DRUG DISCOVERY NEW DRUG DEVELOPMENT PROCESS

BY

Dr. Vikram Kumar (Yadav), M.Pharm PhD Pharmacology Sr. Lecturer, Pharmacology Amity Institute of Biotechnology

Amity University, Rajasthan

DRUG

A substance used in the diagnosis, treatment, or

prevention of a disease or as a component of a medication recognized or defined by the U.S. Food, Drug, and Cosmetic Act.

A drug is any chemical or biological substance, synthetic

or non-synthetic

 A drug is anything that affects the way an

organism works.

Drugs can be taken to enhance function, such as

a student drinking caffeine to enhance alertness.

For now we only consider drugs which are used

to cure a disease.
Continued
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 A disease is often thought of as an infection,

where a bacteria, virus, or other living thing invades the body.

However, a disease is anything which affects the

proper functioning of the body.

It can be an infection, a genetic disorder, or the

result of environmental conditions such as malnourishment, poisoning, or stress.

Continued

 Engineers often find it easy to see the body

as a factory. Individual organs can be seen as machinery. The actual nuts, bolts, screwdrivers, and wrenches that make up all the machinery are the equivalent of proteins, little chunks of organic material that move things around in the body and attach them together. Most of the work in our body is done by proteins.
5 Continued

 The body contains thousands of different

kinds of proteins. The construction of each is determined by the DNA in the nucleus of each cell. DNA may be thought of as long strings of instructions which code for how each protein is too be built. The DNA is just a long string of acids that serves as a message about how to make proteins.
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How Drugs are Developed

The processes of new drug discovery and

development are long, complicated and dependent upon the expertise of a wide variety of scientific, technical and managerial groups. significant challenge to understand the significance of your contribution, even if you belong to one of the teams directly involved; for those on the periphery, the problem is magnified to the point where team interactions and efficiency are adversely threatened.
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If you are new to the industry, it can prove a

Differences and Similarities of Drugs and Medicinal Plants

Today there are at least 120 distinct chemical

substances derived from plants that are considered important drug and are currently in use in one or more countries in the world

Some of these drugs are simply a chemical or chemicals

extracted from plant materials and put into a capsule, tablet or liquid.

Eg. In Germany a Cynarin drug is manufactured and

sold to treat hypertension, liver disorders and highly cholesterol levels.

Differences and Similarities of Drugs and Medicinal Plants

The drug is simply this single chemical or an Artichoke liquid extract,
that has been concentrated and chemically manipulated to contain a specific amount of this one chemical ; such a preparation is called a standardized extract.

However in the U.S artichoke extracts are available as natural products

and sold in health food stores as dietary supplements

Some U.S artichoke products are even standardized to contain a

specific amount of cynarin, yet they can still be purchased here as a natural product without a prescription.

There may be little to no difference between the Cynarin drug produce

in Germany and the artichoke standardized herbal supplements made in the U.S considering that the same amount of Cynarin is being delivered, dose for dose

Need for consumer education about Herbal supplements & Drugs

Consumers find it very frustrating to sort through a lot of

ambiguous information put out by natural product manufacturers who cannot legally label their goods with condition-specific.

Stop them in their tracks in the aisles at the health food

store saying Hey, look at me, if you have high cholesterol.

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More is Not Always Better

Be careful about dosage amounts

Philosophy of excess: if some is good, more is better

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Problem of One Vs Several Chemicals

While many drugs have originated from biologically active

plant chemicals, and many plants, medicine uses can be attributed to various active chemicals found in them, there is a distinct difference between using a medicinal plant and a chemical drug.

The difference is one that scares most conventionally

trained doctors with no training in plants.

Drugs usually consist of a single chemical, whereas

medicinal plants can contain 400 or more chemicals.

Its relatively easy to figure out the activity and side effects
of a single chemical.
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The New Drug Development Process

(Steps from Test Tube to New Drug Application Review)

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Non-clinical Drug Development

Non-clinical drug development is a complex,

regulatory-driven process designed primarily to assess the safety and viability of new molecular entities. toxicology, pharmacology, metabolism, bioanalysis, pharmaceutical analysis and biosafety testing in support of non-clinical drug development.

Non-clinical, or preclinical, services encompass

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Non-clinical Drug Development

A sponsor must first submit data showing that the drug is reasonably
safe for use in initial, small-scale clinical studies.

Depending on whether the compound has been studied or marketed

previously, the sponsor may have several options for fulfilling this requirement. 1. Compiling existing non-clinical data from past in vitro laboratory or animal studies on the compound 2. Compiling data from previous clinical testing or marketing of the drug in the U.S or another country whose population is relevant to the U.S population 3. Undertaking new preclinical studies designed to provide the evidence necessary to support the safety of administering the compound to humans.
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Non-clinical Drug Development

During preclinical drug development, a sponsor

evaluates the drugs toxic and pharmacologic effects through in vitro and in vivo laboratory animal testing.

Genotoxicity screening is performed, as well as

investigations on drug absorption and metabolism, the toxicity of the drugs metabolites and the speed with which the drug and its metabolites are excreted from the body.

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FDA will generally ask

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.
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Subpart E

CFR (Code of Federal Regulations)

establishes procedure to expedite the development, evaluation and marketing of new therapies intended to treat people with life-threatening and severelydebilitating illnesses, especially where no satisfactory alternatives exist.

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Sponsor/FDA Meetings ( Pre-IND)

Prior to clinical studies, the sponsor needs evidence that the

compound is biologically active, and both sponsor and the FDA need data showing that the drug is reasonably safe for initial administration to humans.

Meeting at such an early stage in the process are useful

opportunities for open discussion about testing phases, data, requirements, and any scientific issues that may need to be resolved prior to IND submission

At these meeting, the sponsor and FDA discuss and agree

upon the design of the animal studies needed to initiate human testing
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Synthesis and Purification

The research process is complicated, time-consuming, and

costly and the end result is never guaranteed. Literally hundreds and sometimes thousands of chemical compounds must be made and tested in an effort to find one that can achieve a desirable result. FDA estimates that it takes approximately eight and half years to study and test a new drug before it can be approved for the general public. Computers can be used to simulate a chemical compound and design chemical structures that might work against it. Enzymes attach to the correct site on a cells membrane, which causes the disease. A computer can show scientists what the receptor site looks like and how one might tailor a compound to block an 09/07/2007 Dept. of Pharmaceutics 20 enzyme from attaching there.

Animal Testing

Drug companies make every effort to use as few animals

as possible and to ensure their humane and proper care.

Generally two or more species ( one rodent, one nonrodent).

Animal testing is used to measure how much of a drug is

absorbed into the blood, how it is broken down chemically in the body, the toxicity of the drug and its breakdown products metabolites, and how quickly the drug and its metabolites are excreted from the body
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Short and Long Term Animal Testing

Short-term testing in animals ranges in duration from 2

weeks to 3 months, depending on the proposed use of the substance.

Long-term testing in animals ranges in duration from a

few weeks to several years. - Some animal testing continues after human tests begin to learn whether long-term use of a drug may cause cancer or birth defects.
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Institutional Review Board

Institutional review boards (IRB) are used to ensure the rights

and welfare of people participating in clinical trials both before and during their trial participation. An IRBs at hospitals and research institutions throughout the country make sure that participants are fully informed and have given their written consent before studies ever begin. An IRBs are monitored by the FDA to protect and ensure the safety of participants in medical research. An IRBs must be composed of no less than five experts and lay people with varying background to ensure a complete and adequate review of activities commonly conducted by research institutions. An IRBs must be composed of people whose concerns are in relevant areas. 09/07/2007 Dept. of Pharmaceutics 23

IND Submitted

I.

Introduction Current requirements and practices

II.

III. Clarifications of present IND regulation

A.
B.

Cover Sheet (FDA Form 1571) Table of contents

C.
D.

Introductory statement and general investigational plan

Investigator's brochure
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E. Protocols 09/07/2007

IND Submitted
F. Chemistry, Manufacturing, and Control information

1. Chemistry and manufacturing introduction

2. Drug substance a. A description of the drug substance, including its physical, b. c. d. e.

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chemical, or biological characteristics The name and address of its manufacturer The general method of preparation of the drug substance The acceptable limits and analytical methods used to assure the identity, strength, quality, and purity of the drug substance. Information to support the stability of the drug substance during the toxicology studies and the proposed clinical study
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IND Submitted
3. Drug product

a. A list of all components, which may include reasonable

alternatives for inactive compounds, used in the manufacture of the investigational drug product, including both those components intended to appear in the drug product and those which may not appear, but which are used in the manufacturing process.

b. Where applicable, the quantitative composition of the

investigational new drug product, including any reasonable variations that may be expected during the investigational stage.

c. The name and address of the drug product

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manufacturer

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IND Submitted

d. A brief, general description of the method of manufacturing and packaging procedures as appropriate for the product. e. The acceptable limits and analytical methods used to assure the identity, strength, quality, and purity of the drug product. f. Information to support the stability of the drug substance during the toxicologic studies and the proposed clinical study(ies)
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IND Submitted

4. A brief general description of the composition, manufacture, and control of any placebo to be used in the proposed clinical trial. 5. A copy of all labels and labeling to be provided to each investigator.
6. A claim for categorical exclusion from or submission of an environmental assessment.

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IND Submitted

G. Pharmacology and Toxicology information

1. Pharmacology and drug distribution.

2. Toxicology: Integrated summary.
3. Toxicology- Full data tabulation. H. Previous human experience with the investigational drug

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Phase 1 Clinical Studies

Phase 1 includes the initial introduction of an

investigational new drug into human.

Phase 1 studies usually conducted in healthy volunteer. Phase 1 studies are designed to determine the metabolic
and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and if possible to gain early evidence on effectiveness.

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Phase 1 Clinical Studies

Phase 1 studies also evaluate drug metabolism,

structure-activity relationships, and the mechanism of action in humans.

The total number of subjects included in Phase I

studies varies with the drug, but is generally in the range of 20 to 80

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Phase 2 Clinical Studies

Phase 2 includes the early controlled clinical studies

conducted to obtain some preliminary data on the effectiveness of the drug for a particular indication or indications in patients with the disease or condition. short-term side effects and risks associated with the drug.

This phase of testing also helps determine the common Phase 2 studies are typically well-controlled, closely

monitored, and conducted in a relatively small number of patients usually involving several hundred people.
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Sponsor/FDA Meeting (End of Phase 2)

One month prior to the end of the Phase 2, the sponsor

should submit the background information and protocols for phase 3 studies.

This information should include data supporting the claim

of the new drug product, chemistry data, animal data and proposed additional animal data, results of Phase 1 and 2 studies, statistical methods being used, specific protocols for phase 3 studies, as well as a copy of the proposed labeling for a drug, if available.

This summary provides the review team with information

needed to prepare for a productive meeting.
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Phase 3 Clinical Studies

Phase 3 studies are expanded controlled and

uncontrolled trials.

They are performed after preliminary evidence

suggesting effectiveness of the drug has been obtained in Phase 2 and are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug.

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Phase 3 Clinical Studies

Phase 3 studies also provide an adequate basis for

Phase 3 studies usually include several hundred to
several thousand people.

extrapolating the results to the general population and transmitting that information in the physician labeling.

Great care is taken to ensure that this determination is

not made in isolation, but reflects current scientific knowledge, agency experience with the design of clinical trials, and experience with the class of drugs under investigation
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Accelerated Development/ Review

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.

The fundamental element of this process is that

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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Treatment IND

Treatment investigational new drug are used to make

promising new drugs available to desperately ill patients as early in the drug development process as possible.

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

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Long Term Testing

Long-term testing in animals ranges in duration from a

few weeks to several years.

Some animal testing continues after human tests begin

to learn whether long-term use of a drug may cause cancer or birth defects.

Much of this information is submitted to FDA when a

sponsor requests to process with human clinical trials.

The FDA reviews the preclinical research data and then

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makes a decision as to whether to allow the clinical trials to proceed

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IND Review Process

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NDA Review Process

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Generic Drug (ANDA) Review Process

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OTC Drug Monograph Review Process

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