Investaigational drugs

 After completing this chapter, the reader will be able to
 -List the major legislative acts that led to our current system of
drug evaluation, approval, and regulation.
 -List all of the requirements (as specified by the Office of Human
Research Protections [OHRP]) for an institutional review board
(IRB).
 -Prepare appropriate pharmacy reviews of protocols for use by the
IRB or other review committees when they evaluate new
protocols.
 -List the steps in the drug approval process.
 -Describe the difference between a commercial investigational
new drug (IND), treatment IND, an emergency IND, and an
individual investigator IND.
 -Define orphan drug status and list the advantages of classifying a
drug as an orphan drug.
 -Provide pharmacy support for clinical research

 It is estimated that $802 million is spent to get a
new drug product to market in the United States.
 For every 4000 products synthesized in the lab,
only 5 will ever be tested in humans and only one
of those will ever reach the market.
 The FDA is the federal agency that decides which
drugs, biologics, and medical devices are
marketed in this country. In fact, FDA-regulated
products account for about 25 cents of every
consumer dollar spent.

 The centers of the FDA involved in regulating
drugs, biologics, and medical devices used in
humans are as follows:
 Center for Biologics Evaluation and Research
(CBER)
 Center for Drug Evaluation and Research
(CDER)
 Center for Devices and Radiological Health
(CDRH)

 On average, the FDA approves two new molecular
entities (NMEs) each month.
 Since 1940, more than 1000 NMEs have been
approved in the United States.
 Currently, most investigational drug research is
conducted by medical schools, hospitals, and
organizations specifically designed to conduct clinical
research trials.
 For this reason, the dispensing of investigational
drugs rarely occurs in a community pharmacy setting.
 In some institutions, a pharmacist will be hired
specifically to handle investigational drugs

 In some institutions, a pharmacist will be hired
specifically to handle investigational drugs.
 More frequently, however, this role falls to a
specified staff pharmacist or the drug
information pharmacist.
 To successfully manage investigational drugs,
the pharmacist must be a bookkeeper,inventory
control manager, and, most importantly, an
information disseminator.
 Before proceeding, it is necessary to define a
number of terms that will be used in this chapter

 Clinical investigation :Any experiment in which a drug
is administered or dispensed to one or more human
subjects.
 An experiment is any use of a drug (except for the use
of a marketed drug) in the course of medical practice.
 Although there are many other definitions, this is the
FDA's definition and would seem the appropriate one
to use given the nature of this topic.
 Please note that the FDA does not regulate the
practice of medicine and prescribers are (as far as the
agency is concerned) free to use any marketed drug
for "off-label use."

 Clinical safety officer(CSO):Also known as
the regulatory management officer (RMO).
This will be the sponsor's FDA contact
person.
 Generally the CSO/RMO assigned to a drug's
IND application will also be assigned to the
New Drug Application (NDA).

 Commercial IND: An IND for which the
sponsor is usually either a corporate entity or
one of the institutes of the National Institutes
of Health (NIH)
 Control group:The group of test animals or
humans that receive a placebo (a dosage that
does not contain active medicine) or active
(a dosage that does contain active medicine)
treatment.

 Contract research organization(CRO): An
individual or organization that assumes one or
more of the obligations of the sponsor through
an independent contractual agreement.
 Drug master file(DMF): A submission to the FDA
that may be used to provide confidential
detailed information about facilities, processes,
or articles used in the manufacturing,
processing, packaging, and storing of one or
more human drugs

 Food and Drug Administration(FDA):The
agency of the U.S. government that is
responsible for ensuring the safety and
efficacy of all drugs on the market.
 Institutional Review Board(IRB): A committee
of reviewers that evaluates the ethical
implications of a clinical study protoco

 Investigational New Drug (IND): A drug,
antibiotic, or biologic that is used in a clinical
investigation.The label of an investigational
drug must have the statement: "Caution:
New Drug! ”Limited by Federal (or United
States) law to investigational use.”.

 Investigational New Drug Application
(INDA): A submission to the FDA containing
chemical information, preclinical data, and a
detailed description of the planned clinical
trials.
 Thirty days after submission of this document
to the FDA by the sponsor, clinical trials may
be initiated in humans, unless the FDA places
a clinical hold.

 Investigator:The individual responsible for
initiating the clinical trial at the study site.
 This individual must treat the patients, assure
that the protocol is followed, evaluate
responses and adverse reactions, assure
proper conduct of the study, and solve
problems as they arise.

 New Drug Application(NDA):The application
to the FDA requesting approval to market a
new drug for human use.
 The NDA contains data supporting the safety
and efficacy of the drug for its intended use.

 New Molecular Entity (NME): A compound that
can be patented, that has not been previously
approved.
 Sponsor:An organization (or individual) who
takes responsibility for and initiates a clinical
investigation
 The sponsor may be an individual or
pharmaceutical company, government agency,
academic institution, private organization, or
other organization.

 Sponsor-investigator: An individual who both
initiates and conducts a clinical investigation
(i.e., submits the IND and directly supervises
administration of the drug as well as other
investigator responsibilities)
 Subject: An individual who participates in a
clinical investigation (either as the recipient
of the investigational drug or as a member
ofthe control group)

 For more than a century after the Declaration of
Independence(1776), drug products were not
regulated in this country.
 Available drugs were often ineffective, but some
were addictive, toxic, or even lethal.
 During this same period, doctors were not
license and nearly anyone could practice
medicine.
 The public was, for the most part, responsible
for using common sense when evaluating which
products they would use.

 The first federal law developed to deal with
drug quality and safety was the Import Drug
Act of 1848.This law was passed after it was
discovered that American troops involved in
the MexicanWar had been supplied with
substandard imported drugs.
 The act provided for the inspection,
detention, and destruction or reexport of
imported drug shipments that failed to meet
prescribed standards.

 The Pure Food and DrugsAct was passed in
1906.This law required that drugs not be
mislabeled or adulterated and stated that they
must meet recognized standards for strength
and purity.
 Mislabeling in this context only referred to the
identity or composition of drugs (not false
therapeutic claims).
 False therapeutic claims were prohibited with
the passing of the Sherley Amendment in 1912.

 In 1937, sulfanilamide was released.This drug
showed promise as an anti-infective agent
and was prepared as an oral liquid.
 The vehicle used for this preparation was
diethylene glycol (a sweet-tasting solvent
similar to ethylene glycol, which was used as
an automobile antifreeze
 A total of 107 people died after taking this
preparation.

 Within 1 year of this tragedy, the Food, Drug and
Cosmetic Act of 1938 was enacted
 This law required that the safety of drugs, when used
in accordance with the labeled instructions, be proven
through testing before they could be marketed.
 It was in this law that the submission of an NDA to the
FDA was first described.The NDA was required to list
the drug's intended uses and provide scientific
evidence that the drug was safe.
 If after 60 days the FDA had not responded to the
manufacturer regarding the NDA, the manufacturer
was free to proceed with marketing of the product.

 In 1951 the Durham-HumphreyAmendment
was passed.
 This law divided pharmaceuticals into two
distinct classes:
 1. Over-the-counter (OTC) medications that
could be safely self-administered.
 2. Prescription (Rx) medications that had
potentially dangerous side effects and,
therefore, required expert medical
supervision

 In 1962, another drug tragedy occurred that
resulted in additional regulations. In that
year, an inordinate number of pregnant
women inWestern Europe gave birth to
children with severe deformities.
 Western Europe gave birth to children with
severe deformities.

 These deformities were related to the use of
the drug thalidomide.
 Although U.S. consumers were not directly
affected by this tragedy
 because thalidomide had not been released
in the U.S. mark

 it was a compelling reason for the legislature to
develop stronger laws regarding the testing of new
drug products.
 The Kefauver-Harris Drug Amendment was passed
the same year.This law specified that the
manufacturer had to demonstrate proof of efficacy, as
well as safety, prior to marketing any new drug.
 Additionally, this law required that drug
manufacturers operate in conformity with current
good manufacturing practices (CGMP).
 Finally, it stated that the FDA had to formally approve
an NDA before the drug could be marketed.

 The first step in the drug approval process is
preclinical testing.
 This testing is either in vitro or in animals.
Before filing an IND, the sponsor must have
developed a pharmacologic profile of the
drug, determined its acute and subacute (14
to 90 days) toxicity in at least two species of
animals

 Chronic toxicity studies in animals can
coincide with the use of the drug in clinical
trials in humans (although they must be
initiated at least 13 weeks in advance).
 The preclinical chronic toxicity studies must
be of at least the same duration as any
planned clinical trial (i.e., a 6-month study in
humans requires at least 6 months of
preclinical data)

 After the preclinical testing is completed, the sponsor
will file an IND with the FDA.
 The IND is the application by the study sponsor to the
FDA to begin clinical trials in humans.
 Most often, the sponsor is a pharmaceutical company,
but occasionally an individual investigator will file an
IND and serve as a sponsor-investigator.
 The investigator IND is submitted when a physician
plans to use an approved drug for a new indication
(i.e., one that is outside the package labeling) or on
occasion, for an unapproved product or for an NME.

1-Cover sheet
2-Table of contents
3-Introductory statement
4-General investigational plan
5-Investigator's brochure
6-Clinical protocol
7-Chemistry, manufacturing, and control data
8-Pharmacology and toxicology data
9-Previous human experience

 The IND should be amended as necessary.
There are four types of documents that may
be used to amend the IND.They are as
follows:
 Protocol amendments
 Information amendments
 IND safety reports
 Annual reports

 Once submitted to the FDA, the IND will be
forwarded to the appropriate review division
based on the therapeutic category of the
product.
 The FDA has 30 days after receipt of an IND to
respond to the sponsor.
 The sponsor may begin clinical trials if there is
no response from the FDA within 30 days.
 The FDA delays initiation of a new study or
discontinues an ongoing study by issuing a
clinical hold.

 There are four phases of clinical trials. Clinical
studies generally begin cautiously. As experience
with the agent grows, the dose and duration of
exposure to the agent may also increased. .The
number of patients treated at each phase of
study and the duration of the Studies can vary
significantly depending on statistical
considerations, the prevalence of patients
affected by the disease, and the importance of
the new drug. However, some general guidelines
regarding the four phases of clinical testing are
presented in next slides.

 A phase I trial is the first use of the agent in
humans. As such, these studies are usually
initiated with cautious (low) doses and in small
numbers of subjects.
 Doses may be increased as safety is established.
 A phase I study will usually treat 20 to 80
patients and last an average of 6 months to 1
year.
 The purpose of a phase I trial is to determine the
safety and toxicity of the agent. Frequently
these trials include a pharmacokinetic portion

 These trials assist in identifying the preferred
route of administration and a safe dosage range.
 When possible, these trials are initiated in
normal, healthy volunteers.
 This allows for evaluation of the effect of the
drug on a subject who does not have any
preexisting conditions.
 In situations in which this is not practical, such as
oncology drugs, in which the drug itself can be
highly toxic, these drugs are usually reserved for
patients who have exhausted all conventional
options.

 A phase II trial is one in which the drug is used in a
small number of subjects who suffer from the disease
or condition that the drug is proposed to treat.
 The purpose of a phase II trial is to evaluate the
efficacy of the agent.
 Data from the phase I trial, in vitro testing, and animal
testing may be used to identify which group of
patients is most likely to benefit from therapy with
this agent.
 Phase II trials usually treat between 100 and 200
patients and will average about 2 years in duration

 Phase III trials build on the experience gained
during the phase II trials.
 The purpose of a phase III study is to further
define the efficacy and safety of the agent.
 Frequently, in phase III studies, the new agent is
compared to current therapy.
 These trials are usually Multicenter studies,
generally treat from 600 to 1000 patients, and
usually last about 3 years.
 Some of the phase III trials will be "pivotal"
studies and will serve as the basis for the NDA
for a drug's marketing approval.

 After phase III trials have been completed, the
sponsor will submit an NDA to the FDA
requesting approval of the drug for marketing.
 The FDA requires the completion of two well-
designed, controlled clinical trials prior to
submission to the FDA.
 However, the sponsor will include information
gathered from all of the clinical trials to show
that the drug is safe and effective and to
describe the pharmacology and
pharmacokinetics of the drug

 The NDA will include all preclinical data,
clinical data, manufacturing methods,
product quality assurance, relevant foreign
clinical testing (or marketing experience), and
all published reports of experience with the
drug (whether sponsored by the company or
not). A proposed package insert will be
supplied as well.

 Within 180 days of receipt of an NDA, the
FDA will review the application and send the
applicant an action letter (stating the NDA is
either "approved," "approvable," or "not
approvable")
 When an approval letter is sent, the drug is
considered approved as of the date of the
letter (this rarely occurs with an original
NDA).

 When an approvable letter is sent, it means
that the application "substantially meets the
requirements for marketing approval and the
agency believes that it can approve the
application if specific additional information
or material is submitted or specific conditions
are agreed to by the applicant.“
 The sponsor has 10 days to respond to the
approvable letter.

 A not approvable letter is sent when the FDA
believes the NDA is insufficient for approval.
The letter will describe the deficiencies in the
application.Once again the sponsor has 10
days to respond to the letter.
 The sponsor can amend the NDA, withdraw
the NDA, or request a hearing with the FDA
to clarify whether grounds exist for denying
approval of the application.

 After the drug has been approved, phase IV
trials may be initiated.These trials are also
referred to as postmarketing studies.
 They are conducted for the approved
indication, but may evaluate different doses,
the effects of extended therapy, or the drug's
safety in patient populations that were not
represented in premarketing clinical trials

 These phase IV trials may be requested by the
FDA or they may be initiated by the sponsor
in an attempt to gather more data on the
safety and efficacy of the drug or to identify a
competitive advantage of the drug over other
available therapies.

 The median NDA review process (from
submission to approval) takes 7.7 months for
priority NDAs, while the median approval time
for standard NDAs was 15.4 months.
 Although there has been a significant decrease
in review times since the 1980s, for diseases
(such as AIDS and cancer) where these
investigational drugs may be the only therapy
available, this time delay can still be a significant
factor.

 The IRB is a committee of at least five members
formed to review proposed clinical trials and the
progress of such studies to ensure that the rights
and welfare of human subjects are protected
 The IRB must contain at least one member who
has specialized in a scientific area (usually this
will be a physician) and at least one board
member who has a specialty in a nonscientific
area, such as law, ethics, or religion.

 Common members of IRBs include
physicians, pharmacists, nurses, lawyers,
clergy, and laypeople.
 The IRB is also responsible for ensuring that
the proposed clinical trial is not in conflict
with the institution's research policies or
philosophy

 The IRB should evaluate the research proposal to
ensure that the following requirements are met:
1-The risks to subjects are minimal.
2-The expected risk/anticipated benefit ratio must be
reasonable.
3-Equitable subject selection is used.
4-Informed consent must be received from each
participant (or his or her representative).
5-Informed consent must be documented in writing.
6-Data must be monitored to ensure subject safety.
7-Patient confidentiality must be maintained

8-If appropriate, additional safeguards against
coercion must be included in studies that
include vulnerable subjects (children, prisoners,
pregnant women, mentally disabled people,or
economically or educationally disadvantaged
persons)

 The Orphan DrugAct was passed in 1983.This
act provides incentives for manufacturers to
develop orphan drugs.
 An orphan drug is one used for the treatment of
a rare disease (affecting fewer than 200,000
people in the United States) or one that will not
generate enough revenue to justify the cost of
research and development.
 The Orphan DrugAct is administered by the
FDA's Office of Orphan Products Development.

 The Orphan Drug Act does not provide advantages for
the drug approval process.
 Sponsors seeking approval for drugs that will Be
designated as orphan drugs must still provide the
same safety and efficacy data as all other drugs
evaluated by the FDA.
 Exceptions to the rules governing the number of
patients who should be treated in the clinical trials
may be made based on the scarcity of patients with
the condition. Additionally, because in many cases
there are no alternative therapies for the disease, the
drug may be given a high review priority during the
NDA process.

 The pharmacist can play a vital role in the
clinical research process by
 1-Being the PI on a study.
 2-Reporting adverse events.
 3-Preparing the IND.
 4-Serving on the IRB and, where applicable,
on the Scientific Review Committee.

 5-Providing financial evaluations of
investigational protocols.
 6-Disseminating information regarding both the
protocol and the investigational drug to other
healthcare personnel.
 7-Maintaining drug accountability records.
 8-Ordering, maintaining and, when necessary,
returning drug supplies for ongoing clinical trials.
 9-Randomizing and, when necessary, blinding
drug supplies for a clinical trial.

 The pharmacist can serve as the PI on clinical
research studies.The type of study for which
a pharmacist is PI varies based on the
 Expertise and experience of the pharmacist.
Common types of studies for which
pharmacists serve as PIs include
pharmacoeconomic and
pharmacology/pharmacokinetic studies. For
some of these trials, a physician must be a
co-investigator.

 The pharmacist can assist the investigator by
reporting clinical trial adverse events to the
FDA

 the pharmacist can assist in preparing the
IND by following the guidelines presented
earlier in this chapter

 Preferably, the pharmacist should be a voting
member of the IRB and, as such, may have
some control over clinical trials initiated at
the institution.

 When reviewing a protocol for scientific
purposes, the pharmacist should verify that the
protocol or associated documents such as the
investigator's brochure contain the following
information:
 1.The name and synonyms of the study drug.
 2.The chemical structure of the study drug.
 3.The mechanism of action of the study drug.
 4.The dosage range of the study drug (with
appropriate rationale).

 5. Animal toxicologic and pharmacologic information
(when available, any known human toxicologic and
pharmacologic information should also be presented).
 6. How the drug will be supplied (dosage form and
size).
 7.The preparation guidelines for the drug (including
stability and compatibility information when
appropriate).
 8.The storage requirements of the drug (both before
and, when appropriate, after preparation).
 9.The route of administration (and, if applicable, the
rate of administration).

 With the central role of financial considerations
in today's research environment, pharmacists
can also provide valuable insight into the costs
associated with clinical research.
 Traditionally, the study sponsors would provide
the investigational drug free of charge to the
hospital (and to the patient), and the patient (or
the third-party payer) would be responsible for
paying for all other charges associated with
therapy.

 This leaves the patient, and subsequently the
hospital, in a financially risky situation. A
significant portion of costs associated with
clinical research is pharmacy related (either
supportive care medications or infusion
devices, solutions, and so forth, that are used
to administer the investigational drug).

 If, during the review process, the pharmacist
can provide the investigator and the
scientific review board with information
regarding the potential cost of the research
(at least as it relates to pharmacy charges),
both the investigator and the review board
can make a more educated decision
regarding appropriation of resources for
research purposes.

 When preparing an economic review of a
protocol the pharmacist should pay specific
attention to the following items:
 1. Can the therapy be converted from
inpatient to outpatient?
 2. Can the method of infusion or the infusion
device be changed to one that is more cost
effective?

 3. Does the treatment plan call for
administration of compatible medications
that could be mixed in the same container?
 4. Is the supportive care adequate and not
excessive (this is especially important with
high-cost drugs, such as antiemetics and
growth factors)?

 5. Does the protocol have a high risk of
reimbursement denial? This can be evaluated by
reviewing the package insert,American Hospital
 Formulary Service Drug Information, US
Pharmacopeia ”Drug Information (USP-DI), and for
oncology products, Association of Community Cancer
Centers Compendia-Based Drug Bulletin.
 Other factors in reimbursement risk include the cost
of the drug and the supportive care or tests associated
with the drug.
 If the protocol does have a high risk of reimbursement
denial, can free drug supplies offset part or all of this
risk?

 The pharmacist can assist in disseminating
information regarding both the protocol and
the investigational drug by preparing data
sheets that may be used by pharmacy and
nursing personnel (and in some situations by
physicians who may be unfamiliar with the
research).This information can be distributed
using various methods including paper, the
hospital mainframe, and the intranet.

 The drug data sheet should include the following elements:
 Drug name (synonyms)
 Therapeutic classification
 Pharmaceutical data
 Stability and storage data
 Dose preparation guidelines (where applicable)
 Usual dosage range
 Route of administration
 Known side effects and toxicities
 Mechanism of action
 Status (phase of study)
 Study chairperson
 Date effective (and dates of revision)
 References

 Another role the pharmacist should assume is
maintaining drug accountability records.
These records can be maintained manually or
on a computer.The records must document
all drug shipments, returns, and dispensing to
patients.

 These records should document:
 The date of the transaction.
 The patient initials and an identifying number.
 The dose.
 The number of vials of drug used or received.
 The lot number of the drug (if multiple lot
numbers were used, each one should be
documented).
 The initials of the individual who performed the
transaction

 Computer systems that will maintain drug
accountability records are available
commercially. Personal computer “based, web-
based, and mainframe-based systems exist.
 Some of these systems will also provide drug
labels, drug and protocol information,
summaries of investigational drug dispensing
(useful in the preparation of productivity
reports), and even monthly billing summaries to
be used for posting charges to the study budget

 A web-based system that is currently on the
market is IDEA being marketed by DDOTS,
Inc.
 (http://www.ddots.com/)Another
commercially available system is the IDS
system being marketed by the Manhatten
Group.

 Drug accountability records and drug supplies
may be inspected at any time by the sponsor.
 The frequency of these inspections may vary
according to the wishes of the sponsor.They
may be monthly, quarterly, or annually.The FDA
also has the right to inspect these records.
 The investigational drug pharmacist should play
a key role in providing drug accountability
information to either the FDA or the sponsor
during an audit.

 If proper records are not being maintained, the
sponsor or the FDA may discontinue the
investigator's participation in the clinical
investigation.
 After the clinical trial is complete, records must
be maintained at the study site for the following
time periods:
 Two years after approval of the NDA or
 Two years after the FDA received notification
that the investigation was discontinued.

 The pharmacist should also assume primary
responsibility for randomizing and, where
appropriate, blinding clinical trials.These
Two activities assist the sponsor in reducing
or eliminating the bias of the clinical trial.

 A randomized study is one in which patients
are randomly assigned (similar to flipping a
coin) to different therapies.
 Usually the assignment is done using a
computer-generated randomization list;
however, a manual list may be used as well

 Assisting in implementing and conducting
clinical trials can be a satisfying role for the
pharmacist.
 A large part of the role of the pharmacist will
be providing protocol and drug information
to the investigators and associated study
personnel.
 An even more satisfying role is that of
providing information to the study
participants

 The laws governing these trials can be
complex, but they are understandable once
the pharmacist has taken the time to study
them.
 The pharmacist can and should play an
integral role in the conduct of clinical trials at
their institution

 Patrick M. Malone, Karen L. Kier, John E.
Stanovich (2007) Drug Information: A Guide
for Pharmacists, 3rd edn., United States of
America: McGraw-Hill Education.

Investaigational drugs

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Investaigational drugs

Similar to Investaigational drugs (20)

Recently uploaded

Recently uploaded (20)

Investaigational drugs