CLINICAL TRIALS

 are experiments or observations done in clinical research

 such prospective biomedical or behavioral research studies

on human participants are designed to answer specific questions about biomedical or behavioral
interventions, including new treatments (such as novel vaccines, drugs, dietary choices, dietary
supplements, and medical devices) and known interventions that warrant further study and comparison

 Clinical trials generate data on safety and efficacy

 they are conducted only after they have received health authority/ethics committee approval in
the country where approval of the therapy is sought

 these authorities are responsible for vetting the risk/benefit ratio of the trial—their approval
does not mean the therapy is 'safe' or effective, only that the trial may be conducted

 depending on product type and development stage, investigators initially enroll volunteers or
patients into small pilot studies, and subsequently conduct progressively larger scale
comparative studies

 Clinical trials can vary in size and cost, and they can involve a single research center or multiple
centers, in one country or in multiple countries

 Clinical study design aims to ensure the scientific validity and reproducibility of the results

 Costs for clinical trials can range into the billions of dollars per approved drug

 sponsor may be a governmental organization or

a pharmaceutical, biotechnology or medical device company

 certain functions necessary to the trial, such as monitoring and lab work, may be managed by
an outsourced partner, such as a contract research organization or a central laboratory

 only 10 percent of all drugs started in human clinical trials become approved drugs

 some clinical trials involve healthy subjects with no pre-existing medical conditions

 other clinical trials pertain to people with specific health conditions who are willing to try an
experimental treatment

 Pilot experiments are conducted to gain insights for design of the clinical trial to follow

 there are two goals to testing medical treatments: to learn whether they work well enough,
called "efficacy" or "effectiveness"; and to learn whether they are safe enough, called "safety“

 neither is an absolute criterion; both safety and efficacy are evaluated relative to how the
treatment is intended to be used, what other treatments are available, and the severity of the
disease or condition

 the benefits must outweigh the risks

  for example, many drugs to treat cancer have severe side effects that would not be acceptable
for an over-the-counter pain medication, yet the cancer drugs have been approved since they
are used under a physician's care and are used for a life-threatening condition

 Examples of clinical trial goals include assessing the safety and relative effectiveness of a
medication or device:

-On a specific kind of patient

-At varying dosages

-For a new indication

-Evaluation for improved efficacy in treating a condition as

compared to the standard therapy for that condition

-Evaluation of the study drug or device relative to two or more already

approved/common interventions for that condition

 Clinical trials are classified by the research objective created by the investigators

• observational study

 investigators observe the subjects and measure their outcomes

 researchers do not actively manage the study

• interventional study

 the investigators give the research subjects an experimental

drug, surgical procedure, use of a medical device, diagnostic

or other intervention to compare the treated subjects with those receiving no treatment or the
standard treatment

 then the researchers assess how the subjects' health changes

 Trials are classified by their purpose

 After approval for human research is granted to the trial

sponsor, the U.S. Food and Drug Administration (FDA) organizes and monitors the results of trials
according to type:

• Prevention trials

 look for ways to prevent disease in people who have never had the disease or to prevent a
disease from returning

 these approaches may

include drugs, vitamins other micronutrients, vaccines, or lifestyle changes

 • Screening trials

 test for ways to identify certain diseases or health conditions

• Diagnostic trials

 are conducted to find better tests or procedures for diagnosing a

particular disease or condition

• Treatment trials

 test experimental drugs, new combinations of drugs, or new approaches to surgery or radiation
therapy

• Quality of life trials (supportive care trials)

 evaluate how to improve comfort and quality of care for people with a chronic illness

• Genetic trials

 are conducted to assess the prediction accuracy of genetic disorders making a person more or
less likely to develop a disease

• Epidemiological trials

 have the goal of identifying the general causes, patterns or control of diseases in large numbers
of people

• Compassionate use trials or expanded access trials

 provide partially tested, unapproved therapeutics to a small number of patients who have no
other realistic options

 usually, this involves a disease for which no effective therapy has been approved, or a patient
who has already failed all standard treatments and whose health is too compromised to qualify
for participation in randomized clinical trials

 usually, case-by-case approval must be granted by both the FDA and the pharmaceutical
company for such exceptions

• Fixed trials

 consider existing data only during the trial's design, do not modify the trial after it begins, and
do not assess the results until the study is completed

• Adaptive clinical trials

 use existing data to design the trial, and then use interim results to modify the trial as it
proceeds

 Modifications include dosage, sample size, drug undergoing trial, patient selection criteria and
"cocktail" mix
  Adaptive trials often employ a Bayesian experimental design to

assess the trial's progress

 in some cases, trials have become an ongoing process that regularly adds and drops therapies
and patient groups as more information is gained

 the aim is to more quickly identify drugs that have a therapeutic effect and to zero in on patient
populations for whom the drug is appropriate

INVESTIGATIONAL NEW DRUG (IND)

 refers to a drug developed by a pharmaceutical or biotech company or other

organization that is ready for clinical trials on humans

 when a drug reaches this point, the entity submits an application to get the consent of the Food
and Drug Administration (FDA) to begin these trials

 this step is important as approval for the application allows a sponsor to ship

the drug across the country to begin testing

KEY TAKEAWAYS

 an Investigational New Drug is a drug developed by a sponsor that is ready for clinical trials on
humans

 IND application is submitted by the company or research group responsible for developing the
drug to the FDA

 FDA reviews IND applications and decides whether they are safe for companies to progress to
the clinical trial stage

 when a company develops a new drug, it must get approval from the FDA

 before it can sell it to the general public

 the company must go through a series of steps and applications before it

 can get to this point

 It's up to the company—which is also called the drug sponsor—to run the required tests, gather
data, and to make sure patients aren't exposed to unnecessary risks when they take the drug

 the FDA reviews the results after each phase and makes a determination of whether the drug is
safe for the public

 One of the application steps is the Investigational New Drug (IND) stage

 IND is not an application for marketing approval

 instead, it is the way a sponsor gets an exemption to the federal law that prohibits an
unapproved drug from being transported across state borders from the FDA

 this exemption is a requirement since, in most cases, the sponsor must ship an investigational
drug to investigators in other states

 to obtain the exemption, the sponsor must submit sufficient data through the IND,
documenting the safety of the drug for use in human testing

 The IND application contains information in three broad areas:

Animal Pharmacology and Toxicology Studies:

 companies need to collect enough data from preclinical studies to establish whether the drug is
reasonably safe for initial tests in humans, as well as any previous experience involving human
use of the drug such as any usage in foreign markets

 this step involves testing on animals to determine the drug's safety and its efficacy

Manufacturer Information:

 Information needs to be included about the manufacturer to ensure that the company can
manufacture sufficient batches of the drug and has the proper controls in place to do so safely

Clinical Protocols and Investigator Information:

 detailed protocols are needed to determine if the initial trials will expose human subjects to
needless risks

 this also includes qualifications of the clinical investigators who will oversee the administration
of the compound

 IND is submitted after the sponsor determines that the proposed drug is reasonably safe for
initial use in humans and that it shows sufficient promise as a treatment to justify commercial
development

 FDA reviews the IND application and decides whether it is safe for the

company to progress to the next stage

 this is the clinical trial stage—the point at which the drug is tested on humans

 the sponsor has to wait for 30 calendar days after submitting the IND before commencing any
clinical trials

 it can cost hundreds of millions of dollars—and many years—to

undertake clinical trials to bring a new drug to market

 IND application signifies that the sponsor is willing to make this huge investment

 as such, investor reaction to an IND application—which is merely the first step in a long and
arduous process for drug approval—is typically neutral
 Investor reaction to INDs tends to be neutral because it's just one step in the arduous process
to get approval for a drug

Types of Investigational New Drugs (INDs)

 Investigational New Drugs (INDs) fall into two categories—commercial and research INDs

 the big difference between these two categories is who does the application filing

 as the name suggests, the commercial IND category is sought by a company that wants to test a
drug in order to bring it to market

 any company can apply for this IND, whether it's a large pharma or biotech company, as well as
a nonprofit organization (NPO) such as a cancer research group

 the application process for a commercial IND can be fairly lengthy and complicated

 that's because data is often collected at multiple locations and

involves many investigators

Commercial INDs are filed by companies to obtain marketing approval for a new drug

 the research or non-commercial IND is the step investigators require to run tests on an existing
drug

 researchers require approval when they want to test approved drugs that are already on the
market

 testing may include new dosages or new applications for these drugs

 the majority of INDs are filed for non-commercial research and are of three main types—
Investigator IND, Emergency Use IND, and Treatment IND

Research or investigator INDs

 are non-commercial INDs filed by researchers to study an unapproved drug or to study

an approved drug for a new indication or in a new patient population

Emergency Use INDs

 also called compassionate use or single-patient INDs, are filed for emergency
use of an unapproved drug when the clinical situation does not allow sufficient time to
submit an IND in accordance with 21 CFR

 these are most commonly used for life-threatening conditions for

which there is no standard treatment

Treatment INDs

 are filed to make a drug available for treatment of serious or immediately life-threatening
conditions prior to FDA approval
  serious diseases or conditions are stroke, schizophrenia, rheumatoid arthritis, osteoarthritis,
chronic depression, seizures, Alzheimer's dementia, amyotrophic lateral sclerosis (ALS), and
narcolepsy.

Screening INDs

 are filed for multiple, closely related compounds in order to screen

for the preferred compounds or formulations

 the preferred compound can then be developed under a separate IND

 used for screening different salts, esters and other drug derivatives that are chemically
different, but pharmacodynamically similar

 the application process is generally simpler than that of a commercial IND because testing is
normally done by a smaller group of people and in one location

 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 across state lines (usually to clinical investigators) before a
marketing application for the drug has been approved

 Regulations are primarily similar procedures followed in the European Union, Japan, and
Canada

The IND application may be divided into the following categories:

1) Preclinical testing

 consists of animal pharmacology and toxicology studies to assess whether the

drug is safe for testing in humans

 also included are any previous experience with the drug in humans