Date:  2021-03-08 17:35:47
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The approval of medical products is necessary for the safety of the patients. In this regard, before a company is licensed to trade a medical product, the Foods and Drugs Agency must perform a due diligences exercise to get sufficient information on the safety and quality of the product. Indeed, all companies applying for a NDA/BLA for their products must demonstrate the safety, efficiency and exceptional quality of their drugs. Before approval, the drugs must undergo several tests, which are closely monitored by the FDA. These tests are meant to ensure that the drug is indeed important of the ailment that it is intended to treat. In this case, the risk versus benefits test is done. This test establishes the risks that the product poses to the patients against the benefits that the drug will bring. If the risks are more than the benefits, then a license for trade in the product will be denied unless improvements are made to mitigate the risk. This paper will examine the grounds under which the FDA approved a product known as Xarelto.

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Xarelto is the trade name for the product while its scientific name is Rivaroxaban. Johnson and Johnson Pharmaceutical Research and Development, LLC applied the approval for the product via an application number 022406Orig1s000. After review by the Office of New Drugs, Division of Drug Marketing, Advertising and Communication and Office of Surveillance and Epidemiology, the product was approved on the 1st day of July 2011. However, before approval, the product had to undergo several cycles of review (RECORD 1, 2, 3, 4). After passing all those tests, the drug was then approved for use in the prophylaxis of deep vein thrombosis and pulmonary embolism. This was to be applied in patients undergoing either a surgery for the replacement of the hip or a surgery for the replacement of the knee. The following were stated as the grounds for approval by the relevant regulatory body.

Xarelto is one of those products that emerged from the increased developments in the understanding of coagulation pathways by the biological and chemical scientists. In this regard, the product contains an oral Factor Xa inhibitor, which contains specific enzymes whose main target is the coagulation cascade. In this regard, Factor Xa is an effective anticoagulation that transforms prothrombin to thrombin in a better way than its comparisons. It is because of this that the Xarelto product was approved for the prophylaxis of deep vein thrombosis (DVT). If not prophylaxed, the net effect of DVT is to cause pulmonary embolism (PE) in patients undergoing a surgery for the replacement of either the hip or the knee. Compared to other similar products Xarelto is far much better and safer. In this regard, unlike Warfain, which requires anticoagulation constraints, Xarelto does not need any observance of the prombrothin time (PT). PT is a blood test that is intended to measure the time span that the blood takes to clot after surgery. In this regard, PT is used to observe patients who take particular Medications so that any clotting disorders as well as partial thromboplasting time (PTT) can be identified.

The safety of the drug was another reason as to why it was approved. In this regard Xarelto was far much safer compared to other similar products. However, at this stage, it was established that the product did not meet several standards with regard to the areas of chemistry, manufacturing, clinical safety as well as the integrity of their data. Specifically, it was very difficult to differentiate between the rivaroxaban and enoxaparan patients which is a contention that was based on the indications of liver toxicity in the collection of the aforesaid data. Therefore, the company was required to review this area. Subsequently after the review led by two doctors, the product was found to be safe. In particular, the following were the reviews and subsequent rectification that led to the approval of the product.

Chemistry Manufacturing and Control

After inspecting the issues related to chemistry, manufacturing, clinical safety as well as the integrity of their data, the committee was not satisfied with the information provided by the company about the said issues. As such, it made recommendations on the rectifications that they needed to make to convince the Clinical Pharmacology Review Team. In this regard, the company was required to provide adequate information about the drug substance with relation o the nomenclature, description. Physiochemical properties, specifications, control, primary stability data, etc. Additionally, it was the opinion of the review team that the containers and the closure systems were not adequately described. However, after review the data was confirmed.

Data Integrity

Apart from the issues related to chemistry, manufacturing and control, the review team was also not convinced by the findings of the studies that had been performed by the company on the drug substance (RECORDS 1, 2, 3, 4). Two of the data that was established after the studies were considered unreliable and hence had to be reviewed. In the third data set, serious deficiencies were noted raising concerns about the ability of the drug to protect human beings. The fourth data set was considered entirely unreliable. The reasons for these finding were that the company did not report any defects that they noted to the sponsor. Additionally, they did not obtain the required informed consent and neither did they maintain the drug accountability records. Further, it was the opinion of the review team that the subjects that were studied during the drug testing did not meet the study eligibility criteria stated in the relevant regulations. Moreover, the subjects of the study were not randomized preoperatively.

Clinical Safety

The review team had some reservations about the data on the clinical safety of the drug. Specifically, it was not satisfied with the data presented on full characterization of a potential risk for liver toxicity. As such, the review team requested for additional information relating to several aspects. First, a report had to be presented that assessed the potential signals for severe liver toxicity in any of their major ongoing clinical studies of patients with atrial fibrillation disorder. Secondly, a report enumerating the safety findings from the sponsors marketing experience for the drug. Thirdly, the review team wanted additional information on the post marketing studies initiated outside the United States. Finally, the company was required to provide a final report labeled ATLAS ACS TIMI46 study. Apart from the various issues of concern that the company was required to address, the sponsor was required to address the following;

First, the sponsor had to provide a description of the plan that the company sets up to a low strength formulation and which are intended to be used for the modification of doses in population of patients that have special requirements. The names of cartons and containers that were to be used in the packaging of the drugs had to be revised to increase the size of the graphic on the principal display panel. This was intended to make the principal display panel more pronounced than the name of the propriety or the established name. After the clinical review team made their recommendations, the sponsor made rectifications and the following were the notable ones.


The review of this supplement was done by three doctors; Dr, Chris Brown, Pope-Miksinski, and Dr. Lostritto. In their wise and competent review, they concluded that the NDA recommendations were for a 30-month shelf life for the Xarelto if packed in HDPE bottles. Additionally, they stated that the shelf life would be for 18 months when packed in blisters under the recommended temperatures (controlled room temperature).

Non-Clinical Pharmacology/Toxicology

Following the review teams recommendation, Dr. Chopra and Dr. Laniyonu made a cycle review of the same. However, they did not establish any condition that could lead to the denial of approval. When they studied wistar rats and CD-1 mice in 2-year carcinogenicity, they established an insignificant growth of tumors in the wistar rats. As such, this did not warrant any denial of the approval.

Clinical Pharmacology/Biopharmaceutics

The recommended dosage for this drug substance was 10mg per day, with or without a meal. However, for those taking the Xarelto with a strong PgP and CYP inducer, a dose modification was suggested for their sake. In relation to the cycle review, the sponsor made a commitment to propose and develop a 5mg dosage that has the same concentration and effectiveness as the one containing the 10mg. This, among other things, made the drug substance get an approval.

Clinical/Statistical Efficacy

To adhere to the recommendation of the review team about the inadequacy of information on efficiency of the drug, the doctors for the sponsors reinstated that the drug substance demonstrated efficacy in the prophylaxis of the total number of VTE patients undergoing either hip or knee replacement surgeries.

Safety and Risks versus Benefits

From the concerns of the review team on the safety of the drug substance, a team of doctors stated that there was increase in the number of bleeding events for the rivaroxaban treated patients although the increase was statistically insignificant. After the patients stopped using the rivaroxaban treatment, there was a high incidence of ischemic stroke. With regard to hepatocixity, there was no significant change in liver toxicity after the use if the drug substance. The benefits of the drug outweighed the risks hence paving the way for its approval.

After the response to the recommendation of the review team, the safety and quality of the drug substance was established. In this regard, the clinical safety, proper labeling, risk benefit assessment, and all other regulatory issues were complied with. As a result, rivaroxaban was approved by the regulatory authority for the prevention of VTE in hip and knee replacement surgeries, which was to be orally administered. The approval number was NDA 022406. In this regard, the process of approval for the drug substance was transparent and fair. The grounds for the approval were succinctly stated out in the approval letter. Specifically, the drug substance had passed all the safety and regulatory requirements. Indeed, it was safe and beneficial.


Accessdata.fda.gov,. (2016). [email protected]: FDA Approved Drug Products. Retrieved 14 February 2016, from https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=XARELTO

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