Introduction to Drug Development, Nomenclature, and Drug Regulations PDF

Introduction to Drug Development, Nomenclature, and Drug Regulations MBP Lecture 1 Mary Beth Babos PharmD BCPS [email protected] DCOM 230 About the Course Course director: Mary Beth Babos Course director: Dr. Quadri ([email protected] ) aka The Man, The Myth, The Legend Cumulative by na...

Introduction to Drug Development, Nomenclature, and Drug Regulations MBP Lecture 1 Mary Beth Babos PharmD BCPS [email protected] DCOM 230 About the Course Course director: Mary Beth Babos Course director: Dr. Quadri ([email protected] ) aka The Man, The Myth, The Legend Cumulative by nature (including previous courses (esp MFM I & II and Physio)) It is important to know what drugs go in what class You have 2 primary tasks: memorize the drugs in each class, understand how the class works How do you learn all the drug names? Repetition. Mnemonics? Focusing on how the drugs work more than what they’re “for” – aim to predict effects based upon mechanism Antimicrobials are a different world… Brand names may be included in lecture but you will be responsible for knowing the generic names on the exams (here and COMLEX/USMLE) You will have to know this information next year…. And forever. Text: Basic & Clinical Pharmacology by Katzung (Available on Access Medicine) Log on to library > Reed Health Science Library Website > Access Medicine Items labeled FYI = for your information – not a focus for exam, but you‘ll likely need to know it SOMETIME... WILL BE ON TEST. WBOT means..seriously! You have to understand the concepts (and usually know the drug name) to get the question correct (not just memorizing the words) Course Objectives 1. 2. 3. 4. 5. 6. Explain how the US drug are development/ approval process affects patient outcome and access Explain how state and national laws regulating prescription and over-the-counter medications protect and disadvantage patients Use basic pharmacologic principles including mechanism of action, pharmacokinetics, pharmacodynamics (including interactions), and pharmacogenomics for selected xenobiotics to predict the effect on biochemical and physiological functions on a molecular level to that of the whole body Use biochemical, physiological, microbiologic, and pharmacologic concepts to select xenobiotics to manage pathologic states, especially infectious disease, cancer, and ocular disease Predict toxicological effects of xenobiotics and identify appropriate antidotes, explaining their mechanism of action when applicable Apply knowledge of epidemiology and disease risk factors to formulate patient specific pharmacologic recommendations to prevent disease and maintain good health The Pharm Team Mary Beth Babos PharmD DCOMH 230 Wishes she could teach herbology (and she’s part Hufflepuff) “old” pharmacist (just ask Dr. Weaver) Anna Huskey PhD DCOMH Seeking causes of canine cancer…likes dogs better than people PhD Pharmacology/ Computational Biology/ Genetics Lori McGrew, PhD DCOMH 229 Lover of birds and reptiles, queen of the Zebrafish PhD in neuropharmacology Syed Quadri, PhD DCOMK 1-234 Master of cool physiology drawings! PhD in pharmacology, focus on RAS system Mohammed Sayed, PhD DCOMK 1-239 His in-class questions will REALLY TEACH PHARM!! PhD Clinical and Experimental Therapeutics Where to get info? Authoritative Book: Goodman and Gilman Our Text: Basic and Clinical Pharmacology (Katzung) Basic concepts – an overview of what you need Review Text with Questions: Pharmacology Exam and Board Review Other Texts: There are many other great texts out there. The above are available for free on Access Medicine UpToDate: Contains Gold standard drug database LexiComp Wikipedia???? (PLEASE NO!!!!!) HON websites – Health on the net – The logo will include a date that reflects the last time the site was certified. When you click on the logo, match the date with the date HON claims to have certified it, and be sure they match FYI: some electronic resources in our library Access Medicine Up to Date Epocrates Medical Letter 1. Free text journals 2. Search “title equals” Medical Letter Lecture Objectives 1.1 Identify the steps and basic type of information gleaned in each step of the US Drug Development Process 1.2 Describe the potential impact of the drug development process on patients and providers, particularly the phase IV post-marketing surveillance Define common terminology, drug classifications, and functions of drugrelated regulatory bodies in the US and apply relevant regulations in prescription writing Recognize the components of written outpatient prescriptions required by law in TN, federal law (including DEA), and incorporate features to improve safety and reduce potential for error 1.3 1.4 A brief history in US drug regulation (do not memorize, just FYI!) Food and Drug Act 1906 – drug had to meet standards of “strength and purity” Food Drug and Cosmetic act of 1938 – after >100 died from Elixir Sulfanilamide drugs must be safe (unless marketed prior to 1938) 1994 Dietary Supplement Health and Education Act established to prevent adulteration or misbranding of dietary supplements 1962 Kefauver Harris amendment – after thalidomide; drug must be shown safe and effective prior to marketing Today Center for Drug Evaluation and Research (CDER) under FDA approves all new drugs Drug approval process takes an average of 8 years at a cost of over 800M dollars Patent on drugs good for 17 years. Until patent is expired, generic manufacturers can not produce drug for market in US Generic drugs must be “AB” rated – must meet bioavailability standard; listed in FDA Orange Book The development and testing process required to bring a drug to market in the USA. Some of the requirements may be different for drugs used in lifethreatening diseases (see text). Source: Introduction: The Nature of Drugs & Drug Development & Regulation, Basic & Clinical Pharmacology, 14e Citation: Katzung BG. Basic & Clinical Pharmacology, 14e; 2017 Available at: http://accessmedicine.mhmedical.com/content.aspx? bookid=2249&sectionid=175215401 Accessed: January 16, 2018 Copyright © 2018 McGraw-Hill Education. All rights reserved Pre-clinical phase Sponsor must submit data that the drug is reasonably safe for initial small-scale clinical studies. – In vitro – Animal studies – Foreign marketing experience Animal and cell culture toxicity studies – Genotoxicity – Toxicity of metabolites – Basic elimination data Phase I clinical trials After preclinical testing has established reasonable safety, Introduction into a small number of healthy human volunteers Designed to determine drug’s pharmacokinetics (dosing) and pharmacodynamics (effect) Also to evaluate drug metabolism, mechanism of action If drug is determined to be unsafe, Center for Drug Evaluation and Research (CDER) can put a clinical hold on further investigation Phase II clinical trials Small populations (100-200 patients) with the disease or condition for which the medication is to be indicated Preliminary assessment of efficacy in people with the disease Helps determine short-term side effects CDER can again impose a clinical hold Phase III clinical trial Controlled and uncontrolled trials to gather more information about efficacy, safety, and benefit/risk relationship Labeling (product package insert) is approved at this point. Once a drug is approved, the manufacturer must submit an Abbreviated New Drug Application for voluntary changes to label – Definition: Labeled use or indication- CDER can impose a clinical hold Product labeling – must be approved by FDA – ANDA must be filed for approval of change (Details are FYI, don’t memorize the details, please) Boxed Warning Indication and Use 1. Dosage and Administration 2. Dosage Forms and Strengths 3. Contraindications 4. Warnings and Precautions 5. Adverse Reactions 6. Drug Interactions 7. Use in Specific Populations 8. Drug Abuse and Dependence ANDA = abbreviated new drug application 10. Overdosage 11. Description 12. Clinical Pharmacology 13. Nonclinical Toxicology 14. Clinical Studies 15. References 16. How Supplied/ Storage and Handling 17. Patient Counseling information We will talk more about what indication, contraindicaiton, and boxed warning mean Phase IV Post-Marketing Surveillance Post-approval voluntary reporting: MedWatch Adverse Event Reporting System (AERS) at https://www.accessdata.fda.gov/scripts/ medwatch/medwatch-online.htm Vaccine adverse events are reported to the Vaccine Adverse Event Reporting System (VAERS) at www.vaers.hhs.gov Use of drug in large, diverse population allows for identification of idiosyncratic and rare side effects Love from Layla in the Poconos Boxed Warnings – FDA mandated labeling Through voluntary reporting of rare and idiosyncratic effects, the FDA identifies conditions for which a boxed warning is mandated on the package labeling Mandated by the FDA, no ANDA required FYI There are exceptions to the process Fast Tracks Accelerated Development Treatment IND Parallel Track for HIV drugs And let’s not forget what happens when a serious adverse effects is identified (thanks to vigilant reporting) after the drug has hit the market…the BOXED warning!!! Comprehension check (and example of exam) A 24yo male presents with a morbilliform rash on his torso. His medical history is significant for anxiety. He recently began participation in a clinical trial to see whether an investigational new drug produces a reduction in anxiety as hypothesized. If the drug is undergoing development via the usual process, what phase is the trial? A. Phase I B. Phase II C. Phase III D. Phase IV E. Pre-clinical F. Post-clinical Comprehension check answer A 24yo male presents with a morbilliform rash on his torso. His medical history is significant for anxiety. He recently began participation in a clinical trial to see whether an investigational new drug produces a reduction in anxiety as hypothesized. If the drug is undergoing development via the usual process, what phase is the trial? A. Phase I - done in a few (100ish) HEALTHY folks to check pharmacokinetics/dosing B. Phase II – proof of concept – does the drug work as hypothesized? C. Phase III – comparing drug to placebo or standard therapy D. Phase IV – post-marketing surveillance E. Pre-clinical – animal models F. Post-clinical - no such thing Drug nomenclature and classification Drug Nomenclature Pharmacologic class – centrally acting analgesic/antipyretic; cyclooxygenase inhibitor In this course, understanding how the class works AND memorizing the prototypical drug names in the class are the keys to success! Next year in systems and on Level 1 you will need to know more drug names thatn required in this course On rotations you will need to know trade names…you’ll feel like you know no pharm, but the trade names will come with practice Systematic IUPAC name: N-(4-hydroxyphenyl)acetamide Chemical name: N-acetyl-para-aminophenol (dangerously abbreviated APAP) Generic or non-proprietary name: acetaminophen (USAN) or paracetamol (INN) Brand or proprietary name: Tylenol® or Panadol® Legal Classification of Drugs Dietary Supplements – regulated as foods, not drugs Non-legend or OTC – regulated by FDA; Rx for OTC valid 1 year Dispensed only by pharmacist (e.g., Plan B, pseudoephedrine) Legend drugs – Rx only Caution: Federal law prohibits dispensing without a prescription” or “Rx only.” Legend drugs must be stored and maintained according to law. Legend Drugs – Rx valid for 1 year from date written unless drug is controlled or “scheduled” by Drug Enforcement Agency due to risk of abuse: DEA Controlled Substances – restricted by the DEA, must have DEA number written on Rx Schedule I – Cannot be prescribed for medical purpose in US (but may be valid elsewhere, eg heroin) Schedule II (or C-II) Refills cannot be authorized (details beyond the scope of this session) Can write multiple Rx, date with correct date and write “do not fill before” Schedule III (C-III) – up to 5 refills in 6 months Schedule IV (C-IV)– up to 5 refills in 6 months Schedule V – varies state to state, in TN Rx for C-V are the same as non-scheduled legend drugs, in other states, up to 5 refills in 6 months; some states allow pharmacist to dispense without prescription For more info see http://www.usdoj.gov/dea/pubs/scheduling.html State laws may vary Where state law and federal laws vary, the more stringent of the two generally applies Not always! Marijuana is CI by DEA, but legal in some states Tennessee (and some other states) restricts some substances that aren’t restricted by DEA Federal law and some state laws place prescribing limitations on pain medications and benzodiazepines (drugs like lorazepam or Ativan; diazepam or Valium) Drug prescribing and ordering Side effect vs allergy An allergy is an adaptive immune response to an antigen A drug may bind to cellular proteins, and drug + protein = antigen; in this case the drug is a hapten Allergic reactions may be immediate (anaphylaxis with SOB, hypotension) or delayed (rash, immune-mediated hemolytic anemia, serum sickness) If patients report an “allergy”, make sure you ask what type of reaction (they may report side effect as an allergy) A side effect is a predictable, dose-related expression of the drug’s activity For example, drowsiness for diphenhydramine (Benadryl®) or decreased histamine action diphenhydramine (Sominex®) Idiosyncratic reactions are those that we can’t explain due to extension of mechanism and are not dose-related For example, patients deficient in glucose 6 phosphate dehydrogenase will undergo hemolysis with the antimalarial primaquine. Because idiosyncratic effects occur so rarely, they are generally discovered in Phase IV post-marketing surveillance. Comprehension check The local zoo herpetologist reports to ED with their 3rd crotalid snake bite. They report that they are allergic to the antivenin. What next action is most appropriate? Alter therapy Ask what type of allergic reaction Pre-treat with steroid or antihistamine Treat with careful monitoring Comprehension check answer and q2 The local zoo herpetologist reports to ED with their 3rd crotalid snake bite. They report that they are allergic to the antivenin. When asked about the type of rxn, they report fever, joint pain, and malaise. What evaluation and action of these Sx is most appropriate? Not true allergy, move forward with antivenin Type 1 hypersensitivity, alter therapy Type 2 hypersensitivity, pretreat with antihistamines Type 3 hypersensitivity, pretreat with steroids Type 4 hypersensitivity, treat with steroids when sx develop Answer to previous Alter therapy Ask what type of allergic reaction Pre-treat with steroid or antihistamine Treat with careful monitoring Comprehension check answer to q2 The local zoo herpetologist reports to ED with their 3rd crotalid snake bite. They report that they are allergic to the antivenin. When asked about the type of rxn, they report fever, joint pain, and malaise. What evaluation and action of these Sx is most appropriate? So…now you see…you can’t just dump the info from other classes – this is what we mean by inherently cumulative…(don’t worry though, everything on the MBP exam from me is on the slides/summary) Not true allergy, move forward with antivenin – this is a type 3 rxn to soluble antigen (the animal proteins in antivenin) Type 1 hypersensitivity, alter therapy – type 1 is IgE/histamine mediated Type 2 hypersensitivity, pretreat with antihistamines – this is where Ab form against tissue/cell, not histamine related CORRECT: Type 3 hypersensitivity, pretreat with steroids – we need to treat with antivenin, so will dose with steroids to prevent severity of “serum sickness” Type 4 hypersensitivity, treat with steroids when sx develop – this is cell meadiated delayed hypersensitivity, eg urushiol from poison ivy What is a prescription? A prescription is a written, verbal, or electronic order for medication. It can be for the purpose of: – Diagnosis – Prevention – Treatment – It is a legal document, written as part of a proper prescriber-patient relationship – It is a means of communication intended to assure that your patient receives the appropriate care in a timely manner Why Write Right? Institute for Healthcare Improvement estimates that 15 million incidents of medical harm occur each year 1.5 million Americans suffer from medication mistakes each year. Each year 800,000 preventable ADEs (Adverse Drug Event) occur in long-term care facilities. 530,000 preventable ADEs occur among the general population. 1999 Institute of Medicine Report “To Err is Human” reported that 44,000-98,000 people die each year from medical errors A 2016 report estimates that medical error is the third leading cause of death in the US Source: Institute of Medicine (1999). To Err is Human: Building a Safer Health System. Retrieved May 20, 2006 from http://www.iom.edu/CMS/8089/5575.aspx. and NEJM JHACO 2022 Abbreviations – can be an error issue Safe abbreviations Meaning ā (ante) ac (ante cibos) bid (bis in die) c (cum) D5 or D5W Meaning Before Kg Kilogram Before meals mEq milliequivalent Twice daily mg Milligram p (post) Dextrose 5% in water pc (post cibos) Disp Dispense PO by mouth G Gram PR by rectum Gtt Drops PV Vaginally h Hour Prn as needed hs (hora somnos) q every IA Intra-arterial q__h Every ____ hour (eg q6h) IM Intramuscular qs Sufficient quanitity IV Intravenous Rx Take thou; prescription IVPB IV piggyback s without With bedtime after after meals or food UNSAFE ABBREVIATIONS http://www.ismp.org/tools/ errorproneabbreviations.pdf DO NOT USE Problem Solution µg Mistaken as mg Use mcg cc Mistaken as 0 or U Use ml U Mistaken as 0 or CC Unit IU Mistaken as IV unit qd Mistaken for qid or qod Q day or daily qid Mistaken for qd or qod 4 times daily or 4x daily qad, qod Mistaken for qd or qid Every other day or q other day qhs Mistaken for every hour Leave off the q ℨ Confused for fluidounce Use 5ml < or > Confused with each other Less or greater than 1.0 Mistaken as 10 Do not follow.1 Mistaken as 1 Always lead MSO4, MS, MgSO4 Mistaken for one another Morphine, magnesium sulfate “DO NOT USE” lists vary from facility to facility YAY E-Prescribing! Potential Issues: Wrong patient (Jr. or Sr.) Selection of package size or formulation (in outpatient, a pharmacist must call to change the formulation) Directions different in comments vs drop downs Interface issues Cases of prescriptions entered on wrong patient and deleted but still transmitted to the pharmacy Look alike drugs on drop-down menus, selection of prompt release for sustained and vice versa Still does not fix human error Alert fatigue Other Resources For more information and tools to help promote safe practices, visit: www.ismp.org/tools/abbreviations or www.fda.gov/cder/drug/MedErrors 40 Prescriber name, address, phone (preprinted) Patient name Pt address (usually done by pharmacy) Date rx written Name form and strength of drug Quantity to dispense Signatura or “Sig” = directions How much to take, which route, how often to take it (pharmacist usually translates to lay terms) Refills - # times fillable in addition to original Signature of prescriber Indication of supervising physician for midlevel practitioners Prescriber DEA number if controlled (schedule II-V) drug DEA = A or B + 1st initial of last name + 7 digits Tamper proof features are required Most of these things are covered via e-scribing At DCOM, you must print your name beneath your signature Prescriptions – required in TN Brand versus generic In most states, the pharmacist must dispense a generic brand of medication for outpatients unless the prescriber indicates in writing that the brand is medically necessary (“BMN” or “DAW” = dispense as written). If you specify brand, the patient will most often pay a great deal more. For outpatient prescriptions, when generic substitution occurs, the actual drug (chemical entity) is the same, just the manufacturer is different. In hospitals, the P&T (pharmacy and therapeutics) committee will often pre-approve THERAPEUTIC substitution, in which a different drug of the same pharmacologic class is used Prescriptions – helping to prevent error  Patient’s date of birth  Allergy info  Indication for drug  Avoidance of problem-prone abbreviations  For decimals, always lead, never follow  Write out quantities and number of refills (or use blanks with check boxes) for controlled substances  For pediatric patients, include weight Fraud and Diversion Prevention Write numbers out (e.g., eighty) Don’t leave refill line blank Use blanks with check box for refills Use blanks with check box ranges for quantity CMS has guidelines which must be followed in order for a pharmacist to fill the prescription for medicare and medicaid Tennessee has a controlled substance database E-prescribing Writing Right – controlled drugs For a controlled substance your DEA number must be written in. In addition, you will want to write out the quantity (“sixty”) to prevent someone changing the quantity (by adding a “1” in front of 60, for example). A CII (schedule II) medication such as oxycodone can never be refillable, but CIII-V can (up to 5 times in 6 months) It is IMPORTANT to indicate “PRN” if a drug is to be taken only as needed (as apposed to every 2 hours around the clock or 12 times a day) Comprehension check What is incorrect or what required info is missing in this Rx? Cannot refill Rx for OTC med Cannot write Rx for OTC medication Date Rx written missing DOB missing Physician name printed beneath signature missing Icant Sleep Diphenydramine 25mg capsule Disp 30 Sig: 1 cap po at bedtime prn sleep Ima Right DO 5 Comprehension check answer What is incorrect or what required info is missing in this Rx? Cannot refill Rx for OTC med – refill up to one year post date written Cannot write Rx for OTC medication – can save sales tax, helps improve communication Date Rx written missing DOB missing – helps with safety, not required (prevents wrong patient) Physician name printed beneath signature missing – required at DCOM; note docs name and address are preprinted on Rx Icant Sleep Diphenydramine 25mg capsule Disp 30 Sig: 1 cap po at bedtime prn sleep Ima Right DO 5 Rights of medication Nurses are taught the 5 R’s of medication administration: Right patient Right drug Right dose Right schedule Right route Additionally for prescribers: Right monitoring Right rate for IV’s Patient’s right to informed consent Patient’s right to refuse Right duration of treatment Any questions?