new drug development naser
TRANSCRIPT
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New Drug Development
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What is a drug?
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Drug
• Single chemical entity present in the medicine used for diagnosis, prevention or cure of a disease.
• WHO: – Any substance or a product that is used or
intended to be used to modify or explore the physiological systems or pathological states for the benefit of the recipient
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New Drug
• A substance of chemical, biological or
biotechnological origin for which adequate
data is not available for the regulatory
authority to judge its efficacy and safety for
the proposed claim.
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Not a Easy Process
• Highly complex• Tedious• Competitive• Costly (500 – 1000 million dollars)• Commercially risky• Time consuming (at least 10 years)
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Stages in the new drug development
• Synthesis & isolation of compound – New chemical entity (NCE)– Takes 1-2 years
• Preclinical studies – 2-4 years
• Investigational New Drug Application (IND)– Submission & review by FDA – 3-6 months
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Stages in the new drug development
IND
Clinical Trials •Phase 1•Phase 2•Phase 33 To 10 years
Pre clinical studies continuedPlus • Long term animal toxicity • Product formulation • Manufacturing & controls • Package & label designs
New Drug Application (NDA)• Review & grant of marketing permission• 0.5 to 2 years
Post marketing surveillance (Phase -4)
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Old methods of Drug Discovery• Use crude plant / animal products / minerals to
treat disease (India, China, Egypt and Babylon)• No study before using them. Agents were
selected on the basis of their symbolic qualities & astrological signs– Greek physicians used iron against weakness.– Horn of rhinoceros as a potent aphrodisiac.– many obnoxious remedies, like flesh, excreta & blood
of various animals were used• Drugs were added by considerable trial and error
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Galen
• Concept of polypharmacy • Mixed vegetable crude drugs from
different sources• Galen’s name is retained in the
term ‘galenical’ for preparation of crude vegetable drugs
Aelius Galenus or Claudius Galenus (AD 129 – 200/217), better known as Galen of Pergamum
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Paracelcus
• Paracelsus (AD 1493 – 1541) criticized the polypharmacy of mixed vegetable preparations of Galen
• Pioneered the use of chemicals and minerals in medicine.
• He introduced the use of mercury in the treatment of syphilis.
• "All things are poison and nothing is without poison, only the dose permits something not to be poisonous."
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Important contributions
– 1847: Birth of Pharmacology as a scientific discipline by Rudolf Buchheim at Dorpat
– 1878: Louis Pasteur’s “germ theory” of disease at Paris
– 1890s: The “magic bullet theory” of Paul Ehrlich
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Approaches to drug discovery
• Natural sources • Chemical synthesis • Rational approach • Molecular modelling • Combinatorial chemistry • Biotechnology
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Natural sources
• Plants – Morphine, Ephedrine, reserpine, artermisinin,
quinine, atropine • Animals – Adrenaline, thyroxine, insulin, liver extract,
antisera • Micr-organisms – Penicillin, cephalosporin
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Morphine from Opium
• 1805: Friedrich Serturner, a junior apothecary in Westphalia, Germany isolated and purified morphine.
• He barely survived the test of its potency on himself.
Friedrich Wilhelm Adam Sertürner
• He called the isolated alkaloid "morphium" after the Greek god of dreams, Morpheus.
• First person to isolate the active ingredient associated with a medicinal plant or herb
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Indian Contribution
• Rauwolfia alkaloid form Raulwofia serpentina as antihypertensive and antipsychotic drug
• Gugulipid from Tinospora as lipid-lowering agent
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Chinese Contribution
• Sympathomimetic Ephedrine from Ma huang (Ephedra vulgaris)
• Antimalaial Artemisinin from Quinghasou (Artemisia annua)
• Anticancer drug Camptothecin (Irinotecan and topotecan) from Captotreca acumunata
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Chemical synthesis
• Randomly synthesized compounds tested for pharmacological activity – Barbiturates, chlorpromazine synthesized by this approach
• Synthesis of chemical congeners – More rational – Me too drugs fathered by lead compounds – Thiazide drugs from acetazolamide, TCA from
phenothiazines – Structure activity relationship– Enantiomers
• Serendipity
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SULPHONAMIDES
CA inhibitors (Diuretics)
Thiazide Diuretics
Loop Diuretics
Sulfonylureas (Oral
Hypoglycaemic agents)
Carbimazole, Methimazole
(Anti-thyroid Drugs)
Diazoxide (Anti-hypertensive)
Dapsone (Anti-leprotic)
Sulthiam (Anti-epileptic)
Cotrimoxazole
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Drug Discovery by Serendipity
• 1785: Withering’s discovery of Digitalis in treating cardiac failure (dropsy)
• 1914: Wenkeback’s discovery of antidysrhythmic effect Quinidine when treating a patient with malaria who also happened to suffer from atrial tachycardia.
• 1937: Use of amphetamine in treatment of attention deficit hyperactivity disorder (ADHD) by Bradley
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Sidenafil as anti-impotence Drug
• Sildenafil citrate (vigra), an anti-impotence drug. It was initially studied for use in hypertension and angina pectoris. Phase I clinical trials under the direction of Ian Osterloh suggested that the drug had little effect on angina, but that it could induce marked penile erections.
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Enantiomers
• Many drugs are having two types of 3D structure (chiral compounds)– Enantiomeres: ‘R’ & ‘S’; l & d– Combination of both (recemate)
• Enantiomers are non superimposable mirror images (• Enantiomers of chiral drugs differ in biological activity,
metabolic degradation etc. • Single enantiomer of a drug may be better to its
racemate • E.g dextro dopa more toxic than levo dopa
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• Now Regulatory authority grants permission after chiral separation of recemate drugs when a single enantiomer is better than the recemate preparation
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Drugs as single enantiomers
• Antihypertensive– (S) atenolol : 50% dose, better tolerated– (S) metoprolol : 50% dose– (S) amlodipine : 50% dose, better tolerated
• Proton-pump inhibitors in peptic ulcer– (S) omeprazole (esomeprazole) : bioavailability– (S) pantoprazole: More potent
• Anti-asthmatic drug– (R) Salbutamol: More active, ‘S’ antagonizes ‘R’
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Drugs as single enantiomers
• Antidepressant (SSRI)– (S) Citalopram (escitalopram) : dose, S/E
• Chemotherapeutic Agent– Levofloxacin (l –isomer): more active, slower
elimination• Antihistamine– Levocetirizine (l-isomer): 50% dose as ‘d’ form is
inactive
– Desloratadine (d-isomer) : 50% dose
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Rational approach
• Depends on sound knowledge & identification of specific target for drug action
• Receptor based approach ( target oriented)
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Target oriented approach
• Receptors– GPCR, Receptors with intrinsic ion channels,
enzyme linked receptors, Receptor regulating gene expression.
• Ion channels – Na+, K+, Ca++ and Cl–
• Transporters– Na+/K+ ATPase, H+/K+ ATPase, Na+-K+-2Cl–
• Enzymes
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Combinatorial Chemistry
• Chemical groups are combined in random manner to yield innumerable compounds
• These compounds subjected to high through put screening on cells, genetically engineered microbes, enzymes, enzymes in robotically controlled automated assay systems
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Biotechnology • Hormones
– Insulin, Growth hormones, Erythropoietin• Growth factors
– GM-CSF• Cytokines
– Interleukins• Monoclonal Antibodies
– Trastuzumab, Rituximab, Omalizumab etc.• DNA products
– Antisense oligonucleotides: Vitravene• Enzymes:
– Cerebrosidase, Dornase, Galactosidase
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Drug Development1. Pre-clinical Study– ADME – Safety and Toxicity prior to human trial – FIM (First in Man) / FHD (First Human Dose)
2. CMC (Chemistry, Manufacturing & Control)3. Clinical Study– Phase I, II & III
4. Registration5. Phase IV (Post-marketing Surveillance)
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Pre-clinical study
• Aim: – Is it effective?– Is it not toxic?– Is its side effect is minimum?
• Test is done on– Cultured cell line– Isolated organ– Intact animals
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Preclinical StudiesSynthesis / Identification of Lead Compound(s)
(Thousands)
Few out of Thousands
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Pre-clinical Studies
• Screening Tests• Tests on isolated organs• Tests on bacterial cultures• Tests on animal models of human diseases– Diabetic rats / dogs by diazoxide – Kindled animals for anti-epileptic drugs
• General observational tests on intact animals
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Preclinical Studies
• Pharmacokinetics• Systemic pharmacodynamics• Study of Mechanism of Action• Quantitative tests– Dose-Response Relationship– Maximal Effect– Efficacy testing in relation to existing drugs
• Toxicity Studies
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Toxicity Studies
• Acute Toxicity Studies (1 – 3 days)– LD50– Organ toxicity
• Subacute Toxicity Studies (2 – 12 weeks)– Therapeutic index, Eating behavior, Wt, Haematology
• Chronic Toxicity Studies (6 – 12 months)• Special Long-term Toxicity Studies (after 1 Ph)– Reproduction ( including Teratogenicity)– Mutagenicity– Carcinogenicity
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Good Laboratory Practice (GLP)
• Embodies a set of principles that provides a framework within which laboratory studies are planned, performed, monitored, recorded, reported and archived.
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Before Clinical Studies
• Drug is formulated into a suitable dosage form• The clinical trials are done under the guideline
of Good Clinical Practice (GCP) laid down by International Conference on Harmonization (ICH)
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Investigational New Drug (IND)
• IND license is obtained after successful completion of pre-clinical studies from regulatory authorities.
• Regulatory Authority– India: Drug Control General of India (DCGI)– USA: FDA (Food and Drug Administration)
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Good Clinical Practice (GCP)
• GCP include – protection of human rights as a subject in clinical
trial. – provides assurance of the safety and efficacy of the
newly developed compounds.• Good Clinical Practice Guidelines include
standards on – how clinical trials should be conducted, – define the roles and responsibilities of clinical
trial sponsors, clinical research investigators, and monitors.
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Why Clinical Trials?
• To discover or verify:
–Pharmacodynamics (how it works)
–Pharmacokinetics (what happens to it)
– Therapeutic effects (efficacy)
–Adverse reactions (safety)
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History of Clinical Trial
James LindClinical trials for cure of scurvy in 1747
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JAMES LIND, CONQUERER OF SCURVY
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Regulatory Process in Drug trial
• 1937: Use of diethylene glycol as a solvent for sulfonamide preparation caused death of 107 in USA.
• 1938: FDA revised its old rules and made it compulsory to demonstrated safety before marketing
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• 1959: Thalidomide Disaster in Europe and Australia
• 10,000 cases of severe congenital malformation cases were seen
Regulatory Process in Drug trial
Phocomelia = Greek phoco-, "seal (flipper)" + Greek melia, "limb, extremity" = human limb like a seal's flipper
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Unethical trial
• In 1932, a clinical trial named Tuskegee was conducted in patients with syphilis in USA. Study group comprised of 400 African-American poor men with syphilis. Control group was 200 healthy men. The doctors offered treatment without paying; but they only observed the patients without treatment during many years without telling anything. Ten years later, death rate was two-fold in the study group. Penicillin was developed in 1952. No patient was administered any antibiotics including penicillin until the end of study in 1972.
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New York Times described this study as
“The longest clinical trial in human body without treatment in the medical history”
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May 16, 1997
Tuskegee trial
President Clinton apologised from USA citizens because of Tuskegee trial
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Phases of Clinical Trials
• Phase I Early Clinical Pharmacology & Safety
• Phase IITherapeutic exploration and dose ranging
• Phase IIITherapeutic confirmation and comparison
• Phase IVPost-marketing Surveillance / Studies
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Phases of Clinical Trials
• In Each Phase– Exposure to greater numbers of human
subjects to the drug – Collection of increasing amounts of data on
safety and efficacy of the drug
I II III IV
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PHASE I
• First study done on healthy human volunteers (sometimes in patients)
• N = 20 – 40
• Carried out by qualified clinical pharmacologists or trained physicians
• Venue: A place where all vital functions are monitored and emergency / resuscitative facilities are available
• No blinding, open label
• Duration of study: 1 yr (approximately)
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PHASE I
• Emphasis : Safety and Tolerability
• Started with lowest estimated dose and stepwise increased to effective dose.
• Data collection on – Pharmacokinetics
– Systemic pharmacodynamics
– General adverse effects
• Acceptable dosing level is found
• Provisional safe dosage established
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PHASE II
• Patients suffering from the disease• Inclusion and exclusion criteria are fixed• N = 100 – 400• Carried out by physicians who are trained as
clinical investigators• Duration: 2-3 years• Type: Open label / Blind• Venue: 2 - 4
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PHASE II
• Establishment of therapeutic efficacy•Define most appropriate dose range
and ceiling effect in a controlled setting• Study of tolerability and
pharmacokinetics as an extension of Phase I
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PHASE III
• Randomized• Placebo controlled• Comparative• Double-blind •Multi-centric • Patients study• Involves several physicians• N = 500 to 3000
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PHASE III
• Value of the drug in relation to existing therapy• Safety, tolerability, drug interactions
• Additional information on pharmacokinetic data • Finalization of indication
• Formulation of guidelines for therapeutic use
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Registration
• New Drug Application (NDA) along with the Data (safety and efficacy) of Clinical Trials are submitted to relevant Regulatory Authority– India: DCGI (Drug Controller General of India)– USA: FDA (Food and Drug Administration)
• Chirality of drug is considered by RA
• Regulatory Authority, in convinced, gives a ‘marketing permission
• Average time for approval: 2.5 yr
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PHASE IV: Post-marketing Surveillance (PMS)
• Clinical trials do not end with approval• Practicing physicians are indentified and
from them data are collected on a structured proforma regarding– Efficacy– Acceptability– Adverse effects
• n = 4000 – 5000 patients or more
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PHASE IV: Post-marketing Surveillance (PMS)
• Uncommon adverse effects
• Long term adverse effects
• Adverse drug reactions (e.g. idiosyncrasy etc.)
• Unsuspected drug interactions
• Patterns of drug utilization
• Additional indications
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• Effect on special groups – Elderly & Neonates– Pregnancy & Lactation – Liver &Renal impairment
• Exploration of possibilities– Modified release dosage form– Additional route of administration– Fixed dose combination
• Even drugs / formulations are withdrawn from the market if found to be injurious to health
PHASE IV: Post-marketing Surveillance (PMS)
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Examples of drug withdrawal
• Antihistamine: Terfenadine, Astemizole for producing “torsa de pointes”
• Selective COX-II inhibitor: Rofecoxib and Celecoxib for producing cardiotoxicity
• NSAIDs: Nimesulide is banned for all age groups in Western countries and for paediatric age group in India
• Aspirin liquid formation: due to possibilities of producing Reye’s Syndrome in children
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Phase 0(Human Micro-dosing)
• Offers a way of developing drugs in a faster,
more cost effective and ethical way than ever
before.