drug discovery new drug development process
TRANSCRIPT
Dept. of PharmaceuticsDept. of Pharmaceutics 1109/07/200709/07/2007
DRUG DISCOVERY – NEW DRUG DEVELOPMENT PROCESS
BY
Dr. BASAVARAJ K. NANJWADE
Department of Pharmaceutics
K L E UNIVERSITY
JN MEDICAL COLLEGE
BELGAUM – 590010
E-mail: [email protected]
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• A substance used in the diagnosis, treatment, or A substance used in the diagnosis, treatment, or prevention of a disease or as a component of a prevention of a disease or as a component of a medication recognized or defined by the U.S. Food, medication recognized or defined by the U.S. Food, Drug, and Cosmetic Act. Drug, and Cosmetic Act.
• A A drugdrug is any chemical or biological substance, is any chemical or biological substance, synthetic or non-synthetic synthetic or non-synthetic
DRUG
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• 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
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• A disease is often thought of as an A disease is often thought of as an infection, where a bacteria, virus, or other infection, where a bacteria, virus, or other living thing invades the body. living thing invades the body.
• However, a disease is anything which However, a disease is anything which affects the proper functioning of the body. affects the proper functioning of the body.
• It can be an infection, a genetic disorder, It can be an infection, a genetic disorder, or the result of environmental conditions or the result of environmental conditions such as malnourishment, poisoning, or such as malnourishment, poisoning, or stress. stress.
Continued
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• 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
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• 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.
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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.
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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.
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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 artichoke extracts are available as natural However in the U.S 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 artichoke products are even standardized to contain a Some –U.S artichoke products are even standardized to contain a specific amount of cynarin, yet they can still be purchased here specific amount of cynarin, 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 Cynarin drug There may be little to no difference between the Cynarin drug produce in Germany and the artichoke standardized herbal produce in Germany and the artichoke standardized herbal supplements made in the U.S considering that the same amount supplements 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
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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.
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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”
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Problem of One Vs Several Problem of One Vs Several ChemicalsChemicals
• While many drugs have originated from biologically While many drugs have originated from biologically active plant chemicals, and many plants, medicine active plant chemicals, and many plants, medicine uses can be attributed to various active chemicals uses can be attributed to various active chemicals found in them, there is a distinct difference between found in them, there is a distinct difference between using a medicinal plant and a chemical drug.using a medicinal plant and a chemical drug.
• The difference is one that scares most conventionally The difference is one that scares most conventionally trained doctors with no training in plants.trained doctors with no training in plants.
• Drugs usually consist of a single chemical, whereas Drugs usually consist of a single chemical, whereas medicinal plants can contain 400 or more chemicals.medicinal plants can contain 400 or more chemicals.
• It’s relatively easy to figure out the activity and side It’s relatively easy to figure out the activity and side effects of a single chemical.effects of a single chemical.
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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
09/07/200709/07/2007 Dept. of PharmaceuticsDept. of Pharmaceutics 1414
Drug/Chemical Action/Clinical Use Plant Source
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
Plant Based Drugs and Medicines
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Drug/Chemical Action/Clinical Use Plant Source
Camphor Rubefacient Cinnamomum camphora
Camptothecin Anticancerous Camptotheca acuminata
(+)-Catechin Haemostatic Potentilla fragarioides
Chymopapain Proteolytic, mucolytic Carica papaya
Cissampeline Skeletal muscle relaxant Cissampelos pareira
Cocaine Local anaesthetic Erythroxylum coca
Codeine Analgesic, antitussive Papaver somniferum
Colchiceine amide Antitumor agent Colchicum autumnale
Colchicine Antitumor agent, anti-gout
Colchicum autumnale
Convallatoxin Cardiotonic Convallaria majalis
Curcumin Choleretic Curcuma longa
Plant Based Drugs and Medicines
09/07/200709/07/2007 Dept. of PharmaceuticsDept. of Pharmaceutics 1616
Drug/Chemical Action/Clinical Use Plant Source
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
Plant Based Drugs and Medicines
09/07/200709/07/2007 Dept. of PharmaceuticsDept. of Pharmaceutics 1717
Drug/Chemical Action/Clinical Use Plant Source
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
Plant Based Drugs and Medicines
09/07/200709/07/2007 Dept. of PharmaceuticsDept. of Pharmaceutics 1818
Drug/Chemical Action/Clinical Use Plant Source
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
Plant Based Drugs and Medicines
09/07/200709/07/2007 Dept. of PharmaceuticsDept. of Pharmaceutics 1919
Drug/Chemical Action/Clinical Use Plant Source
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
Plant Based Drugs and Medicines
09/07/200709/07/2007 Dept. of PharmaceuticsDept. of Pharmaceutics 2020
Drug/Chemical Action/Clinical Use Plant Source
Phyllodulcin Sweetner Hydrangea macrophylla
Physostigmine Cholinesterase Inhibitor Physostigma venenosum
Picrotoxin Analeptic Anamirta cocculus
Pilocarpine Parasympathomimetic Pilocarpus jaborandi
Pinitol Expectorant Several plants
Podophyllotoxin Antitumor anticancer agent
Podophyllum peltatum
Protoveratrines A, B Antihypertensives Veratrum album
Pseudoephredrine* Sympathomimetic Ephedra sinica
Pseudoephedrine, nor- Sympathomimetic Ephedra sinica
Quinidine Antiarrhythmic Cinchona ledgeriana
Plant Based Drugs and Medicines
09/07/200709/07/2007 Dept. of PharmaceuticsDept. of Pharmaceutics 2121
Drug/Chemical Action/Clinical Use Plant Source
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
Plant Based Drugs and Medicines
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Drug/Chemical Action/Clinical Use Plant Source
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
Plant Based Drugs and Medicines
09/07/200709/07/2007 Dept. of PharmaceuticsDept. of Pharmaceutics 2323
Drug/Chemical Action/Clinical Use Plant Source
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
Plant Based Drugs and Medicines
09/07/200709/07/2007 Dept. of PharmaceuticsDept. of Pharmaceutics 2424
Drug/Chemical Action/Clinical Use Plant Source
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
Plant Based Drugs and Medicines
09/07/200709/07/2007 Dept. of PharmaceuticsDept. of Pharmaceutics 2525
The New Drug Development Process (Steps from Test Tube to New Drug Application Review)
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• 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
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• 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.
Non-clinical Drug Development
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• 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.
Non-clinical Drug Development
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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.
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• 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
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• 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)
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• 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 membrane, Enzymes attach to the correct site on a cell’s membrane, which causes the disease.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
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• 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 drug Animal testing is used to measure how much of a drug is absorbed into the blood, how it is broken down 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
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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.
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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.
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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
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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
IND IND SubmittedSubmitted
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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
IND IND SubmittedSubmitted
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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)
IND IND SubmittedSubmitted
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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.
IND IND SubmittedSubmitted
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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
IND IND SubmittedSubmitted
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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.
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• Phase 1 studies also evaluate drug Phase 1 studies also evaluate drug metabolism, structure-activity metabolism, structure-activity relationships, and the mechanism of action relationships, and the mechanism of action in humans.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 1 Clinical StudiesPhase 1 Clinical Studies
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Phase 2 Clinical StudiesPhase 2 Clinical Studies
• 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..
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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.
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• 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 Clinical StudiesPhase 3 Clinical Studies
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• 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
Phase 3 Clinical StudiesPhase 3 Clinical Studies
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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.
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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.
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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
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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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