Mifamurtide (Mepact, Takeda) is an immune macrophage stimulant. It has a marketing authorisation for use in ‘children, adolescents and young adults for the treatment of high-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection’. The
marketing authorisation further states that mifamurtide is used in combination with postoperative multi-agent chemotherapy, and that safety and efficacy have been assessed in studies of patients 2 to 30 years of age at initial diagnosis. It is not recommended for use in children below the age of 2 years.

ACS encompass a spectrum of unstable coronary artery disease, ranging from unstable angina to transmural myocardial infarction. All forms of ACS begin with an inflamed and complicated fatty deposit (known as an atheromatous plaque) in a blood vessel, followed by blood clots
forming on the plaque. The principles behind the presentation, investigation and management of these syndromes are similar, but there are important distinctions depending on the category of ACS.
Hyperglycaemia is common in people admitted to hospital with ACS. Recent studies found that approximately 65% of patients with acute myocardial infarction who were not known to have diabetes had impaired glucose regulation when given a glucose tolerance test.
Hyperglycaemia at the time of admission with ACS is a powerful predictor of poorer survival and increased risk of complications while in hospital, regardless of whether or not the patient has diabetes. Despite this, hyperglycaemia remains underappreciated as a risk factor in ACS and is frequently untreated.
Persistently elevated blood glucose levels during acute myocardial infarction have been shown to be associated with increased in-hospital mortality, and to be a better predictor of outcome than admission blood glucose. Management of hyperglycaemia after ACS is therefore an important clinical issue.
A wide range of national guidance is available for the care of people with diabetes in hospital with relevance to ACS patients. For example the NHS Institute for Innovation and Improvement

NICE encourages use of the EOS 2D/3D imaging system in specialist research settings to
collect evidence about potentially important clinical benefits associated with 3D reconstruction,
single image weight-bearing whole-body imaging and simultaneous PA and lateral imaging.

• With ST-segment-elevation myocardial infarction (STEMI) – defined as ST elevation or new left bundle branch block on electrocardiogram – that cardiologists intend to treat with primary percutaneous coronary intervention (PCI) or
• with non-ST-segment-elevation myocardial infarction (NSTEMI) or
• admitted to hospital with unstable angina – defined as ST or T wave changes on electrocardiogram suggestive of ischaemia plus one of the characteristics defined in section 1.2. Before ticagrelor is continued beyond the initial treatment, the diagnosis of unstable angina should first be confirmed, ideally by a cardiologist.

For the purposes of this guidance, characteristics to be used in defining treatment with ticagrelor for unstable angina are: age 60 years or older; previous myocardial infarction or previous coronary artery bypass grafting (CABG); coronary artery disease with stenosis of 50% or more in at least two vessels; previous ischaemic stroke; previous transient ischaemic attack, carotid stenosis of at least 50%, or cerebral revascularisation; diabetes mellitus; peripheral arterial disease; or chronic renal dysfunction, defined as a creatinine clearance of less than 60 ml per minute per 1.73 m2 of body-surface area.

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These techniques are frequently used patient selection stratification or treatment strategies of patient groups, and the EMA is concerned the appropriate steps are not been taken hence the publication of this guidance.

excerpt from guidance

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The availability of techniques that facilitate study of the human genome has led to an exponential increase in investigation into genomic biomarkers (GBMs) for diagnosis of specific diseases, as a marker of response to treatment or of prognosis. Theoretically genomic BMs should offer the advantage of improved specificity and reduction of heterogeneity that is an integral part of phenotypic population grouping. This is very attractive in drug development because of their potential ability to reduce drug attrition and to reduce overall developmental costs, that are achieved through improved understanding of the mechanism of drug action, predict adverse events to individual drugs or as a group effect (e.g. CYP poor metabolisers), and use of novel development strategies in pre-clinical and clinical phases.
In clinical drug development, GBMs may aid and influence a wide range of areas: patient selection, stratification of treatment strategies or patient groups, early evaluation of treatment effect including adverse reactions, and prognosis. There is opportunity for the GBMs to be used for pre-defined subgroup analysis or to enable novel trial designs that might not be possible otherwise due to heterogeneity of clinical characteristics.1,2 GBMs could also play a valuable role in the risk management strategies including risk minimisation by aiding a priori identification of patients susceptible to develop severe adverse effects (e.g. HLA B*- 5701 and use of Abacavir).
While a number of these aspects are discussed in many publications in the recent years, specific aspects relating to drug development and discussion on regulatory considerations have lagged behind. The intention of this paper is therefore to provide an evidence based consideration of GBM related issues from a regulatory viewpoint. Mention is also made of co-development of a GBM diagnostic test for use with a medicinal product.
The principles established in the reflection paper are based on the experiences gained from the evaluation of dossiers within the EU regulatory processes —including marketing authorisation applications reviewed by CHMP, the scientific advice documents and additionally, the voluntary genomic data submission meetings (briefing meetings) at the Pharmacogenomic Working party (PGWP) over the last several years. It is expected that these principles guide both industry and the assessors in the evaluation of such biomarkers in relation to the qualification process in the context of clinical development (BM qualification in EU) and the assessment of benefit: risk balance of medicinal products or selection of the relevant target population. The paper should also be read in conjunction with other relevant guidelines listed at the end of the documents under section “Other aspects”.
Development of GBMs and diagnostic tests may involve additional development of tests (companion diagnostics) or specific kits (platforms) to detect for the presence or absence of the GBM. Issues relating to these are outside the scope of this paper but a short discussion is included. The readers are referred to appropriate guidelines/ papers for details (see section on other aspects).

excerpts from guidance

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This guideline defines key elements necessary for the validation of bioanalytical methods. The guideline focuses on the validation of the bioanalytical methods generating quantitative concentration data used for pharmacokinetic and toxicokinetic parameter determinations. Guidance and criteria are given on the application of these validated methods in the routine analysis of study samples from animal and human studies.

Measurement of drug concentrations in biological matrices (such as serum, plasma, blood, urine, and saliva) is an important aspect of medicinal product development. Such data may be required to support applications for new actives substances and generics as well as variations to authorised drug products. The results of animal toxicokinetic studies and of clinical trials, including bioequivalence studies are used to make critical decisions supporting the safety and efficacy of a medicinal drug substance or product. It is therefore paramount that the applied bioanalytical methods used are well characterised, fully validated and documented to a satisfactory standard in order to yield reliable results.
Acceptance criteria wider than those defined in this guideline may be used in special situations. This should be prospectively defined based on the intended use of the method.

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This guideline describes the information to be documented when an application for a marketing authorisation for recombinant or human plasma-derived factor IX products is made for use in treatment and prevention of bleeding in patients with haemophilia B. The guideline covers clinical investigations to be conducted pre- and post-marketing authorisation. Guidance is also provided for authorised products where a significant change in the manufacturing process has been made.
Timeline history of guideline: The original Note for Guidance on Clinical Investigation of Human Plasma Derived FVIII and FIX Products (CPMP/BPWG/198/95) came into operation on 14 February 1996. The first revision (CPMP/BPWG/198/95 Rev. 1) came into operation in April 2001. The original Note for Guidance on Clinical Investigation on Recombinant FVIII and FIX Products (CPMP/BPWG/1561/99) came into operation in April 2001. Draft revisions of CPMP/BPWG/1561/99 and CPMP/BPWG/198/95 were released for public consultation in July 2007. Following this consultation, it was decided to reorganise the guidance to have separate documents: The Guideline on clinical investigation of recombinant and plasma derived factor VIII products (EMA/CHMP/BPWP/144533/2009) and the Guideline on clinical investigation of recombinant and plasma derived factor IX products (EMA/CHMP/BPWP/144552/2009).

It is considered to have considerable public health impact in a small subpopulation of menstruating women. This guideline is to provide guidance on the clinical evaluation of products to treat this patient group.

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There are substantial research data available to support premenstrual dysphoric disorder (PMDD) as a diagnostic entity of a severe form of premenstrual disorder, which causes clinically relevant functional impairment and requires treatment. It is considered a disorder with substantial clinical and public health impact in a [small] subpopulation of menstruating women. The aim of this guideline is to provide guidance for the evaluation of medicinal products in the treatment of PMDD.
The present document should be conceived as general guidance, and should be read in conjunction with other applicable EU and ICH guidelines (see Section 3)..

Up to 70-90 % of women of reproductive age have one or more signs of physical discomfort or emotional symptoms in the premenstrual, i.e. luteal phase of their menstrual cycle. About 20-40 % of menstruating women have premenstrual syndrome (PMS) and experience luteal phase symptoms that are bothersome. A smaller number, up to 8 %, experience more severe symptoms, which lead to substantial distress or functional impairment and are referred to as premenstrual dysphoric disorder (PMDD) (10, 11, 13, 14, 23, 38, 39, 42). Although PMDD, like PMS includes physical symptoms, it always involves a worsening of mood that interferes significantly with the woman’s quality of life. The burden of illness of PMDD results from the severity of luteal phase symptoms, the chronicity of the disorder and the impairment in work, relationships and activities.
In the last decades a very broad diagnostic concept of the premenstrual disorders PMS and PMDD has been used in clinical research, which produced different diagnostic criteria and highly heterogeneous study populations.
Recent advances and research data improved the knowledge on diagnosis, frequency, pathophysiologic mechanisms, and treatment options in PMDD. This led to treatment recommendations by learned societies for PMDD.