Health & Medical Question

View the FDA information on this website: 

https://www.fda.gov/drugs/risk-evaluation-and-mitigation-strategies-rems/whats-remsLinks to an external site.

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. Have fun with this!!

Pharmacogenetics / Pharmacogenomics HCR 555 Pamela Potter, Ph.D. ©PE Potter/ASU 2022 Pharmacogenetics • There are large individual responses to treatment with different drugs • These range from potentially lifethreatening adverse effects on one end of the spectrum, to having no useful drug effect on the other end • While many factors influence our response to drugs, genetic variation is increasingly being recognized as an important factor in how drugs work in different people Drug Toxic but beneficial Patients Drug Toxic & NOT beneficial Same diagnosis and prescription Drug not toxic but not beneficial Drug not toxic AND beneficial Pharmacogenetics History • The term “pharmacogenetics” was first used in a research article in 1959 • However, observations of genetic differences in reactions to drugs were observed much earlier than that- as depicted in the pictures below • There were many clinical observations that different people responded quite differently to drugs, even if the mechanism was not known at the time Pharmacogenetics • For example: – 1926: Primaquine, an antimalarial drug, was shown to cause hemolytic anemia (HA) in some people – 1948: HA seen in 5-10% of African Americans but rarely in Caucasians – 1954: HA problem was in the erythrocyte itself – 1955: HA susceptibility occurred with many drugs – 1956: Glucose-6-phosphate-dehydrogenase (G-6-PD) deficiency was identified as the cause – 1957-1960: G-6-PD deficiency inherited in a sex-linked, partial dominant manner, therefore, primaquine-induced HA was due to a genetic variation • Thus, pharmacogenetics was known for a long time, we just hadn’t yet developed all the tools we have today • We have varying family histories and likelihood of different disease • Our response to a drug depends on multiple factors • Our genetics controls how our body works • Outside factors affect our genetic makeup as well as our current physiological and disease status • All of these will influence whether a drug works well for us, or cause us side effects • Pharmacogenomics can help decide which drug will work best for a particular patient Pharmacogenomics • Molecular biology has advanced rapidly over the last several decades, and the convergence of genomics and molecular pharmacology has spurred the evolution of pharmacogenetics into pharmacogenomics • More and more understanding of the specific genetic differences underlying responses to drugs is occurring • There are now several known variations and tests that can predict the degree of response to drugs or the likelihood of adverse reactions Pharmacogenomics • Pharmacogenetics: the effect of genetic variation on drug response, including disposition, safety and tolerability, and efficacy. • Pharmacogenomics: the application of genome science (genomics) to the study of human variability in drug response. Genetic Organization- Chromosomes • Every human cell, with the exception of gametes, has 23 pairs of chromosomes • Chromosomes contain all of the genetic material coding for proteins in every cell • They consist of DNA tightly wound around histones DNA • DNA consists of nucleotide bases, A,G, T and C, that are linked in a double helix. Bases are matched A-T and C-G. • In the replication process, the strands are split and bases are added. T • This can result in mutations Pharmacogenomics • The human genome contains about 3 billion nucleotides • About 25,000 genes • These may encode over 100,000 proteins • On average, every 2 people have variation in about about one nucleotide per 100, which means that we have an average difference of 3 million base pairs – Many of these are single nucleotide polymorphisms (SNPs- “snips”) – If it changes an amino acid, it is a cSNP (coding SNP) Pharmacogenomics • cSNPs could lead to an amino acid substitution, causing a change in a protein • There are also other changes that can occur – Insertions and deletions in the DNA – Duplications and reshuffling of nucleotides – Sometimes whole genes are duplicated or deleted • Functionally significant changes will alter gene transcription or mRNA stability or transcription, resulting in altered protein synthesis Genetics • Allele = one of 2 or more alternate forms of a gene • Genetic polymorphisms – Very large  chromosomal duplications – Very small  nucleotide changes • Gene duplication or deletion  not common • Nucleotide-based mutations  most common Genetics • Dominant or recessive gene – Major impact on pharmacogenetic effects – A single dominant allele  consequences when only one copy is present, heterozygous – For recessive alleles, must be homozygous  recessive response, seen only when both copies are present – An example is brown or blue eyes Br/Br= brown; Br/Bl= brown; Bl/Bl= blue Genetic Mutations – Major Classes single nucleotide polymorphism (SNP) Can cause frameshifts Consequences of Genetic Mutations Consequent Mutation Frameshift mutation In-frame deletion or insertion Definition Insertion or deletion that alters the reading frame of a gene Deletion or insertion of a multiple of three nucleotides that introduces a new (or removes) amino acid(s) into the protein, but does not alter the reading frame Protein-level Consequences Protein Effect Definition Changes the amino acid sequence of a protein Neutral mutation without altering its ability to function Loss-of-function mutation Cause a complete or partial loss of function of the protein Gain-of-function mutation Causes over-activity of the protein or the appearance of a new trait or function or causes the appearance of a trait in inappropriate tissue or at an inappropriate time. Genes and Alleles • Genes encode for proteins that influence many things, such as hair and eye color, etc The genotype consists of the entire set of genes • What is an allele? • When genes mutate, they can take on multiple forms, with each form differing slightly in the sequence of their base DNA. • These gene variants still code for the same trait (i.e. hair color), but they differ in how the trait is expressed (i.e. brown vs blonde hair). • Different versions of the same gene are called alleles. Pharmacogenetically-Important Genes • Genes that are involved in: – Drug metabolism – Signal transduction (receptors, channels, etc.) – Drug transport – Cancer treatments – Etc. • Have all been identified to have pharmacogenetic variations Pharmacogenetically-Important Mutations • Any mutation that: • Changes gene copy number – Gene duplication – Gene deletion • Protein or DNA level • Early nonsense mutation = gene deletion • Loss-of-function = partial or complete loss (gene deletion) • Changes the function of the protein – Gain-of-function – Loss-of-function • Can have pharmacological consequences Pharmacokinetics • Many of the genetic differences that have been described result from alterations in pharmacokinetics • These changes were seen when a “standard” dose of drug was used, but people had strikingly different responses to the drug, often as a result of different levels of the drug in the plasma • There are now several known variations in drug metabolism that may account for differing responses to drugs NAT2 • Change in protein function example • N-acetyltransferase 2 gene • Transfers an acetyl group from acetyl-CoA to the acceptor amine resulting in formation of an amide on the drug • Many drugs (e.g., isoniazid, procainamide, hydralazine) • Two alleles: Rapid allele (R) Rapid NAT activity Dominant Slow allele (r) Slow NAT activity Recessive • Slow acetylation leads to adverse drug reactions: – Lupus  hydralazine, procainamide – Hepatotoxity  isoniazid R/R R/r or No. of Subjects 24 r/r Fast rate of acetylation Slow rate of acetylation 12 0 0 4 8 Plasma Isoniazid (μg/ml) 12 CYP2D6 • Gene copy number example • 2nd most common metabolizing enzyme • > 90 alleles that will make a patient be a: – Poor metabolizer – Intermediate metabolizer – Extensive (normal) metabolizer – Ultrarapid metabolizer • These differences in metabolism will affect the optimal dose and occurrence of adverse effects. CYP2D6 • Drugs metabolized or activated by CYP2D6 include – Antidepressants, haloperidol – Opioids- codeine, oxycodone, hydrocodone, dextromethorphan – Metoprolol – Tamoxifen Variation in different ethnic groups 5-10% of Caucasians are poor metabolizers, but only 1-2% of East Asians 30% of East Africans may be ultrarapid metabolizers, 13% of Ethiopians, but only 3% of Spaniards Doses for the antidepressant nortriptyline will be different depending on rate of metabolism Poor metabolizers will be easily overdosed Rapid metabolizers may find the drug ineffective because they do not reach a high enough concentration Gene copy number is changed The number of copies of the CYP2D6 gene affects the metabolism of many drugs Metabolism in Twins Pharmacogenetic contribution to pharmacokinetic parameters. t1/2 of antipyrine is more concordant in identical in comparison to fraternal twin pairs. Bars show the t1/2 of antipyrine in identical (monozygotic) and fraternal (dizygotic) twin pairs. (Redrawn from data in Vesell and Page, 1968.) CYP2D6 Interactions • Codeine, oxycodone, hydrocodone • These have to be metabolized to active compound – Less pain relief if 2D6 inhibited – Codeine may be toxic in 2D6 extensive metabolizers – A nursing baby died because his mother was an ultrarapid metabolizer of codeine Spina, E et al, Clin Ther 2008, 30, 1206-1227 http://www.pharmacytimes.com/issue/pharmacy/2008/200807/2008-07-8624 Tamoxifen and CYP2D6 • Tamoxifen is used in the treatment and prevention of breast cancer – It acts by blocking estrogen receptors – It is a pro-drug that has to be activated by CYP2D6 – The active metabolites are about 100 times more potent than the parent drug – Patients who are poor metabolizers will not respond to tamoxifen – If EM patients are being treated with antidepressants (which often inhibit CYP2D6), they don’t do as well – This genotype can now be assessed with a genetic “chip” Tamoxifen and CYP2D6 CYP2D6 Clinical Importance Also, with Antidepressants • There are variations in the genes for serotonin receptors and for the serotonin transporter • Some genetic variants are more likely than others to suffer from depression • Some genetic variants are more likely than others to experience successful treatment with the antidepressants • This genotyping is still fairly experimental TMPT • Thiopurine methyltransferase – Catalyzes the S-methylation of 6mercaptopurine, used in cancer treatment, and azathioprine, an immunosuppressant – These drugs have a narrow therapeutic range- myelosupression is a serious toxicity if the drug concentration is too high TMTP – 5% of Caucasians have the TMPT*3 allele – 1 in 300 are homozygous – Decreases the amount of TMPT significantly, so can’t metabolize the drugs and get toxicity This puts people at very high risk of myelosupression, which can be life-threatening! •Clinical testing for these alleles is now available •FDA requires package labeling to include this information Warfarin • Finding the right dose is a challenge – Dosed to the INR, but.. – If initial dose too high, may get excessive bleeding before you know how strong the effect is – Or, you may not get enough effect fast enough if the initial dose is too low • Warfarin is metabolized by CYP2C9 – The CYP2C9*2 allele has 12% activity – The CYP2C9*3 allele has 5% activity – These patients may need lower doses Warfarin • But, there’s MORE! not just metabolism • The target of warfarin is vitamin K epoxide reductase complex 1 (VKORC1) – There are various haplotypes (from several SNPs on a single chromosome) – One haplotype is associated with much higher effectiveness of warfarin than normal – Thus, some variation is VKORC1 alterations and some is CYP2C9 metabolism variability • They can recommend doses based on the combination of the genotype and haplotype Pharmacogenetics of warfarin dosing. Warfarin is metabolized by CYP2C9 to inactive metabolites, and exerts its anticoagulant effect partly via inhibition of VKORC1 (vitamin K epoxide hydrolase), an enzyme necessary for reduction of inactive to active vitamin K. Common polymorphisms in both genes, CYP2C9 and VKORC1, impact on warfarin pharmacokinetics and pharmacodynamics, respectively, to affect the population mean therapeutic doses of warfarin necessary to maintain the desired degree of anticoagulation (often measured by the international normalized ratio [INR] blood test) and minimize the risk of too little anticoagulation (thrombosis) or too much anticoagulation (bleeding). Genes involved in drug metabolism HLA-B*5701 • There were reports of VERY serious hypersensitivity reactions in some patients who took abacavir and carbamazepine – These patients had the HLA-B*5701 allele – Abacavir is a reverse transcriptase inhibitor for HIV – It is normally well tolerated and effective – In a large double blind study, pre-testing for HLA-B*5701 was able to almost eliminate hypersensitivity reactions by excluding these people from the trial – Patients must be tested for HLA-B*5701 if they are to take carbamazepine, an anticonvulsant, for trigeminal neuralgia • This is a case where an idiosyncratic response can be tested for and prevented by not giving the drug Pharmacogenomics • SNP maps  pharmacogenomics • Identify alleles in individuals before prescribing drugs • Allow researchers to look at all alleles of any gene to see if it can be related to adverse drug reactions • Personalized medicine! – Like never before CYP2C19/Proton Pump Inhibitors Japanese and Chinese population more likely PM, greater efficacy Effect of CYP2C19 genotype on proton pump inhibitor (PPI) pharmacokinetics (AUC), gastric pH, and ulcer cure rates. Depicted are the average variables for CYP2C19 homozygous extensive metabolizers (homEM), heterozygotes (hetEM), and poor metabolizers (PM). (Reproduced with permission from Furuta et al., 2004.) Midazolam / Tacrolimus An intronic SNP can affect splicing and account for polymorphic expression of CYP3A5. A common polymorphism (A>G) in intron 3 of CYP3A5 defines the genotypes associated with the wild-type CYP3A5*1 allele, or the variant nonfunctional CYP3A5*3 allele. This intronic SNP creates an alternative splice site that results in the production of an alternative CYP3A5 transcript carrying an additional intron 3B (panel B), with an accompanying early stop codon and truncated CYP3A5 protein. Thus, whereas the wild-type gene (more common in African than Caucasian or Asian populations) results in production of active CYP3A5 protein (panel A), the *3 variant results in a truncated and inactive CYP3A5 protein. Thus, metabolism of CYP3A5 substrates is diminished in vitro (panel C, shown for midazolam) and blood concentrations of such medications are higher in vivo (panel D, shown for tacrolimus) for these with the *3 than the *1 allele. (Based on data from Haufroid et al., 2004; Kuehl et al., 2001; Lin et al., 2002.) Testing for Response to Antidepressants and Antipsychotics • It is often hard to predict who will respond well to various types of antidepressants or antipsychotic drugs • Treatment is generally a trial and error process, and error can be very problematic • A few companies have developed genetic tests to determine by genotype the likelihood of which drugs will work for which patients • (disclaimer- I had a friend go through this, and the drug recommended caused her serious side effects….) http://www.suregenetest.com/ http://genesight.com/clinicians/genesight -tests/psychotropic/index.html Pharmacogenomic Future • More powerful medicines • Better, safer drugs the first time • More accurate methods of determining appropriate drug dosages • Better vaccines • A lot of these ideas depend on genomic technologies like microarrays Microarrays • “Gene chips” • Have the ability to: – Measure gene expression level – Identify alleles • Contains complementary DNA (cDNA) to many sequences of interest. cDNA fluoresces when it hybridizes with a matching DNA fragment in the sample Drug Labelling • Drug labelling will indicate if there are relevant genetic markers for the drug • A list of all drugs with genetic labelling is available from FDA • https://www.fda.gov/drugs/science-andresearch-drugs/table-pharmacogenomicbiomarkers-drug-labeling • Here is an example for abacavir, used to treat HIV Clinical Trials • Genotyping may be very useful for clinical trials – Most current trials are storing blood samples for current or future genotyping – may determine why drug failed or who is most likely to benefit – Focusing trial on patients who would benefit or be unlikely to have side effects may increase likelihood of success • Excluding patients likely to have adverse reactions safer for them • However, it may erode safety testing • It is important to discover who is at risk from the drug • Drug might be eventually have to be marketed to a limited population – Most clinical trials for Alzheimer’s disease drugs are now genotyping and using other indications of disease prior to the trial – Kits used for genetic testing also need to be evaluated and monitored by FDA Pharmacogenetics in Clinical Trials Pharmacogenomics / Globalization • Pharmacogenomics is important when thinking about clinical trials, especially in terms of globalization • e.g, poor metabolizers of CYP2D6 – 2-4% in western Caucasians – 15-25% in Asians – 60-70% in some Pacific Islands • Drugs tested in one population would be wrong doses for other populations Pharmacogenomics / Globalization • Multi-drug resistance from P-glycoprotein – 62% variant in European Americans – 13% in African Americans • Many other examples of ethnic variation – Differences in beta receptors in asthma vary with ethnicity, but not as well established • Thus, it is important to specify ethnicity when reporting clinical trials – Pharmacokinetics, pharmacodynamics, dose-response curves, efficacy and safety need to be established in different ethnic groups Pharmacogenomics: Future Hopes • These tests are expensive, e.g. Amplichip (CYP2D6): $600-$1300 • Insurance is beginning to cover these, e.g. https://www.bluecrossnc.com/sites/default/files/document/attachment/servi ces/public/pdfs/medicalpolicy/pharmacogenetics_testing.pdf • In new drug clinical trials comprehensive microarrays (like the DMET™) can be used to identify all key genes important to that drug • In the clinic, less expensive, easier, smaller, more directed tests can be done • There are a LOT of clinical trials with “pharmacogenomics”, so the future does look hopeful Pharmacogenomics: Current Problems and Future Hopes • May provide optimum target dose for specific populations • May give better drug interaction information • Prescribing may be limited to specific genotypes – May prevent incidence of serious side effects – May prevent using drugs that won’t work • BUT- Genotyping might prevent patients from getting treatments that could work in them, but don’t have a high chance • It will be hard to assess level of physician compliance with genotyping and following guidelines In a Perfect World…… Getting the Information • • • • • The NIH “All of Us” research program aims to sequence 1 million people The VA Million Veteran program has the same goal These should generate really good information that can be used to treat disease Ethical concerns as well- what if they find a genetic disease that is not treatable? They have begun to provide results to people and will inform if they find something that CAN be fixed • What if the information gets out? (there seem to be hackers everywhere, but these site will be quite secure) What do YOU think? Will you participate? There is a site here in Phoenix Have you done other genetic testing like 23and me or Ancestry? 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