HCR 555 MCCCD Health & Medical Drug Risk Mitigation Plan

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Health Medical

HCR 555

Maricopa County Community College District



View the FDA information on this website: https://www.fda.gov/drugs/risk-evaluation-and-mitigation-strategies-rems/whats-rems

Discuss the ways that the information from the FDA website above would make it easier to read, interpret and develop REMS if you were require to do that in your future career.

Write a risk-minimization plan for the following hypothetical drug.The drug is called Quierta. It is designed to help people sleep. It is taken once a day at bedtime, and it is recommended to have at least 8 hours to sleep. Its half life is 1 hour, so it will wear off by morning (it takes about 5 half lives to eliminate a drug). It is potentially teratogenic. It can cause severe allergic reactions. It has to be activated by CYP2D6 (genetics might matter here) but can inhibit metabolism of other drugs metabolized by CYP3A4. It has the potential to cause Stevens-Johnson syndrome in people with the allele for it. It is not recommended for patients with poor kidney function (GFR less than 30), nor in patients with liver disease. It has the potential to be addicting in patients with a history of drug addiction. It can cause breathing problems in patients with COPD.Make sure you do both parts of the assignment. 

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Risk Evaluation and Mitigation Strategies HCR 555 Pamela E. Potter ©PE Potter/ASU Background • In 1960, the FDA instituted a policy that drug companies had to provide full disclosure on the effects of their drugs – Included in the product labeling- adverse effects, interactions, dosing, indications for use • In 1970, the Controlled Substances Act – Put drugs with abuse potential into “Schedules” – Schedule II: highest potential, prescribing restrictions – Schedule III: less potential, more lenient rules – IV and V: less potential, more refills allowed, etc – Warnings, Dear Doctor letters used to inform about risk Patient Package Inserts • In the late 1970s, the FDA began to require patient package inserts (PPIs) – This was spurred by prescriptions for oral contraceptives to large numbers of healthy young women – There had been some serious adverse effects of these drugs in the past – These are elective drugs, so FDA felt patients should have the ability to make an informed decision about use • Patient Medication Guides required since 1990s for drugs with “serious and significant health concerns” – More than 70 drugs require these be issued – Info to prevent serious AEs, decisions should be informed – Patient adherence essential for effectiveness of drug Specific Programs for Risk • Between 1988 and 1998, three products had programs specifically designed to manage risk – Clozapine for schizophrenia in 1990 • “No blood, no drug”- weekly blood test for agranulocytosis required • Physicians need to provide results prior to refill being issued • Patients entered in a registry – Thalidomide for leprosy, AIDS, and other uses • STEPS- System for Thalidomide Education and Prescribing Safety • Requires pregnancy tests, patients, doctors and pharmacists must be registered to prescribe and fill Isotretinoin (Accutane) • Used for treatment of severe acne • Structural malformations – Craniofacial, cardiac, thymus, CNS – 20-30% exposed fetuses develop • Functional impairment – Intellectual impairment • Increased spontaneous abortion & premature birth • Single dose teratogenic • May occur before awareness of pregnancy Managing Isotretinoin Teratrogenicity • 1988- Pregnancy Prevention Program • 1999- Targeted Pregnancy Prevention Program • 2001 SMART- System to Manage Accutane Related Teratrogenicity • 2006- IPledge – Physician, pharmacist and patient must be registered – Two negative pregnancy tests required before starting – Two methods of birth control used at all times – Before each refill, must have negative pregnancy test and verify birth control – Must register and log in monthly to web site – Birth control pills good treatment option for acne anyway Drug Safety in the 1990s • The Prescription Drug User Fee Act of 1992 required the FDA to approve drugs more quickly • Concerns arose that potentially dangerous drugs were being approved • Many drugs were withdrawn from the market during this decade due to safety concerns – E.g. fenfluramine for weight loss, alosetron for IBS with diarrhea, roglitazone for diabetes • FDA created Office of Surveillance and Epidemiology • FDA devised new plans for managing risk of drugs The FDA • 1999-2005: Managing the Risks from Medical Product Use and Creating a Risk Management Framework – Premarketing Risk Assessment • Applies throughout development of new products • Diversified patients and doses in Phase II and III – Development and Use of Risk Minimization Action Plans (RiskMAPs) • Establish framework to ensure benefits exceed risks • Get input from users and evaluate MAPS – Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment • Reporting during post-marketing period Premarketing Risk Assessment • Already occurs in Phase II and III – If adverse effects are horrible, the drug won’t go any farther • Size of the group tested needs to be adequate, especially if drug is for chronic use > 6 months – 1500 subjects, 300-600 for 6 months, 100 for a year • Group size generally determined as that necessary for efficacy, not safety • Number of patients needs to be higher if: – Safety issues from the animal studies – Similar drugs have safety issues – Pharmacokinetic/ pharmacodynamic AEs likely – Benefit small or rare- need to pick up rare AEs – Treatment is for healthy populations (vaccines) Premarketing Risk Assessment • Long-Term Placebo controlled trials – Useful if AE is common in the population already – Useful if long-term exposure increases toxicity • Open-Label Trials – Useful when AE is very rare and only caused by drug – Useful when placebo trials would be unethical- i.e. treatment of a serious disease • Comparative Effectiveness Trials – Studying effect of your drug vs the current standard of care – This may make it harder to show efficacy – It may show that your drug works better or has fewer side effects – This is becoming a requirement Premarketing Risk Assessment • Diversity – Drug companies prefer a homogenous population to decrease variability in drug effect and keep sample size lower – BUT- drugs will be given to many different types of people – The FDA would like more diversity – Globalization of clinical trials may increase or reduce diversity • Dose Effects – Normally in Phase II, FDA also wants in Phase III • Drug Interactions – Drug-drug interactions for logical combinations – Drug-dietary supplement interactions – Drug-disease state or population subtype interactions Premarketing Risk Assessment • Comparative Safety Data – Companies often submit little comparative data – Placebo trials imperative if background rate of AE is high – Need to compare AE of your drug vs already known treatments, where placebo trial is unethical – Should look to see if less frequent dosing or reduced dose will decrease toxicity of drugs with long half-lives or dose-related toxicity – For some drugs, dose should be titrated and effective scheme should be done pre-marketing – If special tests are needed to assess AEs, these should be conducted and discussed – Growth and development concerns should be addressed for pediatric drugs – Blood, tissues and fluids should be kept from patients for later study if necessary Premarketing Risk Assessment • Medication Errors – Need to look for possible sources of error before marketing – This includes labeling, packaging, drug name similarities • Measurements of Safety – In humans • QT interval lengthening • Drug-drug interactions • Polymorphic metabolism – In animals • Liver, kidney and bone marrow toxicity at higher doses – Biologics • Immunogenicity • Transfection of non-target cells or infection of close contacts • AEs related to distribution, migration and growth of cell-based products beyond intended administration FDA • 2007- Food and Drug Amendments Act (FDAAA) passed by Congress – Introduced Risk Evaluation and Management Strategies (REMS) – All products need lifetime risk management – Some may need more specific REMS beyond normal, tailored to the risks of the product – Must be able to minimize risk in a quantifiable way – Must modify the plan if it isn’t working – Ensure effective communication with the FDA and practitioners REMS replaced RiskMAP from 2005 FDA • 2009- “Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments and Proposed REMS Modifications” issued by FDA – Submission of new drugs, biologics, and abbreviated submissions will require REMS if FDA feels they are needed – RiskMAPs will continue if they are in place, but may be converted to REMS – Companies may voluntarily submit REMS – Large fines for failure to comply with the law Proposed REMS • Templates are available from RDA • Table of Contents • Background • Goals • Elements • Assessment Plan • Other information and supporting documents • http://www.accessdata.fda.gov/scripts/cder/rems/index.cfm Proposed REMS • Background- What do you know? – What is known about the risks of the drugs – Describes the clinically important risks seen in clinical trials – Risks seen with use of drugs in the same class – Risks expected due to the disease in the population being treated with the drug – Groups most at risk, e.g., young, old, ethnic groups, genetic testing – Risks with drugs having similar effects Proposed REMS • Goals- What do you hope to accomplish? • • • • Specific, safety directed outcome Understanding for use by practitioners and patients Should strive to achieve the maximum risk reduction Should also strive to reduce risk while still allowing the drug to be available and useful to patients • Specific and measurable – Patients on statins must be aware of risk of rhabdomyolysis – Patients taking statins should not be given cimetidine or erythromycin – Statins should not be used in pregancy, as it carries a risk of teratogenicity Proposed REMS • Elements of the plan • Medication Guide or Patient Package Insert – Required if it will prevent serious Adverse Events – if it will influence patient’s decision to take the drug – if following directions exactly crucial to success of drug • Communication Plan to Healthcare Providers – Includes letters, information re monitoring and tests • Elements to Assure Safe Use – Prescribers have specific training or experience – Only certain facilities or certain settings may dispense drug – Lab tests required – Patients monitored and in a registry Proposed REMS • REMS Elements • Implementation System – Describes system to be used for implementing, monitoring and evaluating intended goals/effects • Timetable for Assessments – At minimum at 18 months, 3 and 7 years • Assessment Plan – How you are going to assess the success of the program • Other information and supporting documents Good Pharmacovigilance Practices • Post-marketing • Identifying signals • Reports contain – Description of AE, and time to onset – Suspected and concomitant medications, including OTC – Patient demographics, medical history, other conditions, risk factors, family history – Documentation of diagnosis and procedures regarding AE – Clinical course of event and outcome (hospital, death?) – Laboratory findings and other relevant tests – Response to stopping and re-challenging, if appropriate Good Pharmacovigilance Practices • • • • • • • • • Post-marketing Identifying and reporting signals Other similar cases Causality Data mining for more cases Further investigation when required Reporting rates and incidence rates of AE over time Estimates of background occurrence in population Interpreting the signal and estimate benefit-risk Pharmacovigilance Plan • Based on: – Whether AE is a potential safety risk – Frequency and severity of the event – Populations at risk and who is likely to be treated – Method for dispensing the product • REMS will be created for a product in which serious safety risks have been identified or where at-risk populations are not adequately studied • This may include – Submissions to FDA – Active surveillance to identify Aes/ formation of registries – Epidemiological studies or controlled clinical trials An Example: Long-Acting, Extended Release Opioids • Oxycodone was developed as an extended release preparation – Oxycontin • Came on the market in 1996 – Gives patients a long-lasting pain management – Highly effective drug, large quantity released slowly over 12 hours to provide stable pain relief • Label says – “tablets are to be swallowed whole and are not to be broken, chewed or crushed. Taking, broken, chewed or crushed Oxycontin tablets leads to rapid release of a potentially fatal dose of oxycodone” • Well, yippeee!!! Long-Acting, Extended Release Opioids • By 2000, reports occurring of abuse of Oxycontin in Maine and Appalachia – By 2001 use was increasing and spreading throughout US – Became one of the major drugs of abuse in the US, probably most important prescription drug • Addicts were crushing the pills, and smoking or injecting the drug to get a good “high” • Oxycontin had also become the most widely prescribed drug for moderate-to-severe pain Purdue Pharmaceuticals • The company realized they had a problem • They needed information- how bad was the problem? – How many opioid abusers used Oxycontin and how many used other drugs? • They hired outside experts to assess extent of abuse • They looked for diversion of drugs to street sales • They developed the Researched Abuse, Diversion and Addiction Related Surveillance (RADARS) system in specific ZIP codes and time frames • They developed a risk management program Oyxcontin – What Purdue Did • The biggest risk was the formulation- it was too easy to crush – They reformulated the drug in 2010 so that it was not crushable – Street sales went down dramatically – Abuse of the short acting, fast release form went up, but its expensive – An unintended consequence- addicts now using heroin instead • They took the highest dose form- 160 mg- off the market • They added new warnings to the labeling • Widespread prescribing led to “doctor shopping” – They sent letters to doctors educating them about abuse • Also forged prescriptions were a problem – Purdue encouraged and supplied tamper-proof pads – Now electronic prescribing makes it harder to forge prescriptions Oyxcontin – What Purdue Did • Established an advisory board to work on prevention of drug abuse in young people • They gave community grants to programs working to reduce drug addiction • They provided grants and support to law enforcement • They hired former law enforcement officials with experience in drug diversion to work with and support local law enforcement agencies • They set up RxPATROL to inform law enforcement and pharmacies about robberies: http://www.rxpatrol.com/ • They worked with CrimeStoppers to provide rewards for people selling their products illegally What’s Happening Now • RADAR has been successful • Collaboration with law enforcement resulted in many arrests • Risk management program has been a model for other companies/other drugs • Non-medical use of Oxycontin declined • BUT- opioid addiction is a major medical crisis in the US • Drug overdose is the leading cause of accidental death in the US, with 47,055 lethal drug overdoses in 2014 • Opioid addiction drives this epidemic, with 18,893 overdose deaths related to prescription opioids, and 10,574 related to heroin in 2014 Opioid Overdose at Crisis Levels https://www.cdc.gov/drugoverdose/epidemic/index.html https://www.nytimes.com/interactive/2017/06/05/upshot/opioid-epidemicdrug-overdose-deaths-are-rising-faster-than-ever.html CDC Issues New Guidelines and States Institute New Rules https://www.cdc.gov/drugoverdose/pdf/g uidelines_factsheet-a.pdf http://www.azdhs.gov/prevention/womenschildrens-health/injury-prevention/opioidprevention/index.php Opioids with Naloxone • Manufacturers have added naloxone to extended release oxycodone so that it will work orally but won’t work if injected (naloxone isn’t well absorbed orally) • CIGNA has just decided that it will cover the combo drug - even though it is more expensive and many are not likely to abuse oxycodone • Buprenorphine with naloxone is already used for treatment • Naloxone is being made available to people with concerns about relatives with addiction and to EMTs http://www.cnn.com/2017/10/05/health/cignaoxycontin-xtampza/index.html http://www.fda.gov/AboutFDA/Transparency/Basics/ucm325201.htm The Bottom Line Pharmacovigilance is important to identify post-marketing issue and create a plan to deal with them Use of REMS has allowed some drugs to stay on the market
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Drug Risk Mitigation Planning- Outline
I. REMS Information
A. The risk evaluation and mitigation strategy (REMS) is a plan developed for a
specific drug to reduce the risks associated with prescribing, distributing, and
using the drug.
B. Additionally, information from the page can be used in reading and preparing
REMS for new medications.
II. Risk Mitigation Plan for Quierta
A. Goals
1. Educating prescribers and pharmacists about the adverse events and risks
2. Informing patients about the risk
3. Ensuring prescribers conduct a risk-benefit analysis
B. Summary
1. Healthcare providers who prescribe Quierta must- Review the drug’s
prescription information and be registered to prescribe the drug as a
prescription-only medication.
2. Inpatient and outpatient pharmacies that dispense Quierta must- Become
certified for the specific dispensation of this drug.
3. Patients prescribed with Quierta must- Receive counselling from the provider

before treatment initiation to understand the risks and potential adverse events
associated with the drug.


Drug Risk Mitigation Planning



Great study resource, helped me a lot.


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