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DRUG DISCOVERY & DRUG DEVELOPMENT Drug discovery is an expensive (1/10,000 molecules), labour intensive (involving scientists of multiple

disciplines), time consuming process. Researchers must identify & validate a drug target (typically a protein), determine 3-D structure of that target, discover a lead compound that would bind to the target and develop that lead into a drug candidate. I. 1st step in new-drug discovery involves identification of possible target

receptor-site or ion-channel, or influencing at molecular level the patho-physiological mechanism of the disease process, where the new drug molecule might act. This hit-identification is carried out by developing suitable assay method, High Throughput Screening (HTS) followed by hit-validation (by selecting sensitive & reproducible end-points and bio-markers). After selecting or getting the lead compound, the next step is to work out for optimization of the lead-compound (optimization means identifying the molecule having maximum safety & efficacy) through chemistry manipulation, SAR, analog synthesis based on cell-based studies and/or based on experiments on validated animal models (pharmacology) [where similar disease pattern can be produced] and/or based on in-vitro animal tissue experiments. After the lead compound or its analog is optimized with reference to its chemical & /or biological character standardization, drug-development proceeds by conducting toxicity studies in small (rats, mice) & big (dogs, rabbits, g.pigs) mammalian species of known strains, pharmacokinetic studies (Cmax, Tmax, AUC, life) and ADME studies (absorption, distribution, matabolism and excretion). [Target identification, Hit-identification, Lead optimization & Drug development (toxicology, kinetics, ADME-studies would fall under discovery & pre-clinical drug development phase) ]

Pre-clinical development is followed by Clinical Development or Clinical testing in human subjects or in selected patients (Phase I, Phase II, & Phase III studies & after that Phase IV PMS studies).

Because of high failure rate of candidate molecules passing all the development tests, thousands of molecules or their analogs are synthesized. On an average 1 out of 10,000 compounds pass all the tests and can see the light of the market. It takes 8 to 10 years for a molecule to be screened through all the tests & regulatory approval before the successful molecule is marketed costing about 900 million $.

II. Important historical events that resulted into strict Regulatory laws for IND & NDA in Clinical Research are outlined below : 1937: Elixir Sulfanilamide, containing solvent diethylene glycol killed 107 persons (many of whom were children). This tragic incident caused the mandatory need in the US & globally to establish drug safety before marketing 1938 : US Federal Food, Drug & Cosmetic Act 1940 : Indian Drugs & Cosmetics Act & Rules there under(1945) 1947 : Nuremberg Codex 1952 : FDA in the US defines Rx or OTC drug 1962 : Thalidomide(a new sleeping pill, popularly taken by pregnant women) caused millions of babies mothers 1962: Kefauver-Harris Drug Amendments: Manufacturers required to prove to FDA the new drug not only safe but also effective. 1964 : Introduction of declaration of Helsinki (dignity, protection, safety, consent of subjects participating in clinical studies) 1966 : Creation of IRB for funding by US Public Health Service 1975 : Declaration of Helsinki revised 1976 : Medical Device Amendment to US Food, Drug, Cosmetic ACT 1977 : Publications of general considerations for CT of drugs in the US born with birth-defect (phocomelia, cleft palate) in western Europe) caused mandatory teratogenicity tests in animals for drugs to be given to-be

1983 : Declaration of Helsinki revised 1984 : Drug Price & Patent Term Restoration Act(Waxman & Hatch) 1985 : NDA rewrite 1987 : IND rewrite 1988 : GuidelinesFormat & content of the CT & statistics of an application 1989 : Declaration of Helsinki revised 1990 : Publication of EC GCP Guidelines 1992 :Prescription Drug User Fee Act & FDA accelerated approval 1996 : Declaration of Helsinki revised 1997 : ICH guidelines on GCP and FDA Modernization Act 1998 : FDA promulgates Pediatric Rule 2000 : Declaration of Helsinki revised 2003 : Pediatric Research Act in the US for CT in children 2004 : Declaration of Helsinki revised

III. Approaches for New Drug Discovery: Chemical modification of known molecule (SAR) Screening natural products Screening libraries of peptides, nucleic acid or other large molecules Rational drug design based on understanding of biologic mechanisms & chemical structure Biotechnology and cloning using genes to produce larger peptides & proteins [Automation has generated the process known as High Through Screening, which permits millions of assays per month]. Pharmacogenemic approach involves gene analysis to identify genes with altered expression as a result of exposure to a drug (with the help of markers of exposure, known as marker compounds). Markers of efficacy provide molecular evidence

beyond traditional clinical endpoints. Stratification markers can identify a subset of patients who may benefit best from a given therapy. Toxicity markers can predict & prevent adverse events. IV. CLINICAL PHASE - DRUG DEVELOPMENT: 1. Phase I (Human clinical pharmacology) study in healthy human volunteers after taking their informed consent to determine upto what dose the new drug is safe & well tolerated (MTD) without giving any discomfort & without any clinical and/or laboratory adverse sign-symptoms. Phase I study includes pharmacokinetic & pharmacodynamic studies. Phase I trial usually progress from single-dose trials to multple-dose trials & include as much pharmacokinetic evaluation as appropriate. MTD evaluation is stressed as it provides an upper limit in planning Phase II and Phase III trials. This philosophy has attracted criticism from ethical point of view. The counterargument given is MTD is not always the effective dose reported in many Phase II trials & it may be necessary to evaluate higher doses. Pharmacokinetic studies are really special studies, the programming of which can only be done by experts in the field depending upon age group & underlying disease conditions. Therefore many pharmacokinetic studies are conducted during late Phase II & throughout Phase III. Patients are evaluated instead of volunteers in Phase I when the medicine is too toxic to test ethically in volunteers (anticancer agents), the therapeutic ratio is too narrow and when it is believed that the therapeutic dose in patients will be greater than normal volunteers can tolerate

2. Phase II (Exploratory trials) conducted in limited patients to explore both effectiveness & safety of the drug in dose range suggested through Phase I trial to determine safe & effective dose range in selected patients for conducting large scale Phase III CTs. Phase II study also evaluate potential clinical & laboratory end-points,

therapeutic regimens including concomitant medications and selecting target populations (mild versus severe disease).

3. Phase III (Confirmatory Study) conducted multicentric in large number of patients following the same Protocol under the supervision of well qualified & experienced Investigators under GCP & GLP conditions (Responsibilities of Sponsor and /or CRO, responsibility of monitors, appointed by Sponsor or CRO, of research associate, appointed by the Investigator well defined under GCP & GLP including taking informed consent from screened & enrolled patients, approval of IRB based on submission of investigator-brochure, approval of DCGI for IND based on pre-clinical, clinical data generated on the new drug including marketing or CT status in other countries & PSUR and consent given by investigators in writing for conduct of the CT and names of the hospitals/institutions that would be involved in the proposed CT, compliance of CT as per approved Protocol and filling of the case-report-form for each patient(CRF) which should tally with the source documents). 4. Phase IV (PMS) study conducted after marketing approval granted by the regulatory authority for optimizing the drug use including surveillance of ADRs. V. Clinical Data Management : It includes PROTOCOL DEVELOPMENT, CRF DEVELOPMENT, DATA BASE DEVELOPMENT & VALIDATION, DATA ENTRY, QUERY & CORRECTION, DATA QA and DATA LOCK, ARCHIVE & TRANSFER.

VI. Formulation Development Flow-sheet for Investigational New Drug : Receive new-drug substance. Check basic structure & if antioxidant required to prevent light-oxidation-degradation Enquire dosage-form requested Determine drug substance physical & chemical requirements to suit dosage form

Obtain all available information from the inventor/ literature search Determine physical properties Microscopic & macroscopic examination If poor solubility, make new salts or esters Determine particle size, polymorphs (if steroid structure), solvates, hydrates Determine solubilities, PKAS, Dissolution Set on stability at normal & exaggerated conditions Select most stable & active form for biological testing Check lot to lot uniformity Set drug on stability with possible excipients Preparation of final preformulation report for issuing to Product Development Group

[Make sure CT samples manufactured under GMP conditions and properly packaged & labelled] VII. Difference between the Discovery & Development Environment Discovery Overall objective Select target for lead compound Development Select target for

lead compound Corporate mandate Compounds tested Regulatory Control broad, loosely defined Many & diverse in nature little or none Narrow, focused One Extensive NDA, Time Table Recognition Basis Culture Flexible, loose Innovation Chaotic (GMP, ANDA and

GLP, GCP (IND, requirement) Strict Constrained Speed Structured

Work style

Entrepreneurial

Interdependent

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