MODULE - 5

Syllabus

• IND (investigational New Drug Applications with FDA)

– Types of IND,
– IND application,
– Preliminary testing, chemical structure, side effect in animals,
preliminary manufacturing plan,
– Detailed clinical studies approved by Institutional Review
board(IRB)
 Investigational New Drug (IND) Applications
• The United States Food and Drug Administration's Investigational New Drug (IND) program is the
means by which a pharmaceutical company obtains permission to start human clinical trials and to
ship an experimental drug  (usually to clinical investigators) before a marketing application for the
drug has been approved.
• During a new drug's early preclinical development, the sponsor's primary goal is to determine if
the product is reasonably safe for initial use in humans, and if the compound exhibits
pharmacological activity that justifies commercial development. When a product is identified as a
viable candidate for further development, the sponsor then focuses on collecting the data and
information necessary to establish that the product will not expose humans to unreasonable risks
when used in limited, early-stage clinical studies.
• FDA's role in the development of a new drug begins when the drug's sponsor (usually the
manufacturer or potential marketer), having screened the new molecule for pharmacological
activity and acute toxicity potential in animals, wants to test its diagnostic or therapeutic potential
in humans.  At that point, the molecule changes in legal status under the Federal Food, Drug, and
Cosmetic Act and becomes a new drug subject to specific requirements of the drug regulatory
system. 
• Regulations are primarily at 21 C.F.R. (is the portion of the Code of Federal Regulations that
governs food and drugs within the United States for the Food and Drug Administration (FDA),
the Drug Enforcement Administration (DEA), and the Office of National Drug Control
Policy (ONDCP)) Similar procedures are followed in the European Union, Japan, and Canada.
• IND is known as CTA (clinical trial application) in the European Union
 IND Application
• The IND application must contain information in three broad areas:
– Animal Pharmacology and Toxicology Studies - Preclinical data to permit an
assessment as to whether the product is reasonably safe for initial testing in
humans.  Also included are any previous experience with the drug in humans (often
foreign use).
– Manufacturing Information -  Information pertaining to the composition,
manufacturer, stability, and controls used for manufacturing the drug substance and
the drug product.  This information is assessed to ensure that the company can
adequately produce and supply consistent batches of the drug.
– Clinical Protocols and Investigator Information - Detailed protocols for proposed
clinical studies to assess whether the initial-phase trials will expose subjects to
unnecessary risks.  Also, information on the qualifications of clinical investigators--
professionals (generally physicians) who oversee the administration of the
experimental compound--to assess whether they are qualified to fulfill their clinical
trial duties.  Finally, commitments to obtain informed consent from the research
subjects, to obtain review of the study by an institutional review board (IRB), and to
adhere to the investigational new drug regulations.
• Once the IND is submitted, the sponsor must wait 30 calendar days before initiating any
clinical trials.  During this time, FDA  has an opportunity to review the IND for safety to
assure that research subjects will not be subjected to unreasonable risk.
 Types of IND
• There are three IND types:
– An Investigator IND is submitted by a physician who both initiates and conducts an
investigation, and under whose immediate direction the investigational drug is administered
or dispensed.  A physician might submit a research IND to propose studying an unapproved
drug, or an approved product for a new indication or in a new patient population.
– Emergency Use IND  allows the FDA to authorize use of an experimental drug in an emergency
situation that does not allow time for submission of an IND in accordance with  21CFR.  It is
also used for patients who do not meet the criteria of an existing study protocol, or if an
approved study protocol does not exist.
– Treatment IND is submitted for experimental drugs showing promise in clinical testing for
serious or immediately life-threatening conditions while the final clinical work is conducted
and the FDA review takes place.
• There are two IND categories:
– Commercial: Commercial INDs are usually submitted by biopharmaceutical drug companies
with the intent of eventually submitting a marketing application to sell the drug commercially
– Research (non-commercial): Research INDs are submitted by investigators to test a new dose
or indication of an existing drug, but the data to be generated from the study are not intended
to be used for a subsequent application for market approval.
 Types of IND
• Exploratory IND
• For drugs that are in very early development, an abbreviated IND, called an exploratory IND, may
be submitted to allow drug sponsors to evaluate up to five chemical entities or formulations
simultaneously, supported by limited nonclinical data
• Exploratory INDs provide the opportunity to study pharmacokinetic and target interaction early in
drug development.
• When a lead candidate drug has been selected, the exploratory IND is closed, and a traditional IND
is opened.
 Investigator IND
• Investigational New Drug (IND) Application is submitted to FDA if a drug (or biological
product) not previously authorized for marketing in the US is intended to be used for
the purposes of clinical investigation or, in certain cases, for the purposes of clinical
treatment when no approved therapies are available. 
• Clinical investigation is defined as “an experiment in which a drug is administered or
dispensed to, or used involving, one or more human subjects. Such an experiment is
any use of a drug [whether approved or unapproved] except for the use of a marketed
drug in the course of medical practice
• Sponsor of an IND application is the party who submits the application to FDA. In the absence of
any other sponsor (e.g. pharmaceutical company), the investigator conducting the proposed
clinical investigation is the sponsor of the IND application.
• Upon receipt of an IND application, FDA will notify the sponsor of the date it receives the
application through an IND acknowledgment letter.
• An IND application may go into effect:
– 30 days after FDA receives the application, unless FDA notifies the sponsor that the investigations described in the
application are subject to a Clinical Hold; or
– on earlier notification by FDA that the clinical investigations in the IND may begin. 
• Once an IND application is in effect, a drug manufacturer may ship the investigational new drug to
the investigator(s) named in the application. An investigator may not administer an investigational
new drug to human subjects until the IND application goes into effect.
 Investigator IND
• Expanded access, sometimes called "compassionate use," is the use of investigational
new drug products outside of clinical trials to treat patients with serious or immediately
life-threatening diseases or conditions when there are no comparable or satisfactory
alternative treatment options. The rules and regulations related to expanded access are
intended to improve access to investigational drugs for patients who may benefit from
investigational therapies.
• When considering an IND application for expanded access to an investigational product
with the purpose of treating a patient or a group of patients, physicians and
investigators should recognize that such applications would be suitable when all of the
following criteria apply:
– Patient(s) have a serious or immediately life-threatening disease or condition, and there is no comparable
or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition;
– The potential patient benefit justifies the potential risks of the treatment and the potential risks are not
unreasonable in the context of the disease or condition to be treated; and
– The expanded use of the investigational drug for the requested treatment will not interfere with the
initiation, conduct, or completion of clinical investigations that could support marketing approval of the
product. 
 Investigator IND
• An expanded access IND application intended for IND use in non-emergency setting will
go into effect 30 days after FDA receives the application or on earlier notification by FDA
that the expanded access use may begin. Expanded access IND applications submitted
for the purpose of clinical treatment in Emergency Setting may begin as soon as the use
of investigational drug is authorized by an FDA reviewing official.
• As other IND applications, expanded access IND applications may be placed by FDA
on Clinical Hold.
• FDA regulations allow access to investigational drugs for treatment purposes on a case-
by-case basis for:
– individual patients (single-patient IND applications for treatment in emergency settings and non-emergency
settings)
– intermediate-size patient populations (groups of patients, n >1)
– larger populations for use of the drug under a treatment protocol or Treatment IND Application   
 Data Required to Support Initial Clinical Trials
• Administering a new drug to humans has inherent risk.
• Scientists, clinicians, and regulators strive to continuously improve how drug candidates
are evaluated prior to the first‐in‐human (FIH) administration to minimize this risk as
much as possible.
• Years of research in multiple specialties are required to produce the totality of evidence
necessary to support advancing a new drug into human trials.
• The company sponsoring the development of a new drug (Sponsor) is required to
provide a robust data set describing how the drug is made and determined to be pure
and potent, the results of testing the effects of the drug in animals, and the plans for
exploring exposure in humans as safely as possible.
 Data Required to Support Initial Clinical Trials
• Chemistry, manufacturing, and control information
– Before a new drug can be administered to humans, the Sponsor must assure regulators that
the drug is made under controlled conditions, with ongoing tests to ensure that the drug
meets prospective criteria (e.g., identity, purity, potency, and stability). These data are
required to show that a drug is what it is supposed to be, without any contaminants, and that
it will maintain its purity and potency for at least the duration of the studies. Information on
both the drug substance (the active pharmaceutical ingredient) and the drug product (the
formulated drug ready for administration) must be submitted to the regulators. These data
evolve over time as the Sponsor optimizes production and formulation of the drug.
– Information on the drug substance should include the proper identification, quality, purity,
and strength of the active ingredient, with an emphasis on the identification and control of
raw materials and the new drug substance.
– Information on the drug product is also provided, and similar to the drug substance section,
this should include data supporting the assays and acceptable results for assessing its identity,
strength, quality, and purity. It is also necessary to demonstrate stability (evidence on how the
quality varies with time under the influence of a variety of environmental factors, such as
temperature, humidity, light, etc.) for at least the duration of the clinical trial to inform the
drug product shelf life and recommended storage conditions. Early in development, the drug
product may be in a variety of forms; for example, it may be simply the drug substance
handfilled into capsules, or it may be a biologic purified from a small‐scale production.
– Information on the placebo, if included in the clinical study, is also required.
 Data Required to Support Initial Clinical Trials
• Nonclinical pharmacokinetics, pharmacology, and toxicology information
– A multitude of issues must be explored prior to dosing a human with a new drug. What
happens biologically when a person takes a new drug? Does the drug stay in the body long
enough to have any effect? Is it effectively delivered to the site of action? Is the drug
metabolized, and what is the potential impact of the metabolites? Does the drug have an
impact on how the body functions? If so, what body systems are impacted, and at what
doses? Does the drug have any long‐term positive or negative effects? Does the drug have
potential to treat a disease or condition? If a drug has potential therapeutic benefit, do these
benefits outweigh the potential risks?
– Given the risks of administering a new drug to humans, a range of studies are conducted
beforehand in test tubes, human and animal‐derived cell lines, and animal models to explore
the effects of the drug
 Data Required to Support Initial Clinical Trials
• Distribution, metabolism, and pharmacokinetics
• Pharmacokinetics refers to how a drug is processed through the body. These studies explore how
the drug is absorbed once administered, where it distributes to in the body, how it is metabolized,
and how it is excreted. These studies range from the identification of small molecule drug
metabolites in vitro to the measurement of the drug in the blood, urine, and feces obtained from
animals that are administered the drug
 Data Required to Support Initial Clinical Trials
• Pharmacology
• can be broken down into three categories: primary pharmacodynamics, secondary
pharmacodynamics, and safety pharmacology.
• Primary pharmacodynamics explores whether the drug has the intended effect in vitro: if it is a
kinase inhibitor, does it inhibit the kinase in a test tube or cell line? If the drug is supposed to bind
a cell‐surface receptor, does it bind that receptor expressed on a human cell line? In other words,
does the drug have the primary effect one would anticipate and at what concentration?
• Secondary pharmacodynamics explores additional effects of the drug: does it bind any other
proteins or antigens or receptors, and with what affinity? Does it inhibit any enzymes other than
the intended target, and is the inhibition competitive or not? Secondary pharmacodynamics are
key to assessing whether the drug has additional impact other than the intended effect, which may
contribute to a better understanding of the overall safety profile of the drug. For example, this may
include a dose‐ranging study to assess drug binding with other human substrates in vitro. In the
case of a kinase inhibitor, these studies would reveal what other enzymes to which the drug may
bind and at what concentration. This information is critical to understanding the drug's possible
“off‐target” effects or the unintended side effects of drug treatment or overexposure
• Safety pharmacology experiments are designed to assess the impact of the drug on vital functions
and are generally conducted in animal models, such as rodents and nonhuman primates. The core
battery of these assessments includes the central nervous system, cardiovascular system, and
respiratory system in animal species that are considered pharmacologically relevant. Selection of
the pharmacologically relevant species is based on a number of factors, including whether the drug
acts on the animal's system in a way that is similar to how it would act in humans
Data Required to Support Initial Clinical Trials
Data Required to Support Initial Clinical Trials
 Data Required to Support Initial Clinical Trials
• Toxicology
• Toxicology studies are conducted primarily in animal models and are designed to predict, as much
as possible, any potential toxicities (i.e., adverse or negative outcomes) in humans who may be
exposed to the drug. The extent of these studies varies by indication: drugs designed to treat life‐
threatening diseases may not require the same level of evidence to support FIH (first in human)
studies as drugs designed to treat a more chronic disorder. For example, prior to initiating clinical
trials, most drugs are evaluated for the risk of genotoxicity (when the drug changes the recipient's
DNA such that a mutation could be passed to their offspring) using a bacteria‐based assay, whereas
oncology drugs are not required to evaluate genotoxicity until prior to marketing.
• Generally, toxicology studies are required for all drugs to explore the adverse effects of the drug
when administered to one or more animal models as a single dose and after multiple doses. These
studies attempt to predict the highest dose that could potentially be administered to humans
before encountering toxicities. Once toxicities are identified in animals, these studies assess
whether or not the toxicities are reversible. For oncology drugs, data from studies of 28 days in two
different animal species support continuous dosing in patients, as long as the patient is deriving
benefit. Toxicology studies with a duration similar to that in the planned clinical trial are required
for nononcology drugs. Results from these studies are critical in evaluating whether the potential
benefit outweighs the potential risk of administering the drug to humans.
• Additional toxicology studies, including the drug's risk of causing cancer or reproductive harm, may
be evaluated later in the lifecycle of the drug development.
 Institutional Review Board (IRB)
• an IRB is an appropriately constituted group that has been formally designated to review and
monitor biomedical research involving human subjects.
• In accordance with FDA regulations, an IRB has the authority to approve, require modifications in
(to secure approval), or disapprove research.
• This group review serves an important role in the protection of the rights and welfare of human
research subjects.
• The purpose of IRB review is to assure, both in advance and by periodic review, that appropriate
steps are taken to protect the rights and welfare of humans participating as subjects in the
research. To accomplish this purpose, IRBs use a group process to review research protocols and
related materials (e.g., informed consent documents and investigator brochures) to ensure
protection of the rights and welfare of human subjects of research.
 Clinical protocol
• The clinical protocol is the step‐by‐step detailed plan of exactly how the new drug is to be
evaluated in humans.
• The critical chemistry, manufacturing, and control (CMC) and nonclinical safety assessment data
collected to date are briefly summarized and then integrated into the study plan.
• For example, the chemistry of a small molecule drug will determine whether the drug can be
formulated into an orally available pill or if it will be administered intravenously.
• Predictions from pharmacokinetic studies will drive how often the drug is administered, and the
nonclinical safety findings in animal models from the toxicology studies will inform the drug dose
and how human subjects are monitored for potential adverse side effects.
• The protocol should be approved by the IRB
 Key aspects in designing a Clinical protocol
• Study population:
• In designing the clinical trial in which a new drug is administered to humans for the first time (an
FIH study), Sponsors decide whether it is safe to test the drug in healthy volunteers or whether it
would be more appropriate to test the drug in the intended patient population, where the
acceptable risk tolerance may be higher.
• For chronic diseases, it is critical that the clinical safety profile supports long‐term administration.
It may be preferable to initially evaluate these drugs in healthy volunteers, where the safety
assessment is not complicated by the underlying disease.
• In contrast, many oncology drugs have significant adverse effects, and may only be initially tested
in patients with late‐stage cancer, in whom the risk/benefit profile of the drug is acceptable.
• Another aspect to assess is whether the drug may have negative long‐term consequences in the
treated population.
• For example, in the 1990s, a study was conducted in patients with renal failure who were
administered recombinant human erythropoietin to treat anemia. Some of these patients
generated antibodies against their endogenous erythropoietin in response to treatment with the
recombinant erythropoietin, leading to an autoimmune disorder called pure red cell aplasia
 Key aspects in designing a Clinical protocol
• Dose selection:
• Based on the nonclinical safety assessments, a starting dose that is unlikely to result in adverse side
effects is selected .
• A common FIH study design is to test the drug at a low dose in a small number of subjects and
assess for safety concerns for a duration determined by the drug's pharmacokinetic and
pharmacodynamic profile.
• If the safety is acceptable, a higher dose level is similarly assessed in another small group of
subjects.
• This dose‐escalation paradigm is continued until an appropriate pharmacodynamic dose level is
safety attained, unacceptable safety findings are noted, or the dose level approaches an exposure
at which unacceptable safety findings were observed in nonclinical studies.
• In some studies, additional subjects are assessed at this dose level to obtain further safety data.
• In some patient populations, such as rare diseases, in which there are only a small number of
patients in which to assess the drug's safety and efficacy, it may be important to select a dose that
may have the potential for direct benefit for patients enrolled in an FIH study
 Key aspects in designing a Clinical protocol
•  Determining a safe starting dose (FDA and EMA Guidance)
• Step 1: Determine the NOAEL (no-observed-adverse-effect-level)
• NOAEL is the highest dose tested in a nonclinical study that does not produce a significant increase
in adverse effects compared to the control group.
• Step 2: Calculate the HED (Human Equivalent Dose)
• HED is calculated from the exposure defining the NOAEL in each nonclinical toxicology study most
commonly by normalizing to body surface area or body weight
• Alternatives include scaling based on drug levels if dose is limited by local toxicity (e.g., topical
drugs) or based on volume if administration is limited by compartment (e.g., intrathecal
administration)
• Step 3: What is the most appropriate species?
• Sponsors will have several HEDs based on various nonclinical studies.
• The most appropriate HED is selected based on the most appropriate pharmacologically relevant
species.
• Interestingly, the most sensitive species is not always the most relevant (e.g., low doses of NSAIDs
causes gastrointestinal lesions in beagles but are well tolerated in humans)
 Key aspects in designing a Clinical protocol
•  Step 4: The safety factor
• Nonclinical toxicology studies may not perfectly predict the human adverse event profile.
• To account for differences between nonclinical models and humans, Sponsors apply a safety factor,
typically 10‐fold, to the HED to get the recommended starting dose.
• This safety factor may be increased for higher risk drugs (e.g., if there is a nonmonitorable toxicity
or nonlinear pharmacokinetics).
• Alternatively, this factor may be reduced for a drug that belongs to a well‐characterized class or if
toxicities are monitorable, predictable, and reversible.
• Step 5: Consider the estimated PAD (Pharmacologically active dose)
• Sponsors should consider the estimated PAD to determine a starting dose.
• The FDA suggests that the PAD may be a more sensitive estimate of possible toxicities and may
warrant lowering the starting dose to below the PAD.
• The EMA recommends that the starting dose is below the PAD in healthy volunteer studies.
 Key aspects in designing a Clinical protocol
• Safety monitoring plan:
• A clinical safety monitoring plan is designed to assess subjects for any toxicity that may have been
identified by the nonclinical studies, may be of particular importance to the patient population, or
may be a class effect of drugs that hit the same target or pathway.
• The Sponsor will list which potential adverse events may arise, at what exposures, and at what
duration after the drug is administered. Based on this, subjects will undergo safety assessments
during the conduct of the clinical study
 Key aspects in designing a Clinical protocol
• Investigator’s Brochure
• The Investigator’s Brochure (IB) is similar to prescribing information (or drug label), but for an
investigational drug.
• It summarizes all of the known nonclinical and clinical safety and efficacy information of the drug;
the intent is to inform clinicians of the potential toxicity of the drug.
• A key section of the IB defines the adverse events that are considered “expected” for the purposes
of expedited safety reporting for the drug based on observations to date.
• The IB is updated at least annually for as long as the drug is undergoing clinical trials to ensure the
information is current.
To (IND) or not to IND
 Life cycle of an IND
• INDs are not “approved”; they are “cleared.” The FDA reviews initial INDs in 30 days
• Questions from the FDA that arise during the review of the IND are communicated to the Sponsor,
usually during the last 2 weeks of the 30-day review. A teleconference may be needed to clarify
these issues.
• The Sponsor then addresses the FDA’s concerns by providing additional information and/or revising
the IND documents as needed.
• If the FDA’s concerns are adequately addressed such that they consider the study safe to proceed,
the IND is cleared after 30 days. If, however, the FDA’s concerns remain, they may place the IND on
full or partial clinical hold
• A full hold means that no clinical study can be initiated under the IND until the FDA’s issues are
satisfactorily addressed. A partial hold means the clinical study and any other studies submitted
under the IND may proceed with certain constraints (e.g., the investigational drug may not be
administered above a certain dose).
• The Sponsor must then provide a complete response to the clinical hold, which also has a 30-day
review period.
• The FDA may lift the hold if the response addresses the identified issues and clears the IND,
thereby allowing studies under the IND to proceed, or the FDA may maintain the clinical hold.
Because future protocols submitted under an IND are allowed to proceed without the review, the
FDA may be cautious when clearing the initial IND.
• However, the FDA may place an IND on clinical hold if any concerns arise at any time during the
lifecycle of the IND; this prerogative is not restricted to the first 30 days of the IND submission.
 IND maintenance
• Once an IND is in effect, there are three primary maintenance activities and responsibilities for
Sponsors: amendments, safety reporting, and annual reports
• Amendments. The IND is often amended throughout its lifecycle. There are two types of IND
amendments: Protocol Amendments and Information Amendments. Protocol amendments are to
ensure that the clinical investigations are conducted according to the protocols included in the
application. Information amendments are any amendments to information essential to the
investigational drug and can be categorized as relating to chemistry/microbiology, pharmacology/
toxicology, clinical, statistics, or clinical pharmacology
• Safety reporting. Sponsors must notify HAs and all participating investigators of potential serious
risks associated with the use of the investigational drug based on prompt review of all relevant
safety information. These include serious and unexpected suspected adverse reactions, findings
from other studies, findings from animal or in vitro testing, or increased rate of occurrence of
serious suspected adverse reactions
• Annual reports. Sponsors are expected to submit a brief report of the progress of the studies
conducted under their IND application annually within 60  days of the anniversary date that the
IND went into effect