Postapproval Experience Research Articles

Post-Approval Experience with Fully Magnetically Levitated Continuous Flow Left Ventricular Assist Device- Single Center Experience

Overall survival in left ventricular device supported patients has improved due to advancement in device technology. Fully magnetically levitated continuous device (HM3), has shown better hemocompatibility profile. The aim of this study is to compare 1 year survival between patients who received HM3 during the Momentum 3 clinical trial vs. post approval commercial phase. A single center retrospective review of 149 patients undergoing HM3 implant between Aug 2015 -Aug 2019 was carried out. Patients were divided into 2 groups (trial v/s commerical). Patients were compared on their preoperative demographics, medical history, laboratory values, hemodynamics, echo and catheterization records. The primary end point was survival at 1-year. Categorical variables are reported as percentages, whereas continuous variables are reported as mean ± standard deviation (SD), p-value was set at 0.05. We had 67 (44.97%) patients in the commercial arm vs. 82 (55.03%) in the trial arm. Patients in the commercial arm were younger in age when compared to the trial arm group (50.61 ± 12.81 vs. 55.39 ± 11.54 years, p-0.03). More patients in the commercial arm were implanted as destination therapy (DT) when compared to the trial patients [41 (61.19%) vs. 11 (13.41%), p<0.001]. 83.58% of commercial arm patients were INTERMACS 1 and 2 profile vs. 74.39% (p=0.75) for the trial arm. Other than these two variables, the groups were clinically comparable in terms of their pre-operative conditions and post-operative adverse effects related to surgery. One year survival was 94.7% vs.93.9%) for commercial and trail arm respectively. (p=0.57) (figure 1). Even with higher degree of heart failure (INTERMACS 1 and 2) and comorbid conditions (greater percentage of DT) seen in commercial arm group (reflective of a more real world experience), 1 year survival was similar to a highly controlled trial cohort. Larger multi center studies are required to validate these findings.

Early post-approval experience with transcatheter aortic valve replacement in the USA.

Transcatheter aortic valve replacement (TAVR) is changing the treatment of aortic stenosis. We compared cost and clinical outcomes of TAVR versus surgical aortic valve repair (SAVR) in the real-world setting since USA TAVR approval in 2012. The Nationwide Inpatient Sample (NIS) dataset was analyzed by quarter (June 2012 to December 2014). Patients (>65 years old) undergoing TAVR or SAVR were identified and risk stratified based on APR-DRG Mortality risk score. Outcomes were in-hospital mortality, length of stay (LOS), discharge location, and hospitalization cost. TAVR cases per quarter increased from 1900 to 5445 over the study period. TAVR patients were older and had more comorbidities (P<0.001). TAVR patients had longer LOS (8 vs. 7 days; P<0.001), were less likely to discharge to home (67% vs. 73%; P<0.001), had higher inpatient mortality (5.5% vs. 0.69%; P<0.001) and overall hospital cost ($ 227,985 vs. $ 148,019; P<0.001) than SAVR patients. On multivariate analysis TAVR was associated with increased cost (β=0.42; P<0.001) and increased mortality (OR=5.228, CI: 3.508-7.791; P<0.001) but not associated with increased LOS (β=0.297; P=0.078) or discharge to facility (OR=1.004, CI: 0.833-1.213; P=0.960). In the last two quarters of 2014 there was no difference between TAVR and SAVR LOS, however TAVR cost did not decrease over the study period. TAVR patients represented a sicker population, however LOS and discharge location outcomes were equivalent to SAVR. TAVR remained significantly more expensive across all risk groups and cost did not fall over the course of the study.

(81) - HeartMate 3 Left Ventricular Assist Device Pre- and Post-Approval Experience Through 1 Year at a Single Center

The National Research Cardiac Surgery Center (NRCSC) was one of the lead enrolling centers in the HeartMate 3 CE Mark Study and was able to obtain commercial approval for the device in January 2015.The HeartMate3 LVAS (SJM) is a centrifugal-flow device that utilizes full magnetic levitation. The center’s pre and post-approval experience with the HeartMate 3 are presented. NRCSC enrolled the CE Mark Study patients from July 2014 - October 2014. The study was a prospective, multi-center, non-randomizedtrial in which patients ongoing with theHeartMate 3 after the 6 month study endpoint continue to be followed for 2 years. The first commercial implant occurred in January 2015. Post-approval all patients that received the HeartMate 3 were enrolled in the HeartMate 3 Registry, which collects data similar to the CE Mark Study. The Registry patients were consented, consecutively enrolled and prospectively followed. A total of 34 patients were implanted with the HeartMate3at the NRCSC (8 patients in the CE Mark Study and 26 in the HeartMate 3 post-approval Registry). The patients were representative of an advanced heart failure population and were a mix of BTT (62%) and DT (38%) patients. Patients were in INTERMACS profiles 3-4.Currently 30 patients are ongoing with HeartMate3 support, 3 transplanted (day 50, 75 and 231) and 1 expired (day 12 due to multi-organ failure). Survival to date is 97%. Six patients have reached durations > 1 year and 17 patients > 6 months. There have been no strokes, hemolysis or pump thrombosis in the 34 patients. 1 (3%) patient required RVAD support during pump implantation, 4 patients (12%) experienced bleeding requiring surgery, driveline infections were reported in 4 patients (12%) and sepsis in 1 patient (3%). The 6 minute walk test improved from an mean of 247.2 meters at baseline to 427.4 meters at 6 months (P<0.0001). EQ-5Dquality of life score improved from a mean of 35.9 at baseline to 72.5 at 6 months (P<0.0001). The trend for high rates of survival, an adverse event profile without hemolysis or pump thrombosis and significant improvement in functional status and quality of life as seen in the 6-month HeartMate 3 CE Mark study data has continued with longer duration follow-up and with the commercial use of the device at this single center.

POST FDA APPROVAL EXPERIENCE OF LEFT ATRIAL APPENDAGE OCCLUSION IN THE UNITED STATES

The Watchman™ (Boston Scientific Corporation, MA) device for left atrial appendage occlusion for stroke prevention in nonvalvular atrial fibrillation was FDA approved in March of 2015. We now provide the first report of the post-approval experience with the device in the United States. Each

Safety analysis of 10 clinical trials and for 13 years after first approval of ioflupane 123I injection (DaTscan).

Ioflupane is an analog of cocaine that binds reversibly with high affinity to the dopamine transporter (DaT) protein, a marker for presynaptic terminals in dopaminergic nigrostriatal neurons. Ioflupane (123)I Injection is also known as DaTscan or DaTSCAN ((123)I-ioflupane is also called (123)I-2-β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane or (123)I-FP-CIT). The diagnostic efficacy of DaTscan has been described elsewhere. Here, we present a comprehensive analysis of the safety of DaTscan starting from initiation of clinical development through 13 y after the date of first market approval. Safety data in the sponsor's clinical development safety database from 10 completed DaTscan clinical trials were pooled, and postapproval experience was summarized from standardized aggregate safety reports submitted to regulatory agencies. A total of 1,180 clinical trial subjects (92% of 1,284 subjects planned to receive DaTscan in the clinical trials) received DaTscan. Percentages of subjects with adverse events by category were as follows: all (22%), considered at least possibly related to DaTscan by the investigator (4%), any severe (3%), headache (4%), nausea (2%), dizziness (2%), nasopharyngitis (1%), and injection site hematoma (1%). Four percent of subjects had at least 1 serious adverse event; 5 subjects (<1%) had serious adverse events that led to death. All serious adverse events, including those that led to death, were deemed by an expert clinician to be unrelated to DaTscan. An estimated half a million market doses of DaTscan (for single use) were administered from July 2000 through the July 2013 reporting period. In postapproval safety assessment, 1 death was reported 20 d after (and unrelated to) DaTscan administration. Two spontaneously reported serious adverse drug reactions (ADRs) and 32 spontaneously reported nonserious ADRs were submitted, approximately half of which are identified in labeling. Headache (in clinical trials) and injection site pain (postapproval) were the most commonly reported events or reactions. Although adverse events were reported for 1 in 5 clinical trial subjects, most were mild and considered unrelated to DaTscan administration. Severe events were uncommon, and no serious adverse event occurring in more than 1 subject was deemed related to DaTscan administration. In postapproval experience, the frequency of ADRs spontaneously reported was less than 1 per 10,000 doses administered. Comprehensive safety data show that DaTscan was well tolerated.

Postapproval clinical experience in the treatment of Dupuytren's contracture with collagenase clostridium histolyticum (CCH): the first 1,000days.

Dupuytren’s contracture is a benign fibromatosis of the palmar and digital fascia of the hand of uncertain etiology, resulting in nodules and cords beneath the skin of the palm of the hands that may lead to the development of contractures. Surgical intervention is often considered when metacarpophalangeal (MP) joint contracture is 30° or more, or when there is any degree of proximal interphalangeal (PIP) joint contracture. Collagenase clostridium histolyticum (CCH) is a nonsurgical, minimally invasive enzymatic drug indicated for the treatment of adult patients with Dupuytren’s contracture (DC) and palpable cord. CCH has been available for approximately 3.5 years, and postapproval experience indicates that the effectiveness of CCH is equivalent to or better than efficacy observed in clinical trials, as seen by lower injection rates to achieve clinical success. Postapproval experience has shown a risk-benefit profile that favors CCH for patients not indicated for surgery based on current recommendations and shows also that treating earlier-stage vs later-stage joint contracture results in significantly better outcomes on average. Postapproval surveillance reveals a safety profile similar to that observed in clinical trials. Nonserious adverse events are mainly local reactions; tendon rupture, a serious adverse event, is reported rarely in the clinical practice setting and at a lower rate than in clinical trials. Risk Evaluation and Mitigation Strategy (REMS) training is designed to mitigate benefit vs risk to achieve safe and effective use of CCH.

Percutaneous Mitral Valve Interventions in the Real World: Early and 1-Year Results From the ACCESS-EU, A Prospective, Multicenter, Nonrandomized Post-Approval Study of the MitraClip Therapy in Europe

The purpose of this article is to report early and mid-term outcomes of the ACCESS-EU study (ACCESS-Europe A Two-Phase Observational Study of the MitraClip System in Europe), a European prospective, multicenter, nonrandomized post-approval study of MitraClip therapy (Abbott Vascular, Inc., Santa Clara, California). MitraClip has been increasingly performed in Europe after approval; the ACCESS-EU registry provides a snapshot of the real-world clinical demographic data and outcomes. A total of 567 patients with significant mitral valve regurgitation (MR) underwent MitraClip therapy at 14 European sites. Mean logistic European System for Cardiac Operative Risk Evaluation at baseline was 23.0 ± 18.3; 84.9% patients were in New York Heart Association functional class III or IV, and 52.7% of patients had an ejection fraction≤40%. The MitraClip implant rate was 99.6%. A total of 19 patients (3.4%) died within 30 days after the MitraClip procedure. The Kaplan-Meier survival at 1 year was 81.8%. Intensive care unit and hospital length of stay was 2.5±6.5 days and 7.7 ± 8.2 days, respectively. Single leaflet device attachment was reported in 27 patients (4.8%). There were no MitraClip device embolizations. Thirty-six subjects (6.3%) required mitral valve surgery within 12 months after the MitraClip implant procedure. There was improvement in the severity of MR at 12 months, compared with baseline (p< 0.0001), with 78.9% of patients free from MR, severity of >2+ at 12 months. At12months, 71.4% of patients had New York Heart Association functional class II or class I. Six-min-walk-test improved 59.5 ± 112.4 m, and Minnesota-living-with-heart-failure score improved 13.5 ± 20.5 points. In the real-world, post-approval experience in Europe, patients undergoing the MitraClip therapy are high-risk, elderly patients, mainly affected by functional MR. In this patient population, the MitraClip procedure is effective with low rates of hospital mortality and adverse events.

Ten Developments in the Use of Biologicals for Systemic Lupus Erythematosus

Belimumab has recently been approved, and several other types of biological therapy with different mechanisms of action are currently in phase II and III studies. This review puts these approaches in context, emphasizing mechanistic categories and clinical trial designs. Most of the promising approaches involve B cell depletion or modulation. Post-approval experience with belimumab is critically reviewed.

Omalizumab in Asthma: Approval and Postapproval Experience

Omalizumab is a humanized mouse monoclonal antibody that binds specifically to the constant region of the immunoglobulin (Ig)E heavy chain. Omalizumab exerts its effects by reducing free serum IgE levels and FcepsilonRI expression on several cell types. These effects have been shown to result in decreased airway inflammation and clinical improvement. In multiple studies, omalizumab has been shown to be efficacious in the treatment of moderate-to-severe persistent asthma and is currently approved by the US Food and Drug Administration for the treatment of moderate-to-severe allergic asthma in patients age 12 yr and older. Moreover, omalizumab has been demonstrated to be effective in the treatment of children and adults with seasonal and perennial allergic rhinitis. Postmarketing surveillance has shown omalizumab to be a relatively safe and well-tolerated medication.

Amphotericin B lipid complex for the treatment of invasive fungal infections

Amphotericin B lipid complex (ABLC; Abelcet®, Enzon Pharmaceuticals) has become the dominant marketed lipid amphotericin B compound to emerge since the approval of these agents from the mid-1990s onwards. This agent is a 1:1 combination of amphotericin B and a lipid moiety consisting of dimyristoyl phosphatidylcholine and dimyrisoyl phosphatidylcholine, which exists in a ribbon-like molecular structure. ABLC undergoes rapid reticuloendothelial uptake from the circulation and achieves significantly higher tissue concentrations in the liver, spleen and lung compared to comparably dosed conventional amphotericin B. ABLC is approved by the FDA for all mycoses in amphotericin B-intolerant or -refractory infection. Randomised, controlled trials of amphotericin B have shown comparable efficacy in candidiasis and an improved outcome in invasive aspergillosis versus historical controls. ABLC has demonstrated a reduced incidence of nephrotoxicity and infusion reactions versus amphotericin B. Comparative studies against other lipid formulations are quite limited and have shown variable differences in infusion toxicity, nephrotoxicity, hepatotoxicity and clinical efficacy. Postapproval experience has shown substantial efficacy for less common mycotic pathogens including zygomycosis. The precise position of ABLC versus both other lipid formulations and expanding formulary of new antifungal agents is in flux. Future studies which examine its clinical efficacy, role in combination therapy, toxicity and cost-effectiveness in these complex patients are needed.

Weight and consequences of post-marketing (-approval) experience

In the European Union the term pharmacovigilance is normally used to describe post-marketing or, more precisely, post-approval experience after the regulatory approval of drugs and their introduction to the market...