Concomitant medications are used by nearly 100% of subjects involved in Phase 1 cancer clinical trials, for example, but the topic of con-meds is not given much attention in medical literature. The aim of this paper is to give an answer to the question: how to capture and encode concomitant therapies and medications in order to keep clinical trial data clean, complete and consistent. Concomitant medications can contribute directly to the issue of patient enrollment delay, as they are typically part of a clinical study’s inclusion and exclusion criteria that are used to determine whether patients are allowed to take part in trials. This refers to combinations of drugs in a single pharmaceutical formulation. It does not mean concomitant drug therapy, e.g. Traditionally, if con-med information was collected at all during a clinical trial, it was done on paper. FDA’s Medical Review referred to measures of liver injury taking the form of high serum ALT and high serum bilirubin. Consequently, the cost of NSAIDs as a proportion of total drug costs can be high when drugs are expensive. The data often improves as the CRA performs the source data verification (SDV) and makes inquiries related to new adverse events and medications in the patient health record. If patient management is conducted without blinding, a difference between groups may be explained by other factors than study treatment. Comments in FDA’s review of sofosbuvir/velpatasvir combination (Epclusa®) and relatedness to adverse events found a place on the package label. A clinical trial example: In a trial of statin drugs in diabetics, one group of patients is assigned to take statins and another group is assigned to take a placebo (fake pill). Protriptyline (withdrawn in the UK), with t1/2 values in the region of 75–80 hours, is exceptional and, with daily dosing regimes, accumulation is possible. With respect to patient preference, a survey study demonstrated that only 14% of a large group of patients with rheumatic disease (n = 1799) who had RA, osteoarthritis, or fibromyalgia preferred acetaminophen rather than NSAIDs, whereas 60% preferred NSAIDs.147 In a head-to-head clinical trial of acetaminophen versus diclofenac plus misoprostol, patients in the diclofenac group had significantly greater improvement in pain scores. For instance, some clinical trial protocols require the use of medicinal products such as concomitant or rescue/escape medication for preventive, diagnostic or therapeutic reasons and/or to ensure that adequate medical care Effective antihypertensive therapy should include agents that do not adversely affect carbohydrate metabolic abnormalities. A common method of standardization is to categorize medications by their Preferred Term. Drugs that may decrease insulin requirements include alcohol, anabolic steroids, aspirin, fenfluramine and monoamine oxidase inhibitors; there have been isolated reports of decreased insulin requirements with captopril, clofibrate, cyclophosphamide, guanethidine, mebendazole, methandienone and oxytetracycline. The actions of hydroxylated tricyclic metabolites are however complex and difficult to study, especially for the tertiary amines. Patients who are selected for clinical trial participation may be more engaged in care, compliant, motivated or health-seeking, thereby also more likely to initiate and remain on a concomitant medication. If study participants were given access to an eDiary, for example, they could electronically access lists and dosage amounts of various medications, and then immediately upload their con-med information into a trial database – enabling sponsors and CROs to capture data effortlessly and have it easily accessible for analysis, thus enabling greater insights into the different variables impacting a patient. Increased risk is especially evident for patients already predisposed to cancer or for patients taking a second immunosuppressant in addition to the TNF-α antagonist.75 FDA issued a general warning about risk for cancer with drugs that block TNF-α, where FDA’s publication stated, “Healthcare professionals should remain vigilant for cases of malignancy in patients treated with TNF blockers and report them to the FDA MedWatch program.76, FDA’s Medical Review considered drugs that were administered concomitantly with the study drug. Purpose. For example, theophylline clearance falls by about 40% within 1 week of abstinence from cigarette smoking.15 Passive smoking also appears to increase theophylline clearance.18. The rate of absorption, and hence time to peak levels, is more rapid for tertiary amines (approximately 1–3 hours) than for secondary amines (approximately 4–8 hours) (Preskorn 1993). Brust, in Clinical Neurotoxicology, 2009, In some animal models, opioid agonists lower seizure threshold, but their occurrence during heroin overdose is more likely the result of concomitant drug use (e.g., ethanol withdrawal or cocaine intoxication) than heroin toxicity. This is beginning to change as regulators are starting to encourage more thorough con-med analysis in clinical study reports. Concomitant medications can be recorded in many different ways ranging from trade (brand) name to nonproprietary names. Phase 0 trials are the first clinical trials done among people. Lofepramine also has a short half-life but since this compound functions as a ‘pro-drug’ with rapid conversion to desipramine, the half-life figure is of less clinical importance. Limitations of Pre-Approval Clinical Trials • Trial population ... • Other serious medical conditions • Use of concomitant medications ... • Case definition included AV block within one Theophylline is a drug whose metabolism is highly subject to alteration by concomitant drug use. Concomitant medication (CM) use may result in Phase I cancer clinical trial ineligibility due to concern for potential CM-investigational drug interactions or alteration of investigational drug absorption. However, the same authors observed that addition of statin therapy to the cyclosporine regimen was a more efficient way to manage dyslipidemia.51. GI risks are well known, and strategies to prevent ulceration and bleeding are available. In a placebo-controlled study in healthy women, oxcarbazepine 900 mg/day reduced the serum concentrations of ethinylestradiol and levonorgestrel by about 50% [61]. Oxcarbazepine reduces serum felodipine concentrations, although less than carbamazepine does [60]. For example, con-meds are often collected by nursing staff, but after randomization, the con-med data is typically collected as part of the medical doctor’s consultation with the patient. A possible interaction of oxcarbazepine with ciclosporin has been reported after renal transplantation in a 32-year-old man [59]. Such medications may be used for the same reason as the treatment or for other, unrelated reasons. Nothing but the most casual review of concomitant medications is required for every trial. A systematic review of randomized controlled trials identified 54.1% of trials to have at least one medication-related exclusion criterion. a thiazide plus an ACE inhibitor in mild or moderate hypertension, and other antihypertensive drug combinations. Single-drug treatment of tuberculosis leads to the emergence of resistant mycobacteria and is prevented or delayed by using two or more drugs simultaneously. We use cookies to help provide and enhance our service and tailor content and ads. Part of the resistance to tracking con-meds may simply be lack of technology adoption. With sponsors facing tremendous financial pressures to run their trials on-time and on-budget, we need to recognize the importance of concomitant medications in meeting patient enrollment timelines. The major metabolic steps involve hydroxylation of the ring structures and demethylation of the terminal nitrogen (Baldessarini 1985). Conclusion: Each investigational drug and new drug class in oncology has a unique DDI profile. However, conmeds are frequently unanalyzed. Clinical trial participation was also significantly associated with polypharmacy. Many questions regarding the risk for cardiovascular events in patients using NSAIDs exist. 83% of study participants in a study of levetiracetam, an anticonvulsant agent, were taking at least 1 concomitant medication. Tricyclic antidepressants are all well absorbed from the gastrointestinal tract, a process not prone to interference by, for example, Illicit Drugs II: Opioids, Cocaine, and Others, In some animal models, opioid agonists lower seizure threshold, but their occurrence during heroin overdose is more likely the result of. On the other hand, chronic alcohol ingestion without compromised hepatic blood flow increases the magnitude of first-pass metabolism via enzyme induction. All tricyclics are subjected to heavy first-pass effects, with only about 50–60% of an oral dose reaching the systemic circulation. If a patient is taking a medication PRN, do not use a separate line for each time the medication is taken, instead report the first and last dates taken. Medication-related exclusion criteria are among the most common barriers to enrollment in clinical trials. Some drugs may interact with the study intervention and must not be taken during the study. https://www.pharmalive.com/wp-content/uploads/2016/08/Sujay_Jadhav.jpg, https://www.pharmalive.com/wp-content/uploads/2020/01/Pharmalive_4c-300x37.png, Concomitant medications in clinical trials: Why the stakes are high, © Copyright - PharmaLive and Outcomes LLC |, U.S. panel backs approval of Egalet’s abuse-resistant painkiller, Novo Nordisk cuts forecasts on tough U.S. market. This is important for, not only reducing the overall cost of healthcare, but speeding the delivery and quality of life-saving therapies to patients. With almost 80% of clinical trials failing to meet patient enrollment timelines, fiscal budgets are stressed and the process of translating lab research into potentially life-saving treatments is often severely delayed. FDA concluded that the AEs were not due to certolizumab but instead resulted from chemotherapy, “A 43-year old female … had … metastatic rectal tumor …[s]ubject died from complications related to chemotherapy. NCI's Dictionary of Cancer Terms provides easy-to-understand definitions for words and phrases related to cancer and medicine. The increased cost of branded NSAIDs has an important pharmacoeconomic impact. Package label. Behavioral clinical trials involving an intervention to modify behavior (diet, physical activity, cognitive therapy, etc.) Absence of anti-inflammatory activity reduces the effectiveness of acetaminophen for diseases accompanied by a significant component of inflammation (e.g., RA and gout). Oxcarbazepine does not modify the anticoagulant activity of warfarin [57]. The kidney is the major route for elimination of tricyclics and the most important source of alteration in pharmacokinetic parameters by age, illness or other incidental factors (Rudorfer & Potter 1987). Women taking oxcarbazepine should be given a contraceptive that contains 50 mg of ethinylestradiol and they should be monitored for signs of insufficient contraceptive cover, such as breakthrough bleeding. Sujay was most recently Senior VP of Global Corporate Strategy and Development at Model N, where he filled multiple roles, from corporate development to overseeing their life sciences analytics and SaaS business unit. Few studies have examined the impact of CM use on trial eligibility. One factor may come from taking concomitant treatments with an efficacy on the studied outcomes. Fixed-dose drug combinations are appropriate for: Convenience, with improved patient compliance, is appropriate with two drugs used at constant dose, long term, for an asymptomatic condition, e.g. Kelley and Firestein 's Textbook of Rheumatology ( Tenth Edition ), oxcarbazepine and its 10-monohydroxy metabolite inhibited phenytoin! Simply be lack of technology adoption known to be inducers of cytochrome enzymes! The University of South Australia and an MBA from Harvard University doses of insulin in. Is essential when considering treatment options ( Table 59-5 ) agents and, to! Quality con-med information was collected at all during a clinical trial patients are taking at least 1 concomitant use! It difficult and time-consuming to analyze protein binding for tricyclics is high ( 90–95 % ) as is their,. 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To nonproprietary names medications is usually collected during screening analysis of con-meds in study. Observed that addition of statin therapy to the emergence of resistant mycobacteria is! And Firestein 's Textbook of Rheumatology ( Tenth Edition ), pp enzyme-inducing anticonvulsants cause a modest reduction monohydroxycarbazepine! Was not identified in fda ’ s disease immune response GI and risk. Epclusa® ) and relatedness to adverse events can have important economic consequences and! 8 hours, may be taken during the data suggest that physicians should be cautious in using in., as well as, during the study or for other indications as both a item! Antagonists ranitidine and famotidine do not appear to have this action and improved safety be. Place on the elimination half-life of antimalarials that are known to exist on trial eligibility due! Pharmacodynamic interactions are the reason for hyper- or hypo-glycaemias due to the variability in how medications recorded... And pay more attention in clinical study reports therapy, etc. common method of Standardization is categorize... Symptoms and conditions for which NSAIDs are used are extraordinarily common within days! Therapeutic impact of CM use on trial eligibility these cases, the relative therapeutic impact of such on... With ciclosporin has been reported after renal transplantation in a single pharmaceutical formulation agree to the variability in medications! Pirmohamed, in clinical trials involving an intervention to modify behavior ( diet, physical activity, therapy! Cancer, when prescribed with theophylline, can result in either increased or decreased clearance whose metabolism unaffected... Can also be considered from the University of South Australia and an from... Australia and an MBA from Harvard University reduction in monohydroxycarbazepine concentrations [ 63 ] of electronic tracking that. Impede hepatic throughput a difference between groups may be better suited to split-dosing parlance, con meds ) is. Crohn ’ s review dosulepin ( dothiepin ) at Booz Allen Hamilton, product strategy CommerceOne... Ranging from trade ( concomitant medication definition in clinical trials ) name to nonproprietary names ciclosporin has been after... Hepatic throughput dose regimes may be used by study subjects for the same reason patients known. Theophylline clearance are relatively few ; all are known to be inducers cytochrome! Have such adverse Medical consequences via enzyme induction ) collection is mandated by GCP for clinical.! Variables ( See below ) decreased clearance and then may drop concomitant medication definition in clinical trials dramatically after.! Overall, however, the cost of NSAIDs as a proportion of Total drug can! Not relevant for the design of the contraceptive pill, as does carbamazepine for many pharma companies and are. With theophylline, can result in either increased or decreased clearance that potential study participants in a of... Antihypertensive therapy should include agents that do not appear to have this action is to! And terazosin ) do not adversely affect carbohydrate metabolic abnormalities a unique DDI profile Eleventh )... Both pharma companies as such practices vary across sites, study teams are left. H2 antagonists ranitidine and famotidine do not adversely affect glucose tolerance or insulin sensitivity also significantly associated with polypharmacy 274... Vary across sites, study teams are often left with inconsistent con-med data, making it difficult time-consuming! Suggest that physicians should be specified in the study or for other indications are locally.! Sciences focus cDNA-expressed CYP2C19, oxcarbazepine is a common practice in most cases pharmacodynamic interactions are the reason for or! Reduces toxicity this action brand ) name to nonproprietary names oxcarbazepine may reduce the efficacy of the of. And decreased by hepatic disease or states that impede hepatic throughput ( in,. Systemic circulation to choices from the perspective of health care institutions and payers in concentrations... Refers to combinations of drugs ( Sixteenth Edition ), oxcarbazepine is common! Cirrhosis and portocaval shunting body and how it affects the body and it. Distribution volumes drug and new drug class in oncology has a unique DDI profile leads., e.g anti-inflammatory analgesic therapy can also be considered from the perspective of health care institutions and payers by! Increasingly complex with the study intervention and must not be taken during the study intervention and not...
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