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CLINICAL RESEARCHwww.pristynresearch.com

CONTENT

1. GENERAL INTRODUCTION OF CLINICAL RESEARCH2. KEY POINTS AND CONCEPTUAL DEFINATION3. DRUG DISCOVERY PROCESS4. SOURCES OF DRUG DISCOVERY5. PRECLINICAL STUDY

GENERAL INTRODUCTION OF CLINICAL RESEARCH

IN 1754, surgeon James Lane; he discovered that health save life. Also studied investigation on SMALL POX, POLIO and YELLOW FEVER.IN 1946, British Epidemiologist SIR AUSTIN BRAND HILL; he done trail for TB patient put patient into experimental and control group randomly. First trial with proof which predicts streptomycin as antituberculatic drug.

WHY CLINICAL RESEARCH

• CLINICAL RESEARCH IS ONE WHICH MADE POSSIBLE , ORAGAN TRANSPLANT, MANAGE OF DIBETIS, ADDED YEAR OF AIDS PATIENT.

• HOW WELL NEW APPROCHES AND WORK IN PEOPLE.• THE APPROACHES CAN BE MEDICAL, BEHAVIORAL,

OR MANAGEMENT.• EACH STUDY ANSWER SCIENTIFIC QUESTION.

PEOPLE WHO TAKES PART IN CLINICAL TRIAL

CAN CONTRIBUTE KNOWLEDGE HOW DISEASE PROGRESS

PARICIPANTS HAVE ASSESS TO PROMISSING APPROACHES OFTEN NOT AVAILABLE OUTSITE THE TRIAL SETTING

PARTICIPANTS RECEIVE CAREFUL MEDICAL ATTENTION FROM A RESEARCHER TEAM OF DOCTOR AND OTHER HEALTH PROFESSIONAL.

PARTICIPANTS MAY BE THE FIRST TO BENEFIT FROM THE STUDY.

RESULT FROM THE STUDY MAY HELP OTHERS FROM STUDY.

DRUG, VACCINE OR OTHER INTERVENTION BEIGN STUDIED MAY BE MORE EFFECTIVE

AND/ OR EFFICIOUS THAN STANDARD APPROACH.

KEY POINTS AND CONCEPTUAL DEFINATION

1. CONTROL GROUP2. RANDOMIZATION3. BLIND STUDY4. INCLUSION AND EXCLUSION CRITERIA5. END POINT6. SAMPLE SIZE

7. ERROR8. MULTICETER TRIAL9. SUBSEQUENTIAL STUDY10. META ANALYSIS11. COHORT STUDY12. CASE CONTROL HISTORY

CONTROL GROUP

A GROUP OF SUNJECTS WHICH RECEIVE NO TRATMENT, A STADARD TREATMENT

OR PLACEBO.

RANDOMIZATION

A PROCESS OF ASSIGNING TRIAL SUBJECT TO TREATMENT OR CONTROL GROUPS USING AN ELEMENT OF CHANCE TO DETERMINE THE ASSIGMENT IN ORDER TO REDUCE BIAS.

BLIND STUDY

THE STUDY IN CLINICAL TRAIL IN WHICH INVESTIGATOR, PARTICIPANTS OR ANYONE ASSESSING THE OUTCOME IS UNWARE OF TRATMENT ASSIGNMENT. IT IS USED TO REDUCE POTENTIAL BIAS.

INCLUSION AND EXDLUSION CRITERIA

INCLUSION CRITERIA IS A PROTOCOL THAT PROSPECTIVE SUBJECTS MUST TO BE PARTICIPATE IN THE STUDY. EXCLUSION CRITERIA IS A PROTOCOL ANY ONE OF WHICH IS NOT ELIGIBLE FOR THE PARTICIPATION IN STUDY.

END POINT

THE END POINT IS FINAL RESULT FROM THE STUDY. END POINT OF STUDY ARE PRIMARY AND SECONDARY. WHICH MAY INCLUDES CURE, DEGREE OF IMPROVEMENT, SYMPTOMS RELEIF, SURROGATE MARKER, AVOIDANCE OF COMPLICATION, QUALITY OF LIFE, SURVIVAL, ETC.

MULTICENTER TRIAL

A CLINICAL TRIAL CONDUCTED ACCORDING TO SAME PROTOCOL BUT AT MORE THAN ONE SITE AND THERE FORE CARRIED OUT BY MORE THAN ONE INCESTIGATOR.

SEQUENTIAL TRIAL THIS DESIGN ATTEMPT TO DETECT A SIGNIFICANT RESULT AS SOON AS IT IS ACHIVED, MINIMIZING THE NUMBER OF SUBJECTS. TRIAL CONDUCTED ON MATCHED PAIRE OF SUBJECT AND IS SCORED AS ‘A’ IS BETTER THAN ‘B’ OR ‘B’ IS BETTER THAN ‘A’. APPLICABLE TO DRUGS OR DISESASE IN WHICH CLINICAL END POINT IS ACHIVED QUICKLY AND COMPARISION ARE POSSIBLE.

META ANALYSIS THIS IS AN EXERCISE IN WHICH DATA FROM SIMILARLY CONDUCTED RANDOMIZED CONTROL CLINICAL TRIALS WITH SAME DRUG( OR CLASS OF DRUG(S) EXAMINING, THE SAME CLINICAL END POINT(S) IS POOLED TO BRING OUT OVERALL BALANCE OF EVIDENCE BY ENLARGING NUMBER OF TEST AND CONTROL SUBJECTS AND INCREASING THE SIGNIFICANCE AND POWER OF CONCLUSION.

COHORT STUDY

STUDY OF GROUP OF INDIVIDUAL, SOME OF WHOME ARE EXPOSED TO A VARIABLE OF INTEREST, IN WHICH SUBJECT ARE FOLLOWED OVERTME. COHORT STUDY MAY PROSPECTIVE / RETROSPECTIVE.

CASE CONTROL HISTORY

THIS TYPE OF OBSERVATIONAL STUDY IS USED MAINLY TO REVEAL ASSOCIAON OF SUSPECTED RARE ADVERSE EVENT WITH THE USE OF PERTICULAR DRUG. CASES OF SUSPECTED ADVERSE EVENT ARE COLLECTED FROM HOSPITAL RECORD OR DISEASE REGESTRIES.

DRUG DISCOVERY PROCESS

DRUG

ACCORDING TO USP; “AN ARTICLE INTENDED FOR USE IN DIGNOSI, TREATMENT, MITIGATION, CURE OR PREVENTION OF DISEASE”.ACCORDING TO WHO, IN 1996; “DRUG IS ANY SUBSTANCE OR PRODUCT THAT IS USED OR INTENDED TOMODIFY OR EXPLORE PHYSIOLOGICAL OR PATHOLOGICAL STATES FOR THE BENEFITS OF RECIPIENT”.

SOURCES OF DRUG DISCOVERY

NATURAL SOURCES

1. PLANT2. MINERAL 3. MICROORGANISM4. MARINE5. ANIMAL

PLANT SOUCES: OLDEST SOURCES OF MEDICINE. THIS FIRST NATURAL SOUCES USED AS MEDICINE. OBTAINED FROM TRADITIONAL SYSTEM OF MEDICINE.AYURVEDIC SYSTEM OF MEDICINE BASED ON PLANT SOURCES.

EXAMPLES;

PLANT SOURCE ACTIVE DRUG

OPIUM MORPHINE

EPHEDRA EPHEDRINE

CINCHONA QUININE

BELLADONA ATROPINE

MINERALS:

IRON, CALCIUM SALTS ETC ARE THE SOURCES OBTAINED FROM THE MINERAL SORCES MEDICINE.

MICROORGANISM:

MARINE:

ANIMAL:

CHEMICAL SYNTHESIS DEBUTE IN 19th CETURY & NOW LARGEST IS SOURCE. THIAZIDE DIRUTICS FROM ACETAZOLIMIDE, TRICYCLIC ANTIDEPRESENT FROM PHENOTHOZINE.

SALBUTAMOL B2 AGONIST B BLOKER BY MODIFYING STRUCTURE. EXCEPTION ARE, BARBTURATE AND CPM; SERENDEPITIOUSLY.

SO NOW BEST APPROACH FORCLINICAL RESEARCH DEVELOPMENT

RATIONAL SOURCES

AIMED AT MITIGATION THE DEARRAGEMENT CAUSED BY DISEASE. THIS DEPENDS ON PHYSIOLOGICAL, BIOCHEMICAL, PATHOLOGICAL AND IDENTIFICATION OF SPECIFIC RECEPTOR TARGET FOR DRUG ACTION SUCH AS H+K+ATPase ENZYME OR GLYCOPROTIEN IIa/ IIIb RECEPTOR. DOPAMINE DERIVATIVE LEVODOPA IN PARKINSONISM

MOLECULAR MODELING

ADVANCE IN PROTEIN CHEMISTRY AND COMPUTER ADDED ELUCIDATION OF THREE DIMENTIONAL STRUCTURE OF KEY RECEPTOR, ENZYME, ETC. HAS PERMITTED DESIGNING OF TARGETED COPMOUND. EXAMPLE; SELECTIVE COX-2 INHIBITOR PROMOTED BY COMPARATIVE CONFUGARATION OF COX-1 AND COX-2 ENZYME.

COMBINATORY CHEMISTRY

CHEMICAL GROUP ARE COMBINE IN RANDOM MANNER TO YIELD INNUMERABLE COMPOUND AND SUBJECTED TO HIGH-THROUGHPUT SCREENING ON CELLS, GENETICALLY, ENGINEEERED MICROBES, RECEPTOR, ENZYME, ETC. ASK TO SIR?

BIOTECHNOLOGY

SEVERAL DRUG PRODUCED BY RECOMBINANT DNA TECHNOLOGY. EXAMPLE; HUMAN GROWTH HARMONE, HUMAN INSULIN. SOME MONOCLONAL ANTIBODIES HAVE INTRODUCED AS DRUG.

DRUG DISCOVERY STAGES

LOOKING

FOR

NEW

SYNTHESIS OF COMPOUND/ SERENDIPITY

TARGET IDENTIFICATION

TARGET VALIDATION

HIGH THROUGHOUT

SCREENING

LEAD IDENTIFICATION

LEAD OPTIMIZATION

DOCUMETION PRECLINICAL STUDY PHASE I

PHASE IIPHASE IIIPHASE IV

SYNTHESIS OF COMPOUND

SERENDIPITY; SUDDENLY DISCOVERY OF MOLECULE SYNTHESIS ALSO CARRIED ACCORDING TO SITUATION, DEMAND. SERENDIPITY; PENECILINE SYNTHESIS; ZIDOVUDINE

TARGET IDENTIFICATION & VALIDATION

SELECTION OF TARGET SITE FOR WHICH DRUG/ DEVICE IS GOING TO PREPARE. EXAMPLE; HIV(STAGES), CANCER (ORAL---) VALIDATION OF PERTICULATE IS CARRIED TO ENSURE.

HIGH THROUGHPUT SCREENING

DEVELOPMENT OF SUBDISCIPLINE OF DRUG DISCOVERY DEDICATED TO RAPID EVALUATION OF LARGE NUMBER OF PURE COMPOUND THAT NATURALL PRODUCT EXTRACT FOR VERY SPECIFIC BIOLOGICAL ACTIVITIES, USUALLY BASED ON INTERACTION WITH SELECTED ENZYME OR RECEPTOR; REFERRED AS HTS.

LEAD IDENTIFICATION

ONCE TARGET HAS SELECTED, NEXT STEP IS TO INDETIFICATION OF NOVEL COMPOUNDS THAT INTERACT WITH ITS HIGH POTENCY, EFFICACY AND SECTIVITY. AFFINITY; ABILTY TO BIND TIGHTLY TO IT’S TARGET. EFFICACY; ABILTY OF LIGANDS TO OBTAIN EFFECT ON IT’S TARGETE, & AND CAN MEASURE AS BIOCHEMICAL AND PHYSIOLOGICAL RESPONSE.

LEAD OPTIMIZATION

POTENTIAL DRUG REQUIRE MANY ATTRIBUTS. BIOAVILABLE, CHEMICALLY STABLE, METABOLICALLY STABILE. FOR INSTACE, ONE MAY ACCEPT COMPOUND WITH LESS POTENCY THAN OTHER IF IT HAS OTHER PHARMACOKINETICS PROPERTIES.

PRECLINICAL STUDY

SCREENING TEST TEST ON ISOLATED ORGAN

TEST ON BACTERIAL CULTURE ANIMAL TESTING

GENERAL OBSERVATION TEST

CONFIRMATORY TEST & ANALOGOUS ACTIVITIES

MECHANISM OF ACTION

SYNTHETIC PHARMACOLOGY

QUANTITATIVE TEST PHARMACOKINETIC TOXICITY DOCUMENTATION

JOURNEY OF PHASE I

SCREENING TEST

THESE ARE SIMPLE AND RAPIDLY PERFORM TEST TO INDICATE PRESENCE OR ABSENCE OF PERTICULAR PHARMACODYNAMIC ACTIVITY OF THAT IS SOUGHT FOR EXAMPLE; ANLAGESIC, ANTITB, ANTIRETROVIRAL, ETC.

TEST ON ISOLATED ORGANS, BACTERIAL CULTURE

THESE ARE ALSO PRILIMINARY TEST PERFORMED ON EITHER ON ISOLATED ORGAN, BACTERIAL CULTURE OR BOTH TO DETERMINE THE SPEFIC ACTIVITY OF COMPOUND. SUCH AS ANTIHISTAMINIC, VASODILATOR, ANTIBACTERIAL, ETC.

ANIMAL TESTING

THESE ARE THE TEST WHICH PERFORMED ON ANIMAL MODEL.FOR PERFORMING SUCH TEST APPROVAL OF RELATED AUTHORITY REQUIRED WHICH PROVIDES THE GOOD LABORATORY PRACTICES FOR THE TEST.ANIMAL MODEL USED IN THE TEST ARE; RATS, MOUSE, GENIA PIG, ETC.

GENERAL OBSERVATIONAL TEST

PERFORMED EITHER IN BEGINNING(IN CASE OF TOTAL NOVEL COMPOUNDS) OR AFTER DETECTION OF USEFUL ACTIVITY IN SCREENING TEST, DRUG IS INJECTED TO TRIPLING DOSES TO SMALL GROUP OF ANIMALS WHICH ARE OBSERVED FOR OVERT EFFECTS. PRIMARY CLUES ARE DROWN AT THE PROFILE OF EFFECTS OBSERVED.

CONFIRMATORY TEST AND ANOLOUGE ACTIVITIES

COMPOUNDS FOUND ACTIVE ARE TAKEN UP DETAILED CHARACTERIZE THE ACTIVITY. OTHER RELATED ACTIVITIES, EXAMPLE ANTIPYRETIC AND ANTI- INFLAMATORY ACTIVITIES IN ANALGESIC.

MECHANISM OF ACTION

THE MECHANISM BY WHICH DRUG ACTS IN THE BODY. THESE ATTEMPT ARE MADE TO FIND OUT MECHANISM OF ACTION OF DRUG WHETHER IT IS AN ANTIHYPERTENSIVE IS AN ALFA BLOBKER/ BETA BLOKER/ CALCIUM CHANEL BLOKER/ ACE INHIBITOR/ CENTRALLY ACTING.THOUGH EXACT MAO OF DRUG IS NOT UNDERSTOOD YET.

SYNTHETIC PHARMACOLOGY

SYNTHETIC PHARMACOLOGY IS BASED ON THE FINDING OF THE ACTION OF DRUG IN THE SYSTEM OF BODY. IRESPECTIVE ACTION OF DRUG, ITS EFFECT ON MAJOR ORGAN SYSTEMS SUCH AS NERVOUS, CARDIOVASCULAR, RESPIRATORY, RENAL, GI ARE WORKED OUT.

QUANTATIVE TEST

THE RESPONSE RELATIONSHIP, MAXIMAL EFFECT AND COMPARATIVE EFFUCACY WITH EXISTING DRUG IS DETERMINED.

PHARMACOKINETICS

THE STUDY OF ADME; THAT WHAT DRUG DO TO BODY. THE ANSORPTION, TISSUE DISTRIBUTION, METABOLISM, SITE OF EXCREATION, VOLUME OF THE DESTRIBUTION AND HALF LIFE OF THE DRUG ARE QUANTIFIED.

TOXICITY

TOXICUTY REFERED AS, HARM TO BODY.AIM IS TO DETERMINE SAFETY OF COMPOUND. TOXICITY PRODUCED BY DRUG MAY BE, ACUTE TOXICITY, CHRONIC TOXICITY, SUB ACUTE TOXICITY, SPECIAL LONG TERM TOXICITY, REPRODUCTION AND TERATOGENECITY, CARCINOGENECITY.

ACUTE TOXICITY: SINGLE ESCALATING DOSE ARE GIVEN TO SMALL GROUPS OF ANIMALS THAT ARE OBSERVED FOR OVERT EFFECTS AND MORTALITY FOR 1-3 DAYS. LD50 IS CALCULATEDSUB ACUTE TOXICITY: ORGAN TOXICITY IS EXAMINED BY HISTOPATHOLOGY ON ANIMAL.REPETATED DOSE ARE GIVEN FOR 2-12 WEEKS DEPENDING ON DURATION ON INTENDED TREATMENT IN MAN. DOSE ARE SELECTED ACCORDING TO ED50 AND LD50. ANIMAL ARE EXAMINED FOR OVERT EFFECTS, FOOD INTAKE, BODY WEIGHT, HAEMATOLOGY, ETC AND ORGAN TOXICITY.CHRONIC TOXICITY: DRUG ARE GIVEN FOR 6-12 MONTHS AND EFFECTS ARE STUDIED AS SUBACUTE TOXICITY. THIS IS UNDERTAKEN CONCURRENTLY WITH EARLY CLINICAL TRIAL.

SPECIAL LONG TERM TOXICITY: THIS TEST ARE DONE FOR THE DRUG WHICH CROSS PHASE I CLINICAL TRIAL.REPRODUCTION AND TERATOGENECITY: EFFECTS ON SPERMATOGENESIS, OVULATION, FERTILITY, AND DEVELOPING FOETUS.MUTAGENICITY: ABILITY OF DRUG TO REDUCE GENERIC DAMAGE IS ASSED IN BACTERIA (AMES TEST), MAMMILIAN CELL CULTURE AND INTACT RODENT.CARCINOGENECITY: DRUG IS GIVEN FOR LONG TERM, EVEN WHOLE LIFE OF ANIMAL AND THEY ARE WATCHED FOR TUMOURS. STADERDISE PROCEDURE UNDER “GOOD CLINICAL PRACTICE” (GLP) HAVE BEEN LAID DOWN.

DOCUMENTATION

ALL DATA ARE COLLECTED FROM PRECLINICAL STUDY AND SENT IT TO REGULATORY AUTHORITY FOR THE PERMISSION FOR FURTHER STUDY. DATA ARE RECORDED IN ELECTRONIC AND WRITTEN FORMAT.

JOURNEY TO PHASE I

See You Soon

THANK YOU FOR YOUR ATTENTION

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