investigational drug product han-

dling manual will indicate how to obtain the investigational

drug product once a study site is approved to receive the

product from the sponsor. The study site may need to enroll

the first research participant before the product is shipped,

or a study site may be allowed to have the investigational

drug product onsite in anticipation of participant enrollment.

When the product is shipped, the sponsor must ensure it is

appropriately labeled so that it is easily identified as an in-

vestigational drug product for a specific clinical protocol.

The immediate packaging container for the investigational

drug product is required to bear the statement “Caution:

New Drug—Limited by Federal (or United States) law to

investigational use.”

In addition, it is strongly recommended that the spon-

sor’s investigational drug product label contain the follow-

ing information

•

Investigational drug product name

•

Investigational drug product name may be the

generic name, company molecule name, or com-

pound name but must match the name used in

the clinical protocol; the sole use of protocol ac-

ronyms should be avoided.

•

If the investigational drug product used in the

clinical research study is blinded and placebo con-

trolled, the label must indicate “[Investigational

Drug Product Name] or Placebo.”

•

Investigational drug product strength or concentration

unless this aspect of the trial is blinded

•

Investigational drug product quantity (e.g., number of

tablets, volume)

•

Investigational drug product lot number and/or con-

tainer or kit number

•

Lot number(s) should be referenced in the pack-

ing slip or receipt document, and terminology

should be consistent with the clinical research

study-related documentation (i.e., if the lot num-

ber is labeled as “Lot Number” on the package,

it should not be referred to as “Batch Number” in

supporting documentation).

•

Investigational drug products may also contain

a unique container or kit number that will be

used to identify the contents or to assign specific

container or kit to a participant; in that case, the

container or kit number may appear in place of

the lot number, but the container or kit number

must be cross-referenced with the packing slip.

•

Expiration or retest date (period of use) of the investi-

gational drug product

Figure 1. Template of a drug accountability record form. PI = principal investigator, CRA = clinical research associate.

(site name) Clinical Research Pharmacy

Drug Accountability Record Form (DARF)

Protocol Title: Internal Protocol #:

PI: Source: Lot:

Kit:

Exp/Retest:

Study Drug Name:

Synonym:

Str

ength:

Dosage Form:

Units Per Container:

Drug Location:

Drug Storage:

Room T

emp ___ Refrig # ___ Other ____

Receipt

Dispense

Date

dd/mmm/yyyy

Rx# or

Pt Care Unit

Patient

Initials

FML

F - L

Patient Study

Dose/

Frequency

Quantity

Received or

Dispensed

Balance Staff

Init

CRA

Verify

Init

Patient Returns

# Returned Date Returned Staff

Init

Disposition

Return to

Sponsor

or Destroy

Date Staff

Init

CRA

Verify

Init

Comments: ___________________________________________________________________________ Page ____ of ____

Research–Guidelines 651

•

While it is preferred to be on the investigational

drug product label, this information may be pro-

vided on the packing slip or via a memo included

with the shipment to the clinical study site.

•

Sponsor or manufacturer name and address

•

Clinical research protocol number

•

When a sponsor is working on clinical studies

using the same investigational drug product in

parallel protocols for different indications, it

may be difficult for a clinical site to determine

which protocol the product belongs to unless this

information is provided on the container.

•

The sponsor may provide pooled supplies of in-

vestigational drug products to be used for mul-

tiple clinical research studies at the same clini-

cal study site. The investigational drug product

may be labeled with multiple clinical research

protocol numbers, or the clinical research phar-

macy may be required to assign each individual

unit to a specific clinical research study at the

time of dispensing. The assignment process must

be clearly explained in the investigational drug

product handling manual or the clinical protocol

and be communicated clearly to the clinical re-

search pharmacies.

•

Oral medication intended to be dispensed to a partici-

pant for self-administration at home must comply with

the Federal Poison Prevention Packaging Act

and be

packaged in a child-resistant container. If the disease

indicated in the clinical protocol is not conducive to

this type of packaging, a statement must be included in

the consent form alerting the potential participant that

there is a risk to children in the home due to the lack of

child-resistant packaging.

The investigational drug product shipment must be ac-

companied by a packing slip. Clinical research pharmacy

staff are responsible for verifying the contents against the

packing slip and assessing the condition of the package.

Proof of receipt should be provided to the sponsor or sup-

plier; this should be clearly outlined in the protocol or

investigational drug product handling manual or on the

packing slip. Any discrepancies (e.g., broken vials, miss-

ing product, temperature excursions) must be reported

immediately, and the resolution of discrepancies must be

appropriately documented. Sponsors may request that the

product be quarantined in the interim; quarantined product

must be maintained under the specified storage conditions.

Sponsors should be prompt in responding to discrepancies

or temperature excursions. The packing slip, shipment tem-

perature records, and any other documents received with

the investigational product shipment shall be stored in

the pharmacy study-specific file. All investigational drug

products received must be documented on a DARF.

Investigational Drug Product Dose

Preparation and Dispensing

When preparing and dispensing an investigational drug

product, the clinical research pharmacy should utilize site-

developed, study-specific dispensing guidelines to ensure

the investigational drug product handling requirements in

the protocol are met. The clinical research pharmacy may

store partial or empty vials of nonhazardous investigational

drug product in a limited-access, secure area until returned

or destroyed per the sponsor’s direction. Sponsors should be

diligent in the reconciliation and disposition of the used ma-

terials. Used and partial vials of hazardous investigational

drug product should be destroyed according to the institu-

tional policies and procedures immediately after dose prepa-

ration.

Remote Site or Clinic Dispensing

Remote site or clinic dispensing within a health system may

be considered when clinical research pharmacy involvement

may present a hardship for research participants or adversely

affect the conduct of the clinical research study, especially

in situations where timely access to the investigational drug

product may be a challenge.

The clinical research pharmacy should review studies

that may require remote site or clinic dispensing before IRB

review to assist in determining how the investigational drug

product should be managed at the remote site or clinic and

in determining the best dispensing option. In situations in

which pharmacist dispensing is not practical, physician dis-

pensing may be an option. State laws and regulations should

be reviewed to determine whether physician dispensing is

permitted. If physician dispensing is allowed, all applicable

state and federal laws and regulations with respect to han-

dling investigational drug products (e.g., secure storage con-

ditions, labeling requirements for outpatient use) as well as

those regulating accountability and dispensing must be fol-

lowed. The clinical research pharmacy should provide guid-

ance on the applicable state laws and regulations that apply.

In such cases, the PI must maintain appropriate study-

specific accountability records. These records should docu-

ment the investigational drug product received and dis-

pensed to participants enrolled in the clinical research study.

Investigational drug product returned from participants and

final disposition of investigational drug product must also

be recorded.

The clinical research pharmacy should also perform

periodic audits and inspections of storage facilities and drug

accountability procedures that are managed by the PI.

Investigational Drug Product Returned

from Participants

Per GCP, the PI is responsible for ensuring and assessing

clinical research protocol adherence.

This may include

receiving, counting, and documenting investigational drug

product returned from participants in the case report form or

the electronic medication administration record, if required,

in the protocol. This function may be delegated by the PI

to the clinical research pharmacy; in such cases, the unused

supply and empty investigational drug product containers

should be returned to the clinical research pharmacy for

documentation of the unused investigational drug product

returns from participants and its final disposition. The clini-

cal research pharmacy should record on the DARF the date

and the quantity of investigational drug product returned, as

directed in the investigational drug product handling man-

ual. On occasion, the date of the investigational drug product

652 Research–Guidelines

count may differ from the actual date of participant return

because the clinical research pharmacy may not be able to

process the return immediately. Returned investigational

drug product should be deemed not usable and should be

stored in an area separate from the investigational drug prod-

uct that is available for dispensing to research participants.

Used or partially used nonhazardous investigational

drug product returns should be stored by the clinical re-

search pharmacy in a limited-access, secure area until di-

rected by the sponsor to return or destroy the product. The

clinical research pharmacy should determine storage space

availability and notify the sponsors in advance of any space

limitations. The sponsor should visit the clinical research

pharmacy at appropriate intervals based on study activity to

return or destroy used investigational drug product. If such

visits do not occur, the clinical research pharmacy should

contact the sponsor to obtain permission to destroy or return

the product.

Hazardous investigational drug product returns and

returns of investigational drug product supplied by the

National Cancer Institute should not be stored onsite. These

products should be destroyed under the appropriate institu-

tional hazardous drug disposal procedures immediately af-

ter counting and documentation on the DARF; exceptions

should require approval by the clinical research pharmacist

and the PI and should be stated in the dispensing guidelines.

Each site should refer to its specific institutional policies re-

garding the destruction of hazardous drug products.

Investigational Drug Product

Final Disposition

For investigational drug product returned to the sponsor or

destroyed onsite, the return or destruction must be docu-

mented on the DARF by the clinical research pharmacy.

If required by the sponsor, a separate return or destruction

form may be used to document return or destruction of the

investigational drug product. If the return of unused inves-

tigational drug product to the sponsor is required per the

clinical research protocol, instructions on the return proce-

dure should be provided to the clinical research pharmacy

staff by the sponsor. If destruction of investigational drug

product by the clinical research pharmacy is approved by

the sponsor, the product should be destroyed per institu-

tional policy. If the sponsor requests return of a hazardous

investigational drug product, the shipper must comply with

U.S. Department of Transportation regulations for ship-

ping hazardous material.

Investigational drug products

that are controlled substances should be returned to the

sponsor for final disposition or destroyed per institutional

policy; returns of such drug products must adhere to Drug

Enforcement Administration regulations for shipping con-

trolled substances.

Clinical Research Pharmacy Study File

The clinical research pharmacy should create a study-spe-

cific pharmacy file using selected essential documents that

are deemed necessary by the clinical research pharmacist

for the routine management of investigational drug prod-

ucts. Original documents (e.g., DARFs, investigational drug

product physician orders, packing slips) that are part of the

clinical research study-specific pharmacy file are consid-

ered source documentation. These essential clinical research

pharmacy documents will be retained throughout the study

and must be readily available for inspection by the spon-

sor (or designee), PI (or designee), and regulatory agencies

(e.g., FDA). Copies of temperature monitoring logs and pol-

icies do not need to be filed in individual clinical research-

specific files but should be available on request.

Documents in the pharmacy file may be stored in

hard copy or electronic format and should include sponsor-

provided and site-prepared documents. Sponsor-provided

documents should include the following:

•

IRB-approved clinical research protocol and associ-

ated amendments

•

Investigator’s brochure and associated amendments

•

Investigational drug product handling manual (version

controlled) and associated amendments

•

Investigational drug product ordering instructions and

forms

•

IRT (IVRS/IWRS) manuals (instructions and forms)

•

Investigational drug product shipment documentation

(e.g., packing slips, other drug receipt documents)

•

Supporting investigational drug product information

(e.g., package insert, safety data sheet, certificate of

analysis, as applicable)

•

Expiration and retest correspondence (period of use)

•

Temperature excursion forms (if required)

•

Correspondence (e.g., communication sheet, letters, e-

mails)

•

Investigational drug product disposition information

and forms

•

Miscellaneous documents (e.g., worksheets, sponsor-

specific forms)

Site-prepared documents should include the following:

•

IRB approval letter

•

Access to IRB-approved consent (to establish docu-

mentation of research participant-specific medication

training disclosure)

•

Pharmacy-prepared dispensing guidelines

•

Pharmacy fee sheet with billing information

•

Pharmacy computer system entry information

•

Investigational drug product physician order or pre-

scription template(s)

•

List of authorized prescribers for the clinical trial

•

Research participant list and treatment assignment (if

applicable)

•

Clinical research pharmacy and pharmacy satellite

DARFs (if applicable)

•

Monitoring visit and audit forms

•

Notes to file

If an investigational drug product is not dispensed from the

clinical research pharmacy, a satellite-specific file should

be created that includes a research participant list, dispens-

ing guidelines, DARFs, and other study-specific documents

(e.g., investigational drug product dose calculation work-

sheets); the file should be kept in the satellite pharmacy

where the investigational drug product is being dispensed.

Research–Guidelines 653

Monitoring Visits or Audits of the Clinical

Research Pharmacy

It is the responsibility of the sponsor to monitor the prog-

ress of the clinical research study to ensure data integrity

and participant safety.

If the clinical research study is an

investigator-initiated protocol (sponsor–investigator), it is

the responsibility of the local PI to meet all of the require-

ments of the sponsor, including monitoring and safety-

reporting regulations.

The sponsor may delegate the monitoring and auditing

responsibilities to a contract research organization. Clinical

research associates who are employees of the sponsor or

their agents from a contract research organization will be

sent to monitor the clinical site. Sponsor audits at clinical

sites may be conducted by representatives of the sponsor or

independent auditors as well as inspectors from regulatory

authorities. Communication regarding clinical site monitor-

ing expectations will occur during the site initiation visit.

The clinical research associate (monitor) will visit

the clinical study site to review the records and verify the

accuracy of the documentation with the source documents

onsite. Source documents include any original documents,

data, and records, including (but not limited to) patient

medical rec ords, visit notes, protocol data collection forms,

laboratory notes, participant drug administration diaries,

and the clinical research pharmacy DARFs and associated

records. The monitor must have access to the source docu-

ments; in some cases, this may require access to electronic

medical records. Access to these systems should be pro-

vided in accordance with institutional policies.

The monitor should communicate with the clinical

study site to determine a mutually agreeable time to meet

with study staff and reserve a space to work. The clinical

site should accommodate these visits whenever possible.

The clinical study site should have a dedicated space in the

same area as the protocol records where the monitor can

work. The PI must be available for questions and discussion

at some time during the visit. Some research protocols will

allow remote monitoring activities in lieu of a visit to the

site, and monitors may send queries to the clinical site for

clarification. Depending on the time required by the clinical

research pharmacy staff to respond to information requests,

an additional charge may be imposed to accommodate these

remote visits.

The monitor will need to visit the clinical research

pharmacy to review pharmacy documentation. If the clini-

cal research protocol is a blinded study and the clinical re-

search pharmacist is unblinded, there should be a separate

unblinded monitor specifically for clinical research phar-

macy review. The unblinded contact(s) should be clearly

stated in the pharmacy records. All others should be con-

sidered blinded and communications handled accordingly.

An appointment should be made for each clinical research

pharmacy visit to allow the staff to adequately prepare.

The clinical research pharmacy staff should meet with the

monitor and provide access to pharmacy source documents

for review. The monitor should confirm drug account-

ability and storage conditions and review a participant’s

returned investigational drug product. The monitor may

return investigational drug product to the sponsor or au-

thorize its destruction. All personal health information of

the participants should be removed from investigational

product labels and forms before being returned to the

sponsor or should be destroyed.

Monitoring Visit Logs

The clinical research pharmacy staff should docu-

ment monitoring visits and the reason for the meeting.

Information documenting the identity of the monitor,

company affiliation, study reviewed, and the duration of

the visit to the clinical research pharmacy is useful to the

sponsor and the pharmacy department. Figure 2 provides

an IDS monitor/visitor log template to capture such infor-

mation.

At the end of a monitoring visit, the clinical research

pharmacy staff or the sponsor should document any out-

standing requests or issues that need to be completed before

the next visit. A template of a study monitor exit summary

report that can be used to capture issues for follow-up ap-

pears in Figure 3. Both the clinical research pharmacist and

the monitor should sign the form to document their under-

standing of requests.

Study Close and Archiving of the Clinical

Research Pharmacy Study Files

A site is required to retain all rec ords for at least 2 years after

the marketing application is approved for the indication be-

ing investigated. If the drug is not approved or if no applica-

tion is filed, then records must be retained for 2 years after

the investigation is discontinued.

Many institutions have

retention policies that exceed these requirements. Trials tak-

ing place in other countries may also be subject to longer

retention periods. Sponsors should indicate when this is the

case and follow retention requirements where applicable. It

is the responsibility of the sponsor to notify the clinical site

and the clinical research pharmacy of these requirements.

Each site must be familiar with state, local, and institutional

policies and regulations regarding record retention. The clin-

ical research pharmacy should provide written notice to the

sponsor of impending document destruction.

Upon termination of a study, the clinical research phar-

macy should work with the PI to determine who will main-

tain the following pharmacy-related documents:

•

Drug accountability records and documentation of in-

vestigational drug product destruction

•

Investigational drug product shipment documen-

tation

•

Proof of receipt and/or packing list

•

Certificates of analysis

•

Safety data sheets

•

Participant enrollment log

•

Participant identification code list

•

Participant-specific preparation records (batch

control records for compounded items) and

worksheets

•

Certain pharmacy documents, such as

filled prescriptions or medication orders,

must remain with the clinical research

pharmacy in accordance with state board

of pharmacy rules and regulations.

•

IRT-related documents

654 Research–Guidelines

Figure 3. Study monitor exit summary report template. CRP = clinical

research pharmacy.

Clinical Research Pharmacy

Study Monitor Exit Summary Report

Internal Protocol#__________

No Clinical Research Pharmacy action required

Follow-up Clinical Research Pharmacy action required

Study Monitor/Date

Contact Information:

CRP Staff/Date

(R.Ph. required for follow-up)

Figure 2. Template of an investigatioinal drug service monitor/visitor log.

Clinical Research Pharmacy Monitor/Visitor Log Month ____________ Page ____________

DATE Internal

Protocol #

DRUG/STUDY NAME TIME IN TIME OUT REASON FOR VISIT

•

Instructions for handling investigational drug product

•

Site-specific dispensing guidelines

•

Signature sheet and pharmacy delegation log

•

Sponsor investigational drug product and pharmacy-

related correspondence

Nonessential pharmacy documents (e.g., protocols,

amendments, investigator’s brochure, IRB correspondence)

shall be stored by the PI in the investigator study file. The

clinical research pharmacy does not need to maintain copies

of these documents.

The clinical research pharmacy files for terminated

studies that are not returned to the PI should be maintained

onsite, as space allows, and then moved to offsite, long-term

storage as needed and if available. The clinical research

pharmacy should maintain an onsite record of location for

retrieval from long-term storage. Records must be readily

retrievable in the event of an audit.

Clinical Research Pharmacists

as IRB Members

IRB members must disclose any actual and perceived con-

flicts of interest throughout their membership term and must

file a financial disclosure with the IRB office. This informa-

tion should be considered during assignment of IRB submis-

sions for review to avoid conflicts of interest.

An IRB member may be involved in the conduct of a

research study that solely involves the provision of a service

to a study (e.g., a pharmacist from the clinical research phar-

macy who prepares and dispenses study medications, a radi-

Research–Guidelines 655

ologist who performs diagnostic imaging that is part of the

research). In these cases, the IRB should not consider this a

conflict of interest with regard to reviewing an IRB submis-

sion, provided the member’s role in the study is limited to

the provision of a service to the PI and he or she is not oth-

erwise engaged in the study. Under these circumstances, the

clinical research pharmacist serving on an IRB should not

be listed on the Statement of Investigator (Form FDA 1572).

Summary

Clinical study sites that handle a significant volume of clini-

cal studies should establish a formal IDS pharmacy utiliz-

ing these best practices as a foundation. Standardizing the

processes for managing investigational drug products used

by clinical research pharmacies will improve patient safety

and protect study data integrity while maintaining regulatory

compliance. Standardization will also provide guidance for

clinical study sites that are new to handling investigational

drug products. Adopting these best practices will enable

clinical research pharmacies to enhance their collaboration

with sponsors and the biopharmaceutical industry by align-

ing processes and systems to improve clinical study execu-

tion. Ultimately, these best practices will support the devel-

opment of new and innovative medications for the patients

who need them most.

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These guidelines were developed through the ASHP Section

of Inpatient Practitioners and approved by the ASHP Board of

Directors on November 8, 2017.

Stephen C. Kay, B.S.Pharm., Clinical Research Pharmacy, Pfizer,

Andover, MA.

Darlette G. Luke, B.S.Pharm., Investigational Drug Service,

Fairview Health Services, University of Minnesota Medical Center,

Minneapolis, MN.

Helen R. Tamer, Pharm.D., Research Pharmacy, Michigan Medicine

(University of Michigan), Ann Arbor, MI.

ASHP gratefully acknowledges the following individuals for re-

viewing these guidelines (review does not imply endorsement):

Uzma Afzal, Pharm.D.; Beth McLendon Arvik, Pharm.D.; Molly

A. Camis, Pharm.D., BCPS; Scott Fields, Pharm.D.; Mark G.

Klang, Ph.D., M.S., BCNSP; Eimeira Padilla-Tolentino, Pharm.D.;

Michele Page, M.B.A.; John Petrich, M.S.; Marjorie Shaw Phillips,

M.S., FASHP; Kenneth Rockwell Jr., Pharm.D., M.S.; Erika L.

Thomas, M.B.A., B.S. Pharm.; and John Vetrano, Pharm.D.

The authors have declared no potential conflicts of interest.

The bibliographic citation for this document is as follows: American

Society of Health-System Pharmacists. ASHP guidelines for the

management of investigational drug products. Am J Health-Syst

Pharm. 2018; 75:561–73.