Best Practices for Interventional Cardiovascular
Transcription
Best Practices for Interventional Cardiovascular
GLOBAL MEDICAL DEVICE CRO Your goal is to give people a better quality of life. We’re proud to be a part of your mission. Best Practices for Interventional Cardiovascular Medical Device Trials This paper addresses the four clinical trial aspects Novella Clinical considers most critical for medical device developers seeking to enter the US market with implantable cardiovascular devices. These factors are regulatory requirements, reimbursement strategy, clinical challenges and vendor selection. A Novella Clinical White Paper Moving Potential. Forward. Medical Global Device MedicalDevelopment Device CRO Interventional Cardiovascular Medical Device Trials Best Practices for Interventional Cardiovascular Medical Device Trials Heart disease is the leading cause of death worldwidei, and the global cardiac medical devices market could expand to reach $65.6 billionii by 2015, due to aging populations and the prevalence of heart disease, stroke and diabetes. Significant advances in technologybased treatments continue, and bringing interventional cardiac devices to market is big business – and one that is complex. Sponsors seeking to bring implantable cardiovascular products to market, whether they are stents, valves, pacemakers, ventricular assist devices or other novel technologies, face several significant factors in designing and conducting clinical trials. Working with an experienced medical device clinical research organization (CRO) such as Novella Clinical can ensure sponsors consider and confidently address these factors with expertise and efficiency. This paper addresses the four clinical trial aspects Novella Clinical considers most critical for medical device developers seeking to enter the US market with implantable cardiovascular devices. These factors are regulatory requirements, reimbursement strategy, clinical challenges and vendor selection. Sponsors seeking to bring implantable cardiovascular products to market, whether they are stents, valves, pacemakers, ventricular assist devices or other novel technologies, face several significant factors in designing and conducting clinical trials. 2 ©2014 Novella Clinical Medical Device Development Interventional Cardiovascular Medical Device Trials The Heart of the Matter: Leading Global Health Issue Heart disease and stroke are the two leading causes of death globallyiii and rank first and fourth in the United States, respectively.iv Moreover, the total number of inpatient cardiovascular disease (CVD) operations and procedures in the US tallied almost 7.6 million in 2010, an increase of 28 percent since 2000.v Even with noted declines in the prevalence of cardiovascular (CV) risk factors, such as uncontrolled high blood pressure, elevated “bad” cholesterol, and smoking, as well as improvements in treatments and quality of care, other influencers of CVD rates such as diabetes are on the rise. The American Heart Association (AHA) notes that at least 65 percent of people with diabetes die from heart disease or stroke.vi While CVD drugs remain the mainstay of the global CV treatment market, one conservative forecast predicts the global cardiac medical devices market will grow to $65.6 billion by 2015. Regionally, North America accounts for 40 percent of the worldwide CV devices market and Europe, nearly 30 percent.vii Setting the Pace: Regulatory Requirements for Cardiovascular Devices* The existing US dominance of the CV device landscape drives many sponsors to have a strong FDA-focus in their development strategy. However, the size and duration of CV trials, the review cycles involved with the FDA, and pressures to bring a CV device to market quickly or in geographically diverse areas have many sponsors considering trial sites outside the US, which presents regulatory and study execution complexities. Some sponsors may consider the EU as the first step of their trial strategy, especially because of the potential speed to market. Indeed, a 2011 analysis found that complex medical devices received EU approvals nearly Some sponsors may consider the EU as the first step of their trial strategy, especially because of the potential speed to market four years before US approvals.viii Historically, the EU system has required less data than the FDA for approval, particularly for new products deemed substantially equivalent to approved devices. However, the European Society of Cardiology (ESC) has called for more stringent, data-based regulatory decision making in the EU. Recently proposed EU regulations would increase the safety and efficacy scrutiny of high-risk devices. If the regulations are adopted, and more are in the works, the EU approval process may decelerate to resemble the US system. Notably, the FDA’s review time of Premarket Approval (PMA) applications for medical devices increased by 75 percent from 2007 to 2011, driven by intense pressure to focus on trial-documented risks and safety in comparison to benefits.ix 3 *For this paper, references to devices address single-use interventional devices and implantable cardiovascular devices. ©2014 Novella Clinical Medical Device Development Interventional Cardiovascular Medical Device Trials While the EU regulatory timeline and requirements will likely change, Novella Clinical still frequently advises sponsors seeking global markets to consider beginning their clinical testing with a safety and efficacy pilot trial in the EU, which affords an opportunity to identify issues that must be addressed before a new clinical study protocol is submitted to the FDA. Sometimes, these data also can support an investigational device exemption (IDE) submission to the FDA. Novella Clinical often counsels sponsors seeking medical device approval supported by exclusively foreign data and can assist such sponsors as they prepare to meet with the FDA officials in a presubmission meeting. For sponsors who already have an FDA-approved protocol but wish to use it to expand clinical trials to other countries, Novella Clinical has found the national competent authorities and site-based ethics committees in India, the Czech Republic and Poland generally accept FDA-approved protocols without ... beginning clinical testing with a safety and efficacy pilot trial in the EU affords an opportunity to identify issues that must be addressed before a new clinical study protocol is submitted to the FDA. changes. In contrast, the United Kingdom frequently requests significant changes, which can create issues for sponsors seeking to pool study data, particularly if the changes affect patient populations, diagnostic tests or follow-up routines. For example, during its approval of a recent study for a novel device designed to treat mitral valve regurgitation, the UK Medicines and Healthcare Products Regulatory Agency asked for a significant limitation of the age range for patients as an inclusion criteria, as well as for additional imaging procedures, which have the potential to increase adverse events from radiation exposure and contrast agents and can complicate data analyses when pooled. Some sponsors seeking to market their devices in the UK have found it worthwhile to conduct a separate trial series to satisfy its regulatory requirements, even if the data cannot directly support a separate FDA or EU submission. Novella Clinical counsels sponsors undertaking any cross-border trials to carefully account for the standards of care that will vary from country to country because these differences will impact data acceptance in both the FDA’s and subsequent regulatory reviews. These differences can include everything from routine medical care, to screening tests to diagnose a particular condition, to concomitant medications, to treatment paradigms, to protection of participants as outlined in the Declaration of Helsinki, to data validation. In the US, the FDA may approve a PMA based solely on foreign clinical data if these data apply to “the US population and medical practice,” the clinical investigators have “recognized competence” and the FDA considers the data valid without the need for an on-site inspection or such an inspection or “appropriate means” can validate the data.x Sponsors need to capture this information using a detailed rationale that addresses why any variations from US standards will not affect the evaluation of a device’s safety and efficacy. 4 ©2014 Novella Clinical Medical Device Development Interventional Cardiovascular Medical Device Trials The US IDE process has three main categories of devices based on risk: significant risk (SR), nonsignificant risk and exempt. For US clinical studies, sponsors must receive an IDE approval from the FDA before beginning a study for a SR device. Studies for permanent implantable CV devices usually are considered SR because these devices present a potential for serious risk to the health, safety or welfare of a study participant and may support or sustain human life. The SR determination is the responsibility of the study sponsor, but the FDA is willing to help sponsors, investigators and institutional review boards (IRB) make such classification decisions. Institutional Review Board Consideration of Significant Risk Devices* Like pharmaceutical clinical trials, pacemaker might be viewed by an IRB: human studies of devices require the Would, for example, new leads, battery approval of IRB. A CRO, based on pack or software pose a SR because first-hand experience with each trial the device is used to support or sustain site’s IRB, can counsel a sponsor on the human life and it presents a potential proper documentation and presenta- for serious harm to the patients? The tion of data an IRB will review for its SR designation applies, the FDA says, decision making. One aspect of device even though the changed pacemaker trials an IRB must consider is risk, may potentially pose less risk, or only particularly for SR devices. The FDA slightly greater risk, in comparison to asks IRBs to consider if a SR device the commercially available model. may cause harm or requires additional procedures that might cause potential harm. In some situations, the IRB must weigh the potential benefits and risks of an investigational device against those of an existing, approved drug or device. The FDA cites how a trial to examine the safety and efficacy of a The sponsor may send the device to the IRB to aid in its review, but the study cannot begin until the FDA approves the IDE application. Of note, trial sponsors must obtain agreement from the investigators to comply with the applicable regulations governing SR studies. modification to an already approved * FDA, “Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsors; Significant Risk and Nonsignificant Risk Medical Device Studies,” January 2006. Accessed at www.fda.gov/downloads/regulatoryinformation/guidances/ucm126418.pdf on Feb. 7, 2013 5 ©2014 Novella Clinical Medical Device Development Interventional Cardiovascular Medical Device Trials The FDA and EU Regulatory Paths for Class III Devices The FDA requires Class III device sponsors to submit a PMA application that demonstrates “sufficient valid scientific evidence that provides reasonable assurance that the device is safe and effective for its intended use or uses.”xix That evidence comes from nonclinical laboratory studies (e.g., design verification testing such as bench, simulated-use, animal, or biocompatibility studies) and controlled clinical trials. Human studies for these devices have their own set of regulatory requirements, including the FDA’s US FDA EU Agencies Class III HIGH RISK granting of an IDE so the investigational device may be used in a clinical trial. An IDE is required if the device is novel, is a significant modification of an earlier model or if the application is for a new intended use of an already approved and legally marketed device. Sponsors must demonstrate Safety and EFFECTIVENESS + PREMARKET APPROVAL (PMA) Sponsors must demonstrate Safety and PERFORMANCE Both the FDA and the EU classify most permanent implantable CV devices in their highest risk category (Class III) but the requirements for approval differ between the agencies. In contrast, EU member states use Notified Bodies to evaluate devices and render European Conformity (CE) certification decisions, in addition to National Competent Authorities that oversee the Notified Bodies, approve clinical protocols and direct post-marketing surveillance. Because there is no central authorizing organization, a sponsor must choose one Notified Body, which then conducts a device evaluation that will be used for the entire EU. As of February 2014, the European Commission had authorized 73 Notified Bodies in 24 countries to issue CE decisions for medical devices. The same Notified Body will then review future changes to the device. Of note, in May 2011, the ESC called for the EU to create a unified regulatory system, prompted by removal from the EU market of implantable CV devices proven unsafe or ineffective in trials subsequently required by the FDA.xx The ESC asked for an EU system with stronger clinical data requirements and more accountability for Notified Bodies. 6 ©2014 Novella Clinical Medical Device Development Interventional Cardiovascular Medical Device Trials Novella Clinical recommends sponsors become familiar with the regulations and requirements of each regulatory jurisdiction in which they plan to commercialize their device. One of the first documents written for the Design Control process should be a detailed regulatory assessment for each agency that must be specific to the device type and its intended use. The FDA requirements generally are the most stringent globally, so following the Agency’s assessment project plan should work well for most other jurisdictions. For the US, these assessments should include, at minimum: • Rationale for product classification • Rationale for risk significance • Summary pathway to clearance • Applicable consensus standards • Applicable guidance documents • Comparison to predicate devices (if any) • Design verification (bench) testing requirements • Animal (or cadaver) study requirements • Clinical study requirements • Post-market requirements • Submission type / content / format requirements / ancillary document list Readying for Reimbursement: Value Data Considerations for Cardiovascular Devices Escalating health care costs have prompted public and private payers as well as hospital purchasing departments to increasingly scrutinize device costs. As a result, sponsors should include the collection of health economic data and its assessment in clinical trial designs. Moreover, CVD trial protocol planning must include how to measure value, no longer exclusively the purview of drug development. Value is more than the cost of manufacturing and implanting a device. Value also includes measures such as quality adjusted life-years, which helps characterize how a device affects or improves the quality and length of a patient’s life beyond simple measures of functions of daily living and longevity. In addition, sponsors should consider including “soft” health economic measures such as OR/procedure Escalating health care costs have prompted public and private payers as well as hospital purchasing departments to increasingly scrutinize device costs. As a result, sponsors should include the collection of health economic data and its assessment in clinical trial designs. time, blood loss, time in hospital, and time to return to work which all affect the cost of the product beyond that of the purchase price. Such health economic data are useful for pricing strategies and are necessary for reimbursement decisions by both the Centers for Medicare & Medicaid Services (CMS), private payers as well as hospital purchasing departments. McKinsey & Company foresees that without such evidence, products that feature smaller changes and innovations compared to predicate products, for example a new coating on an implant, will be less likely to 7 ©2014 Novella Clinical Medical Device Development Interventional Cardiovascular Medical Device Trials receive incremental pricing and reimbursement.xi Some private payers have already gone as far as to decline reimbursing procedures involving devices lacking available safety, efficacy as well as health economic data, even if such data were not required for market release of that device, like those approved via the FDA’s 510(k) process. In many instances Novella Clinical counsels that trial protocols should capture cost-effectiveness data. Such data helps address the question as to whether the device provides economic benefits compared to already available therapies or the standard of care. All sponsors submitting a PMA aim to answer the question of efficacy and safety of the therapy, but sponsors to date have not fared as well on such comparative value questions. In the past, the question of health economics has been left to post-market studies, but with the current economic climate, the better strategy may be to include measures of health economic data in earlier phase trials. Device sponsors are also beginning to face comparative efficacy scrutiny, which has largely focused on drug development as a means to help inform health care decisions by understanding the relative clinical effectiveness and appropriateness of different treatments for the same condition based on patient’s health, the quality of care, Comparative effectiveness data may include evidence of savings, offsets or outcome value. In considering comparators, Novella Clinical recommends selecting treatments that reflect current standards of care to meet CMS needs, even if the FDA guidance permits sham treatment or historic data. health outcomes and costs as well as other factors. Indeed, a review of high-risk CV devices approved by the FDA from 2000 to 2011 revealed the majority lacked data comparing efficacy at the time of their premarket approval.xii In this analysis, the authors defined comparative efficacy as use of active controls in evaluating primary end points, such as a (preferably randomized, concurrent) control group that received a validated intervention that was not the investigational device. For example, the trial might compare a drug-eluting stent with a bare metal stent; carotid endarterectomy to carotid stenting; or catheter ablation to flecainide for recurrent paroxysmal atrial fibrillation (AF). The Results? • Of 353 primary end points, only 40% were evaluated against an active control. • The use of active controls varied by device category:xiii – – – – 0% bridge-to-transplant LVAD 14% for intracardiac devices 39% for cardiac stents 82% for hemostasis devices The authors noted that use of active controls may not always be possible, such as when testing ventricular-assist devices, and suggest that in such cases the use of a comparator group may provide the information needed for both clinical and regulatory decisions. 8 ©2014 Novella Clinical Medical Device Development Interventional Cardiovascular Medical Device Trials Going forward, the rates for data comparing effectiveness for devices will increase, in part because of the US government’s investment in such research but also as a part of the national healthcare agenda. In the US, the Institute of Medicine developed a list of the top 100 comparative effectiveness priorities, which include devices. AF therapies are in the list’s top quartile, catheter-based treatment of vascular claudication is in the second quartile, while coronary stenting and innovative congestive heart failure therapies are in third quartile.xiv Comparative effectiveness data may include evidence of savings, offsets (higher device cost but subsequent disease-related costs are reduced) or outcome value. In considering comparators, Novella Clinical suggests sponsors select treatments that reflect current standards of care to meet CMS needs, even if the FDA guidance permits sham treatment or historic data. However, if validated historic data will allow a comparison, this standard might not need to be an active control arm in the trial. Sponsors might also need to define additional endpoints such as functional status or quality of life for CMS evaluation, rather than just clinical data like heart function or blood pressure. Also, given the purview of CMS, sponsors should ensure that participants include older individuals in substantial numbers so that findings are readily extrapolated to a Medicare population. Taking the Vitals: Clinical Trials of Cardiovascular Devices The careful consideration and selection of principal investigators, sites and patients as well as treatment protocols, data and endpoints are vital to the success of CV device trials. Principal Investigators and Sites Because many subspecialists are involved in the treatment of patients with CVD, sponsors may find themselves in competition for particular physicians to participate as principle investigators. In addition, when recruiting investigators for a particular trial one must consider that individual interventional cardiologists, for example, may be experts in angioplasty and stenting or in mitral valve repair, but not both. When considering investigators, a sponsor cannot assume that board certification and expertise with one type of device will translate to a different technology. Operator performance also plays a role in selection. An experienced CRO will know which forms of expertise can make an investigator ideal to test a new technology, with appropriate training, guidance and oversight, or if the learning curve is not appropriate for a particular study. Unlike drug trials, device sponsors must plan for lengthy and individualized training to ensure that each investigator can efficiently, safely and accurately use or implant the device and that this training leads to consistent implementation of the procedure across all investigative sites. Frequently, the sponsor, assisted by the CRO, provides such training and is present for each investigator’s first participant procedure. Many sponsors come to a CRO with a desired list of investigators and sites based on their previous device trials or scientific advisory board’s advice. However, while Novella Clinical recognizes the importance of including established key opinion leaders for a company, an experienced CRO can also provide additional context regarding candidates’ availability and suitability and can identify 9 ©2014 Novella Clinical Medical Device Development Interventional Cardiovascular Medical Device Trials new experts or sites. In addition to working with sites that enjoy top-tier reputations, Novella Clinical has also had great success with sites that have less extensive clinical research portfolios. We have found that quality of care is seldom an issue and including such sites may enhance the speed of patient recruitment because of often shorter start-up timelines and less trial competition. One aspect of site selection is determining the facility locale in which the trial procedure will be done. Some hospitals have a cardiac catheterization suite while others may need to book a general operating room. Such infrastructure variations can affect access, i.e., booking time for trial procedures versus ongoing patient care, and can determine the presence of dedicated clinical teams and ancillary personnel with the appropriate CV experience. Treatments CV device trials usually involve patients age 65 and older who are likely to have a higher BMI and other health issues, particularly diabetes. For such patients, a CV device is seldom their only medical treatment, and data collection must carefully account for all interventions, whether investigational or not. For example, a patient may be taking antiplatelet medications or a statin and, because of the frequency of diabetes in the CVD population, perhaps a sulfonylurea, a SGLT2 inhibitor or insulin. The thorough documentation of such concomitant medication is essential for determining if changes in endpoint measures or occurrences of adverse events stem from patients’ illness, treatment, or the investigational device. Another aspect of trial design is the stratification of patients into treatment groups and the goal of the treatment. For example in AF, current guidelines suggest that “rate control may be reasonable initial therapy in older patients with persistent AF who have hypertension or heart disease, while for younger in- ... a CV device is seldom their only medical treatment, and data collection must carefully account for all interventions, whether investigational or not. dividuals, especially those with paroxysmal lone AF, rhythm control may be a better initial approach.”xv The guidelines suggest use of medications, then catheter-based endocardial ablation for patients in whom drugs failed to control the AF. However, in a trial setting, both treatments may need to be considered before use of the investigational device, which may be considered the “last option” for a patient. Such treatment algorithms create complexity in data collection. In addition to examining a device against a standard of care, some trials designs also may involve sham treatments or no interventions, as it is not common for device trials to be double-blinded. A review of PMAs for CV devices approved between 2000 and 2007 found that only 14 percent were blinded.xvi In a drug trial, double- or single-blind studies may use placebos as controls, but in device trials the use of sham devices often is transparent to clinical teams or patients or both. To compensate for this trial design necessity, the evaluation of study data by a single, blinded core laboratory often is essential. For example, investigators will use a baseline angiography to gather 10 ©2014 Novella Clinical Medical Device Development Interventional Cardiovascular Medical Device Trials data documenting how a mitral valve is insufficient in controlling blood flow within the heart, but the core lab will define the degree of insufficiency and determine if the patient can enroll in the study based on the entry criteria. After the intervention, with the investigational valve or sham device, the same core lab will assess and define the degree of residual mitral regurgitation. Of note, in many device feasibility studies, patients serve as their own controls, such as in the evaluation of the degree of mitral regurgitation before and after the implantation of the investigational device. In many pivotal device studies, the design calls for randomization of such patients in comparison to those receiving the standard of care to define the device’s long-term safety and efficacy, usually a minimum of five years. Data and Endpoints Planning for such complex data collection and analyses in CV trials requires a careful definitions process during the protocol design, not just efficient “facts and figures” capturing and database input when the study is underway. Definitions vary, so sponsors, working with the CRO team, should agree on the markers, measures and methods that will precisely define the trial endpoints and assure those assessments are uniformly available at each trial site. Some endpoint definitions are straightforward, such as how to measure blood pressure, while others are characterized by how they are measured or used. A best practice is to consider how other medical professionals and researchers define and use such information, whether for clinical practice or research settings. Some endpoint resources also include well-regarded databases, which may also provide historic data useful for baseline comparisons. For example, a heart attack, which may be a study entry criteria or an endpoint, can be defined by electrocardiographic (ECG) findings, elevated values of biochemical markers, imaging or pathology. The World Health Organization (WHO) has used symptoms, ECG patterns and enzyme elevation to define heart attacks, but as science and technology have advanced, clinicians may now measure tissue-specific cardiac biomarkers or employ advanced imaging techniques that ... use historic or predicate device data in premarket approval to carefully review composite endpoint definitions so the comparisons are accurate. enable detection of very small myocardial injuries or tissue death. Another complication of heart attack definition is that improvements in the management of patients have reduced tissue injuries and necrosis, despite similar presentation in a clinical setting. Moreover, health care professionals can now add to their definitions the cause of a heart attack, such as spontaneous or procedure-related. 11 ©2014 Novella Clinical Medical Device Development Interventional Cardiovascular Medical Device Trials What constitutes a heart attack as trial entry criteria was defined by a global taskforce comprised of ESC, the American College of Cardiology (ACC) Foundation, AHA and World Heart Federation experts in 2012, and the WHO subsequently adopted this universal definition. However, the taskforce noted that as a trial outcome, heart attack definitions still differed, “hampering comparison and generalization between these trials. ... No matter what, investigators should ensure that a trial provides comprehensive data for the various types of MI and includes the 99th percentile [upper reference limit] decision limits of [cardiac troponin] or other biomarkers employed.”xvii Many cardiac device trials use composite endpoints that combine events. For example, a recent study evaluating patients who underwent percutaneous coronary intervention with a drug-eluting stent versus those who received a coronary artery bypass graft used the number of cardiac-related deaths, heart attacks and cerebrovascular events at five years after the intervention as a composite endpoint. The study also had an additional endpoint that included these three events as well as target lesion revascularization (TLR) and target vessel revascularization (TVR).xviii However, Novella Clinical counsels sponsors that use historic or predicate data in their PMA to carefully review composite endpoint definitions so that the comparisons are accurate. Collecting clinical data and adverse events is frequently not the only aspect of trial data management. In studies where a TLR or TVR is an endpoint, imaging data also must be collected to allow determination of why the blockage reoccurred. For example, did a drug-eluting stent incompletely destroy the plaque or move it during the attempt to open a blocked artery? Many CV data assessments require imaging to show the baseline patient status, accurate device placement per the protocol parameters as well as intermediate and long-term effects of the intervention. Unlike a drug trial in which medication is consumed, CV device trials frequently require the investigators to use their own judgment of a visual assessment of the intervention, with the image subject to subsequent data review. Some of these imaging procedures, such as angiograms or IVUS (intravascular ultrasound), have risks, ranging from the contrast agents to radiation exposure to clot formation or dislodgement. Consequently, adverse events can potentially occur each time a visualization procedure is performed, so the trial design should limit imaging as much as possible. For the evaluation of images and other endpoint data, Novella Clinical advises sponsors to control for possible variations via the use of centralized processes. For example, images can be evaluated in a core lab, which provides quality control to the trial by efficiently using the same expert team to provide consistent criteria to their evaluations as well as including QC checks on the image quality and acquisition process used at each site. Similarly, we suggest using a single-charter, multi-country (if a global trial) data safety monitoring board (DSMB) to review trial outcomes as well as a clinical events committee (CEC) to evaluate safety events, which may be part of the endpoint evaluation. Such independent peer-to-peer committees typically are blinded during their assessments regardless of whether the trial is blinded. The use of electronic data capture and centralized databases enable such committees to operate virtually which increases efficiency both operationally and from a cost perspective when compared to face-to-face meetings. 12 ©2014 Novella Clinical Medical Device Development Interventional Cardiovascular Medical Device Trials As noted by the FDA, CECs can be established in certain trials to determine whether the endpoints reported by trial investigators meet protocol-specified criteria. CECs are particularly valuable when endpoints are subjective or require the application of a complex definition or when the intervention is not blinded. For example, the CEC can determine if a heart attack recorded by a site was indeed a heart attack as defined in the study protocol, or another separate event that might have been missed by the team, as well as if underlying factors played a role apart from the device. Although CECs do not share responsibility with DSMBs for evaluating interim data analyses, their assessments, when performed at frequent intervals and incorporated into the database in a timely manner, help ensure that DSMB data reviews are as accurate and free of bias as possible. Novella Clinical has a dedicated team to help sponsors form DSMBs and CECs for their trials to ensure independence and appropriate expertise level. Patients Many CV device sponsors seek to enroll patients that have long-standing heart conditions, whether congenital or acquired, such as arterial stenosis, mitral valve regurgitation, arrhythmia, or heart failure. While standard clinical practice may result in device treatment of patients with acute emergency conditions, such as a heart attack, such settings present time-senstitive levels of complexity for clinical trials to patient identification, informed consent, enrollment and treatment decisions. Emergency room patients may be medicated for pain, unconscious, or, as in the case of many stroke patients, unable to speak or communicate clearly. Because of this, patients treated and admitted via an emergency room can be enrolled but the IRB-approved informed consent must clearly indicate how proxies are used for such patients, who likely will have comorbidities. Regardless of the care setting, specificity of a protocol population will affect data values. For example, in defining a stent intervention patient population, a difference between selecting 50 While standard clinical practice may result in device treatment of patients with acute emergency conditions, such as a heart attack, such settings present time-senstitive levels of complexity for clinical trials to patient identification, informed consent, enrollment and treatment decisions. versus 75 percent stenosis can be a factor in determining the stent efficacy without a significant difference in safety values. A CRO’s team of physicians and biostatisticians can helps sponsors model different trial populations to evaluate the potential efficacy and safety of the device. Although enrolling chronic disease patients may not present significant identification issues, their retention in long-term trials is a challenge for sponsors. While most European Competent Authorities will permit the use of just one year of follow-up safety data for approval decisions, the FDA and UK will want at least five-year data. Consequently, it is prudent for sponsors to consider that they may need to enroll large numbers to yield the patients needed for their long-term assessments. 13 ©2014 Novella Clinical Medical Device Development Interventional Cardiovascular Medical Device Trials Such long trial times, even with many intermediate follow-ups, have additional issues. For example, many patients may stop taking their prescribed medication once they start to feel better, while others may consider the costs of such medication too great for the benefits they perceive. In drug-eluting stent trials, the standard of care involves taking anti-platelet therapy for six to 12 months, but if a patient stops the medication, the data analyses must account for whether subsequent events are due to patient compliance with medication(s), investigational device failure, or both. Trial follow-up also is hindered by patients that develop new illnesses and care issues, move or no longer have the independence to participate in the clinical trial, all of which are required to be documented as discontinuations for regulatory submissions. To help address such issues, sponsors should consider if technology might be an aid, particularly for longitudinal studies, ranging from phone monitoring to emails to online data collection to the use of new technologies. The development of remote cardiac telemetry first enabled intermittent home-based monitoring, but now pacemakers and implantable cardioverter-defibrillators also are used as continuous monitoring devices to capture sporadic episodes of AF. However, for acute care phases of a trial, face-to-face visits are still the primary means of evaluation. Moreover, the type of intervention may dictate what follow up is acceptable to regulatory agencies. For example, the FDA does not consider phone monitoring valid as a way to evaluate efficacy for some treatments, such as ablation therapy for arrhythmia. Picking Partners: Vendors Who Know Cardiovascular Devices For successful CV device trials, sponsors need to have strategic partners with knowledge of the therapeutic area. A CRO with first-hand regulatory and trial knowledge can ensure that sponsors select experienced, certified vendors for the trial conduct, data analyses and marketing approval A CRO with first-hand regulatory and trial knowledge can ensure that sponsors select experienced, certified vendors for the trial conduct, data analyses and marketing approval submissions. submissions. For example, sponsors should expect CROs to make recommendations not just for sites and investigators but also for core laboratories, DSMBs and CECs. The CRO’s own team should also have established skills in the appropriate therapeutic settings, such as cardiac catheterization laboratories. Such practice-based knowledge helps clinical research associates (CRA) understand many aspects of the procedure, ranging from how a catheter works to typical time constraints in treating a patient within a window of a cardiac event. Applying such experience can subsequently help a CRA address protocol deviations and non-compliance at the time of the intervention. Novella Clinical has found that for trial sites outside the US, cardiac-experienced CRAs may be expected to play a broader role, including helping investigators with ethics committee reviews. 14 ©2014 Novella Clinical Medical Device Development Interventional Cardiovascular Medical Device Trials WHO Top 10 Causes of Death, accessed at http://www.who.int/mediacentre/factsheets/fs310/en/index.html Feb. 6, 2014. ii Research and Markets. Global Cardiac Medical Devices - An Analytical Report, 2009-2015. April 2013. Accessed at http://www.researchandmarkets.com/research/2kcqmn/global_cardiac Jan. 30, 2014. iii WHO Top 10 Causes of Death, accessed at http://www.who.int/mediacentre/factsheets/fs310/en/index.html Feb. 6, 2014. iv CDC FASTSTATS, accessed at http://www.cdc.gov/nchs/fastats/deaths.htm Feb. 6, 2014. v Go, A., et. al. “Heart Disease and Stroke Statistics--2014 Update: A Report From the American Heart Association,” Circulation. 2014;129:e28-e292; originally published online December 18, 2013. Accessed at http://circ.ahajournals.org/content/129/3/e28.full.pdf+htm lon Feb. 22, 2014. vi AHA, “Cardiovascular Disease and Diabetes,” Jan. 31, 2013. Accessed at http://www.heart.org/HEARTORG/ Conditions/Diabetes/WhyDiabetesMatters/Cardiovascular-Disease-Diabetes_UCM_313865_Article.jsp Feb. 8, 2014. vii Research and Markets. Global Cardiac Medical Devices - An Analytical Report, 2009-2015. April 2013. Accessed at http://www.researchandmarkets.com/research/2kcqmn/global_cardiac Jan. 30, 2014. viii Boston Consulting Group, “Competitiveness and Regulation: The FDA and the Future of America’s Biomedical Industry,” February 2011. Accessed at http://www.bcg.com/documents/file72060.pdf Feb. 11 2014. ix Boston Consulting Group, “Competitiveness and Regulation: The FDA and the Future of America’s Biomedical Industry,” February 2011. Accessed at http://www.bcg.com/documents/file72060.pdf Feb. 11 2014. x The FDA, “Medical Devices, PMA Clinical Studies, Research conducted outside the United States,” Posted March 1, 2013. Accessed at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/ PremarketSubmissions/PremarketApprovalPMA/ucm050419.htm March 4, 2014. xi Lin, John, et. al. “Comparative Effectiveness Hits Medical Devices,” In Vivo: Business & Medicines Report, March 2010. p 9. Accessed at https://www.mckinsey.com/ Feb. 10, 2014. xii Chen, C.E., et. al. “Inclusion of Comparative Effectiveness Data in High-Risk Cardiovascular Device Studies at the Time of Premarket Approval,” JAMA. 2012;308(17):1740-1742 Accessed at http://jama.jamanetwork.com/ article.aspx?articleid=1389607#ref-jld120026-3 Feb. 11, 2014. xiii Chen, C.E., et. al. “Inclusion of Comparative Effectiveness Data in High-Risk Cardiovascular Device Studies at the Time of Premarket Approval,” JAMA. 2012;308(17):1740-1742 Accessed at http://jama.jamanetwork.com/ article.aspx?articleid=1389607#ref-jld120026-3 Feb. 11, 2014. xiv IOM, “100 Initial Priority Topics for Comparative Effectiveness Research,” June 30, 2009, Accessed at http:// www.iom.edu/Reports/2009/ComparativeEffectivenessResearchPriorities.aspx Feb. 11, 2014. xv “2011 ACCF/AHA/HRS Focused Updates Incorporated Into the ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation,” 2011. 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Accessed at http://interventions.onlinejacc.org/article. aspx?articleid=1111698 Feb. 8, 2014. xix The FDA “Medical Devices, Device Approvals and Clearances, Accessed at http://www.the FDA.gov/ MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/default.htm. May 12, 2013. xx Shuren, Jeff. “Medical Devices: Protecting Patients and Promoting Innovation,” Testimony. Nov. 15, 2011. Accessed at http://www.fda.gov/NewsEvents/Testimony/ucm278960.htm Feb. 11, 2014. i 15 ©2014 Novella Clinical A Novella Clinical White Paper About Novella Clinical Novella Clinical, a Quintiles company, is a full-service clinical research organization specializing in medical device and diagnostic clinical trials. Our medical device division is comprised of clinical trial specialists across all functional areas. 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