August 21, 2023

Were the appropriate QMS elements / Risk Management elements addressed in the paper(s)?

Read two of your peers’ papers . Provide analysis and additional consideration for the process or the QMS integration. Comment on anything that may have been missed or done well.

Based on each company’s issues:

1)Were the appropriate QMS elements / Risk Management elements addressed in the paper(s)?

2)What additional QMS elements . Risk Management element do you recommend adding?

3)What consideration should have been included for those elements and why?

Requirements: NA

RISK MANAGEMENT PROPOSAL FOR VIOXX, A MERCK DRUG PRODUCT Shireen Abesteh MSRC-435 08-13-2023

Shireen Abesteh MSRC-435 1 Introduction Merck is an American biopharmaceutical company that was originally set up as a fine chemicals supplier, however in the early 1930s transitioned to a focus in pharmaceutical research. Today, the company is headquartered in Kenilworth, New Jersey and is one of the largest pharmaceutical companies in the world. They develop and manufacture a broad range of human health products, such as medicines, biologic therapies, and vaccines. Merck’s popular products include Januvia (for Type 2 diabetes), Singulair (to treat asthma), and NuvaRing (contraception). They are also known for their animal health division, making vaccines and diabetes treatments for cats and dogs. Although Merck rakes in tens of billions of dollars per year, they have had their share of legal troubles with thousands of lawsuits, including criminal charges for price gouging (Compton, 2022). Merck is well-known for its Vioxx scandal, a painkiller developed to be an alternative to naproxen because of the claim that it caused fewer gastrointestinal problems. Vioxx was one of Merck’s top five most profitable drugs, however it was withdrawn by Merck in September 2004 due to numerous epidemiological studies showing that Vioxx increased risk of cardiovascular problems. The drug was approved in 1999 to treat pain and stiffness caused by arthritis for both children and adults (O’Rourke, 2006). There are many decision-making factors that Merck was faced with starting in 1999 when the drug first came to market and in 2004, when it was withdrawn from the market (Prakash and Valentine, 2007). In this time frame, more than 80 million people were prescribed Vioxx, and 20 million patients consumed Vioxx. In June 2006, published research estimated 88,000 Americans had heart attacks from taking Vioxx and 38,000 of those patients died (Greener, 2005). Vioxx impacted Merck severely- both their public image and business. Plaintiffs filed around 6400 lawsuits claiming that Vioxx caused their heart attacks or strokes. Instead of settling, Merck vowed to fight every single case in court and set aside approximately $700 million towards this effort (Zwillich, 2005). However, it is clearly known today that the decision-making behind Vioxx staying on the market for 5 years was unethical.

Shireen Abesteh MSRC-435 2 Those on the Data Monitoring Committee (DMC) of the VIGOR trials were financially motivated to say positive things about the drug. There was a lack of Standard Operating Procedures (SOPs) including a proper data analysis plan to assess the interim data indicating Vioxx poses a great risk to the population. To summarize the risk assessment, there are many failure modes associated with the fall of Vioxx, including data exclusion from the VIGOR trial and assumptions about Vioxx being safe, hence the DMC continuing with the trial. There is also residual risk present as the FDA confirmed that risks from Vioxx persist even one year after patients stop taking the drug, which poses a significant risk for the elderly especially (Prakash, 2006). This risk integration proposal will include the implementation of three Quality Management System elements: [1] Establish a reliable basis for decision making and planning. One of the top failures is the decision-making process of the DMC to continue testing Vioxx when it should have been halted. A key part of this is that risk management should be systematic, structured, and timely (Perez, 2012). This element includes evidence-based decision making. [2] Building a risk management framework starting with the Vioxx design process using FMEA and risk-benefit analysis. [3] Continuous improvement through organizational learning and risk communication with patients and other external parties to mitigate risk. QMS #1 – Data (post-production) This QMS focuses on integrating processes into the withdrawal segment of Merck’s journey with Vioxx. When concerns first arose in 2000 about the safety of Vioxx, Merck officials insisted that these claims regarding cardiovascular risk were false. Regardless, the FDA forced Merck to revise the label for Vioxx to warn patients of this risk. It is troubling to find out that internal company documents show that Merck had tried to downplay the drug’s alleged risks for years and published misleading statements about Vioxx via marketing documents and scientific journals. Merck representatives were trained to avoid directly answering questions from doctors. After the APPROVe clinical

Shireen Abesteh MSRC-435 3 trial ended in 2004, which showed statistically significant data that patients taking Vioxx had a likely chance of experiencing heart attacks compared to placebos, did Merck decide to withdraw the drug (Cavusgil, 2007). This was not a mandated recall from the FDA. As mentioned, this is not a mandated recall; however, I would still propose that the Merck team should have performed some sort of Health Hazard Evaluation after receiving this perplex data to better inform their decision making. One factor to consider is whether any disease or injury has already occurred from the product. Another is a gathering of scientific documentation whether any existing condition could expose those in the VIGOR trial or otherwise to a health hazard, paying attention to those at a greater risk. Lastly, an assessment of the degree of seriousness of the cardiovascular risks to various segments of the population, including children and adults. This could be done through an internal or external audit of the data collected during the VIGOR trial. I recommend that an external audit from parties without financial ties to Merck should be performed to classify the findings as critical, major, or minor. This audit program is a risk management tool that the Quality team at Merck would support and create a risk score for every department, not just post-production data. This includes product manufacturing, packaging, quality, training, warehouse, etc. (Perez, 2012). Additionally, in thinking about integrating risk management, I propose a clear outline of supporting statistical tools to enable quantitative quality risk management. This should have been more carefully implemented into the VIGOR trial to determine the statistical significance of the data sets for more reliable decision making. QMS #2 – Design Enabling proper risk assessments of biotechnology products within the company starts with upper management upholding quality values and complying with ICH Q9 guidelines. There is an inherent degree of risk associated with development, manufacturing, and distributing drug products. Using formal procedures, such as SOPs, and having effective training methods and resources are vital for reducing risk. One risk assessment tool that would be valuable for the Merck team to use is an FMEA (failure

Shireen Abesteh MSRC-435 4 modes and effects analysis) to rank risks based on variables with designing Vioxx. I think it would be valuable for management to work with employees within product teams to discuss design options and the associated risks with each outcome. A major goal of Vioxx is to replace naproxen on the market. COX-2 inhibitors can treat a variety of diseases and symptoms associated with chronic pain. Some factors to consider of COX inhibitors are the mechanism of action, adverse effects and contradictions, a review of the toxicity associated, and team strategies for improving care coordination/communication to improve outcomes (Qureshi, 2019). Vioxx is a non-aspirin cox inhibitor, therefore it increases the risk of cardiovascular events, especially myocardial infection. This should be taken into consideration during the design of the drug. One way to effectively facilitate risk management is through flowcharts and process mapping. Having a map of the design process and manufacturing process can help communicate the logic to stakeholders. Was there a lower-level failure associated with Vioxx that could have reduced the risk of cardiovascular events? This failure was likely at the design stage of the process (separate from the post-production data/voluntary recall). The output of the FMEA could then be used as a basis for the design of Vioxx or guide resource deployment (Perez, 2012). FMEA could also be provided as an input into Fault Tree Analysis (FTA). This process should be implemented for future drug design risk management at Merck. The FMEA process should entail the following: [1] Define scope and assemble FMEA team. [2] Analyze process and break into steps [3] Identify the failure modes, consequences, and current controls [4] Calculate the Risk Priority Number (RPN) [5] Establish preventive action to mitigate high priority RPNs [6] Recalculate RPN Lastly, a quantitative risk benefit assessment (RBA) should be built into the risk management framework. With COX-II inhibitors, for example, the risk-benefit ratios are constantly changing over time, as it is an innovative drug such as Vioxx. Therefore, a systematic RBA reassessment should be integrated into Merck’s drug development

Shireen Abesteh MSRC-435 5 process. This can ultimately allow for an additional commitment to safety and contribute to clinical decision-making. One study shows that employing RBA methodologies by pharmaceutical industries can help disclose useful information to inform the company and the public. The following was documented as standard notions of risk and benefit that would be useful in quantifying and defining RBA: [1] Understanding relative risk (RR) by considering differences in exposure to the drug. [2] Calculating attributable risk (AR) to measure the absolute adverse drug events (ADEs) between those who took the placebo and those who were exposed to the drug. Population-based AR is an extension of this, specifically important for public health decision makers. [3] The benefit defined as the ability to reduce an ADE using relative risk reduction (RRR). RBA can be integrated into QMS and act as a guide for making more objective and transparent decisions regarding drug efficacy and safety. One thing to consider is that there should be universal applicability across Merck’s products to allow for inclusiveness. The process should have the ability to incorporate uncertainty, economic evaluations of medications, and have a consistent RBA threshold. This could be a supplemental tool to inform more risk management decision making within the company (Guo et al., 2010). QMS #3 – Service One area Merck desperately needs to improve is risk communication especially in light of Vioxx’s marketing fibs. Management should promote risk awareness through a risk management framework. I recommend management to do the following: [1] Establish and communicate a risk management policy. [2] Periodically review the framework to support organizational performance. [3] Ensure the organization’s culture and risk management policy are aligned (Perez, 2012). [4] Assign accountability and responsibility at the appropriate levels.

Shireen Abesteh MSRC-435 6 By starting with a cultural change at the company, interested parties, such as regulators, the patient, or any industry authority can have the full picture about the risks to quality. It is important to mention that Australian court findings on Vioxx were especially detrimental to Merck, as the conclusion was that Merck’s Australian subsidiary manufacturing Vioxx engaged in negligent and misleading behavior by failing to warn patients about the risks and overemphasized its safety (Moynihan, 2010). This became a class action lawsuit which exposed Merck for trying to discredit doctors critical of Vioxx and even paid experts to help promote it. Through proper risk communication towards patients and affected parties, Vioxx’s devastating impact could have been minimized. One case study from China regarding risk communication during the SARS outbreak showed that risk communication guideline development/implementation and training for public health professionals (including spokespeople) was able to contribute towards enabling global health security (Frost et al., 2019). A similar proposal can be initiated within Merck. Since it is such a large worldwide company, all sites and subsidiaries need to be aligned on risk communication when there is a risk exposure to mitigate it for patients and provide that transparency patients deserve. Roles and Responsibilities [1] Leadership and Risk Management Owner: Ensures collaboration and transparency between parties. Understands risks properly and has deep subject matter knowledge to help protect long-term project success. Ensure risk management is properly implemented. [2] Reviewers: Quality team reviews requirements have been met and complies with ICH Q9 and other relevant guidelines. [3] Subject Matter Experts perform risk analysis when a decision needs to made using multiple different methodologies to help inform decision-making. [4] Individuals with approval authority: Accounts for the business aspect of risk management and makes decisions based on guidance from Leadership. Participates in the risk identification process.

Shireen Abesteh MSRC-435 7 Process Leadership and Risk Management Owner Reviewers Subject Matter Experts Individuals with approval authority Develop risk management plan for risk assessments, data analysis, and risk communication R C C I Review product design and development I A R A Determine acceptable risk via risk acceptance criteria A R C I Verify risk control measurements have been implemented R C I A Verify that the implementation is effective A R R I Monitor and measure post-production information, including documentation of decisions based on risk analysis A R C I R = Responsible, A = Accountable, C = Consulted, I = Informed See Gantt chart for further information. The following metrics should be assessed to monitor effectiveness of the risk management process: [1] Active risk surveys of the drug to screen risks before they are shown as adverse events. The adverse events should be recorded in detail using FTAs or 5 whys to get at the root cause and failure modes if present. [2] Reduction of adverse events during clinical trials or after fast-track approval of drug product. [3] Monitor senior management commitment to being risk champions and risk communicators. [4] Assess data storage techniques and identify gaps in the process for improvement. [5] Compare risk assessment with actual outcomes to further iterate on the process.

Shireen Abesteh MSRC-435 8 The above-mentioned metrics and monitoring techniques should be used for implementing a successful QMS so that a tragedy such as Vioxx does not happen again at Merck. These support the QMS because they monitor pain points that have been identified within the risk management process including data collection, interpretation, and communication. Expected outcomes for 1-2 years: [1] Effective drug design that considers many possible scenarios of adverse events via risk assessment. This would enable Merck’s R&D process to be patient-focused, as it should be, and ultimately reduce the likelihood of SAEs in consecutive studies/trials. [2] Several meetings and reviews of the risk assessment process for a new drug proposal to look for improvements. [3] Better data storage within the company that can be clearly communicated to external parties. [4] Automated data analysis to eliminate bias and enables clear decision making from the Data Monitoring Committee. Expected outcomes for 3-5 years: [1] Cultural change within the quality mindset in the company. [2] Public and patient trust in Merck’s drug products. [3] More stakeholder involvement upfront in the process.

Shireen Abesteh MSRC-435 9 References Cavusgil. (2007). Merck and Vioxx: An Examination of an Ethical Decision-Making Model. Journal of Business Ethics, 76(4), 451–461. https://doi.org/10.1007/s10551-006-9302-3 Compton, K. (2022). Merck & Co. Drugwatch. https://www.drugwatch.com/manufacturers/merck/#:~:text=Merck%20%26%20Co.%20began%20in%201668,became%20a%20manufacturer%20in%201827. Frost, M., Li, R., Moolenaar, R., Mao, Q., & Xie, R. (2019). Progress in public health risk communication in China: lessons learned from SARS to H7N9. BMC public health, 19(Suppl 3), 475. https://doi.org/10.1186/s12889-019-6778-1 Greener M. (2005). Drug safety on trial. Last year’s withdrawal of the anti-arthritis drug Vioxx triggered a debate about how to better monitor drug safety even after approval. EMBO reports, 6(3), 202–204. https://doi.org/10.1038/sj.embor.7400353 Guo, Pandey, S., Doyle, J., Bian, B., Lis, Y., & Raisch, D. W. (2010). A Review of Quantitative Risk–Benefit Methodologies for Assessing Drug Safety and Efficacy—Report of the ISPOR Risk–Benefit Management Working Group. Value in Health, 13(5), 657–666. https://doi.org/10.1111/j.1524-4733.2010.00725.x Moynihan. (2010). Australian court findings on Vioxx may have global ramifications. BMJ, 340(mar16 3), c1485–c1485. https://doi.org/10.1136/bmj.c1485 O’Rourke, J. S. (2006). Merck & Co. Inc.: communication lessons from the withdrawal of Vioxx. Journal of Business Strategy, 27(4), 11-22. Pérez, J. R. (2012). Quality Risk Management in the FDA-Regulated Industry. ASQ Quality Press. Prakash, S. (2006). Data: Vioxx Heart Risks Began Earlier than Thought. National Public Radio. Retrieved from https://www.npr.org/2006/05/18/5413812/data-vioxx-heart-risks-began-earlier- than-thought Prakash, S. and Valentine, V. (2007). Timeline: The Rise and Fall of Vioxx. National Public Radio. Retrieved from https://www.npr.org/2007/11/10/5470430/timeline-the-rise-and-fall-of- vioxx#:~:text=Research%20later%20published%20in%20the,and%2038%2C000%20of%20the m%20died. Qureshi, O., & Dua, A. (2019). COX inhibitors. National Library of Medicine. https://www.ncbi.nlm.nih.gov/books/NBK549795/

Shireen Abesteh MSRC-435 10 Zwillich. (2005). How Vioxx is changing US drug regulation: Merck & Co now faces more than 6000 lawsuits involving the COX2 inhibitor rofecoxib, marketed as Vioxx. But no matter how these legal battles are resolved, the cases are already having an impact on how the pharmaceutical industry and government regulators do business. The Lancet (British Edition), 366(9499), 1763–.

2841118252Mar ’22Apr ’22May ’22MSRC 4350h0% For Data Analysis Post-Production0h0% Develop risk management plan for data acquisition and analysis00% Determine acceptable risk vs risk acceptance criteria00% Train employees (using SOPs) via SMEs on data acquisition and storage00% Verify risk measurements are implemented00% Perform an assessment to ensure implementation has been effective00% Generate a status report and plan for monitoring and measuring incom…00% Document decision making process and findings for improvement00% Communicate risk to external parties00% For Product Design and Development0h0% Perform a literature review on COX-II inhibitors and potential adverse e…00% Decide on goals of the product00% Assemble FMEA team00% Establish performance metrics00% Establish preventive action to mitigate high priority RPNs00%Powered by TCPDF (www.tcpdf.org)

Integrated Risk Management Process Research Paper Alexandra Backlund Northwestern University School of Professional Studies MSRC 435 DL SEC 55 Professor Robert Lechton August 13, 2023

2 Establishing a Quality Management System for Biomedical Devices: Lessons from St. Jude Medical Inc. St. Jude Medical, Incorporated was a biotechnology company that specialized in the produc�on and distribu�on of cardiac medical devices and associated equipment in the biomedical device industry. Founded in St. Paul Minnesota, St. Jude Medical originated a�er a group of scien�sts developed the mechanical heart valve at the University of Minnesota in the 1970s, and the organiza�on aimed to further cardiovascular device development (Encyclopeida.com, 2018). These devices primarily include implantable cardiac medical instruments such as heart valves, cardioverter deﬁbrillators for various heart arrhythmias, pacemakers, and cardiac catheters (Encyclopeida.com, 2018). A�er receiving full Food and Drug Administra�on Approval for its mechanical heart value in 1982. St. Jude Medical transformed into a prominent global lead in the cardiac medical device industry and expanded to facili�es across the world in addi�on to forming many partnerships and joint ventures over the years (Encyclopeida.com, 2018). Throughout the many years of cardiac device innova�on, St. Jude Medical developed a myriad of devices that signiﬁcantly impacted the prognosis of cardiac condi�ons and incorporated notorious technologies, one of which is called Mediguide which is a 3-dimensional naviga�on system in which cardiac anatomy can be viewed via a pre-recorded ﬂuoroscopic image (Diagnos�c and Interven�onal Cardiology, 2012). Other signiﬁcant biotechnological developments include Nanotism which is a leadless pacemaker device and CardioMems which is a wireless sensor directly implanted in the pulmonary artery that can provide instantaneous blood pressure readings (Hodsden, 2016). Due to the vast array of cardiac complica�ons, the need for technological innova�on to treat these speciﬁc condi�ons was apparent. St. Jude Medical built oﬀ the revolu�onary bileaﬂet mechanical heart valve product that was developed in 1972 which used a new material type of pyroly�c carbon, which can remain in the human body for years and does not form blood clots (Encyclopedia.com, 2018). Success was found in cardiac biomedical device produc�on, speciﬁcally in the Implantable Cardiac Deﬁbrillator (ICD) devices used to treat cardiac arrhythmia (Oﬃce of Public Aﬀairs, 2021). According to the Mayo Clinic (2023), cardiac arrhythmia is a comprehensive medical term for heartbeat irregulari�es stemming from various sources such as rapid heartbeat known as

3 tachycardia such as atrial ﬁbrilla�on, atrial ﬂuter, supraventricular tachycardia, ventricular ﬁbrilla�on, and ventricular tachycardia and low heartbeat known as bradycardia such as conduc�on block and sick sinus syndrome (Mayo Clinic, 2023). Implantable Cardiac Deﬁbrillators are small, surgically implanted devices placed subcutaneously into a pa�ent’s chest region near the collarbone and contain lithium batery-operated devices that analyze a pa�ent’s heart rhythm via wires referred to as leads, which establish a connec�on between the device and the heart (Turner, 2022). The leads rely on computerized technology from the ICD device to detect any irregular heartbeat and in response can send an electric shock to the heart to restrain regular cardiac rhythm heart (Turner, 2022). St. Jude Medical Inc. also developed a sister ICD product called Cardiac Resynchroniza�on Therapy Deﬁbrillators (CRT-D) which func�on as pacemakers, meaning they are designed to transmit electrical impulses to the heart when in instances of sinus bradycardia (Turner, 2022). Together, these two types of cardioverter deﬁbrillators can provide life-sustaining treatment for ventricular arrhythmias (Oﬃce of Public Aﬀairs, 2021). Although these products can have a presence of ongoing beneﬁts for pa�ents, detrimental design malfunc�ons emerged with both forms of ICD device bateries between 2014 and 2017, in which premature device batery failures caused death in 2014 at Duke University (Turner, 2022). As a response to the presented catastrophic risk scenario, St. Jude Medical atempted to ﬁx the mechanical issue with the batery in 2015 and con�nued to manufacture and sell the ICD devices without a new product design (Oﬃce of Public Aﬀairs, 2021). Due to St. Jude Medical’s mismanagement of this risk assessment plan, another pa�ent tragically died in 2016 due to the same result of a premature batery failure in addi�on to numerous reported safety events from medical teams across the country, speciﬁcally repor�ng 729 safety events and 29 major safety events directly due to the ICD device loss of pacing due to the lithium batery short-circui�ng (Oﬃce of Public Aﬀairs, 2021). Although the first instance of device malfunction occurred in 2014, it is inferred that the first defective ICD and ICD CRT-D devices were based on product model identification tracing, manufactured in early 2010, yet the actual date is unknown (Turner, 2022).

4 Due to the reported medical device major safety breaches, The U.S. Food and Drug Administra�on (FDA) conducted an inves�ga�on into the proposed concerns for the St. Jude Medical Inc ICD and ICD CRT-D devices, speciﬁcally that of the Fortify and Fortify Assura, Quadra Assura, Unify, Unify Assura, and Unify Quadra models which fell under the direct product classiﬁca�on of “deﬁbrillator, automa�c implantable cardioverter, with cardiac resynchroniza�on (CRT-D)” (U.S. Food and Drug Administra�on, 2016). The inves�ga�on resulted in a direct Class I FDA Recall, ini�a�ng the removal of the associated products from the market to prevent further harm. Speciﬁcally, Class I Recalls are the most severe form of recalls, deﬁned by the FDA as scenarios “in which there is a reasonable probability that the use of or exposure to a viola�ve product will cause serious adverse health consequences or death” (Oﬃce of Regulatory Aﬀairs, 2014). According to the FDA’s Class I device recall leter posted on October 21, 2016, the recall reason is for device design malfunc�on, the number of devices recalled equates to 193,954 device units (U.S. Food and Drug Administra�on, 2016). The associated product models of the devices are as follows: “Quadra Assura, Model No. CD3265-40, CD3265-40Q, CD3365-40C, CD3365-40Q and Quadra Assura MP, Model No. CD3269-40, CD3269-40Q, CD3369-40”’ (U.S. Food and Drug Administra�on, 2016). The two pa�ent deaths, numerous adverse events, and the poten�ality for subsequent a�er-eﬀects due to the faulty devices s�ll being implanted in pa�ents support the FDA’s evidence for this recall classiﬁca�on. As a result, St. Jude Medical sent a leter in April 2017 to all impacted customers to inform them of a major global recall due to a batery malfunc�on, which serves as a risk to all pa�ents who currently have an implanted device (Oﬃce of Public Aﬀairs, 2021). Yet, the residual risk was imposed as the defec�ve devices were s�ll being distributed and used by pa�ents and caused subsequent adverse events, highligh�ng concerns about a faulty risk management plan and transparency of the issue, and as a result, St. Jude Medical Inc. agreed to a $27 million setlement (Oﬃce of Public Aﬀairs, 2021). Because these devices were directly implanted into pa�ents and because these devices caused serious harm, the impact was catastrophic. To make maters worse, the inappropriate risk response and ac�ons By St. Jude Medical, which con�nued to ship faulty devices, directly impacted the health and safety of other pa�ents even a�er the risk was known.

5 Following the FDA recall, the subsequent inves�ga�on by The United States Defense Criminal Inves�ga�ve Service (DCIS) concluded that St. Jude Medical knowingly con�nued to sell defec�ve ICD devices that were implanted into pa�ents (Oﬃce of Public Aﬀairs, 2021). St. Jude Medical has since been acquired by Abbot Laboratories in 2017, with the acquisi�on collabora�on covering a merged por�olio of a staggering $30 billion cardiovascular medical device market (Abbot Laboratories, 2017). This merger allowed further development of these cardiovascular products and ini�ated innova�ve approaches for cardiac interven�on and specializing in aid for cardiac disorders including but not limited to heart failure, chronic pain, atrial ﬁbrilla�on, and mitral valve disease (Abbot Laboratories, 2017). In an analysis of the hazardous situa�on per the Interna�onal Organiza�on for Standardiza�on (ISO) 14971 guidelines (2019) which establish risk management tools for biomedical devices, the hazard, foreseeable sequence of events, failure modes, hazardous situa�on, and harm are categorized as follows: Hazard Foreseeable Sequence of Events Failure Modes Hazardous Situa�on Harm ICD device malfunc�on due to batery failure. Premature device batery defects lead to loss of pacing in the devices. 1) Inadequate design of the ICD product 2) Inadequate design of product bateries 3) Inadequate tes�ng measures of product 4) Incorrect decision to forego product recall a�er ﬁrst major safety breach. 5) Inadequate communica�on by St. Jude Medical, Inc. to inform aﬀected customers and pa�ents. 6) Inadequate established risk management plan 7) Con�nuance of faulty device distribu�on a�er ﬁrst defects were discovered. Batery failure in ICD devices can lead to loss of pacing in pa�ents. Occurrences of major safety incidents including death and residual risk for devices s�ll implanted in pa�ents. High Risk – Catastrophic (Interna�onal Organiza�on for Standardiza�on: 14971, 2019). In the United States, The Code of Federal Regula�ons Sec�on 820.5 enforces that manufacturers of medical devices enforce quality management systems (21 CFR 820.5, 2018). Recent FDA guidance suggests

6 integra�ng the Interna�onal Organiza�on for Standardiza�on (ISO) 13485 (2016) for regulatory review of quality management systems of biomedical devices (Center for Devices and Radiological Health, 2022). The speciﬁcs for Quality Management Systems (QMS) for medical devices in ISO 13485 are listed in speciﬁc that lay out quality management systems for medical devices, and also require the incorpora�on of an organiza�on’s quality management system to ensure its products meet regulatory requirements and customer expecta�ons (Interna�onal Standards Organiza�on, 2016). It is evident that the integra�on of a QMS plan into St. Jude Medical systems could greatly assist the company’s reputa�on and its product produc�on moving forward. Speciﬁcally, this QMS plan will follow ISO 13485 standards which focus on product manufacturing and quality management, risk management, regulatory adherence, and product tracing (Interna�onal Standards Organiza�on, 2016). A strong QMS analysis should begin with an assessment of current product development and produc�on, the iden�ﬁca�on of any obvious hazards in the current standard opera�ng procedures, and should aim to control foreseeable hazards before they occur (Lechton, 2023). St. Jude Medical’s QMS analysis will focus on the overarching issues that were categorized as high risk and catastrophic per ISO 14971 due to their impact on pa�ent safety, which include the following: 1) failure of the device func�on, 2) failure to ini�ate an ini�al recall of the product, and 3) poor transparency to the public with device defects. First, the QMS plan will address the overarching issue of company oversight of product safety in the defec�ve device design. The ICD device malfunc�on occurred due to a design fault of which lithium clusters formed on some of the bateries (Oﬃce of Public Aﬀairs, 2021). Since the ICD device products are designed to detect cardiac arrhythmias which can have severe to fatal eﬀects, defects in the devices can directly aﬀect pa�ents’ safety so the risk assessment can be categorized as high with catastrophic implica�ons. Per ISO 13485 7.3.5-7.37, product designs must be thoroughly reviewed to abide by all regula�ons, and per ISO 13485 7.3.9, if any updates to the design are required, established guidelines and measures must be followed to accurately review and approve design changes (Interna�onal Standards Organiza�on, 2016). Here, St. Jude Medical must review the ini�al faulty design of the ICD devices and their

7 associated bateries to determine where exactly the fault is at play and then need to establish appropriate standard opera�ng procedures with a documenta�on when the product design is updated. It is evident that this system was not ini�ally followed since the ICD devices with defec�ve designs were s�ll manufactured without a redesign, even though St. Jude Medical was oﬃcially no�ﬁed of their defects (Oﬃce of Public Aﬀairs, 2021). A checks and balances system will be established for design development, review, and veriﬁca�on, and proposed changes per ISO 13485 will prevent an issue with product design in the future (Interna�onal Standards Organiza�on, 2016). This process can occur by implemen�ng a documenta�on storage system which will include documenta�on product design veriﬁca�on, proposals for design updates, and conﬁrma�on of any design changes. Addi�onally, this storage system will have an electronic audit trail to document all device design decisions which can be accessed by the appropriate personnel. Next, the QMS plan will address the lack of a risk management plan and the failure of St. Jude Medical to recall the device, even a�er receiving data on a pa�ent casualty. Although it is a tricky situa�on that involves the recall of implanted devices, St. Jude Medical is directly at fault due to its failure to halt manufacturing of the faulty design of the ICD device and for its con�nuance to ship the devices to hospitals, which subsequently allowed the devices to be implanted in addi�onal pa�ents, leading to increased risk and catastrophic results (Oﬃce of Public Aﬀairs, 2021). When the eventual recall was issued by St. Jude Medical in August 2016, it was too late since addi�onal incidents directly related to defec�ve bateries occurred, resul�ng in a loss of pacing incidents an addi�onal death, and thousands of more device implants (Oﬃce of Public Aﬀairs, 2021). Per ISO 13485 8.3.2, organiza�ons must establish a risk management plan to adequately handle product recalls, including a series of objec�ves to review to determine if the medical device must be pulled from the market (Interna�onal Standards Organiza�on, 2016). Here, St. Jude Medical must review the presented objec�ves to determine if the product met the means for recall. Since the ini�al incidents of product defect caused adverse events and pa�ent death, it can be inferred that the situa�on was high-risk and the product recall at this �me was required. The establishment of a beter risk management system for poten�al product recalls will prac�ce will establish a standardized plan for future events. Addi�onally, ISO

8 13485 8.5.2 and 8.5.3 lay out the framework for the implementa�on of Correc�ve and Preventa�ve Ac�on Plans (CAPAs), which will help to iden�fy the root cause of the product defect a�er produc�on is halted and will determine if a total product recall is required (Interna�onal Standards Organiza�on, 2016). Furthermore, the establishment of the preventa�ve ac�on component of the CAPA will ensure there are policies in place to avoid this catastrophe in the future. Thirdly, the QMS plan will focus on the failure of St. Jude Medical to provide transparency and accuracy of the situa�on due to a lack of communica�on to the public, which the consequences were found in the subsequent inves�ga�on by the U.S. Department of Jus�ce. Communica�on improvement is a crucial step of the QMS plan as St. Jude Medical’s products con�nued to be implanted in human subjects due to their failure to communicate known signiﬁcant device safety hazards, leading to high-risk behaviors and catastrophic results (Oﬃce of Public Aﬀairs, 2021). ISO 13485 7.4.3 and 8.4.2 highlight the importance of communica�on in �mes of product risk management, including the requirement for organiza�ons to accurately communicate new safety ﬁndings with authori�es and impacted subjects in a �mely manner (Interna�onal Standards Organiza�on, 2016). In turn, the establishment of proper communica�on methods and internal quality control checks of safety repor�ng will help prevent addi�onal major safety events in the future. The enforcement of eﬀec�ve communica�on regarding any device faults and instruc�ons on what to do in these events must occur, including the establishment of a secure portal for pa�ents to immediately no�fy the company of any device malfunc�ons, the re-training of employees on the importance of communica�on, no�fying customers and staﬀ members about any new product defects, and le�ng the public know immediately when major safety breaches occur. To ensure the ongoing success of the QMS plan and to avoid another signiﬁcant safety breach of the product, it is essen�al to focus on a top management buydown approach to address the issues. All three of the QMS addressed items of could have been avoided if a beter-quality management system was already in place. It is obvious that there need to be dras�c changes in company leadership as the noted ﬂaws have major ethical, mechanical, and safety viola�ons. Therefore, top management should impose new measures

9 to ensure that a situa�on such as this does not happen again, which can include but is not limited to quality control checks of all products, the establishment of, risk management and mi�ga�on plans, and the ini�a�on of a predisposed crisis management plan (Lechton, 2023). Addi�onally, these quality control checks will apply speciﬁcally to the manufacturing, packaging, and labeling of the IVD devices to abide by ICH Current Good Manufacturing Prac�ce (CGMP) guidelines (21 CFR 820.1, 2018). Company funding will be pulled away from new device innova�on in the interim as the priority needs to be in risk response and mi�ga�on of current devices, instead of funding new devices without the establishment of these compliance measures. Finally, rou�ne spot checks and audits by third-party contractors will ensure the processes are followed objec�vely and free of bias. In addi�on to the safeguards put into eﬀect under the top management buydown approach, the implementa�on of addi�onal regulatory measures for all employees is required. This includes the establishment of educa�on con�nua�on for all manufactured products, including speciﬁcs about product design, safety, and risk control, and will limit variances in produc�on which will, in turn, produce safer products (Lechton, 2023). Addi�onal product sustainability measures be conducted per ISO 8.2.3 guidelines and will include rou�ne safety tes�ng of all devices, a review of submited product-related adverse events in real-�me, and the establishment of monitoring plans that include rou�ne measurements and inspec�ons of products, documenta�on that these measures occurred per ISO 13485 8.2.4 (Interna�onal Standards Organiza�on, 2016). Special guidance will be made for any outsourced manufactured product to ensure it abides by St. Jude Medical guidelines, and these metrics will be measured over the course of 2 and 5-year periods to ensure their eﬀect. The eﬀec�veness of these implica�ons will be measured via the recorded rate of device incidents, the amount of �me it takes for the company to complete a root cause analysis to determine poten�al product recalls, CAPA �melines, an analysis of proposed preventa�ve measures, and the assessment of device adverse events over �me. Even a�er the establishment of these measures, all data will be reviewed on a quarterly basis to check for any new or residual risk.

10 References Abbot Laboratories. (2017). Abbott Completes the Acquisition of St. Jude Medical. Abbott MediaRoom. https://abbott.mediaroom.com/2017-01-04-Abbott-Completes-the-Acquisition-of-St-Jude-Medical Bruun, A. M. (2023). Medical Device Quality Management System (QMS). SimplerQMS. https://www.simplerqms.com/medical-device-quality-management-system/#:~:text=A%20Medical%20Device%20Quality%20Management,effective%20for%20their%20intended%20use Center for Devices and Radiological Health. (2022, February 22). Quality System (QS) Regulation/Medical Device Good Manufacturing Practices. U.S. Food and Drug Administration. https://www.fda.gov/medical-devices/postmarket-requirements-devices/quality-system-qs-regulationmedical-device-good-manufacturing-practices Diagnositc and Interventioanl Cardiology. (2012, October 8). St. Jude Medical announces launch of its MediGuide technology. DAIC.. https://www.dicardiology.com/product/st-jude-medical-announces-launch-its-mediguide-technology Encyclopedia.com. (2018, May 23). St. Jude Medical Inc. https://www.encyclopedia.com/social-sciences-and-law/economics-business-and-labor/businesses-and-occupations/st-jude-medical-inc#1 Hodsden, S. (2016, April 22). St. Jude “on track” With heart failure portfolio, cardiac rhythm still “under pressure.” Med Device Online. https://www.meddeviceonline.com/doc/st-jude-on-track-with-heart-failure-portfolio-cardiac-rhythm-still-under-pressure-0001

11 International Standards Organization. (2020, March 11). ISO 13485 – Medical devices — Quality management systems — Requirements for regulatory purposes. ISO. https://www.iso.org/iso-13485-medical-devices.html International Standards Organization. (2019, December 10). ISO 14971 – Medical devices — Application of risk management to medical devices. ISO. https://www.iso.org/standard/72704.html Lechton, R. (2023). Session 6 Video: Quality Management System [Video]. Canvas. https://canvas.northwestern.edu/courses/199110/pages/session-6-videos?module_item_id=2689919 Mayo Clinic. (2023, April 21). Heart arrhythmia – Symptoms and causes – Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/heart-arrhythmia/symptoms-causes/syc-20350668 Office of Public Affairs. (2021, July 8). St. Jude Agrees to Pay $27 Million for Allegedly Selling Defective Heart Devices. U.S. Department of Justice. https://www.justice.gov/opa/pr/st-jude-agrees-pay-27-million-allegedly-selling-defective-heart-devices Office of Regulatory Affairs (2014, July 13). Recalls Background and Definitions. U.S. Food and Drug Administration. https://www.fda.gov/safety/industry-guidance-recalls/recalls-background-and-definitions Quality Systems, 21 C.F.R § 820.5 https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=820.5 Quality System Regulation, 21 C.F.R § 820.1 https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=820&showFR=1

12 U.S. Food and Drug Administra�on. (2016, October 21). Class 1 Device Recall: For�fy, Unify, Assura, including Quadra. U.S. Food And Drug Administra�on. htps://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfres/res.cfm?id=150193 Turner, T. (2022, November 22). St. Jude Medical Deﬁbrillators – Devices at risk, recalls. Drugwatch.com. htps://www.drugwatch.com/deﬁbrillators/

Integrated Risk Management Process Research Paper Alexandra Backlund Northwestern University School of Professional Studies MSRC 435 DL SEC 55 Professor Robert Lechton August 13, 2023

RISK MANAGEMENT PROPOSAL FOR VIOXX, A MERCK DRUG PRODUCT Shireen Abesteh MSRC-435 08-13-2023

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