RSC Health New Drug Approval Process Clinical Trial Discussion

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 discuss the process by which drugs are taken from idea to wide scale use in humans or animals, and the factors that may limit or influence the overall quality of clinical trials. You can use rivaroxaban and the other oral anticoagulants as examples if you wish, or discuss another drug of your choosing. 

In particular:

Discuss the approval process for a new drug

Discuss what you can learn from clinical trials that have been conducted and which are ongoing

  • Discuss  real-world safety issues that may  appear after approval and how they might be mitigated
  • What could have been done differently?
  • Students often ask how long I want the assignment to be. I am not going to set a target for that, it really depends on your writing style and what you have to say. I am looking for original thought, not just repeating what you read in the powerpoint. A highly insightful and concise paper can be less than a page, where another might be two or three. I will be looking for structure, grammar and logical thinking. 
  • Some web sites that may be helpful include: to an external site. to an external site. to an external site.

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BMJ 2016;352:i575 doi: 10.1136/bmj.i575 (Published 3 February 2016) Page 1 of 4 Feature FEATURE INVESTIGATION Rivaroxaban: can we trust the evidence? An investigation by The BMJ has uncovered the use of a faulty device in a regulatory drug trial, potentially putting patients at unnecessary risk, Deborah Cohen reports Deborah Cohen associate editor, The BMJ Doctors and scientists are calling for an independent investigation into the key trial underpinning use of rivaroxaban to prevent ischaemic stroke in non-valvular atrial fibrillation after The BMJ found that a defective point of care device was used in the warfarin arm of the trial. Doctors and scientists have also told The BMJ that the validity of the trial—called ROCKET-AF and published in the New England Journal of Medicine in 20111—is in question until such independent analysis is done. The drug was manufactured by Bayer and marketed in the United States by Janssen, part of Johnson and Johnson, and the companies relied on a single trial–ROCKET-AF—to gain approval from the US and European regulators. The trial included over 14 000 patients and found that rivaroxaban was non-inferior to warfarin for preventing ischaemic stroke or systemic embolism. There was no significant difference between groups in the risk of major bleeding—although intracranial and fatal bleeding occurred less often in the rivaroxaban group. But there are now concerns about these outcomes. In a letter submitted to the NEJM (as yet unpublished) and shown to The BMJ, former FDA cardiovascular and renal drug reviewer, Thomas Marcinicak, says: “The care for the warfarin control arm patients [in ROCKET-AF] appears to have been compromised.” Earlier last year, The BMJ found that the point of care device used to measure international normalised ratio (INR) in patients taking warfarin in ROCKET-AF had been recalled in December 2014. An FDA class I recall notice (the most serious kind) said that certain INR devices could deliver results that were “clinically significantly lower” than a laboratory method. It added that Alere—the device manufacturer—had received 18 924 reports of malfunctions, including 14 serious injuries. The company confirmed to The BMJ that the fault went back to 2002, before the ROCKET-AF trial started. A falsely low reading could mean that patients had their warfarin dose unnecessarily increased, leading to a greater risk of bleeding. In terms of the trial results, it could make rivaroxaban seem safer than it was in terms of the risk of bleeding and throws doubt on outcomes used to support the use of the world’s best selling new oral anticoagulant.2 Back in September 2015, The BMJ asked the investigators named in the NEJM paper about the recall. They included researchers from Bayer, Johnson and Johnson, and the Duke Clinical Research Institute, which carried out the trial on behalf of the drug companies. None of the authors responded, but a spokesperson for Johnson and Johnson contacted The BMJ to say that they were “unaware of this recall” and they took the journal’s concerns “seriously.” But it took months of probing by The BMJ before the companies, world drug regulators, and Duke began to investigate the problem in earnest. Joining the dots As for the regulators, when The BMJ contacted the European Medicines Agency in April 2015 and subsequently the Food and Drug Administration, both said they did not know that the recalled device had been used in ROCKET-AF. It’s new territory for the regulators. What happens to a pivotal drug trial when a device used is found to be defective? In November the EMA told The BMJ it was investigating, and the agency subsequently told journalists: “Due to the defect it is now thought that the INR device may have impacted the clotting results in some patients in the warfarin group.”4 Executive director of EMA, Guido Rasi, also called for further independent investigation into direct oral anticoagulants. “It would be nice to have some independent study carried out to give confidence in the use of this medicine,” he said. The FDA also told The BMJ that it is “aware of concerns regarding the INR device and its use in the ROCKET-AF trial and is reviewing relevant data.” It subsequently announced that it will hold a public workshop about the safety and effectiveness” of point of care INR devices in March “to seek and identify potential solutions” to what it said were “scientific and regulatory challenges.” However, in the meantime spokespeople for Johnson and Johnson and Bayer issued identical statements in December 2015: “We have conducted a number of sensitivity analyses. For personal use only: See rights and reprints Subscribe: BMJ 2016;352:i575 doi: 10.1136/bmj.i575 (Published 3 February 2016) Page 2 of 4 FEATURE Direct oral anticoagulants Rivaroxaban is a factor Xa inhibitor and belongs to a class of medicines known as the direct oral anticoagulants (DOAC), which also includes dabigatran, apixaban, and edoxaban. They have gained popularity in place of warfarin for the prevention of ischaemic stroke in non-valvular atrial fibrillation because routine blood monitoring is not required.3 These sensitivity analyses confirm the results of the ROCKET-AF study and the positive benefit-risk profile of Xarelto (rivaroxaban) in patients with non valvular atrial fibrillation.” But what should happen amid the uncertainty? Harlan Krumholz, professor of medicine (cardiology) at Yale University, says that the NEJM should place an “immediate expression of concern” on the paper to notify the medical community. “The study should be considered of uncertain validity until a more thorough review can be done,” he says, adding that there should be “an investigation by an independent group of experts to quickly determine if there are grounds for retraction.” Concerns about warfarin control Even before rivaroxaban was approved in Europe and the US in 2011 for use in non-valvular atrial fibrillation, regulatory officials raised concerns about the warfarin control in the ROCKET-AF trial. Two primary clinical FDA reviewers of the drug recommended that it should not be approved for the US market. “ROCKET provides inadequate information to assess the relative safety and efficacy of Xarelto in patients whose warfarin administration can be well-controlled,” they wrote in an FDA decisional memo—which outlines clinical reviewers’ view on whether a drug should be approved.5 However, they were seemingly unaware that there are other reasons to be concerned about the adequacy of the warfarin control in the ROCKET-AF trial that have since emerged. Lack of transparency over devices in trials Currently, there is little public information about which diagnostic point of care devices are used in any of the direct oral anticoagulant trials (box). They are not named in the published phase III trials. The BMJ became aware that the problematic device was used in the ROCKET-AF trial only by reviewing European regulatory documents in April last year. Marciniak says that the NEJM, which published the trials for three of the direct oral anticoagulants, should rectify that. “You should require that the devices used in trials are clearly and specifically identified in your publications,” he wrote in his letter. How has this come to happen? In tracking the faulty recall and its potential effect on the outcomes of a global clinical trial, The BMJ has once again come across flaws in device regulation. A series of journal investigations have highlighted the lack of clinical data required by US and Europe regulators for high risk implants, such as metal on metal hips, before they are put on the market.8 They have also shown how slow regulators can be to act when problems do emerge and shown how oversight can be lacking on the performance diagnostic tests.9 10 In 2005, a warning letter from the FDA to HemoSense—the company that marketed the faulty device before Alere bought For personal use only: See rights and reprints it—reprimanded them for failing to investigate “clinically significant erroneous” high and low INR results generated by the point of care device. “Both high and low test [INR] results have the potential to cause or contribute to a death or serious injury, because: they may result in erroneous dosing and thus improper control of coagulation,” the letter said.11 Despite these warning letters, the FDA cleared subsequent iterations of the device through its 510(k) regulatory system. This system requires makers of such devices to show only that the new version is “substantially equivalent,” or similar, to one already on the market. It has been criticised by the likes of the Institute of Medicine for not providing enough evidence that a device is safe and effective.12 Johnson and Johnson, however, has lobbied against tightening up this aspect of device regulation and the need to provide more evidence.13 But the lack of a regulatory requirement for the diagnostic accuracy of the device to be checked before it came on to the market has allowed the fault to creep through the system. Alere has confirmed to The BMJ that the fault dates back to 2002 and it may occur in all devices and not just one batch. However, neither it nor the FDA responded to questions about why nothing had been done about the problem earlier. Were the companies aware of any problems during the trial? The BMJ asked Johnson and Johnson, Bayer, and Duke if any investigator complained to them about mismatched point of care and laboratory INR readings if someone had a bleed in the trial. The BMJ also asked if they had validated the device at any point before or during the trial. None responded to the questions. According to former FDA clinical pharmacologist, Bob Powell, who has also worked with industry and academia, the specificity and reproducibility of a diagnostic test or assay is vital to the performance of a trial. “The fact that this was apparently not previously done nor reported in the primary publication is concerning as this is a basic principle in drug development,” he says. What next? The EMA has told The BMJ that it has asked the companies for analyses and would consider any analyses by Duke too. During the trial INR at 12 and 24 weeks was measured at a central laboratory as well as with the point of care device. Powell says that “a comparison should be made between the defective point of care readings and the two sets of ‘gold standard’ central lab readings” as this would “determine whether this defective device undermined the integrity of the trial results.” It is not clear that this has happened. In December last year, Duke issued a press release with a summary report of the results of their “secondary analysis of the trial findings.” “The findings from the analysis are consistent with the results from the original trial and do not alter the conclusions of ROCKET-AF—rivaroxaban is a reasonable alternative to warfarin and is non-inferior for the prevention of stroke and Subscribe: BMJ 2016;352:i575 doi: 10.1136/bmj.i575 (Published 3 February 2016) Page 3 of 4 FEATURE Devices used in other trials Given the lack of publicly available information about the point of care testing devices used in the other direct oral anticoagulant trials, The BMJ sought to find out what they are. Lars Wallentin, corresponding author of the phase III ARISTOTLE trial (Apixaban versus Warfarin in Patients with Atrial Fibrillation)6 said that the trials used the ProTime POC device made by International Technidyne Corporation, Edison, NJ, USA. Daiichi-Sankyo, the manufacturers of edoxaban, also said that the ProTime POC device was supplied to all study sites in the Edoxaban versus Warfarin in Patients with Atrial Fibrillation Trial (ENGAGE AF)7 and in its venous thromboembolism trial. systemic embolism with less intracranial hemorrhage and fatal bleeding” it said. But Powell says this statement is “misleading” because of the lack of information. Krumholz also thinks that this statement did not give enough information about what Duke found in terms of the major safety endpoint—major bleeds. “The DCRI is among the most respected research institutions, but this statement suggests that they know important information that relates to the ROCKET-AF trial but are delaying in disseminating the information until it can be published,” he says. Hugo ten Cate, medical director of the Maastricht thrombosis anticoagulation clinic and coeditor in chief of Thrombosis Journal, says that major bleeds have serious consequences. “Large bleeds mostly occur in the gastrointestinal tract and can be lethal if substantial blood loss occurs, especially in elderly subjects with comorbidity; this can be a devastating complication,” he says. Any changes to the ROCKET-AF trial will have a broader effect on the literature. Carl Heneghan is an author on a forthcoming Cochrane Collaboration review of “direct thrombin inhibitors and factor Xa inhibitors for atrial fibrillation,” which includes the ROCKET trial. He has written to Duke to ask if the results for the main outcome measures in the reanalysis are the same as in the original published paper and, if not, what the differences are after the reanalysis. A spokesperson for Duke did not answer the question but said that the ROCKET-AF executive committee “intends to publish a full description of its analysis as rapidly as possible.” Independent oversight But given the lack of clarity over the outcomes and the methods used, is a reanalysis by Duke enough? Marciniak is unequivocal. He says that he would not rely on any reanalyses done by Duke, Johnson and Johnson, or the FDA. “Because they already missed the problems both in the trial and with the public marketing, I would not trust them to publish anything that is accurate—or that provides any details,” he told The BMJ. He added that the datasets need to be released as “the only solution that would lead to unbiased analyses.” But previous attempts to do this have been thwarted. Krumholz has approached Johnson and Johnson for access to the trial data. His Yale University Open Data Access (YODA) project has an agreement with Johnson and Johnson to make all of the clinical trial data available for its approved products. However, although the company agreed to allow access to the data, Bayer refused. For personal use only: See rights and reprints “This is an ideal situation for data sharing. The evaluation of the data in this trial should not go on behind the curtain. And it seems imprudent to allow those who conducted the trial to be the only ones who can touch the data,” Krumholz says. But it doesn’t look like the data release is going to be sanctioned by Bayer any time soon. A spokesperson for the company told The BMJ that this is because they have signed up to sharing information only on “study reports for new medicines approved in the US and the EU after January 1, 2014.” The request does not fit in their “current scope of clinical trial data sharing.” Good outcome for patients? But in the end might this series of errors lead to a favourable outcome for the regulators—and perhaps patients? At the end of 2015, both the EMA and the FDA held meetings to discuss the need to measure blood levels of direct oral anticoagulants and adjust the dose accordingly to maximise benefit and minimise harm—despite all the manufacturers claiming that this is not necessary. The meetings were held after The BMJ revealed that Boerhinger Ingelheim, manufacturers of dabigatran, withheld analyses from the regulators that showed how many major bleeds could be prevented by monitoring anticoagulant activity and adjusting the dose.14 A presentation to EMA last year by Robert Temple, deputy director for clinical science at the FDA’s Center for Drug Evaluation and Research, suggests that the FDA believes there is a scientific argument for measuring the blood levels of these drugs and adjusting the dose. “Being too low leads to a stroke, a very bad outcome, and being too high leads to major bleeds, also bad, so that early optimization [of the dose] seems worthwhile,” he said adding that direct oral anticoagulants are “very good, but could probably be better.” But once a drug is on the market, regulators lack a mandate to act unless there are safety concerns. However, according to Powell, depending on the outcomes of any reanalysis of the ROCKET-AF trial, this might allow them to take action. “After a drug is approved, it usually takes a safety signal to prompt significant action on the part of the FDA. It is this lack of safety signal that appears to be hindering the FDA in their desire to pursue tailored dosing for DOACs. If it turns out that the issue with the [INR] device changes the safety profile of rivaroxaban, this may constitute the safety signal necessary for the FDA to act in this regard,” he said. Competing interests: I have read and understood BMJ policy on declaration of interests and have no relevant interests to declare. Provenance and peer review: Commissioned; externally peer reviewed. 1 2 3 Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91. Top 50 pharmaceutical products by global sales. 50_pharmaceutical_products_by_global_sales. Cohen D. Concerns over data in key dabigatran trial. BMJ 2014;349:g4670. Subscribe: BMJ 2016;352:i575 doi: 10.1136/bmj.i575 (Published 3 February 2016) Page 4 of 4 FEATURE 4 5 6 7 8 9 10 Burger l. Trial for Bayer drug Xarelto under scrutiny over defective device. Reuters 2015 Dec c4qYKB7bEseov2Fl.97. FDA. Drug approval package Xarelto. 2015. nda/2011/202439toc.cfm. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-104. Cohen D. How safe are metal-on-metal hip implants? BMJ 2012;344:e1410. (http://www. Cohen D. How a fake hip showed up failings in European device regulation. BMJ 2012;345:e7090. Cohen D, Swift G. Laboratories and regulator misled over antibiotic susceptibility test discs. BMJ 2013;346:f837. For personal use only: See rights and reprints 11 12 13 14 FDA. Warning letter. HemoSense Corporation, 4 Oct 2005. EnforcementActions/WarningLetters/2005/ucm075594.htm Meier B. Study faults approval process for medical devices. N Y Times 2011 Jul 29. www. Mundy A. Firms warn of delays from FDA scrutiny. Wall Street J 2009 Sep 30. www.wsj. com/articles/SB125426793950751021. Cohen D. Dabigatran: how the drug company withheld important analyses. BMJ 2014;349:g4670. Cite this as: BMJ 2016;352:i575 © BMJ Publishing Group Ltd 2016 Subscribe: Clinical Therapeutics/Volume 40, Number 12, 2018 Review A Review of the Efficacy and Safety Profiles of the Novel Oral Anticoagulants in the Treatment and Prevention of Venous Thromboembolism Alexis A. Coulis, MS; and William C. Mackey, MD Tufts University School of Medicine, Boston, MA, USA ABSTRACT Purpose: This study aims to review the published literature concerning the use of novel oral anticoagulants (NOACs) in the treatment and prevention of venous thromboembolism (VTE) and to identify the appropriate niche for each NOAC by comparing their behaviors in Phase III and Phase IV clinical trial settings. Methods: The database was used to identify Phase III and postmarketing (Phase IV) randomized controlled trials concerning the efficacy and safety profiles of the oral NOACs (apixaban, dabigatran etexilate, exodaban, and rivaroxaban) for the treatment or prevention of VTE. Studies of special interest included those that compared the administration of a NOAC versus standard anticoagulation therapy with lowmolecular-weight heparin and/or a vitamin K antagonist. Findings: Overall, the NOACs offer a simplified anticoagulation regimen that has noninferiority and similar rates of bleeding when compared with standard therapy throughout multiple studies. This finding held true across several VTE conditions that required anticoagulation, such as the treatment and prophylaxis of acute VTE, including both deep vein thrombosis and pulmonary embolism. Absence of dietary restrictions and fixed oral dosing that does not require monitoring makes NOACs ideal for the outpatient setting. Apparent niches for each individual NOAC are discussed in detail; however, the paucity of trials comparing NOAC performance in specific clinical settings makes precise definition of these niches problematic. Implications: It now seems reasonable for clinicians to consider NOACs as first-line agents for both the treatment and prophylaxis of VTE and to attempt to tailor their particular medication choices for each patient scenario. More trials comparing NOAC performance in specific clinical settings are essential to 2140 ensure these medications are being used to their full potential. (Clin Ther. 2018;40:2140e2167) © 2018 Elsevier Inc. All rights reserved. Keywords: NOACS, novel oral anticoagulants, venous thromboembolism, VTE. INTRODUCTION Venous thromboembolism (VTE) is the third most prevalent vascular diagnosis after myocardial infarction and stroke. It is estimated to affect 300,000 to 600,000 persons in the United States each year.1 Deep vein thrombosis (DVT) and pulmonary embolism (PE) are the 2 acute manifestations of VTE. The mainstay of treatment and prophylaxis of VTEdanticoagulation therapydworks to inhibit blood clotting, lowering the risks of DVT or PE. An overview of the coagulation cascade and the antithrombotic therapy targets are illustrated in Figure 1. Conventional anticoagulants include heparin, a naturally occurring anticoagulant produced by basophils and mast cells that works by activating antithrombin, an inhibitor of thrombin formation. Unfractionated heparin (UFH), the pharmaceutical version of heparin, contains polysaccharide molecular chains of varying lengths. Low-molecular-weight heparin (LMWH), commonly enoxaparin sodium,* is ® * Trademark: Lovenox Bridgewater, New Jersey). (sanofi-aventis U.S., LLC, Accepted for publication October 9, 2018 0149-2918/$ - see front matter © 2018 Elsevier Inc. All rights reserved. Volume 40 Number 12 December 2018 Coagulation Cascade and Antithrombotic Therapy Targets. Warfarin inhibits the synthesis of Vitamin K-dependent clotting factors including FII (Prothrombin), FVII, FIX (not pictured), and FX. Direct Thrombin Inhibitors including Dabigatran inhibit FIIa (Thrombin). Direct Factor Xa Inhibitors including Apixaban, Edoxaban, and Rivaroxaban inhibit FXa. Heparins facilitate the physiological anticoagulant Antithrombin (AT). Low Molecular Weight Heparin (LMWH) and Fondaparinux preferentially work through AT's inhibition of FXa while Unfractionated Heparin (UFH) preferentially works through AT's inhibition of FIIa (Thrombin). Working to disrupt platelet aggregation, Aspirin inhibits the generation of TxA2 while Clipidogrel inhibits the ADP receptor P2Y12. 2141 A.A. Coulis and W.C. Mackey Figure 1. Clinical Therapeutics a further modified version of heparin that has undergone fractionation to sequester only short-chain polysaccharides. This helps to increase its pharmacodynamic predictability. LMWH preferentially works to activate antithrombin's inhibition of clotting factor Xa. Fondaparinux sodiumy is a synthetic pentasaccharide factor Xa inhibitor that also binds antithrombin but instead accelerates its inhibition of thrombin. UFH, LMWH, and fondaparinux must be administered by injection. The effects of UFH and LMWH can be reversed with protamine sulfate, a medication that binds to these agents and inhibits their anticoagulant activity. A second major class of conventional anticoagulants includes the vitamin K antagonists (VKAs), most notably warfarin.z By inhibiting the vitamin Kedependent synthesis of several clotting factors, VKAs effectively decrease patients' coagulation activity. Although given orally, and therefore easily administered to outpatients, VKAs have a narrow therapeutic window and require regular blood tests to monitor their therapeutic effect. Prothrombin time and the international normalized ratio (INR) are 2 values obtained to ensure correct dosing. Failure to properly monitor blood clotting parameters could result in subtherapeutic anticoagulation, risking thrombus propagation, or a supratherapeutic effect that increases the risk of major bleeding. In addition, because the effectiveness of VKAs is a direct result of their ability to inhibit a vitamin Kedependent pathway, this therapy is extremely sensitive to dietary intake of vitamin K. Patients undergoing anticoagulant treatment with VKAs must work daily to regulate their diet to ensure their medication remains in a therapeutic range. Although this often complicates patients' daily eating habits, one clinical benefit is vitamin K's ability to reverse VKA anticoagulation in the event of major bleeding or VKA overdose. Although these anticoagulation regimens have been used in clinical practice for many years, they have numerous limitations. Characteristics of an ideal anticoagulant include a simple dosing regimen with a y Trademark: Arixtra United Kingdom). ® (GlaxoSmithKline, Brentford, ® z Trademark: Coumadin York, New York). 2142 (Bristol-Myers-Squibb, New wide therapeutic window that eliminates the need for frequent clinical monitoring, easy oral administration, minimal food and drug interactions, and the availability of an antidote that quickly and effectively reverses anticoagulation. Recently, pharmaceutical companies developed novel oral anticoagulants (NOACs) with many of these attributes. Three of the 4, apixaban,x edoxaban,jj and rivaroxaban,¶ are direct factor Xa inhibitors. Although the heparins achieve anticoagulation by increasing antithrombin's inhibition of factor Xa, these medications inhibit factor Xa directly. The fourth NOAC, dabigatran etexilate,# is the prodrug of dabigatran, which is a direct thrombin inhibitor. Taken once or twice daily at fixed oral doses, these 4 medications are approved by the US Food and Drug Administration (FDA) for a variety of anticoagulant regimens in the treatment and prophylaxis of VTE as well as in the prevention of stroke and systemic embolism in adults with nonvalvular atrial fibrillation. Figure 2 describes the current FDA dosing and administration recommendations regarding NOAC anticoagulation therapy for clinical conditions related to VTE. Benefits of anticoagulation with the NOACs include ease of their oral administration, fewer drug and dietary interactions, and predictable pharmacokinetic properties that do not require clinical monitoring (see Table I for a full comparison of anticoagulation regimens). However, because less is known about these newer medications and there is limited research to speak to their behavior in clinical practice, efficacy and complication rates in comparison with traditional VKA or heparin therapies are of major interest. Although these drugs have great promise, further investigation is needed to firmly establish their place in clinical practice and define the optimal role(s) for each of the 4 agents. ® x Trademark: Eliquis (Bristol-Myers-Squibb, New York, New York). ® jj Trademark: Savaysa (Daiichi Sankyo Co, Ltd, Tokyo, Japan). ® ¶ Trademark: Xarelto (Janssen Pharmaceuticals Inc, Raritan, New Jersey) . ® # Trademark: Pradaxa (Boehringer Ingelheim Pharmaceuticals, Inc, Ingelheim am Rhein, Germany). Volume 40 Number 12 December 2018 2143 A.A. Coulis and W.C. Mackey Figure 2. Anticoagulation Regimens in Treatment and/or Prevention of VTE. Regimens are according to the FDA prescribing recommendations in the United States. Of note, Edoxaban is not currently approved by the FDA for the extended treatment of VTE or prophylactic treatment following Total Knee or Hip Arthroplasties (TKA/THA). Additionally, Dabigatran Etexilate is not approved by the FDA for prophylactic treatment following a TKA. *Reduced 30mg dose is intended for patients with CRCL 15-50 mL/min, body weight £60kg, or those taking concomitant P-gp inhibitors. **Reduced 2.5mg dose is intended for patients with at least 2 of the following characteristics: age 80, body weight £60kg, or serum creatinine 1.5 mg/dL. Clinical Therapeutics Table I. Comparison of anticoagulants. Variable Heparins Administration Dosing Food-drug interactions Reversal agent Clinical reliability Vitamin K Antagonists Novel Oral Anticoagulants Parenteral (intravenous or Oral Oral subcutaneous) Wide therapeutic Dose adjusted to INR 2.0e3.0 Dose adjusted to INR 2.0e3.0 window and requiring frequent monitoring requiring frequent monitoring because of a narrow therapeutic because of a narrow therapeutic predictable dose response allows for window and varied dose window and varied dose fixed dosing response response Low potential for drug Fewer drug interactions Many drug interactions and interactions and directly affected by foods rich unaffected by diet in vitamin K Protamine sulfate Vitamin K Andexanet alfa,* idarucizumaby Reliably used for years in clinical Reliably used for years in clinical Short history of clinical practice practice use INR ¼ international normalized ratio. * Antidote for factor Xa inhibitors, approved by the US Food and Drug Administration in 2018 as a reversal agent for apixaban and rivaroxaban. y Antidote for direct thrombin inhibitors, approved by the US Food and Drug Administration in 2015 as a reversal agent for dabigatran etexilate. METHODS The database was used to identify published Phase III and postmarketing (Phase IV) randomized controlled trials concerning the efficacy and safety profiles of the oral NOACs (apixaban, dabigatran etexilate, edoxaban, and rivaroxaban). Each of these primary sources was subsequently reviewed for their results concerning the treatment or prevention of VTE. This process excluded active trials that were not yet published during or after February 2018 and Phase I or Phase II trials. Particular studies of interest included those that compared the administration of a NOAC versus standard anticoagulation therapy with LMWH and/or a VKA. Additional exclusions included trials focused on the prevention of stroke or systemic embolism in adults with atrial fibrillation because this topic was beyond the scope of the present review. In addition, although the oral direct thrombin inhibitor ximelagatran** was evaluated in Phase III clinical trials and was approved ** Trademark: Exanta United Kingdom). 2144 ® (AstraZeneca, Cambridge, for use internationally, it was also excluded from this review because this medication did not gain approval from the FDA because of concerns regarding hepatotoxicity. Electronic searches to supplement the reported data with additional relevant articles were conducted as needed. This review aimed to speak to the practical clinical applications of each of these medications by comparing their efficacy and safety profiles in Phase III and Phase IV trial settings. As such, reported data include the individual trial designs, study outcomes, and trial authors’ commentary regarding the studied drug in clinical practice. Specifically, the measured efficacy end points included VTE progression or recurrence in treatment studies and incidence of DVT and PE in prophylaxis studies, whereas rates of major bleeding and/or clinically relevant nonmajor (CRNM) bleeding events were primary safety profile end points. The Phase III and Phase IV clinical trials, which constituted most of the reported results, were funded by the medications’ respective pharmaceutical companies; however, a formal risk of bias assessment was not performed. Volume 40 Number 12 A.A. Coulis and W.C. Mackey RESULTS Medication Characteristics Although the NOACs can be misinterpreted as a homogeneous group of medications with similar routes of administration and mechanisms of action, there are slight variations that could have clinical relevance. Table II provides an overview of these characteristics, which are discussed below. Adverse Effects In Phase III clinical trials, all 4 NOAC regimens revealed a relatively low adverse effect profile2e5 Besides bleeding, the only frequently reported significant adverse effect was dyspepsia associated with dabigatran etexilate. In clinical study, this affected 3% of patients.2 Drug Interactions As substrates of the P-glycoprotein (P-gp) transporter, all 4 NOACs interact with medications, inducing or Table II. inhibiting P-gp. Specifically, strong P-gp inhibitors (eg, antifungals such as ketoconazole as well as the HIV protease inhibitor ritonavir) increased medication effect and therefore elevated the risk of bleeding.6e9 For this reason, coadministration of rivaroxaban or dabigatran etexilate with the aforementioned medications or other strong P-gp inhibitors is not recommended.6,8 Conversely, P-gp inducers, such as the antibiotic rifampicin, or hypericum (commonly known as St. John's wort, an herb thought to calm feelings of anxiety or depression), decrease NOAC effect and could lead to subtherapeutic levels of anticoagulation.6e9 In addition, because apixaban, edoxaban, and rivaroxaban are all metabolized by liver oxidative pathways, including cytochrome P450 3A4 (CYP3A4), medications that induce or inhibit this enzyme will affect these anticoagulants. Including the anticonvulsants carbamazepine and phenytoin as well Medication characteristics according to the highlights of prescribing information published by the US Food and Drug Administration. Variable Dosage forms Adverse effects Drug interactions Contraindicated patient populations Antidote Apixaban Tablets: 2.5 and 5 mg Bleeding Dabigatran Etexilate Capsules: 75 and 150 mg Dyspepsia, bleeding P-gp inducers Strong dual (rifampin), P-gp inhibitors or inhibitors inducers of (dronedarone, CYP34A and Psystemic gp ketoconazole) Elderly people Breastfeeding mothers, pregnancy, severe hepatic impairment Andexanet alfa Idarucizumab Edoxaban Rivaroxaban Tablets: 15, 30, and Tablets: 10, 15, and 60 mg 20 mg Bleeding Rash, abnormal liver function test results, anemia, bleeding Anticoagulants, P-gp Strong dual inhibitors inducers (rifampin) or inducers of CYP34A and P-gp, anticoagulants Breastfeeding mothers, Breastfeeding mothers, renal renal impairment, impairment, moderate-severe hepatic impairment hepatic impairment Procoagulant agents (prothrombin complex, recombinant factor VIIa) Andexanet alfa CYP34A ¼ cytochrome P450 3A4; P-gp ¼ P-glycoprotein. December 2018 2145 Clinical Therapeutics as many of the same medications mentioned above, coadministration with apixaban, edoxaban, or rivaroxaban should be avoided.6,7,9 However, because of its limited hepatic metabolism and primarily renal elimination, dabigatran etexilate is not significantly affected by pharmaceuticals that alter CYP3A4 activity.8 Finally, concomitant use of apixaban or rivaroxaban with other medications that affect hemostasis is not recommended.6,7 Because both these medications are intended to be used as a monotherapeutic, singledrug approach to anticoagulation, overlapping administration with an additional anticoagulant increases the risk of bleeding. With regard to common antiplatelet agents, such as aspirin or clopidogrel,yy although coadministration with apixaban or rivaroxaban is not specifically contraindicated, FDA prescribing information in the United States includes a warning regarding the increased risk of bleeding and recommends that concomitant use be conducted with caution.6,7 Specific Populations Systemic anticoagulation effect increases with decreasing renal function for all 4 NOACs.6e9 For this reason, patients with severe renal insufficiency (creatinine clearance [CLCR] 2 to 14 days before switching to rivaroxaban) revealed that this patient population experienced higher rates of major bleeding (1.4% vs 0.7%) and recurrent VTE (2.2% vs 1.4%) than the original rivaroxaban cohort.17 In addition, all 4 NOACs depicted similar or lowered bleeding profiles.2e5 Apixaban, however, was the only NOAC to reveal a clinically relevant reduction in major bleeding events. Specifically, only 0.6% of patients taking apixaban compared with 1.8% of those receiving conventional therapy experienced major bleeding (relative risk ¼ 0.31; 95% CI, 0.17e0.55; P < 0.001 for superiority).4 The numerical results from each trial are given in Table III. In their investigations of NOACs versus standard anticoagulation therapy, 2 separate Cochrane reviews spoke to the effectiveness and tolerability of these oral medications for the treatment of acute DVT and PE. In the review concerning DVT, 11 randomized controlled trials in which participants had confirmed DVT were evaluated. Meta-analysis of the 3 studies (n ¼ 7596) concerning the oral direct thrombin inhibitors dabigatran etexilate and ximelagatran found no difference in the rates of recurrent VTE (odds ratio [OR] ¼ 1.12; 95% CI 0.80e1.49) and associated these 2 medications with reduced rates of bleeding (OR ¼ 0.68; 95% CI 0.47e0.98).18 2147 Variable Trial results for the treatment of acute VTE.* Apixaban AMPLIFY4 Dabigatran Etexilate AMPLIFY-J13 RE-COVER2 RE-COVER II14 Edoxaban Hokusai VTE Cancer Trial3 Rivaroxaban EINSTEIN-DVT5 EINSTEIN-PE15 Rivaroxaban 15 mg LMWH or UFH LMWH or UFH for Enoxaparin or UFH Rivaroxaban 15 Apixaban 10 mg Apixaban twice daily for 7 mg twice daily 5e11 days, then for up to 5 days, 10 mg twice for 5e11 days, twice daily for 7 for 7 weeks, then weeks, then then edoxaban then dabigatran dabigatran daily for 7 days, then 5 mg 20 mg/d for 3, 6, 20 mg/d for 3, 6, etexilate 150 mg 60 mg/d (or etexilate days, then twice daily for 6 30 mg/d) for 3e12 or 12 months vs or 12 months vs twice daily for 6 150 mg twice 5 mg twice months vs enoxaparin and months vs warfarin enoxaparin and months vs daily for 6 daily for 6 enoxaparin and VKA VKA warfarin months vs months vs warfarin warfarin UFH and warfarin Edoxaban (n ¼ Dabigatran Dabigatran Apixaban Patients Apixaban Rivaroxaban Rivaroxaban etexilate (n ¼ 40; 22 etexilate (n ¼ 2691; (n ¼ 2419 with (n ¼ 1731 with 4118; 2468 with (n ¼ 1273; 880 (n ¼ 1280; 877 with DVT, 1749 with DVT, PE), enoxaparin DVT), DVT, 1650 with with DVT, 298 18 with PE), with DVT, 270 678 with PE), or VKA enoxaparin or PE), warfarin with PE), with PE), UFH and enoxaparin and (n ¼ 2413 with VKA (n ¼ 1718 (n ¼ 4122; 2453 warfarin warfarin warfarin warfarin PE) with DVT) with DVT, 1669 (n ¼ 2704; 1783 (n ¼ 40; 23 (n ¼ 1266; 869 (n ¼ 1288; 873 with PE) with DVT, 297 with DVT, 271 with DVT, with DVT, 681 with PE) 17 with PE) with PE) with PE) Recurrent VTE Recurrent VTE Recurrent VTE or Recurrent VTE or Recurrent VTE Results Recurrent VTE Recurrent VTE occurred in 2.1% occurred in 2.1% occurred in 3.2% death occurred death occurred occurred in 2.3% occurred in of patients taking in 2.3% of in 2.4% of 0 patients of patients of patients of patients edoxaban and 3.5% taking patients taking patients taking taking taking apixaban taking of those receiving dabigatran dabigatran apixaban and 2.7% of rivaroxaban and rivaroxaban and warfarin etexilate and subjects and etexilate and those taking 1.8% of those 3.0% of those (HR ¼ 0.89; 95% 2.2% of those 2.1% receiving 1 patient enoxaparin and raking taking CI, 0.70e1.13; receiving warfarin taking UFH warfarin (−0.4% enoxaparin or enoxaparin or P < 0.001) warfarin (HR ¼ 1.10; difference in risk; or warfarin VKA (HR ¼ 0.68; VKA (HR ¼ 1.12; (HR ¼ 1.08; 95% 95%, CI 0.65 95% CI, −1.3 to 95% CI, 0.75 95% CI, 0.44 CI, 0.64e1.80; e1.84) 0.4; P < 0.001) e1.68; e1.04; P < 0.001) P ¼ 0.003) P < 0.001) Dosing Clinical Therapeutics 2148 Table III. Volume 40 Number 12 December 2018 Table III. Variable (Continued ) Apixaban AMPLIFY4 Dabigatran Etexilate AMPLIFY-J13 RE-COVER2 RE-COVER II14 Edoxaban Hokusai VTE Cancer Trial3 Rivaroxaban EINSTEIN-DVT5 EINSTEIN-PE15 2149 AMPLIFY ¼ Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy; AMPLIFY-J ¼ Japanese AMPLIFY; CRNM ¼ clinical relevant nonmajor; DVT ¼ deep vein thrombosis; EINSTEIN-DVT ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Deep Vein Thrombosis; EINSTEIN-PE ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism; HR ¼ hazard ratio; LMWH ¼ low-molecular-weight heparin; PE ¼ pulmonary embolism; RE-COVER ¼ Randomized Trial of Dabigatran Versus Warfarin in the Treatment of Acute Venous Thromboembolism; RR ¼ relative risk; UFH ¼ unfractionated heparin; VKA ¼ vitamin K agonist; VTE ¼ venous thromboembolism. * Major bleeding and clinically relevant nonmajor bleeding were defined according to the International Society on Thrombosis Haemostasis and bleeding scale. LMWH and VKA were dose adjusted to INR of 2.0e3.0. A.A. Coulis and W.C. Mackey Major or CRNM Major bleeding ¼Major bleeding Major or CRNM Major bleeding Major or Major bleeding or CRNM bleeding occurred in 1.2% bleeding occurred occurred in occurred in 0.6% CRNM occurred in 8.1% bleeding in 8.5% of patients 1.6% of patients of patients bleeding of patients occurred in of patients taking edoxaban taking taking occurred in taking apixaban 10.3% of and 10.3% of those taking dabigatran dabigatran 7.5% of and 1.8% of patients rivaroxaban and receiving warfarin etexilate and etexilate and patients those taking 8.1% of those (HR ¼ 0.81; 95% 1.7% of those 1.9% of those taking undergoing rivaroxaban taking CI, 0.71e0.94; receiving receiving apixaban enoxaparin and and 11.4% of enoxaparin or P ¼ 0.004) warfarin warfarin warfarin therapy and 28.2% those taking VKA (HR ¼ 0.69; 95% (HR ¼ 0.82; (RR ¼ 0.31; 95% of those enoxaparin or CI, 0.36e1.32) 95% CI, 0.45 taking UFH CI, 0.17e0.55; VKA e1.48) or warfarin P < 0.001) (HR ¼ 0.90; 95% CI, 0.76 e1.07; P ¼ 0.23) Pooled analysis revealed HRs of 1.09 Pooled analysis revealed HRs of 0.89 for recurrent VTE (95% CI, 0.66 (95% CI, 0.76e1.57) for recurrent e1.19; P < 0.001) and 0.54 for VTE and 0.73 for major bleeding major bleeding (95% CI, 0.37e0.79; (95% CI, 0.48e1.11) P ¼ 0.002) Noninferior Noninferior efficacy Noninferior Noninferior No clinically Noninferior Outcome Noninferior efficacy with a efficacy with a with significantly efficacy with a efficacy with a important efficacy with a potentially potentially less bleeding lowered risk of clinically relevant difference in similar safety improved improved bleeding efficacy with profile reduction in benefit-risk benefit-risk a favorable major bleeding profile profile safety profile Clinical Therapeutics Concerning the oral factor Xa inhibitors apixaban, edoxaban, and rivaroxaban, meta-analysis of 8 studies (n ¼ 16356) found similar rates of recurrent VTE (OR ¼ 0.89; 95% CI, 0.73e1.07) and reduced rates bleeding (OR ¼ 0.84; 95% CI, 0.43e0.76).18 In the review concerning PE, 5 randomized controlled trials in which participants had confirmed PE were evaluated. For direct thrombin inhibitors, analysis of 2 studies (n ¼ 1602) indicated no difference in the effectiveness of dabigatran etexilate or ximelagatran versus standard anticoagulation in the prevention of recurrent VTE (OR ¼ 0.93; 95% CI, 0.52e1.66) or in the number of major bleeding events (OR ¼ 0.50; 95% CI, 0.15e1.68).19 In the analysis of direct factor Xa inhibitors, 3 studies (n ¼ 6295) also indicated no significant difference in the rates of recurrent VTE (OR ¼ 0.85; 95% CI, 0.63e1.15) or major bleeding (OR ¼ 0.97; 95% CI, 0.59e1.62).19 Summarizing their results, the Cochrane review authors concluded that both oral direct thrombin inhibitors and oral factor Xa inhibitors may be tolerable and effective alternatives to conventional anticoagulation for the treatment of both acute DVT and PE.18,19 Subgroup Analysis Subgroup analysis of the Phase III trials investigated whether the results reported above could be generalized to vulnerable populations, specifically patients with active cancer, impaired renal function, or advanced age. Active Cancer Although patients with cancer are at risk for developing VTE, anticoagulant treatment with VKAs in this population is associated with an elevated risk of recurrent VTE and higher rates of bleeding. As such, current guidelines recommend that patients with cancer and VTE be treated with a monotherapy of LMWH for 6 months. However, because a longterm regimen of this subcutaneous injection is extremely inconvenient, many patients with cancer and VTE continue to be treated with VKAs. If NOACs had noninferiority with respect to VKAs in the prevention of recurrent VTE while additionally exhibiting fewer rates of bleeding, these medications could be convenient options for patients with active cancer and VTE who decide against LMWH monotherapy as per current recommendations. On 2150 subgroup analysis for each NOAC regarding its performance in patients with active cancer, these 4 medications remained noninferior to warfarin in the prevention of recurrent VTE and continued to be associated with a lower risk of bleeding (Table IV).20e23 Edoxaban was the only medication to undergo further research to investigate its performance against the recommended long-term LMWH monotherapy. Evaluating the efficacy and tolerability of edoxaban 60 mg/d after a 5-day regimen of LMWH, the Hokusai VTE Cancer trial established edoxaban's noninferiority to LMWH monotherapy in the prevention of recurrent VTE in patients with cancer (12.8% in the edoxaban group compared with 13.5% in the dalteparin group; HR ¼ 0.97; 95% CI, 0.70e1.35; P ¼ 0.006 for noninferiority and P ¼ 0.87 for superiority).24 However, the rate of major bleeding was significantly higher with edoxaban (6.9% in the edoxaban group compared with 4.0% in the dalteparin group; 2.9% difference in risk; 95% CI, 0.1e5.6).24 Impaired Renal Function Because renal function directly affects the rate at which a medication is eliminated from the body, renal impairment could increase NOAC exposure and potentially result in more adverse bleeding events. Acknowledging this, subgroup analyses of renally impaired patients in the RE-COVER II and the Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Deep Vein Thrombosis (EINSTEIN-DVT) and in Patients With Acute Symptomatic Pulmonary Embolism (EINSTEIN-PE) studies examined the effect of decreased renal function on dabigatran etexilate's (primarily renal clearance) and rivaroxaban's (both hepatic and renal clearance) efficacy and tolerability compared with the warfarin standard (primarily hepatic clearance). On subgroup analysis of patients taking dabigatran etexilate with mild (CRCL 50e80 mL/min) to moderate (CRCL 30e50 mL/min) renal impairment, decreasing renal function was associated with lowered rates of recurrent VTE. This trend was not reflected in the warfarin group. In both the dabigatran etexilate and warfarin groups, however, the rates of bleeding increased with decreased renal function.25 Similar subgroup analysis of patients taking rivaroxaban revealed slightly different results because decreased renal function was associated with increased rates of recurrent VTE and bleeding for both rivaroxaban and Volume 40 Number 12 A.A. Coulis and W.C. Mackey Table IV. Results of subgroup analysis for patients with active cancer.* Variable Apixaban (AMPLIFY4) Dabigatran Etexilate (RE-COVER II2,14) Edoxaban (Hokusai VTE Cancer Trial3) Rivaroxaban (EINSTEINDVT and EINSTEINPE5,15) Edoxaban (n ¼ 378), Rivaroxaban (n ¼ 354), Dabigatran etexilate Patients Apixaban (n ¼ 88), warfarin (n ¼ 393) enoxaparin or VKA (n ¼ 114), warfarin enoxaparin and (n ¼ 301) (n ¼ 107) warfarin (n ¼ 81) Recurrent VTE occurred Recurrent VTE occurred in Results Recurrent VTE occurred in Recurrent VTE or 5% of patients taking in 4% of patients 3.7% of patients taking related death rivaroxaban and 7% of taking edoxaban and occurred in 5.8% of apixaban and 6.4% of those receiving 7% of those taking those taking enoxaparin patients taking enoxaparin or VKA warfarin (HR ¼ 0.53; or warfarin (RR ¼ 0.56; dabigatran etexilate (HR ¼ 0.67; 95% CI, and 7.4% of patients 95% CI, 0.28e1.00; 95% CI, 0.13e2.37) 0.35e1.30) P ¼ 0.0007) taking warfarin Major and CRNM Major bleeding Major bleeding Major bleeding occurred bleeding occurred in occurred in 3.8% of occurred in 2.3% of in 2% of patients taking 12% of patients taking patients taking patients taking rivaroxaban and 5% of edoxaban and 19% of dabigatran etexilate apixaban patients and those receiving those taking warfarin and 4.6% of those 5.0% of those taking enoxaparin or VKA (HR ¼ 0.64; 95% CI, taking warfarin enoxaparin and (HR ¼ 0.42; 95% CI, 0.45e0.92; P ¼ 0.017) 0.19e0.99) warfarin (RR ¼ 0.45; 95% CI, 0.08e2.46) AMPLIFY ¼ Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy; CRNM ¼ clinically relevant nonmajor; EINSTEIN-DVT ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Deep Vein Thrombosis; EINSTEIN-PE ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism; HR ¼ hazard ratio; RE-COVER ¼ Randomized Trial of Dabigatran Versus Warfarin in the Treatment of Acute Venous Thromboembolism; RR ¼ relative risk; VKA ¼ vitamin K agonist; VTE ¼ venous thromboembolism. * Major bleeding and CRNM bleeding were defined according to the International Society on Thrombosis Haemostasis bleeding scale. VKA was dose adjusted to international normalized ratio of 2.0e3.0. warfarin.26 In both subgroup analyses, however, the rates of recurrent VTE and bleeding were lower in the NOAC groups than in their warfarin counterparts, maintaining their noninferiority to standard anticoagulation treatment in patients with mild-to-moderate renal impairment (Table V).25,26 Advanced Age In conjunction with the investigations on the effect of renal impairment, subgroup analyses regarding elderly patients (75 years old) were additionally performed for dabigatran etexilate and rivaroxaban. Analysis of the RE-COVER II subgroups revealed no increase in VTE recurrence or bleeding in older (75 years old) versus younger (75 years, CLCR
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The idea in which drugs are taken from an idea to wide-scale use in humans and
animals is called the drug discovery process. This process involves the discovery of drugs,
every clinical phase of tests and processes in which the approvals happen. This essay will
demonstrate the processes by identifying the approval process of a new drug and what lessons
to learn from ongoing and already done clinical trials with a focus on Rivaroxaban. The essay
will discuss real-world safety issues after approval and how they can be mitigated. The essay
will lastly address what could have been done correctly.
Approval process
Rivaroxaban was approved by the ACS, in 2011, as a drug to prevent blood clots
relating to deep vein thrombosis. However, the FDA refused to approve the drug under the
same indications tested by ACS because there was no follow-up data to prove the results of
the indications. Although the processes used by the FDA and the EMA to approve i...

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