Patient Specific Studies

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For your respiratory studies, we can support you by applying our robust team of project managers specialized in the unique aspects of multi-site clinical recruiting, monitoring, specialty sample processing and direct management of important biomarker assays. Our specialization lies within four respiratory disease areas:

  • Asthma,
  • COPD,
  • Cystic fibrosis,
  • Bronchiectasis.

Other target patient populations are also possible in view of our established network of respiratory physicians and expertise with inhaled drugs and special design features of clinical studies in the therapeutic area respiratory.

First-In-Man studies with inhaled drugs

At NUVISAN, we have strong experience and expertise in many of the unique aspects that define early clinical research with respiratory and inhaled drug products. We help our customers navigate the complex challenges of respiratory clinical studies with our experienced clinical development team and our deep relationship to scientific experts as well as key opinion leaders.
When conducting clinical safety studies with inhaled drugs, there are some specific aspects to consider, such as avoidance of contamination, correct inhalation technique, PK blood samples in tight time intervals shortly after inhalation, and investigation of local tolerability which often requires the prior identification of patients with hyper reactive bronchial system. But there are more specific points to consider for which our study staff is experienced and qualified.

Respiratory studies in patients with complex endpoints

Examples for respiratory studies in patients with complex endpoints include the following:

  • First-in-Man studies with thorough safety measurements or continuous monitoring of pO2,
  • Other dedicated safety studies in the target patient population or in patients with hyperreactive bronchial system (may be identified by methacholine challenge),
  • Pharmacodynamic studies / early clinical efficacy studies using surrogate parameters, e.g. Fraction of exhaled NO (FeNO) as a biomarker, Multiple-Breath-Washout (MBW) to measure lung volumes and ventilation inhomogeneity,
  • Diffusing capacity of the lung for carbon monoxide (DLCO),
  • Special biomarkers, e.g., in sputum, which requires special technique of sample handling and processing,
  • Body plethysmography to measure lung volumes and specific airway conductance or resistance,
  • Challenge tests (or provocation tests) which may allow early Proof-of-Concept (PoC) in an experimental setting, e.g. spiroergometry, intrabrochial allergen challenge in subjects with allergic asthma, followed by determination of Early and Late Asthmatic Responses (EAR and LAR),
  • Clinical studies with pharmacodynamic and pharmacokinetic endpoints to allow for PK/PD modelling.

Multicenter clinical studies in asthma, COPD and cystic fibrosis

NUVISAN is able to organize even large-scale multi-center clinical studies in the therapeutic area respiratory. A track record of successfully conducted projects is available. Depending on the number of patients, target indication and objectives, the setting of a multi-center clinical study may be national or international. Multi-center clinical efficacy studies that have been conducted by NUVISAN in the past comprise:

  • Complex phase IIa Proof-of-Concept studies conducted by highly specialized investigational sites (including NUVISAN’s own facilities taking advantage of the first-class recruitment opportunities in the greater Ulm and Munich areas in Germany and the established network of clinical specialists),
  • Dose-range finding, phase II studies that were conducted quickly in Germany,
  • Large-scale multinational pivotal phase III studies with innovative drugs,
    Therapeutic equivalence studies with inhaled generic drug-device combinations as requested by the FDA,
  • Handling studies of novel inhaler systems in a clinical setting.

A network of experienced onsite monitors is available across Germany, keeping travel times and costs low.

Flow-profile / Peak Inspiratory Flow (PIF) studies

Flow-profile studies are a special class of medical device studies. Regulatory agencies usually request at least one flow-profile study for the marketing authorization of a novel inhaler device to characterize the inspiratory flow manoeuvres in the target patient populations compared to healthy subjects. A reduced study design with the endpoint Peak Inspiratory Flow (PIF) may be sufficient. The characteristics of the novel inhaler system are usually compared to a marketed reference inhaler system. This is a quite specific type of medical device study which requires being able to deal with the technical requirements of flow measurements and to recruit target patient populations, such as severe asthma or COPD, or even children in case of pediatric asthma.

A track record of successfully conducted flow-profile studies is available at NUVISAN. All these studies were conducted in a short period of time. As always, NUVISAN offers full-service solutions including Clinical Investigational Plan (CIP) writing, clinical conduct, evaluation, and reporting. Moreover, NUVISAN’s project managers are experienced in the management of the submission procedure for medical device studies and can deal with some of the special regulatory features required for this study type.

Allergen challenge tests in asthmatic patients or allergic subjects

NUVISAN offers a clinical Center of Excellence in our Gauting clinic (near Munich, Germany), including challenge models for bronchoconstriction and pulmonary inflammation, pulmonary sample collection, and full spectrum of pulmonary function tests. Our specialized early phase clinic for respiratory research is supported by staff specifically trained in techniques and equipment used for respiratory clinical research studies.
Allergen challenge by inhalation is a very useful clinical and research tool for evaluating the efficacy of investigational compounds in allergic airway disease under highly controlled conditions. The onset of bronchoconstriction, representing the Early phase of the Asthmatic Response (EAR), can be detected within 10 min of the inhalation, reaches a maximum within 30 min, and usually resolves within 3 hours. The Late phase Asthmatic Response (LAR) starts between 4 and 8 hours and is accompanied by cellular inflammation of the airway and mucus secretion.
The model of intrabronchial allergen challenge can be used in a placebo-controlled Proof-of-Concept (PoC) study with a new investigational compound. The use of such a provocation model under highly controlled and standardized conditions requires only a limited number of cases to demonstrate a drug effect. As there are different pathways leading to EAR and LAR, the allergen inhalation challenge model may also help to confirm the mechanism of action of a novel anti-allergic or anti-inflammatory drug for the treatment of allergic asthma.
PoC studies using the model of intrabronchial allergen challenge may be carried out in a multicenter setting with a few highly qualified investigational sites in Germany. The top recruiters and renowned clinical experts for this method are all known to us from previous collaborations.

Inhaled bioequivalence studies in patients

The development of generics for inhaled formulations can be challenging since the device technology and aerosol characteristics have a significant impact on the lung deposition of the active component. A generic drug product must be bioequivalent in terms of rate and extent of absorption of the active pharmaceutical ingredient. Determination of clinical bioequivalence (BE) of inhaled drug products can be split into three approaches:

1) Lung deposition as determined by pharmacokinetics (with charcoal block),
2) Demonstration of therapeutic equivalence (usually requested for US registration),
3) Lung deposition as determined by imaging technology.

Pharmacokinetic studies with inhaled drugs are usually the basis of any inhaled generic development. Pilot PK studies are typically conducted in a first step for device optimization. Marketing authorization of inhaled generics in the EU is usually based on pharmacokinetic BE studies. In addition to the assessment of inhaled BE with charcoal block, regulatory agencies often ask for another study arm without charcoal block to make sure systemic exposure is also comparable for safety reasons. That means inhaled BE studies are often large-scale studies, and large cohorts should be investigated to streamline the study conduct. Moreover, it is essential that these clinical studies are conducted in good quality in terms of inhalation, accurate timing of PK blood samples, and prevention of contamination.
NUVISAN is your expert CRO for inhaled BE studies and can also give valuable advice regarding the optimization of the study design.

Early clinical studies with inhaled bronchodilators

It is very important that healthy subjects or patients participating in a clinical study with an inhaled drug are adequately trained about the correct inhalation technique because the effectiveness in delivering drugs to the lung – and thus systemic exposure – depends on correctly performed inhalation maneuvers. But there are more aspects that need to be considered such as accurate pharmacokinetic blood sampling (blood samples often have to be taken at very short intervals at the beginning due to rapid change in plasma concentrations) and avoidance of contamination. Our staff is very experienced in complying with all quality measures when conducting studies with inhaled investigational compounds.

Even in early-phase clinical studies with healthy subjects, the pharmacodynamic effect of inhaled bronchodilators can be detected and quantified by measuring specific airway conductance (sometimes expressed as specific airway resistance) by using the method of body plethysmography. This opens the possibility to determine the onset of the pharmacodynamic effect even in healthy volunteers as part of an ascending-dose study (e.g., FIM Study) and to obtain valuable information on the dose-response relationship at a very early stage, which helps to estimate the clinical dose range and to design later patient studies correctly, and thus save costs.

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