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

CLINICAL TRIALS: DRUG DISCOVERY – NEW DRUG DEVELOPMENT PROCESS BY Dr. M. Rafiq Khanani Associate Professor, Pathology, Dow International Medical College Director, Dow Diagnostic Reference & Research Lab Dow University of Health Sciences (DUHS) President, Infection Control Society Pakistan Pathologist Citilab Email: [email_address] , [email_address] www.duhs.edu.pk : www.infectioncontrolsociety.org

Global Clinical Trial Market
Globally the Clinical trial market is more then 200 billion market and growing day by day with the annual rate of 12% – 13%

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

Why do the research studies?
To collect the Data on usual & unusual events, conditions and population groups
To test the hypothesis formulated from observations and/or intuition
Ultimately, to understand better one’s world and make “sense of it”.

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
01/03/2011 DUHS-Pharma Envir Res Lab

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.
01/03/2011 DUHS-Pharma Envir Res Lab Continued How Drugs are Discovered

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.
01/03/2011 DUHS-Pharma Envir Res Lab Continued How Drugs are Discovered

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.
01/03/2011 DUHS-Pharma Envir Res Lab How Drugs are Discovered

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.
If you are new to the industry, it can prove a 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.

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.

More is Not Always Better
Be careful about dosage amounts
Philosophy of excess: “ if some is good, more is better”

01/03/2011 DUHS-Pharma Envir Res Lab Plant Based Drugs and Medicines 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

01/03/2011 DUHS-Pharma Envir Res Lab Plant Based Drugs and Medicines 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

01/03/2011 DUHS-Pharma Envir Res Lab Plant Based Drugs and Medicines 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

01/03/2011 DUHS-Pharma Envir Res Lab Plant Based Drugs and Medicines 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

01/03/2011 DUHS-Pharma Envir Res Lab Plant Based Drugs and Medicines 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

01/03/2011 DUHS-Pharma Envir Res Lab Plant Based Drugs and Medicines 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

01/03/2011 DUHS-Pharma Envir Res Lab Plant Based Drugs and Medicines 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

01/03/2011 DUHS-Pharma Envir Res Lab Plant Based Drugs and Medicines 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

01/03/2011 DUHS-Pharma Envir Res Lab Plant Based Drugs and Medicines 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

01/03/2011 DUHS-Pharma Envir Res Lab Plant Based Drugs and Medicines 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

01/03/2011 DUHS-Pharma Envir Res Lab The New Drug Development Process (Steps from Test Tube to New Drug Application Review)

Non-clinical drug development is a complex, regulatory-driven process designed primarily to assess the safety and viability of new molecular entities.
Non-clinical, or preclinical, services encompass toxicology, pharmacology, metabolism, bioanalysis, pharmaceutical analysis and biosafety testing in support of non-clinical drug development.
01/03/2011 DUHS-Pharma Envir Res Lab 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.

During preclinical drug development, a sponsor evaluates the drug’s 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 drug’s metabolites and the speed with which the drug and its metabolites are excreted from the body.

FDA will generally ask
Develop a pharmacological profile of the drug
Determine the acute toxicity of the drug in at least two species of animals
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.

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 severely-debilitating illnesses, especially where no satisfactory alternatives exist.
01/03/2011 DUHS-Pharma Envir Res Lab Subpart E

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
01/03/2011 DUHS-Pharma Envir Res Lab Sponsor/FDA Meetings ( Pre-IND)

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 cell’s 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 enzyme from attaching there.
01/03/2011 DUHS-Pharma Envir Res Lab Synthesis and Purification

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 non-rodent).
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
01/03/2011 DUHS-Pharma Envir Res Lab Animal Testing

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.

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.

IND Submitted
Introduction
Current requirements and practices
Clarifications of present IND regulation
Cover Sheet (FDA Form – 1571)
Table of contents
Introductory statement and general investigational plan
Investigator's brochure
Protocols

F. Chemistry, Manufacturing, and Control information
Chemistry and manufacturing introduction
Drug substance
A description of the drug substance, including its physical, 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
IND Submitted 01/03/2011 DUHS-Pharma Envir Res Lab

3. Drug product
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.
Where applicable, the quantitative composition of the investigational new drug product, including any reasonable variations that may be expected during the investigational stage.
The name and address of the drug product manufacturer

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)

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.

G. Pharmacology and Toxicology information
Pharmacology and drug distribution.
2. Toxicology: Integrated summary.
3. Toxicology- Full data tabulation.
H. Previous human experience with the investigational drug

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.

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
01/03/2011 DUHS-Pharma Envir Res Lab Phase 1 Clinical Studies

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.
This phase of testing also helps determine the common short-term side effects and risks associated with the drug.
Phase 2 studies are typically well-controlled, closely monitored, and conducted in a relatively small number of patients usually involving several hundred people .

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.

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.

Phase 3 studies also provide an adequate basis for extrapolating the results to the general population and transmitting that information in the physician labeling.
Phase 3 studies usually include several hundred to several thousand people.
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

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.

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 drug’s safety and effectiveness.

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

01/03/2011 DUHS-Pharma Envir Res Lab IND Review Process

01/03/2011 DUHS-Pharma Envir Res Lab NDA Review Process

01/03/2011 DUHS-Pharma Envir Res Lab Generic Drug (ANDA) Review Process

01/03/2011 DUHS-Pharma Envir Res Lab OTC Drug Monograph Review Process

01/03/2011 DUHS-Pharma Envir Res Lab Thank you for.....

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

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