The document discusses the stages of clinical drug development, including preclinical testing, Phase I-III trials, and regulatory approval. Preclinical testing assesses safety in animals before human trials. Phase I trials primarily evaluate safety in small human groups. Phase II trials further assess safety and preliminary efficacy. Phase III trials are large-scale, placebo-controlled trials to prove efficacy and long-term safety for regulatory approval. The goal is to advance safely from preclinical to clinical testing and approval.

1. The Drug Development Process
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The Drug Development Process – Clinical Development
The Progressive Stages of Clinical Development
• Following the “Drug Discovery” process, a “Drug Candidate”
is nominated for clinical development
• A single “Lead Compound” is chosen to move forward.
• There may also be additional “back-up” compounds
nominated, but treated with a (much) lower priority.

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The Drug Development Process – Clinical Development
Stages of Clinical Development
1.) Preclinical
2.) Phase I
3.) Phase II (Phase IIa & Phase IIb)
4.) Phase III
5.)Registration
6.) Commercial Launch
7.) Phase IV

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The Drug Development Process – Preclinical Development
Preclinical Development
• Before testing a new medicine in humans, researchers conduct
extensive “preclinical testing” of the molecule.
• They perform various experiments with “in vitro” (i.e. in a petri dish,
vial, or beaker in the laboratory) or in animal models (usually simpler
species such as rodents).
• The activity of the drug candidate is carefully examined under many
different conditions prior to moving it into human testing in medical
clinics.

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Preclinical Development (continued)
• Under FDA requirements, a company must first submit data showing
that the drug is reasonably safe for use in initial, small-scale clinical
studies.
• Genotoxicity screening is performed, as well as investigations on
drug absorption and metabolism, the toxicity of the drug's metabolites,
and the speed with which the drug and its metabolites are excreted
from the body.
The Drug Development Process – Preclinical Development

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Preclinical Development (continued)
At the preclinical stage, the FDA will generally ask, at a minimum,
that the developers:
(1) develop a pharmacological profile of the drug;
(2) determine the acute toxicity of the drug in at least
two species of animals.
(3) conduct short-term toxicity studies ranging from 2 weeks to
3 months, depending on the proposed duration of use of the
substance in the proposed clinical studies.
The Drug Development Process – Preclinical Development

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Preclinical Development (continued)
Sponsor/FDA Meetings (Pre-IND)
• Prior to clinical studies, the sponsor needs evidence that the compoun
is biologically active, and both the sponsor and the FDA need data
showing that the drug is reasonably safe for initial administration to
humans.
The Drug Development Process – Preclinical Development

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Investigational New Drug Application
• The investigational new drug (IND) application is the result of a
successful preclinical development program.
• The IND is also the vehicle through which a company advances to the
next stage of drug development known as clinical trials (human trials).
• The IND is not an application for marketing approval.
• It is a request for an exemption from the Federal statute that prohibit
an unapproved drug from being shipped in interstate commerce.
The Drug Development Process – Preclinical Development

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Investigational New Drug Application(continued)
• Animal Pharmacology and Toxicology Studies
Preclinical data to permit an assessment as to whether the product
is reasonably safe for initial testing in humans.
• Manufacturing Information
Information pertaining to the composition, manufacture, stability,
and controls used for manufacturing the drug substance and the
drug product. This information is assessed as to ensure the company
can adequately produce and supply consistent batches of the drug.
The Drug Development Process – Preclinical Development

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Investigational New Drug Application (continued)
• 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.
The Drug Development Process – Preclinical Development

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Phase 1 Considerations
•CMC safety issues as they relate to the quality aspects of product
•What is the risk for human subjects? Are there any signals from
preclinical studies?
•The product class and the individual product affect, to some extent,
the type and extent of information needed to assess safety.
–Often novel and complex products require additional
information to address unknowns and added
complexity (e.g., transgenic, xenotransplantation)
The Drug Development Process – Preclinical Development

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The Drug Development Process – Phase I Clinical Development
Phase I Clinical Development
• Phase I clinical trials are designed to examine the safety of a
drug candidate.
• Further clinical trials and development cannot happen unless Phase I
trials demonstrate the drug candidate to be reasonably safe when
administered to humans.
• Some side effects may be acceptable in relation to the severity of
the targeted disease (i.e. chemotherapy).
• Participants in Phase I are closely monitored for the smallest
indication of harm caused by the medicine.

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Phase I Clinical Development (continued)
• Safety is the key issue. Thus these trials are purposely conducted
with a small scope (limited number of participants).
• An attempt is made to establish the dose range tolerated by
volunteers for single and for multiple doses. .
•Phase I trials are sometimes conducted with severely ill patients
(e.g. in the field of cancer).
The Drug Development Process – Phase I Clinical Development

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Phase I Clinical Development (continued)
• In Phase 1 studies, CDER can impose a clinical hold (i.e., prohibit
the study from proceeding or stop a trial that has started) for reasons
of safety, or because of a sponsor's failure to accurately disclose the
risk of study to investigators.
FDA Role in Phase I
CDER = Center for Drug Evaluation & Research
The Drug Development Process – Phase I Clinical Development

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Phase I Clinical Development
Phase I Clinical Development is important
Why?
Because that is when the dosage form is beginning to
be determined.

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The Drug Development Process – Clinical Development
Phase IIa Clinical Development
•Pilot clinical trials (“Pilot” means focused on obtaining information
and working out trial logistics) evaluate efficacy (and safety) in
selected populations of patients with the disease or condition to be
treated, diagnosed, or prevented.
•Objectives may focus on dose-response, type of patient, frequency
of dosing, or numerous other characteristics of safety and efficacy.

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The Drug Development Process – Clinical Development
Phase IIb Clinical Development
Well-controlled trials to evaluate efficacy (and safety) in patients
with the disease or condition to be treated, diagnosed, or prevented.
These clinical trials usually represent the most rigorous demonstration
of a medicine’s efficacy. Sometimes referred to as pivotal trials.

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The Drug Development Process – Clinical Development
Phase II Clinical Development
• Phase II clinical trials are designed to further assess safety and
evaluate efficacy in humans over the short term.
• Phase II clinical trials help set up parameters (e.g. dosage) of
the longer-term Phase III trials.
• Phase II trials are typically placebo controlled and double
blinded.
• Neither the patient nor the medical personnel know whether
the patient is receiving the drug or the placebo.

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The Drug Development Process – Clinical Development
Phase II Clinical Development (continued)
• These trials are larger in scope than Phase I and take more time.
• In an effort to save time and money, some companies try to
minimize the size and scope of Phase II trials.
• Some companies rely on information from preclinical and Phase I
trials to design comprehensive Phase II trials that can clearly
demonstrate the efficacy (or lack thereof) of a drug before a
Phase III trial.
• This approach minimizes the risk of unpleasant surprises
following the far more expensive Phase III trials.

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The Drug Development Process – Clinical Development
Phase III Clinical Development
•Phase III trials are designed to prove the efficacy and confirm
the safety of the drug.
• They are usually double-blinded and placebo-controlled and can
involve hundreds or even thousands of patients over many months
or even years.
• Though the numbers of patients involved can be great, the risks
are relatively minimal because of the earlier testing to establish safety

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The Drug Development Process – Clinical Development
Phase IIIa Clinical Development
•Trials conducted after efficacy of the medicine is demonstrated, but
prior to regulatory submission of a New Drug Application (NDA)
or other dossier.
•These clinical trials are conducted in patient populations for which
the medicine is eventually intended.
•Phase IIIa clinical trials generate additional data on both safety and
efficacy in relatively large numbers of patients in both controlled
and uncontrolled trials.

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The Drug Development Process – Clinical Development
Phase IIIa Clinical Development
•Clinical trials are also conducted in special groups of patients
(e.g. renal failure patients), or under special conditions dictated
by the nature of the medicine and disease.
•These trials often provide much of the information needed for the
package insert and labeling of the medicine.

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The Drug Development Process – Clinical Development
Phase IIIb Clinical Development
•Clinical trials conducted after regulatory submission of an NDA or
other dossier, but prior to the medicine’s approval and launch.
•These trials may supplement earlier trials, complete earlier trials, or
may be directed toward new types of trials (e.g. quality of life,
marketing) or Phase IV evaluations.
•This is the period between submission and approval of a regulatory
dossier for marketing authorization.
•Comparisons to standard therapy (termed comparator studies) can
be included in either Phase IIIa or Phase IIIb.

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The Drug Development Process – Clinical Development
Phase II & III Clinical Development
FDA Involvement
• In both Phase 2 and 3, CDER can impose a clinical hold if a study
is unsafe (as in Phase 1), or if the protocol is clearly deficient in
design in meeting its stated objectives.

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The Drug Development Process – Clinical Development
Phase IV/Registration
• Once all phases of clinical testing have been completed, if the data
warrants it, the company applies to the Food and Drug Administration
for regulatory approval to market the medicine in the United States.
• If the FDA agrees that the data proves the safety and efficacy of the
drug, approval may come in several months or years, with those
medicines with the most urgent medical need typically approved
more quickly.
• The company should work closely with regulatory agencies at all
stages of clinical development to help ensure it can provide needed
data to obtain approval as quickly as possible.

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The Drug Development Process – Clinical Development
New Drug Application
• Since 1938, every new drug has been the subject of an approved NDA
before U.S. commercialization.
• The data gathered during the animal studies and human clinical trials
of an Investigational New Drug (IND) become part of the NDA.
• The components of any NDA are, in part, a function of the nature
of the subject drug and the information available to the applicant at
the time of submission.
• The NDA must provide all relevant data and information
that has been collected during the product's research and development

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The Drug Development Process – Clinical Development
New Drug Application (continued)
• Although the quantity of information and data submitted in NDAs
can vary significantly, the components of NDAs are more uniform.
• NDAs can consist of as many as 15 different sections:

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The Drug Development Process – Clinical Development
New Drug Application (continued)
•Index;
•Summary;
•Chemistry, Manufacturing, and Control;
•Samples, Methods Validation Package, and Labeling;
•Nonclinical Pharmacology and Toxicology;
•Human Pharmacokinetics and Bioavailability;
•Microbiology (for anti-microbial drugs only);
•Clinical Data;
•Safety Update Report (typically submitted 120 days after the NDA's
submission);
•Statistical;
•Case Report Tabulations;
•Case Report Forms;
•Patent Information;
•Patent Certification; and
•Other Information.

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NDA Actions
• Once an approval, approvable, or non-approvable recommendation is
reached by the reviewers and their supervisors, the decision must be
evaluated and agreed to by the director of the applicable drug review
division or office.
• The division director generally serves as the final FDA ruling.
• Once the division director (or office director, as appropriate) signs an
approval action letter, the product can be legally marketed starting that
day in the United States.

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The Drug Development Process – Clinical Development
Phase IV
•Studies or trials conducted after a medicine is marketed to provide
additional details about the medicine’s efficacy or safety profile.
•Different formulations, dosages, durations of treatment, medicine
interactions, and other medicine comparisons (termed comparator
studies) may be evaluated.
•New age groups, races, and other types of patients can be studied.
•Detection and definition of previously unknown or inadequately
quantified adverse reactions and related risk factors are an important
aspect of many Phase IV studies.

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The Drug Development Process – Clinical Development
Phase IV
•If a marketed medicine is to be evaluated for another (i.e. new)
indication, then those clinical trials are considered Phase II clinical
studies.
•The term post-marketing surveillance is frequently used to describe
those clinical studies in Phase IV (i.e. the period following marketing)
that are primarily observational or non-experimental in nature, to
distinguish them from well controlled Phase IV clinical trials or
marketing studies.

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Other Types of Approvals/Reviews

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Accelerated Development/Review
Other Types of Approvals/Reviews
• Accelerated development/review is a highly specialized
mechanism for speeding the development of drugs that promise
significant benefit over existing therapy for serious or
life-threatening illnesses for which no therapy exists.
• This process incorporates several novel elements aimed at making
sure that rapid development and review is balanced by safeguards
to protect both the patients and the integrity of the regulatory process
• The fundamental element of this process is that the manufacturers
must continue testing after approval to demonstrate that the drug
indeed provides therapeutic benefit to the patient. If not, the FDA
can withdraw the product from the market more easily than usual.

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Other Types of Approvals/Reviews
Treatment IND
• Treatment Investigational New Drugs are used to make promising new
drugs available to desperately ill patients as early in the drug
development process as possible.
• FDA will permit an investigational drug to be used under a treatment
IND if there is preliminary evidence of drug efficacy and the drug is
intended to treat a serious or life-threatening disease, or if there is no
comparable alternative drug or therapy available to treat that stage of
the disease in the intended patient population.
• In addition, these patients are not eligible to be in the definitive clinical
trials, which must be well underway, if not almost finished.

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Other Types of Approvals/Reviews
Treatment IND (continued)
• An immediately life-threatening disease means a stage of a disease
in which there is a reasonable likelihood that death will occur
within a matter of months or in which premature death is likely
without early treatment.
• Treatment INDs are made available to patients before general
marketing begins, typically during Phase 3 studies.
• Treatment INDs also allow FDA to obtain additional data on the
drug's safety and effectiveness.

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Other Types of Approvals/Reviews
Parallel Track
• The "parallel track" policy was developed by the U.S. Public Health
Service in response to AIDS.
• Under this policy, patients with AIDS whose condition prevents them
from participating in controlled clinical trials can receive
investigational drugs shown in preliminary studies to be promising.

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•An orphan drug is any drug developed under the Orphan Drug Act of
January 1983 ("ODA"), a federal law concerning rare diseases
("orphan diseases"), defined as diseases affecting fewer than 200,000
people in the United States or low prevalence (prevalence of less than
5 per 10,000 in the community.
•This has been adopted as a subclause of the Food and Drug
Administration (FDA) regulations. The granting of orphan drug
status is designed to encourage the development of drugs which are
necessary but would be prohibitively expensive/un-profitable to
develop under normal circumstances.
Orphan Drug

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Because medical research and development of drugs to treat such
diseases is financially disadvantageous, companies that do so are
rewarded with tax reductions and marketing exclusivity (a "monopoly")
on that drug for an extended time (seven years post-approval).
The concept behind the ODA is that the longer period of exclusivity
will encourage more companies to invest money in research.
Orphan Drug

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Under the act many drugs have been developed, including drugs to
treat glioma, multiple myeloma, cystic fibrosis, phenylketonuria and
snake venom.
In the US, from January 1983 to June 2004, a total of 1,129 different
orphan drug designations have been granted by the Office of Orphan
Products Development (OOPD) and 249 orphan drugs have received
marketing authorization in the US.
In contrast, the decade prior to 1983 saw fewer than ten such
products come to market.
Orphan Drug

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