New Drug Development

What is a drug?

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

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.

Not a Easy Process

• Highly complex• Tedious• Competitive• Costly (500 – 1000 million dollars)• Commercially risky• Time consuming (at least 10 years)

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

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)

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

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

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."

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

Approaches to drug discovery

• Natural sources • Chemical synthesis • Rational approach • Molecular modelling • Combinatorial chemistry • Biotechnology

Natural sources

• Plants – Morphine, Ephedrine, reserpine, artermisinin,

quinine, atropine • Animals – Adrenaline, thyroxine, insulin, liver extract,

antisera • Micr-organisms – Penicillin, cephalosporin

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

Indian Contribution

• Rauwolfia alkaloid form Raulwofia serpentina as antihypertensive and antipsychotic drug

• Gugulipid from Tinospora as lipid-lowering agent

Chinese Contribution

• Sympathomimetic Ephedrine from Ma huang (Ephedra vulgaris)

• Antimalaial Artemisinin from Quinghasou (Artemisia annua)

• Anticancer drug Camptothecin (Irinotecan and topotecan) from Captotreca acumunata

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

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

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

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.

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

• Now Regulatory authority grants permission after chiral separation of recemate drugs when a single enantiomer is better than the recemate preparation

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’

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

Rational approach

• Depends on sound knowledge & identification of specific target for drug action

• Receptor based approach ( target oriented)

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

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

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

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)

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

Preclinical StudiesSynthesis / Identification of Lead Compound(s)

(Thousands)

Few out of Thousands

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

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

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

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.

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)

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)

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.

Why Clinical Trials?

• To discover or verify:

–Pharmacodynamics (how it works)

–Pharmacokinetics (what happens to it)

– Therapeutic effects (efficacy)

–Adverse reactions (safety)

History of Clinical Trial

James LindClinical trials for cure of scurvy in 1747

JAMES LIND, CONQUERER OF SCURVY

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

• 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

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.

New York Times described this study as

“The longest clinical trial in human body without treatment in the medical history”

May 16, 1997

Tuskegee trial

President Clinton apologised from USA citizens because of Tuskegee trial

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

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

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)

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

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

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

PHASE III

• Randomized• Placebo controlled• Comparative• Double-blind •Multi-centric • Patients study• Involves several physicians• N = 500 to 3000

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

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

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

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

• 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)

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

Phase 0(Human Micro-dosing)

• Offers a way of developing drugs in a faster,

more cost effective and ethical way than ever

before.