Products For Human Use Research Articles

On the Lower Predictive Bound Approach for Noninferiority Clinical Trials with Binary Data

Clinical trials are mostly designed to provide data that allow direct inference of the underlying hypotheses. This, however, is not the case for noninferiority trials where placebo controls are absent due to ethical considerations, resulting in the need for indirect inference about the underlying hypotheses of the treatment effect of a new drug against a putative placebo control. In particular, the European Committee for Medicinal Products for Human Use (CHMP) guideline for noninferiority trials requires indirect confidence bounds for the “putative” effect of the new drug. To meet this requirement, we develop a new approach by which the lower predictive bound of a given confidence level is used to determine the noninferiority margin. For this approach, we provide methods for calculating the sample size and for making indirect statistical inference (i.e., p-values, confidence intervals, and point estimates) on the putative effect of the new test drug. For an actual trial example, we assess designs by the lower predictive bound approach as well as other approaches for determining noninferiority margins.

PCN106 - Cost-Effectiveness Analysis of Panitumumab Plus Mfolfox6 Versus Bevacizumab Plus Mfolfox6 for First-Line Treatment of Patients with Wild-Type Ras Metastatic Colorectal Cancer

 Approximately 20% to 25% of patients with CRC have metastatic disease (mCRC) at diagnosis, and up to 50% of all patients will develop metastases, which are associated with signifi cant morbidity and diminished quality of life. 2  Panitumumab (a monoclonal antibody against epidermal growth factor receptor [EGFR]), as well as bevacizumab (a vascular endothelial growth factor [VEGF] inhibitor) in combination with chemotherapy are both options in the treatment of patients with wild-type RAS mCRC. 3,4  In 2007, panitumumab was initially approved by the European Medicines Agency (EMA) for patients with refractory mCRC with nonmutated (wild-type) KRAS genes. 3  Identifi cation of additional RAS mutations beyond KRAS exon 2 (i.e., mutations in KRAS exons 3 and 4 and NRAS exons 2, 3, and 4) predict lack of response to panitumumab and have driven new labels for EGFR inhibitors. 5  The European Committee for Medicinal Products for Human Use (CHMP) stated recently that the benefi t-risk balance of panitumumab has improved in its newly approved wild-type RAS indications, due to the exclusion of patients with additional RAS mutations outside those initially investigated in the KRAS exon 2 analyses.  In such a context of improved benefi t-risk balance of panitumumab, a legitimate question arises regarding the relative value for money of panitumumab versus bevacizumab given the health care costs challenges faced in France and in Europe generally.  Head-to-head data are available from a prospectiveretrospective analysis of the phase 2 PEAK (NCT00819780) trial, the only fi rst-line clinical trial of panitumumab plus mFOLFOX6 (oxaliplatin, 5-fl uorouracil, and leucovorin) versus bevacizumab plus mFOLFOX6 conducted in patients with mCRC (extended RAS analysis of panitumumab plus mFOLFOX6 [n = 88] and bevacizumab plus mFOLFOX6 [n = 82]; incremental benefi t in favor of panitumumab: progression-free survival [PFS] = 2.9 months, P = 0.03; overall survival [OS] = 12.4 months, P = 0.06; event rate = 41.1%, hazard ratio = 0.63; 95% CI 0.39-1.02, P = 0.06). 6

Biosimilars: Challenges and path forward

Development of biosimilar proteins is the fastest growing sector in the biopharmaceutical industry, as patents for the top 10 best-selling biologics will expire within one decade. The world’s first biosimilar of infliximab, Remsima® (CT-P13) made by Celltrion, was approved by the Committee for Medicinal Products for Human Use (CHMP) of European Medicine Agency (EMA) in June 2013. This has ignited competition between related companies for prior occupation of the global market on blockbuster biologics. However, to achieve approval for biosimilars, developing companies face many hurdles in process development, manufacturing, analysis, clinical trials, and CMC (chemical, manufacturing and controls) documentation. Recent evolutionary progress in science, engineering, and process technology throughout the biopharmaceutical industry supports to show similarity between originator and biosimilar products. The totality of evidence has been able to demonstrate the quality, efficacy, and safety of biosimilars whereas a lack of interchangeability and international standards has to be addressed. Further understanding of the timing importance by regulatory agencies will be key to maximizing the value of biosimilars.

Challenges of safety evaluation

Each application for authorisation of a medicinal product must be accompanied by the particulars and documents referred to in Directive 2001/83/EC on the Community code relating to medicinal products for human use. Details on the documentation needed for traditional herbal medicinal products (THMP) are given in article 16c of the above mentioned Directive. It is pointed out that a bibliographic review of safety data together with an expert report and additional data, if necessary, are required.The Committee on Herbal Medicinal Products (HMPC) provides in its “Guideline on the use of the CTD format in the preparation of a registration application for traditional herbal medicinal products” (EMA/HMPC/71049/2007 Rev. 1) guidance on how to present the information and the dossier needed for an application. There, in agreement with the Directive 2001/83/EC, a bibliographical review of safety data is required within the “Non-clinical Overview”. However, it is assumable that for such products, with a long tradition of usage bibliographical information relating to non-clinical safety are available, even if incomplete or not in accordance with today׳s state of the art. In the “Guideline on non-clinical documentation for herbal medicinal products in applications for marketing authorisation (bibliographical and mixed applications) and in applications for simplified registration” (EMEA/HMPC/32116/2005) it is reflected how to deal with such an incomplete set of data for traditional herbal medicinal products and crucial information are highlighted.This article will focus on the explanation of the requirements needed for the non-clinical safety evaluation of THMPs and some detailed explanations of the performance and interpretation of the mutagenicity studies.

Optimising the use of commercial LAL assays for the analysis of endotoxin contamination in metal colloids and metal oxide nanoparticles

Engineered nanoparticles (NP) are generally contaminated by bacterial endotoxin, a ubiquitous bacterial molecule with significant toxic and inflammatory effects. The presence of endotoxin, if not recognised, can be responsible for many of the in vitro and in vivo effects attributed to NPs. The Limulus Amoebocyte Lysate (LAL) assay, the test requested by regulatory authorities for assessing endotoxin contamination in products for human use, is not immediately applicable for testing endotoxin in NP preparations, mainly due to the possible interference of NPs with the assay readouts and components. In this study, we have compared different commercially available LAL assays for detecting endotoxin in gold, silver and iron oxide NPs. Different NP chemistry, concentrations and surface coatings could differently interfere with the LAL assays’ results. After accurate testing of the possible interaction/interference of NPs with the various assay components, the modified chromogenic LAL assay proved the most suitable assay for measuring endotoxin in NP samples, provided the appropriate controls are performed. Thus, endotoxin determination can be performed in NP preparation with commercial LAL assays only after assay validation, i.e. once possible interference of NPs with the assay components and readouts has been excluded.

Emerging treatments in type 2 diabetes: focus on canagliflozin.

Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder, which affects more than 300 million people globally. The common effect of uncontrolled diabetes is the state of hyperglycemia, which results from beta-cell dysfunction as well as insulin resistance, which is accompanied with microvascular and macrovascular complications. As hyperglycemia defines diabetes, glycemic control is fundamental to the management of diabetes. Sodium glucose co-transporter 2 inhibitors (SGLT2) are a new group of oral antidiabetic medications that act by blocking the reabsorption of glucose, causing it to be excreted in the urine. Canagliflozin was the first SGLT2 inhibitor to be approved in the US by the Food and Drug Administration for the treatment and control of T2DM and on September 19, 2013, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Invokana®. Canagliflozin is a SGLT2 inhibitor, which acts upon the proximal tubules of the kidneys and reduces the renal threshold for glucose. It is highly selective, binding 250 times more potently to SGLT2 than sodium glucose co-transporter 1 inhibitor. This action allows a higher amount of glucose to be excreted within the urine, causing the patient’s plasma glucose level to be decreased and indirectly causing weight loss. Among the most common adverse events are hypoglycemia, headache, nausea, female genital and urinary tract infections, nasopharyngitis, and transient postural dizziness. Given its high efficacy in reducing hyperglycemia and good safety profile as either monotherapy or an add-on treatment to metformin, sulfonylureas, or insulin, canagliflozin seems to be a promising antihyperglycemic drug. Nevertheless, further large-scale and long-term studies should be conducted to evaluate the impact of canagliflozin on cardiovascular risk in T2DM patients.

Industry Update

The month of May 2014 brought the news that AstraZeneca had rejected Pfizer's last and final offer to take over the company, while Valeant's attempts to acquire Allergan continued (both topics are covered in detail in last month's edition of Therapeutic Delivery). Companies that did agree to work together in May, at least in the form of licensing and collaboration agreements, included Avalanche and Regeneron (gene therapy via an adeno-associated virus-based delivery system), AADi and Celgene (in-licensing of sirolimus or rapamycin, formulated as albumin-bound nanoparticles), AntiOp and Reckitt Benckiser (nasal naloxone), Bristol-Myers Squibb and CytomX (Probody™ antibodies against immuno-oncology targets) and PolyTherics and Alpha Cancer Technologies (novel drug conjugates of alpha-fetoprotein). May also brought good news for Veloxis in the form of a positive opinion from the Committee for Medicinal Products for Human Use for its MeltDose® formulation of tacrolimus, and for RXi Pharmaceuticals which received a Notice of Allowance from the United States Patent and Trademark Office on a key patent for its self-delivering RNAi technology.

The European Medicines Agency approval of ingenol mebutate (Picato) for the cutaneous treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis in adults: Summary of the scientific assessment of the Committee for Medicinal Products for Human Use (CHMP)

The European Commission has recently issued a marketing authorisation valid throughout the European Union for ingenol mebutate (Picato) in the cutaneous treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis in adults. The objective of this paper is to summarise the scientific review of the application leading to regulatory approval in the EU. The full scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website (www.ema.europa.eu). The application was supported by 25 clinical studies, of which 18 were performed in patients with actinic keratosis. The active substance is a pure ingenol angelate obtained from the aerial parts of the plant species Euphorbia peplus by extraction and purification. One tube of ingenol mebutate 150 mcg/g gel or 500 mcg/g gel should be applied once daily to the affected area for 3 or 2 consecutive days on the 'face and scalp' or 'trunk and extremities', respectively. Complete response rate is 42.2% on the 'face and scalp' and 34.1% on the 'trunk and extremities'. The most common side effects are local skin responses including erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation and erosion/ulceration at the application site. The benefits of ingenol mebutate are its ability to improve the complete response rate of actinic keratosis, the short duration of treatment and the ease of self-application.

Development of nanoparticles for clinical use.

During recent years, there has been much interest in using nanoparticles (NPs) for delivery of therapeutic drugs or contrast agents. Many interesting in vitro and animal studies have been reported [1–3], and some NP-based products are already in clinical use. Iron-oxide containing NPs have been used as iron supplement or contrast agents in MRI for more than 20 years [4,5]. Albumin and liposomal-based products containing anticancer drugs have also been available for several years, and new NP-based products are in clinical trials [2,6]. The discrepancy between the large number of papers published about NPs and other drug candidates versus the few new drugs entering the market is heavily debated, and important discussions regarding what is needed to bring new products to the market have been published [6–9]. No doubt, there are many challenges to overcome before NPs may become common tools in clinical practice.

Coalition Against Major Diseases/European Medicines Agency biomarker qualification of hippocampal volume for enrichment of clinical trials in predementia stages of Alzheimer's disease

BackgroundRegulatory qualification of a biomarker for a defined context of use provides scientifically robust assurances to sponsors and regulators that accelerate appropriate adoption of biomarkers into drug development. MethodsThe Coalition Against Major Diseases submitted a dossier to the Scientific Advice Working Party of the European Medicines Agency requesting a qualification opinion on the use of hippocampal volume as a biomarker for enriching clinical trials in subjects with mild cognitive impairment, incorporating a scientific rationale, a literature review and a de novo analysis of Alzheimer's Disease Neuroimaging Initiative data. ResultsThe literature review and de novo analysis were consistent with the proposed context of use, and the Committee for Medicinal Products for Human Use released an opinion in November 2011. ConclusionsWe summarize the scientific rationale and the data that supported the first qualification of an imaging biomarker by the European Medicines Agency.

Siltuximab: first global approval.

The anti-interleukin-6 (IL-6) chimeric monoclonal antibody siltuximab is the first drug to be approved for the treatment of multicentric Castleman's disease (MCD) in the US and European union (EU), having gained approval under the FDA priority review program in the US and from an accelerated assessment and recommendation by the Committee for Medicinal Products for Human Use (CHMP) in the EU. Development of the drug is continuing in smoldering multiple myeloma. This article summarizes the milestones in the development of siltuximab leading to this first approval for MCD.

A dose-ranging study of MF59®-adjuvanted and non-adjuvanted A/H1N1 pandemic influenza vaccine in young to middle-aged and older adult populations to assess safety, immunogenicity, and antibody persistence one year after vaccination

Background During development of an A/H1N1 pandemic influenza vaccine, this study was performed to identify the antigen and adjuvant content which would provide optimal antibody response and persistence in adults and the elderly. Dose-sparing strategies, such as inclusion of adjuvants, are critical in ensuring the widest possible population coverage in the event of an influenza pandemic, despite a limited global capacity for vaccine manufacture.Methods Healthy subjects aged 18−64 years (n = 1240) and ≥65 years (n = 1352) were vaccinated with 1 of 8 investigational vaccine formulations varying in antigen quantity (3.75 µg to 30 µg of hemagglutinin) and MF59® adjuvant (none, half dose, or full dose). All subjects received 2 vaccine doses administered 3 weeks apart. Antibody response was assessed by hemagglutination inhibition assay 1 and 3 weeks after administration of first and second doses. Antibody persistence was assessed after 6 and 12 mo. Vaccine safety was monitored over 12 mo.Results All 8 investigational A/H1N1 vaccine formulations were well tolerated, and rapidly induced high antibody titers which met all of the Center for Biologics Evaluation and Research (CBER) and Committee for Medicinal Products for Human Use (CHMP) licensure criteria 3 weeks after one dose. The highest antibody titers were observed in participants vaccinated with higher quantities of antigen and adjuvant.Conclusion A single vaccine dose containing 3.75 µg of A/California/7/2009 (H1N1) antigen with MF59 adjuvant was identified as optimal for young to middle-aged (18−64 years) and older (≥65 years) adult populations.

The European Medicines Agency Review of Pertuzumab for the treatment of adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer: summary of the scientific assessment of the committee for medicinal products for human use.

Pertuzumab is a recombinant humanized monoclonal antibody that specifically targets the extracellular dimerization domain (subdomain II) of HER2. Based on the positive opinion from the European Medicines Agency (EMA) on March 4, 2013, a marketing authorization valid throughout the European Union (EU) was issued for pertuzumab (Perjeta) for use in combination with trastuzumab and docetaxel for the treatment of adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease. The demonstration of clinical benefit for pertuzumab was based on a single, phase III, randomized, double-blind, placebo-controlled trial comparing the efficacy and safety of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel in previously untreated patients with locally advanced or metastatic HER2-positive breast cancer. In the primary analysis, median progression-free survival was 18.5 months in the pertuzumab group compared with 12.4 months in the placebo group (hazard ratio [HR]: 0.62; 95% confidence interval [CI]: 0.51-0.75; p < .0001). For the secondary endpoints, overall survival (HR: 0.66; 95% CI: 0.52-0.84; p = .0008) and objective response rate (80.2% vs. 69.3%) were also favored in the pertuzumab group. Toxicity was similar between groups except for higher incidence of diarrhea, rash, mucosal inflammation, dry skin, and neutropenia for pertuzumab compared with placebo. This paper summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website (http://www.ema.europa.eu).

À propos des ivacaftor, bédaquiline, florbétapir F18 et propranolol

Among the new molecular entities approved by the EMEA and the FDA in 2012, four have caught our attention for their significant contribution to the health of patient. First of all, among the notable 2012 approvals, is ivacaftor or Kalydeco®. This is the first treatment that targets one of the gene defects that is underlying cause of cystic fibrosis. This is also an example of the promise of personalized medicine. The benefits with bedaquiline or Sirturo® are its ability to likely provide clinically relevant activity as part of multi-drug regimens against tuberculosis (TB) based on clinical data in multi-drug resistant tuberculosis (MDR TB) patients, who were defined as being at least resistant against the two major tuberculostatic medicines (isaoniazide and rifampicine). On December 2012 and then, on December 2013, the FDA and European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has recommended granting a conditional marketing authorization for Sirturo® (bedaquiline), respectively, for use as part of a combination therapy for pulmonary multidrug resistant tuberculosis in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability. Amyvid®, which is a solution for injection that contains the active substance florbetapir (18F), is a radiopharmaceutical that emits low amounts of radiation and works by targeting and attaching to β-amyloid plaques in the brain. This enables doctors to know whether or not significant amount of plaques are present in order to know if the patient is unlikely or not, to have Alzheimer's disease. Finally, the last topics addresses the propranolol, which is a beta-blocker, used alone or together with other medicines to treat high blood pressure. Propranolol is gaining a new lease of life for treating infantile hemangioma.

BG-12 (dimethyl fumarate) in the treatment of multiple sclerosis

BG-12 was recently approved in the USA, Canada and Australia as an oral treatment for relapsing–remitting multiple sclerosis after positive results from two large pivotal Phase III studies. Approval is also imminent in the EU, where BG-12 has received a positive opinion from the European Medicines Agency Committee for Medicinal Products for Human Use in March 2013. The active ingredient, dimethyl fumarate, is thought to act mainly by inducing NF-E2 p45-related factor, thereby reducing oxidative stress, which is considered to be one of the pathogenic mechanisms in multiple sclerosis. The agent is not only highly effective at reducing relapse rate but also appears to slow disability progression across a wide variety of patient groups. With the oral route of administration and a good safety profile, BG-12 will likely become a valuable treatment option for multiple sclerosis patients and neurologists.

PDB152 - A Regulatory Compararison Of Non-Insulin Dependent Type Ii Diabetes Drug Approvals In The United States And European Union

In 2012, Downing et al published a novel study in the NEJM that compared the speed of regulatory agencies between 2001-2010, which demonstrated the FDA’s relative quickness. This paper narrows the scope to new non-insulin dependent type II diabetes drugs approved by the EMA and FDA (using their respective websites) during 2005-2013, accounting for new drug approvals and legal updates to regulatory systems in a disease condition that has faced a plethora of regulatory challenges. Unlike Downing, this study looks at the European Commission’s (EC) decision, instead of the Committee for Medical Products for Human Use’s (CHMP) recommendation. A Marketing Authorization is issued upon EC decision, making it analogous with the data captured surrounding the FDA’s approval process. Additionally this analysis looks at the date submitted to the FDA and EMA as well as the approval date. The data consists of 12 non-insulin dependent moieties approved between 2005 and 2013. Out of the 12 new treatments, 10 were approved first by the FDA (83%). Additionally, the FDA began reviews before the EMA with a median time of 126.5 days. The FDA also completed 8 of the 12 regulatory reviews faster than the EMA while beginning regulatory review first in each case. Three of the four regulatory decisions in which the FDA was slower were outliers in terms of approval time. Additionally, when looking at the median, the FDA approved these moieties 77 days faster than the EMA while Downing’s findings only showed a 44-day differential. This was expected because the analysis included the EC decision takes about 2 months on average. After updating the data, restricting it to a particular subset of diabetes treatments, and altering the EMA regulatory endpoint, Downing et al’s findings not only still hold true, but become even more pronounced.

Challenges for the Development of Bone-Forming Agents in Europe

In recent years, significant advances have been made in the management of osteoporosis, particularly with respect to the development of pharmacological interventions to reduce fracture risk. Approved pharmacological interventions in Europe include bisphosphonates, strontium ranelate, raloxifene, bazedoxifene, denosumab, and parathyroid hormone peptides [1–4] (Table 1). Treatments are approved for osteoporosis in postmenopausal women, but alendronate, etidronate, risedronate zoledronic acid, and teriparatide are also approved for the prevention and treatment of glucocorticoid-induced osteoporosis in Europe [3], and alendronate, risedronate, zoledronic acid, strontium ranelate, and teriparatide are approved for the treatment of osteoporosis in men. Most of these agents are primarily inhibitors of bone turnover, sometimes referred to as anticatabolic agents [5], whereas teriparatide, parathyroid hormone (PTH), and, arguably, strontium ranelate act in part or predominately by the stimulation of bone formation (anabolic agents). There is now a number of bone-forming agents in clinical development, including agents targeting the endogenous inhibitors of bone formation sclerostin and dickkopf-1, cathepsin K inhibitors, new formulations of PTH and PTH related protein (PTHrp) analogs, and calcilytics. The clinical use of these agents in the management of osteoporosis is dependent on marketing authorization from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency. Guidelines for product development are available and are regularly updated. The last revision came into effect in 2007 [6]. In phase 3 (the demonstration of efficacy), authorization is dependent on the demonstration of significant efficacy on fracture risk reduction and acceptable safety in postmenopausal women at high or imminent risk of experiencing osteoporotic fractures on the basis of an increased 10-year probability of fractures. Because treatment to prevent fractures may be regarded as a long-term treatment, the CHMP recommends that a duration of randomized JAK has received consulting fees, advisory board fees, lecture fees, and/or grant support from the majority of companies concerned with skeletal metabolism. C C has received consulting fees and paid advisory boards for Alliance for Better Bone Health, GlaxoSmithKline, Roche, Merck Sharp and Dohme, Lilly, Amgen, Wyeth, Novartis, Servier, and Nycomed. RR: Paid advisory boards and lecture fee for Merck Sharp and Dohme, Eli Lilly, Amgen, Servier, Takeda, and Danone. J-Y R on behalf of the Department of Public Health, Epidemiology and Health Economics of the University of Liege, Liege, Belgium. Consulting fees or paid advisory boards: Servier, Novartis, Negma, Lilly, Wyeth, Amgen, GlaxoSmithKline, Roche, Merckle, Nycomed, NPS, Theramex, UCB. Lecture fees when speaking at the invitation of a commercial sponsor: Merck Sharp and Dohme, Lilly, Rottapharm, IBSA, Genevrier, Novartis, Servier, Roche, GlaxoSmithKline, Teijin, Teva, Ebewee Pharma, Zodiac, Analis, Theramex, Nycomed, Novo-Nordisk.

Elosulfase alfa: First Global Approval

Elosulfase alfa (Vimizim™) is a recombinant form of N-acetylgalactosamine-6-sulfatase (GALNS) that was developed by BioMarin Pharmaceutical Inc. as an enzyme replacement therapy for patients with mucopolysaccharidosis type IVA (MPS IVA), also known as Morquio A syndrome. Patients with MPS IVA have a GALNS deficiency, which results in serious musculoskeletal, cardiorespiratory and other system disturbances. Elosulfase alfa was approved by the US FDA on 14 February 2014 for the treatment of MPS IVA. The European Medicines Agency Committee for Medicinal Products for Human Use (CHMP) has recently recommended that elosulfase alfa be approved for use in the EU in the same indication. Within the last year, the manufacturer has also filed applications for approval for the use of elosulfase alfa in MPS IVA in Brazil, Australia, Canada and Mexico. This article summarizes the milestones in the development of elosulfase alfa leading to its first global approval in MPS IVA.

The European Medicines Agency Review of Bosutinib for the Treatment of Adult Patients With Chronic Myelogenous Leukemia: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use

On March 27, 2013, a conditional marketing authorization valid throughout the European Union was issued for bosutinib (Bosulif) for the treatment of adult patients with chronic-phase, accelerated-phase, and blast-phase Philadelphia chromosome positive (Ph⁺) chronic myelogenous leukemia (CML) previously treated with one tyrosine kinase inhibitor or more and for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment options. Bosutinib is a kinase inhibitor that targets the BCR-ABL kinase. The recommended dose is 500 mg of bosutinib once daily. The main evidence of efficacy for bosutinib was based on a CML subgroup analysis of study 3160A4-200, a phase I/II study of bosutinib in Ph⁺ leukemia in imatinib-resistant or intolerant CML. The subgroup was defined based on the presence of a BCR-ABL kinase domain mutation that would be expected to confer resistance to dasatinib (F317, E255) or nilotinib (E255, Y253, F359) and expected to have sensitivity to bosutinib or based on the presence of medical conditions or prior toxicities that may predispose the patient to unacceptable risk in the setting of nilotinib or dasatinib therapy. A conditional marketing authorization was granted because of the limited evidence of efficacy and safety currently supporting this last-line indication.

Legal debate about the definition of medical device and of medicinal drug for human use

On 3 October 2013 the European Court of Justice made a decision regarding the interpretation of definitions of medical devices (Directive 93/42/EC) and medicinal product for human use (Directive 2001/83/EC), based on the Article 267 TFEU preliminary ruling. Orv. Hetil., 2014, 155(11), 429-433.