The document summarizes the new drug development process. It begins with drug discovery through screening compounds and understanding interactions with biological targets. Candidate drugs then undergo preclinical safety testing in animals. If results are promising, drugs enter clinical trials with humans which have four phases to test for safety, efficacy, and side effects. The entire process from discovery to marketing approval can take over 11 years. Confounding factors like placebo effects and variability in diseases make evaluating drugs in humans challenging.
The document summarizes the new drug development process. It begins with drug discovery through screening compounds and understanding interactions with biological targets. Candidate drugs then undergo preclinical safety testing in animals. If results are promising, drugs enter clinical trials with humans which have four phases to test for safety, efficacy, and side effects. The entire process from discovery to marketing approval can take over 11 years. Confounding factors like placebo effects and variability in diseases make evaluating drugs in humans challenging.
The document summarizes the new drug development process. It begins with drug discovery through screening compounds and understanding interactions with biological targets. Candidate drugs then undergo preclinical safety testing in animals. If results are promising, drugs enter clinical trials with humans which have four phases to test for safety, efficacy, and side effects. The entire process from discovery to marketing approval can take over 11 years. Confounding factors like placebo effects and variability in diseases make evaluating drugs in humans challenging.
molecule “me-too” analog - Usually begins w/ 3. Identification/elucidation of a new drug o Discovery or synthesis of potential new target drug 4. Rational design of new molecule based o Elucidation of a new drug target on biologic mechanisms and receptor - Synthesized or extracted from a natural source structure - Understanding drug’s interactions w/ biologic targets Drug screening - Repeated application leads to related compounds w/ increased safety, potency, and - Assays to define pharmacologic profile – activity selectivity and selectivity - In vivo studies in animals before human drug - Type and number of screening depends on trials pharmacologic & therapeutic goal o Relevant biologic effects - Eg, anti-infective drug o Drug metabolism o Tested against infectious organisms o Pharmacokinetic profiles - Hypoglycemic drugs o Relative safety of the drug o Tested for ability to lower blood sugar - Human testing for regulatory approval and - Mechanism of action and selectivity of the drug approval for general use – 3 phases - Reveal expected and unexpected toxic effects - 4th phase – data gathering and safety monitoring - Compound optimization - Highly toxic drugs are nevertheless valuable in o Further chemical modification to achieve lethal diseases and approved for restricted use more desirable pharmacokinetic or - In vitro studies pharmacodynamic properties o Biologic compounds; chemical - Lead compound synthesis, optimization Lead o Desired result after screening compound procedures, ie, leading candidate for a o 2 years successful new drug - Animal testing (preclinical) Preclinical Safety and Toxicity Testing o Efficacy, safety, mechanism o 2 years - Candidate drugs that survived initial screening o Apply for Investigational New Drug (lead compound) (IND) o Evaluated for potential risks before and - Clinical testing during clinical test o Drug metabolism, safety assessment - No chemical is certified completely “safe” o Phase 1-3 - Only estimate the risk associated with exposure o 4-6 years to the drug candidate o Apply for New Drug Application (NDA) - Goals of preclinical toxicity studies: identify - Marketing potential hu man toxicities, define toxic o Phase 4 – postmarketing surveillance mechanisms, predict most relevant toxicity to be o 11 years (year 20) monitored o Patent expires 20 years after filing of - Safety tests: application o Acute toxicity test Generics become available Determines no-effect dose – max dose that has no toxic Drug discovery effect - Most new drugs/drug product discovered or Maximum tolerated dose developed in the ff approaches Median lethal dose (LD50) – 1. Screening for biologic activity of dose that kills approx. half of Large no. of natural products animals Banks of previously discovered o Subacute/subchronic chemical entities 2 wks – 3 mos before clinical Large libraries of peptides, trial nucleic acids, and other organic Determines biochemical, molecules physiologic effects
PHBS 2A (Pharmacology I & Therapeutics)
Tecson, 2018 o Chronic When drug is to be used in humans for prolonged periods 3. Subject and observer bias and other factors Run with clinical trials o Placebo response Same as subacute Positive responses as many as o Effects on reproductive performance 30-40% (Test for capability to induce congenital o Subject bias diseases) Quantitated and minimized by Animal mating behavior, single-blind design reproduction, parturition, o Observer bias progeny, birth defects, postnatal Minimized by double-blind dev’t design o Carcinogenic potential (test for o Compliance/adherence carcinogenicity) Necessary element to consider When drug is to be used in Clinical trials humans for prolonged period Determine gross and histologic - Phase 1 pathology o Safety; pharmacokinetics (absorption, o Mutagenic potential (test for half-life, metabolism) mutagenicity) o 20-100 subjects – healthy volunteers Effects on genetic stability and o In research centers mutations on bacteria or - Phase 2 mammalian cells o Efficacy (proof of concept) Dominant lethal test o Dose Clastogenicity in mice o Single-blind - Sulfanilamide death (Federal Food, Drug, and o 100-200 patients Cosmetic Act of 1938) o In special clinical centers, eg, university - Thalidomide phocomelia (Kefauver-Harris hospitals Amendment of 1962) - Phase 3 - Hormone replacement therapy breast cancer o Double-blind; crossover technique - Celecoxib heart problems o Minimize errors caused by placebo o 1 000-6 000 patients Evaluation in Humans - New Drug Application (NDA) - Less than 1/3 survive clinical trials - Biologic License Application (BLA) - Confounding factors in clinical trials 1. Variable natural history of diseases o Take into account the natural history by evaluating a large enough pop’n o Crossover design Alternating periods of administration of test drug, placebo, and standard treatment Protects against errors in interpretation caused by disease fluctuations 2. Presence of other diseases o May alter pharmacokinetics o Avoided by crossover technique and proper selection and assignment of pt to each study group