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 Why/How are new drugs discovered ?  What process is involved in the discovery and development of new drugs?

 1. Identification or elucidation of a new drug target 2. Rational design of a new molecule 3. Screening for biologic activity of large numbers of natural products 4. Chemical modification of a known active molecule, resulting in a me-too analog Drug Discovery

 The development and testing process a drug to market

In vitro studies

 Animal studies  Efficacy  Mechanism  Selectivity  Safety (Toxicity)

  All drugs are toxic in some individuals at some dose  No-effect dose Maximum dose at which a specified toxic effect is not seen  Minimum lethal dose The smallest dose that is observed to kill any experimental animal  Median lethal dose (LD50) The dose that kill approximately 50% of the animals  The initial dose to be tried in humans _ the no-effect dose in animals Preclinical Safety & Toxicity Testing Preclinical Safety & Toxicity Testing

 Animal Studies Acute toxicity testsSubacute toxicity testsSubchronic toxicity testsChronic toxicity tests

  Two species, usually mouse and rat  Two routes of administration  Single dose or multiple doses in 24 hours ( exposure ˂ 24 houres)  Mortality, weight, sign of intoxication, lethargy, behavioral modification, morbidity, food consumption for 14 days  Determination of the no-effect dose and the maximum tolerated dose  In some cases, determination of the LD50 Acute Toxicity Tests Approach and Goals

  1 days to 30 days  Two species  Two routes of administration  Three doses  Determination of biochemical, physiologic effects  Information on the toxicity of a chemical after repeated administration Subacute Toxicity Tests Approach and Goals

  30 days to 90 days  Two species  Two routes of administration  Three doses ( high, intermediate, and low dose)  NOEL (no observed effect level)  NOAEL (no observed adverse effect level)  LOAEL (lowest observed adverse effect level) Subchronic Toxicity Tests Approach and Goals

  NOEL (no observed effect level) An exposure level at which there are no statistically or biologically significant increases in the frequency or severity of any effect between the exposed population and its appropriate control  NOAEL (no observed adverse effect level) The highest dose or concentration of a substance (i.e. a drug or chemical) or agent (e.g. radiation), at which no adverse effect is found  LOAEL (lowest observed adverse effect level) The lowest dose or concentration of a substance (i.e. a drug or chemical) or agent (e.g. radiation), at which adverse effect is found Important Definitions

  3 months to 24 months  Two species  Two routes of administration  Three doses ( high, intermediate, and low dose)  Drug prolonged use effects  Drug cumulative effects Chronic Toxicity Tests Approach and Goals

  Time-consuming and expensive  Large numbers of animals may be needed to obtain valid preclinical data  Extrapolation of animals data to humans are often difficult  For statistical reasons, rare adverse effects are unlikely to be detected in preclinical testing Limitations of Preclinical Testing

  Placebo An inactive dummy medication made up to resemble the active investigational formulation  Crossover design Alternating periods of administration of test drug, placebo preparation (the control), and the standard treatment (positive control), if any, in each subject Important Definitions

  Single blind design Investigators but not the subjects know which subjects are receiving active drug and which are receiving placebos  Double blind design Neither the investigators nor the subjects know which subjects are receiving active drug and which are receiving placebos  Bias Bias is defined as any tendency which prevents unprejudiced consideration

 1. The Variable Natural History of Most Diseases a)Large enough population b)Sufficient period of time c)Crossover design 2. The Presence of Other Diseases and Risk Factors a)Crossover design b)Accurate diagnostic tests, medical and pharmacologic histories c)Statistically valid methods 3. Subject and Observer Bias and Other Factors a)Single-blind design b)Double-blind design Confounding Factors in Clinical Trials

Food And Drug Administration of The Islamic Republic of Iran

 1.Composition and source information 2.Chemical and manufacturing information 3.All data from animal studies 4.Proposed plans for clinical trials 5.The names and credentials of physicians 6.Compilation of the key data relevant to study of the drug in humans Investigational New Drug (IND)

  Investigational Exemption for a New Drug (IND)  Requires 4–6 years of clinical testing  Subject : human  Four phase : I, II, III, IV Clinical Trials

  20–100 of healthy volunteers  Often “non-blind” or “open” alternatively double blind  In research centers by clinical pharmacologists  Many predictable toxicities, Pharmacokinetic are detected  If significant toxicity is expected, in cancer and AIDS therapy, volunteer patients with the disease are used in phase I rather than normal volunteers Phase I

  100 – 200 of patients  Determination of drug efficacy  Single-blind design  Inert placebo medication, established active drug (positive control) and investigational agent  In special clinical centers (university hospitals)  Highest rate of drug failures. Only 25% of innovative drugs move on to phase 3 Phase II

  Large number of patients (1000 – 5000)  Double-blind and crossover designs  Multicentre ( in several hospital) by specialists  Certain and rare toxic effects especially immunologic processes  Marketing approval requires submission of a New Drug Application (NDA) to the FDA Phase III

  Post marketing surveillance (PMS)  Very rare toxic effects  An important part of the science of pharmacovigilance  Period : unlimited  The sample size required is very large  The time from the filing of a patent application to approval for marketing : 5 years or longer  The average effective patent life for major pharmaceuticals : years Phase IV

 The development and testing process a drug to market

  Drugs developed for rare diseases  Proof of drug safety and efficacy in small populations  In USA: fewer than people  Supported by “ not for profit” foundation Orphan drugs

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Real case?

 در فاز I کارآزمایی بالینی داروی A تعداد 8 بیمار مبتلا به بیماری X تحت درمان قرار گرفتند و با توجه به نتایج معاینات بالینی و آزمایشات انجام شده تعداد 5 بیمار به درمان پاسخ قابل قبول و معنا دار داده اند، لذا داروی مذکور می تواند وارد فاز II کارآزمایی بالینی شود ?