clinical trials and drug discovery & development 01-03-2011

CLINICAL TRIALS: DRUG DISCOVERY – NEW DRUG DEVELOPMENT PROCESS

BY

Dr. M. Rafiq KhananiDr. M. Rafiq KhananiAssociate Professor, Pathology, Associate Professor, Pathology,

Dow International Medical CollegeDow International Medical College

Director, Dow Diagnostic Reference & Research LabDirector, Dow Diagnostic Reference & Research Lab

Dow University of Health Sciences (DUHS) Dow University of Health Sciences (DUHS)

President, Infection Control Society PakistanPresident, Infection Control Society Pakistan

Pathologist CitilabPathologist Citilab

Email: Email: [email protected], , [email protected]: www.infectioncontrolsociety.org: www.infectioncontrolsociety.org

mailto:[email protected]

mailto:[email protected]

http://www.duhs.edu.pk/

Global Clinical Trial Global Clinical Trial MarketMarket Globally the Clinical trial market Globally the Clinical trial market

is more then 200 billion market is more then 200 billion market and growing day by day with the and growing day by day with the annual rate of 12% – 13%annual rate of 12% – 13%

Indian Clinical Research Indian Clinical Research BusinessBusiness

The present Indian CRO market size The present Indian CRO market size is estimated at $10 billion and is estimated at $10 billion and growing, with revenue increasing at growing, with revenue increasing at an annual rate of 14-16%. An an annual rate of 14-16%. An extensive evaluation of the Indian extensive evaluation of the Indian CRO sector emerge as a forerunner CRO sector emerge as a forerunner amongst the highly competitive amongst the highly competitive global CRO market. global CRO market.

Why do the research Why do the research studies?studies?

• To collect the Data on usual & To collect the Data on usual & unusual events, conditions and unusual events, conditions and population groupspopulation groups

• To test the hypothesis formulated To test the hypothesis formulated from observations and/or intuitionfrom observations and/or intuition

• Ultimately, to understand better Ultimately, to understand better one’s world and make “sense of it”. one’s world and make “sense of it”.

DRUGDRUG

• A substance used in the diagnosis, A substance used in the diagnosis, treatment, or prevention of a disease treatment, or prevention of a disease or as a component of a medication or as a component of a medication recognized or defined by the U.S. recognized or defined by the U.S. Food, Drug, and Cosmetic Act. Food, Drug, and Cosmetic Act.

• A drug is any chemical or biological A drug is any chemical or biological substance, synthetic or non-synthetic substance, synthetic or non-synthetic

01/03/201101/03/2011 DUHS-Pharma Envir Res LabDUHS-Pharma Envir Res Lab 55


• A drug is anything that affects the way an A drug is anything that affects the way an organism works. organism works.

• Drugs can be taken to enhance function, Drugs can be taken to enhance function, such as a student drinking caffeine to such as a student drinking caffeine to enhance alertness. enhance alertness.

• For now we only consider drugs which are For now we only consider drugs which are used to cure a disease. used to cure a disease.

Continued

How Drugs are Discovered


• Engineers often find it easy to see the Engineers often find it easy to see the body as a factory. body as a factory.

• Individual organs can be seen as Individual organs can be seen as machinery. The actual nuts, bolts, machinery. The actual nuts, bolts, screwdrivers, and wrenches that make screwdrivers, and wrenches that make up all the machinery are the equivalent up all the machinery are the equivalent of proteins, little chunks of organic of proteins, little chunks of organic material that move things around in the material that move things around in the body and attach them together. body and attach them together.

• Most of the work in our body is done by Most of the work in our body is done by proteins.proteins.

Continued



• The body contains thousands of The body contains thousands of different kinds of proteins. different kinds of proteins.

• The construction of each is The construction of each is determined by the DNA in the determined by the DNA in the nucleus of each cell. nucleus of each cell.

• DNA may be thought of as long DNA may be thought of as long strings of instructions which code for strings of instructions which code for how each protein is too be built. how each protein is too be built.

• The DNA is just a long string of acids The DNA is just a long string of acids that serves as a message about how that serves as a message about how to make proteins. to make proteins.



How Drugs are DevelopedHow Drugs are Developed

• The processes of new drug discovery and The processes of new drug discovery and development are long, complicated and development are long, complicated and dependent upon the expertise of a wide dependent upon the expertise of a wide variety of scientific, technical and managerial variety of scientific, technical and managerial groups. groups.

• If you are new to the industry, it can prove a If you are new to the industry, it can prove a significant challenge to understand the significant challenge to understand the significance of your contribution, even if you significance of your contribution, even if you belong to one of the teams directly involved; belong to one of the teams directly involved; for those on the periphery, the problem is for those on the periphery, the problem is magnified to the point where team magnified to the point where team interactions and efficiency are adversely interactions and efficiency are adversely threatened.threatened.


Differences and Similarities of Drugs Differences and Similarities of Drugs and Medicinal Plantsand Medicinal Plants

• Today there are at least 120 distinct chemical Today there are at least 120 distinct chemical substances derived from plants that are substances derived from plants that are considered important drug and are currently in considered important drug and are currently in use in one or more countries in the worlduse in one or more countries in the world

• Some of these drugs are simply a chemical or Some of these drugs are simply a chemical or chemicals extracted from plant materials and put chemicals extracted from plant materials and put into a capsule, tablet or liquid.into a capsule, tablet or liquid.

• Eg. In Germany a Eg. In Germany a Cynarin Cynarin drug is manufactured drug is manufactured and sold to treat hypertension, liver disorders and and sold to treat hypertension, liver disorders and highly cholesterol levels.highly cholesterol levels.


Differences and Similarities of Differences and Similarities of Drugs and Medicinal PlantsDrugs and Medicinal Plants

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

• However in the U.S However in the U.S artichoke extracts are available as natural artichoke extracts are available as natural products and sold in health food stores as “dietary supplements”products and sold in health food stores as “dietary supplements”

• Some –U.S Some –U.S artichokeartichoke products are even standardized to contain a products are even standardized to contain a specific amount of specific amount of cynarincynarin, yet they can still be purchased here , yet they can still be purchased here as a natural product without a prescription.as a natural product without a prescription.

• There may be little to no difference between the There may be little to no difference between the Cynarin drug Cynarin drug produce in Germany and the produce in Germany and the artichoke standardized herbal artichoke standardized herbal supplementssupplements made in the U.S considering that the same amount made in the U.S considering that the same amount of Cynarin is being delivered, dose for dose of Cynarin is being delivered, dose for dose


Need for consumer education Need for consumer education about Herbal supplements & about Herbal supplements & DrugsDrugs

• Consumers find it very frustrating to sort through Consumers find it very frustrating to sort through a lot of ambiguous information put out by natural a lot of ambiguous information put out by natural product manufacturers who cannot legally label product manufacturers who cannot legally label their goods with condition-specific.their goods with condition-specific.

• Stop them in their tracks in the aisles at the Stop them in their tracks in the aisles at the health food store saying “ Hey, look at me, if you health food store saying “ Hey, look at me, if you have high cholesterol.have high cholesterol.


More is Not Always More is Not Always BetterBetter

• Be careful about dosage amountsBe careful about dosage amounts

• Philosophy of excess: “ if some is good, more is Philosophy of excess: “ if some is good, more is better”better”


Drug/Chemical Action/Clinical Use Plant Source

Acetyldigoxin Cardiotonic Digitalis lanata

Adoniside Cardiotonic Adonis vernalis

Aescin Anti-inflammatory Aesculus hippocastanum

Aesculetin Anti-dysentery Frazinus rhychophylla

Agrimophol Anthelmintic Agrimonia supatoria

Ajmalicine Circulatory Disorders Rauvolfia sepentina

Allantoin Vulnerary Several plants

Allyl isothiocyanate Rubefacient Brassica nigra

Anabesine Skeletal muscle relaxant Anabasis sphylla

Andrographolide Baccillary dysentery Andrographis paniculata

Anisodamine Anticholinergic Anisodus tanguticus

Plant Based Drugs and Medicines



Anisodine Anticholinergic Anisodus tanguticus

Arecoline Anthelmintic Areca catechu

Asiaticoside Vulnerary Centella asiatica

Atropine Anticholinergic Atropa belladonna

Benzyl benzoate Scabicide Several plants

Berberine Bacillary dysentery Berberis vulgaris

Bergenin Antitussive Ardisia japonica

Betulinic acid Anticancerous Betula alba

Borneol Antipyretic, analgesic, antiinflammatory

Several plants

Bromelain Anti-inflammatory, proteolytic

Ananas comosus

Caffeine CNS stimulant Camellia sinensis


http://biotech.icmb.utexas.edu/botany/betul.html



Cynarin Choleretic Cynara scolymus

Danthron Laxative Cassia species

Demecolcine Antitumor agent Colchicum autumnale

Deserpidine Antihypertensive, tranquillizer

Rauvolfia canescens

Deslanoside Cardiotonic Digitalis lanata

L-Dopa Anti-parkinsonism Mucuna sp

Digitalin Cardiotonic Digitalis purpurea

Digitoxin Cardiotonic Digitalis purpurea

Digoxin Cardiotonic Digitalis purpurea

Emetine Amoebicide, emetic Cephaelis ipecacuanha

Ephedrine


http://www.rain-tree.com/artichoke.htm

http://www.rain-tree.com/canafistula.htm

http://www.rain-tree.com/nescafe.htm



Etoposide Antitumor agent Podophyllum peltatum

Galanthamine Cholinesterase inhibitor Lycoris squamigera

Gitalin Cardiotonic Digitalis purpurea

Glaucarubin Amoebicide Simarouba glauca

Glaucine Antitussive Glaucium flavum

Glasiovine Antidepressant Octea glaziovii

Glycyrrhizin Sweetener, Addison's disease

Glycyrrhiza glabra

Gossypol Male contraceptive Gossypium species

Hemsleyadin Bacillary dysentery Hemsleya amabilis

Hesperidin Capillary fragility Citrus species


http://biotech.icmb.utexas.edu/botany/potox.html

http://biotech.icmb.utexas.edu/botany/mayhist.html

http://www.rain-tree.com/simaruba.htm

http://www.rain-tree.com/licorice.htm

http://www.rain-tree.com/orange.htm



Hyoscyamine Anticholinergic Hyoscyamus niger

Irinotecan Anticancer, antitumor agent

Camptotheca acuminata

Kaibic acud Ascaricide Digenea simplex

Kawain Tranquillizer Piper methysticum

Kheltin Bronchodilator Ammi visaga

Lanatosides A, B, C Cardiotonic Digitalis lanata

Lapachol Anticancer, antitumor Tabebuia sp.

a-Lobeline Smoking deterrant, respiratory stimulant

Lobelia inflata

Menthol Rubefacient Mentha species

Methyl salicylate Rubefacient Gaultheria procumbens


http://biotech.icmb.utexas.edu/botany/cpt.html

http://biotech.icmb.utexas.edu/botany/camphist.html

http://biotech.icmb.utexas.edu/botany/beta.html

http://www.rain-tree.com/paudarco.htm

http://www.rain-tree.com/hortela.htm



Monocrotaline Antitumor agent (topical)

Crotalaria sessiliflora

Morphine Analgesic Papaver somniferum

Neoandrographolide Dysentery Andrographis paniculata

Nicotine Insecticide Nicotiana tabacum

Nordihydroguaiaretic acid

Antioxidant Larrea divaricata

Noscapine Antitussive Papaver somniferum

Ouabain Cardiotonic Strophanthus gratus

Pachycarpine Oxytocic Sophora pschycarpa

Palmatine Antipyretic, detoxicant Coptis japonica

Papain Proteolytic, mucolytic Carica papaya


http://www.rain-tree.com/papaya.htm



Qulsqualic acid Anthelmintic Quisqualis indica

Rescinnamine Antihypertensive, tranquillizer

Rauvolfia serpentina

Reserpine Antihypertensive, tranquillizer

Rauvolfia serpentina

Rhomitoxin Antihypertensive, tranquillizer

Rhododendron molle

Rorifone Antitussive Rorippa indica

Rotenone Piscicide, Insecticide Lonchocarpus nicou

Rotundine Analagesic, sedative, traquillizer

Stephania sinica

Rutin Capillary fragility Citrus species


http://www.rain-tree.com/orange.htm



Salicin Analgesic Salix alba

Sanguinarine Dental plaque inhibitor Sanguinaria canadensis

Santonin Ascaricide Artemisia maritma

Scillarin A Cardiotonic Urginea maritima

Scopolamine Sedative Datura species

Sennosides A, B Laxative Cassia species

Silymarin Antihepatotoxic Silybum marianum

Sparteine Oxytocic Cytisus scoparius

Stevioside Sweetner Stevia rebaudiana

Strychnine CNS stimulant Strychnos nux-vomica


http://www.rain-tree.com/canafistula.htm

http://www.rain-tree.com/stevia.htm



Taxol Antitumor agent Taxus brevifolia

Teniposide Antitumor agent Podophyllum peltatum

a-Tetrahydrocannabinol(THC)

Antiemetic, decrease occular tension

Cannabis sativa

Tetrahydropalmatine Analgesic, sedative, traquillizer

Corydalis ambigua

Tetrandrine Antihypertensive Stephania tetrandra

Theobromine Diuretic, vasodilator Theobroma cacao

Theophylline Diuretic, brochodilator Theobroma cacao and others

Thymol Antifungal (topical) Thymus vulgaris


http://biotech.icmb.utexas.edu/botany/tax.html

http://biotech.icmb.utexas.edu/botany/yewhist.html

http://biotech.icmb.utexas.edu/botany/potox.html

http://biotech.icmb.utexas.edu/botany/mayhist.html

http://biotech.icmb.utexas.edu/botany/thc.html

http://biotech.icmb.utexas.edu/botany/thc.html



Topotecan Antitumor, anticancer agent Camptotheca acuminata

Trichosanthin Abortifacient Trichosanthes kirilowii

Tubocurarine Skeletal muscle relaxant Chondodendron tomentosum

Valapotriates Sedative Valeriana officinalis

Vasicine Cerebral stimulant Vinca minor

Vinblastine Antitumor, Antileukemic agent

Catharanthus roseus

Vincristine Antitumor, Antileukemic agent

Catharanthus roseus

Yohimbine Aphrodisiac Pausinystalia yohimbe

Yuanhuacine Abortifacient Daphne genkwa

Yuanhuadine Abortifacient Daphne genkwa



The New Drug Development Process (Steps from Test Tube to New Drug Application Review)


• Non-clinical drug development is a Non-clinical drug development is a complex, regulatory-driven process complex, regulatory-driven process designed primarily to assess the safety designed primarily to assess the safety and viability of new molecular entities. and viability of new molecular entities.

• Non-clinical, or preclinical, services Non-clinical, or preclinical, services encompass toxicology, pharmacology, encompass toxicology, pharmacology, metabolism, bioanalysis, pharmaceutical metabolism, bioanalysis, pharmaceutical analysis and biosafety testing in support of analysis and biosafety testing in support of non-clinical drug development.non-clinical drug development.

Non-clinical Drug Development


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

• Depending on whether the compound has been studied or Depending on whether the compound has been studied or marketed previously, the sponsor may have several options for marketed previously, the sponsor may have several options for fulfilling this requirement.fulfilling this requirement.

1. Compiling existing non-clinical data from past 1. Compiling existing non-clinical data from past in vitroin vitro laboratory or animal studies on the compoundlaboratory or animal studies on the compound

2. Compiling data from previous clinical testing or marketing of the2. Compiling data from previous clinical testing or marketing of the drug in the U.S or another country whose population is relevant drug in the U.S or another country whose population is relevant

toto the U.S populationthe U.S population

3. Undertaking new preclinical studies designed to provide the 3. Undertaking new preclinical studies designed to provide the evidence necessary to support the safety of administering the evidence necessary to support the safety of administering the compound to humans.compound to humans.



• During preclinical drug development, a sponsor During preclinical drug development, a sponsor evaluates the drug’s toxic and pharmacologic evaluates the drug’s toxic and pharmacologic effects through effects through in vitroin vitro and and in vivoin vivo laboratory laboratory animal testing.animal testing.

• Genotoxicity screening is performed, as well as Genotoxicity screening is performed, as well as investigations on drug absorption and investigations on drug absorption and metabolism, the toxicity of the drug’s metabolites metabolism, the toxicity of the drug’s metabolites and the speed with which the drug and its and the speed with which the drug and its metabolites are excreted from the body.metabolites are excreted from the body.



FDA will generally askFDA will generally ask

1.1. Develop a pharmacological profile of the Develop a pharmacological profile of the drugdrug

2.2. Determine the acute toxicity of the drug in Determine the acute toxicity of the drug in at least two species of animalsat least two species of animals

3.3. Conduct short-term toxicity studies ranging Conduct short-term toxicity studies ranging from 2 weeks to 3 months, depending on from 2 weeks to 3 months, depending on the proposed duration of use of the the proposed duration of use of the substance in the proposed clinical studies.substance in the proposed clinical studies.


• CFR (Code of Federal Regulations) CFR (Code of Federal Regulations) establishes procedure to expedite establishes procedure to expedite the development, evaluation and the development, evaluation and marketing of new therapies intended marketing of new therapies intended to treat people with life-threatening to treat people with life-threatening and severely-debilitating illnesses, and severely-debilitating illnesses, especially where no satisfactory especially where no satisfactory alternatives exist.alternatives exist.

Subpart E


• Prior to clinical studies, the sponsor needs evidence Prior to clinical studies, the sponsor needs evidence that the compound is biologically active, and both that the compound is biologically active, and both sponsor and the FDA need data showing that the drug sponsor and the FDA need data showing that the drug is reasonably safe for initial administration to humans.is reasonably safe for initial administration to humans.

• Meeting at such an early stage in the process are Meeting at such an early stage in the process are useful opportunities for open discussion about testing useful opportunities for open discussion about testing phases, data, requirements, and any scientific issues phases, data, requirements, and any scientific issues that may need to be resolved prior to IND submissionthat may need to be resolved prior to IND submission

• At these meeting, the sponsor and FDA discuss and At these meeting, the sponsor and FDA discuss and agree upon the design of the animal studies needed to agree upon the design of the animal studies needed to initiate human testinginitiate human testing

Sponsor/FDA Meetings ( Pre-IND)


• The research process is complicated, time-consuming, The research process is complicated, time-consuming, and costly and the end result is never guaranteed.and costly and the end result is never guaranteed.

• Literally hundreds and sometimes thousands of chemical Literally hundreds and sometimes thousands of chemical compounds must be made and tested in an effort to find compounds must be made and tested in an effort to find one that can achieve a desirable result.one that can achieve a desirable result.

• FDA estimates that it takes approximately eight and half FDA estimates that it takes approximately eight and half years to study and test a new drug before it can be years to study and test a new drug before it can be approved for the general public.approved for the general public.

• Computers can be used to simulate a chemical Computers can be used to simulate a chemical compound and design chemical structures that might compound and design chemical structures that might work against it.work against it.

• Enzymes attach to the correct site on a cell’s Enzymes attach to the correct site on a cell’s membrane, which causes the disease.membrane, which causes the disease.

• A computer can show scientists what the receptor site A computer can show scientists what the receptor site looks like and how one might tailor a compound to block looks like and how one might tailor a compound to block an enzyme from attaching there.an enzyme from attaching there.

Synthesis and Purification


• Drug companies make every effort to use as few Drug companies make every effort to use as few animals as possible and to ensure their humane and animals as possible and to ensure their humane and proper care.proper care.

• Generally two or more species ( one rodent, one non-Generally two or more species ( one rodent, one non-rodent).rodent).

• Animal testing is used to measure how much of a Animal testing is used to measure how much of a drug is absorbed into the blood, how it is broken down drug is absorbed into the blood, how it is broken down chemically in the body, the toxicity of the drug and its chemically in the body, the toxicity of the drug and its breakdown products metabolites, and how quickly the breakdown products metabolites, and how quickly the drug and its metabolites are excreted from the bodydrug and its metabolites are excreted from the body

Animal Testing


Short and Long Term Animal TestingShort and Long Term Animal Testing

• Short-term testing in animals ranges in duration Short-term testing in animals ranges in duration from 2 weeks to 3 months, depending on the from 2 weeks to 3 months, depending on the proposed use of the substance.proposed use of the substance.

• Long-term testing in animals ranges in duration Long-term testing in animals ranges in duration from a few weeks to several years.from a few weeks to several years.

- Some animal testing continues after human - Some animal testing continues after human tests begin to learn whether long-term use of a tests begin to learn whether long-term use of a drug may cause cancer or birth defects.drug may cause cancer or birth defects.


Institutional Review BoardInstitutional Review Board

• Institutional review boards (IRB) are used to ensure the Institutional review boards (IRB) are used to ensure the rights and welfare of people participating in clinical trials rights and welfare of people participating in clinical trials both before and during their trial participation.both before and during their trial participation.

• An IRBs at hospitals and research institutions throughout An IRBs at hospitals and research institutions throughout the country make sure that participants are fully informed the country make sure that participants are fully informed and have given their written consent before studies ever and have given their written consent before studies ever begin.begin.

• An IRBs are monitored by the FDA to protect and ensure An IRBs are monitored by the FDA to protect and ensure the safety of participants in medical research.the safety of participants in medical research.

• An IRBs must be composed of no less than five experts An IRBs must be composed of no less than five experts and lay people with varying background to ensure a and lay people with varying background to ensure a complete and adequate review of activities commonly complete and adequate review of activities commonly conducted by research institutions.conducted by research institutions.

• An IRBs must be composed of people whose concerns are An IRBs must be composed of people whose concerns are in relevant areas.in relevant areas.


IND IND SubmittedSubmitted

I.I. IntroductionIntroduction

II.II. Current requirements and practicesCurrent requirements and practices

III.III. Clarifications of present IND regulationClarifications of present IND regulation

A.A. Cover Sheet (FDA Form – 1571)Cover Sheet (FDA Form – 1571)

B.B. Table of contentsTable of contents

C.C. Introductory statement and general investigational planIntroductory statement and general investigational plan

D.D. Investigator's brochureInvestigator's brochure

E.E. ProtocolsProtocols


F.F. Chemistry, Manufacturing, and Control information Chemistry, Manufacturing, and Control information

1.1. Chemistry and manufacturing introductionChemistry and manufacturing introduction

2.2. Drug substanceDrug substancea.a. A description of the drug substance, including its A description of the drug substance, including its

physical, chemical, or biological characteristicsphysical, chemical, or biological characteristicsb.b. The name and address of its manufacturerThe name and address of its manufacturerc.c. The general method of preparation of the drug substanceThe general method of preparation of the drug substanced.d. The acceptable limits and analytical methods used to The acceptable limits and analytical methods used to

assure the identity, strength, quality, and purity of the assure the identity, strength, quality, and purity of the drug substance.drug substance.

e.e. Information to support the stability of the drug substance Information to support the stability of the drug substance during the toxicology studies and the proposed clinical during the toxicology studies and the proposed clinical studystudy



3. Drug product3. Drug product

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

b.b. Where applicable, the quantitative composition of Where applicable, the quantitative composition of the investigational new drug product, including any the investigational new drug product, including any reasonable variations that may be expected during reasonable variations that may be expected during the investigational stage.the investigational stage.

c.c. The name and address of the drug product The name and address of the drug product manufacturermanufacturer



d. A brief, general description of the method of d. A brief, general description of the method of manufacturing and packaging procedures as manufacturing and packaging procedures as appropriate for the product.appropriate for the product.

e. The acceptable limits and analytical methods e. The acceptable limits and analytical methods used to assure the identity, strength, quality, and used to assure the identity, strength, quality, and purity of the drug product.purity of the drug product.

f. Information to support the stability of the drug f. Information to support the stability of the drug substance during the toxicologic studies and the substance during the toxicologic studies and the proposed clinical study(ies)proposed clinical study(ies)



4. A brief general description of the composition, 4. A brief general description of the composition, manufacture, and control of any placebo to be manufacture, and control of any placebo to be used in the proposed clinical trial.used in the proposed clinical trial.

5. A copy of all labels and labeling to be provided to 5. A copy of all labels and labeling to be provided to each investigator.each investigator.

6. A claim for categorical exclusion from or 6. A claim for categorical exclusion from or submission of an environmental assessment.submission of an environmental assessment.



G. Pharmacology and Toxicology informationG. Pharmacology and Toxicology information

1.1. Pharmacology and drug distribution.Pharmacology and drug distribution.

2. Toxicology: Integrated summary.2. Toxicology: Integrated summary.

3. Toxicology- Full data tabulation.3. Toxicology- Full data tabulation.

H. Previous human experience with the H. Previous human experience with the investigational druginvestigational drug



Phase 1 Clinical StudiesPhase 1 Clinical Studies

• Phase 1 includes the initial introduction of an Phase 1 includes the initial introduction of an investigational new drug into human.investigational new drug into human.

• Phase 1 studies usually conducted in healthy Phase 1 studies usually conducted in healthy volunteer.volunteer.

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


• Phase 1 studies also evaluate drug Phase 1 studies also evaluate drug metabolism, structure-activity metabolism, structure-activity relationships, and the mechanism of relationships, and the mechanism of action in humans.action in humans.

• The total number of subjects included in The total number of subjects included in Phase I studies varies with the drug, but is Phase I studies varies with the drug, but is generally in the range of 20 to 80generally in the range of 20 to 80




• Phase 2 includes the early controlled clinical studies Phase 2 includes the early controlled clinical studies conducted to obtain some preliminary data on the conducted to obtain some preliminary data on the effectiveness of the drug for a particular indication or effectiveness of the drug for a particular indication or indications in patients with the disease or condition.indications in patients with the disease or condition.

• This phase of testing also helps determine the This phase of testing also helps determine the common short-term side effects and risks associated common short-term side effects and risks associated with the drug.with the drug.

• Phase 2 studies are typically well-controlled, closely Phase 2 studies are typically well-controlled, closely monitored, and conducted in a relatively small monitored, and conducted in a relatively small number of patients usually involving several hundred number of patients usually involving several hundred peoplepeople..


Sponsor/FDA Meeting (End of Sponsor/FDA Meeting (End of Phase 2)Phase 2)

• One month prior to the “end of the Phase 2”, the One month prior to the “end of the Phase 2”, the sponsor should submit the background information and sponsor should submit the background information and protocols for phase 3 studies.protocols for phase 3 studies.

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

• This summary provides the review team with This summary provides the review team with information needed to prepare for a productive meeting.information needed to prepare for a productive meeting.


• Phase 3 studies are expanded controlled and Phase 3 studies are expanded controlled and uncontrolled trials.uncontrolled trials.

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



• Phase 3 studies also provide an adequate basis for Phase 3 studies also provide an adequate basis for extrapolating the results to the general population extrapolating the results to the general population and transmitting that information in the physician and transmitting that information in the physician labeling.labeling.

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

• Great care is taken to ensure that this Great care is taken to ensure that this determination is not made in isolation, but reflects determination is not made in isolation, but reflects current scientific knowledge, agency experience current scientific knowledge, agency experience with the design of clinical trials, and experience with the design of clinical trials, and experience with the class of drugs under investigationwith the class of drugs under investigation



Accelerated Development/ Accelerated Development/ ReviewReview

• Accelerated development/review is a highly Accelerated development/review is a highly specialized mechanism for speeding the specialized mechanism for speeding the development of drugs that promise significant development of drugs that promise significant benefit over existing therapy for serious or life-benefit over existing therapy for serious or life-threatening illnesses for which no therapy exists.threatening illnesses for which no therapy exists.

• The fundamental element of this process is that The fundamental element of this process is that manufacturers must continue testing after manufacturers must continue testing after approval to demonstrate that the drug indeed approval to demonstrate that the drug indeed provides therapeutic benefit to the patient.provides therapeutic benefit to the patient.

• If not, the FDA can withdraw the product from the If not, the FDA can withdraw the product from the market more easily than usual. market more easily than usual.


Treatment INDTreatment IND • Treatment investigational new drug are used to make Treatment investigational new drug are used to make

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

• An immediately life-threatening disease means a stage of An immediately life-threatening disease means a stage of a disease in which there is a reasonable likelihood that a disease in which there is a reasonable likelihood that death will occur within a matter of months or in which death will occur within a matter of months or in which premature death is likely without early treatment.premature death is likely without early treatment.

• Treatment INDs are made available to patients before Treatment INDs are made available to patients before general marketing begins, typically during Phase 3 general marketing begins, typically during Phase 3 studies.studies.

• Treatment INDs also allow FDA to obtain additional data Treatment INDs also allow FDA to obtain additional data on the drug’s safety and effectiveness.on the drug’s safety and effectiveness.


Long – Term TestingLong – Term Testing

• Long-term testing in animals ranges in duration Long-term testing in animals ranges in duration from a few weeks to several years.from a few weeks to several years.

• Some animal testing continues after human tests Some animal testing continues after human tests begin to learn whether long-term use of a drug may begin to learn whether long-term use of a drug may cause cancer or birth defects.cause cancer or birth defects.

• Much of this information is submitted to FDA when Much of this information is submitted to FDA when a sponsor requests to process with human clinical a sponsor requests to process with human clinical trials.trials.

• The FDA reviews the preclinical research data and The FDA reviews the preclinical research data and then makes a decision as to whether to allow the then makes a decision as to whether to allow the clinical trials to proceedclinical trials to proceed


IND Review Process


NDA Review Process


Generic Drug (ANDA) Review Process


OTC Drug Monograph Review Process

clinical trials and drug discovery & development 01-03-2011

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