DEVELOPMENT AND REGULATION OF DRUGS

Anita Q. Sangalang, MD, FPOGS FACULTY OF PHARMACY UNIVERSITY OF SANTO TOMAS

DRUG DISCOVERY 1. Discovery or synthesis of a potential new drug 2. Rational design of a new molecule based on an understanding of biologic mechanism and drug receptor structure 3. Random screening of the biological products 4. Chemical modification of known active molecule resulting in a me-too analog DRUG SCREENING Process of testing a drug candidate which involves a sequence of experimentation and characterization to be able to define the pharmacologic profile of the drug at the molecular, cellular, organ, system and organism levels ---- Biologic products ---- Chemical synthesis Lead compound o Leading candidate for a successful new drug PRECLINICAL SAFETY AND TESTING Effective assessment and management of risk versus benefit and not total risk avoidance Identifies potential human toxicities Designs tests to further define the toxic mechanisms Predicts the most relevant toxicities to be monitored in clinical trials Amount of animal testing required before human studies begin is a function of the proposed use and the urgency of the application Quantitative estimates o No-effect-dose-maximum dose at which a specific toxic effect is not seen o Minimum lethal dose-smallest dose that is observed to kill any experimental animal o Median lethal dose(LD50)- if necessary only, dose that kills approximately 50% of the animals. This is usually estimated from the smallest number of animals possible SAFETY TESTS 1. ACUTE TOXICITY Administration of single doses to the lethal doses 2 species, 2 routes 2. SUBACUTE E doses, 2 species 2 weeks to 3 months Determine biochemical and physiologic effects 3. CHRONIC TOXICITY Rodent and nonrodent 6-24 months 2 and 3 tests are conducted for at least the length of time proposed for human

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TERRATOGENICITY Induction of developmental defects in somatic tissues of the fetus MUTAGENICITY Induction of changes in the genetic material of animals of any age inducing heritable abnormalities AMES TEST Standard in vitro test for mutagenicity Uses a special strain of Salmonella bacteria that naturally depends on specific nutrients in the culture medium Loss of this dependence during exposure to the test drug signals mutation CARCINOGENICITY Induction of malignant characteristics in cells

EVALUATION IN HUMANS CLINICAL TRIALS 4-6 years Natural variable history of the diseases Cross-over design 2 groups of patients One group is given the standard One group the placebo prep (control) and the standard treatment (positive control) if any Presence of other disease and risk factors Proper selection and assignment of the patients to each of the study groups Subject and observer bias Single-blind Double-blind Compliance or adherence with the protocols BUREAU OF FOOD AND DRUG (BFAD) (FDA- USA) Administrative body that oversees the drug evaluation in the Philippines Submit evidence of safety and effectiveness of the drug to this body A. PHASE I Careful evaluation of the dose-response relationship in a small number of normal healthy human volunteers (20-100) Determine the maximum tolerated dose, designed to prevent severe toxicity Except for trials of chemotherapeutic drugs (cancer and AIDS)and other highly toxic drugs carried by administering to patients with target disease Performed in research centers B. PHASE II Studied in patients with the target disease (100-200) Determine its efficacy or therapeutic effects (proof of concept) and the doses for follow-on trials Placebo or positive control is included in a single-blind or double-blind study Done in special clinical centers under carefully controlled conditions and very closely monitored Highest rate of drug failures

C. PHASE III Large design involving many patients (1000-5000) or more in many centers and many clinicians/specialists who are using the drug in the manner proposed for its general use Further establish and confirm safety and efficacy Drug is formulated as intended for the market Placebo, double-blind crossover trial Explore the spectrum of beneficial actions of the new drug, compare with older therapies Discover toxicities D. PHASE IV Begins once approval to market a drug has been obtained Toxicities that occur very infrequently will be detected and reported early enough to prevent a major therapeutic disasters Post marketing surveillance Not rigidly regulated by the Bureau of Food and Drugs (BFAD) Trademark Drugs proprietary name and is usually registered, it is legally protected al long as it is used ADVERSE DRUG REACTIONS (ADRs) Adverse drug event (ADE) Harmful or unintended response ORPHAN DRUGS Drugs for rare diseases Difficult to research, develop and market