Clinical Development

Healthy Volunteers Studies Phase 1

NUVISAN has extensive experience with first-in-human and dose escalation studies for healthy volunteers, special populations, and patients. We can help with starting dose calculations, dose escalation methods, and defining the maximum tolerated dose, as well as provide valuable input during protocol development. We are familiar with regulatory requirements in Germany and can support you with dose group size, dose limiting tolerability/toxicity, and selection of recommended doses for future studies.

Regulatory Strategy

We have successfully implemented different strategies when submitting FIH trials. One approach is to submit SAD and MAD clinical studies under an umbrella protocol. For this approach it is necessary to lay down very clear rules for dose escalation and a cap on maximum AUC and Cmax. Based on the most relevant safety data from the immediately preceding cohort the next cohort can often be started once these pertinent safety data are available. Furthermore, the MAD can sometimes be started while the SAD is still ongoing as long as sufficient safety data have been obtained and as long as none of the stopping criteria apply to the MAD. The ethics committee may agree to a “tell–and-do” approach where they do not require a new vote for the next step. Nevertheless, this approach often requires submission of an amendment at least following the SAD.

The other strategy is to submit the SAD and the MAD separately, but as part of a development program based on the same IMPD which permits shortened timelines for approval by ethics and CA within 14 days from when the MAD is submitted.

Safety

One advantage of conducting a FIH trial at NUVISAN is the availability of bioanalysis, immunology and safety laboratories under one roof. Exposure has become an important criterion for dose escalation and as a stopping criterion. Having bioanalysis available in-house reduces the time until the most important PK results from the immediately preceding cohort are available. Furthermore, having immunology in house allows online evaluation of safety parameters, such as pro-inflammatory cytokines, during dose escalation. Safety laboratory parameters being determined in our own laboratory also assures a short turn-around time. Last but not least exploratory metabolite investigations in a FIH study will help to understand human biotransformation and can make possible a first evaluation of the metabolite exposure versus the respective safety species evaluated.

For almost all of our SAD cohorts a sentinel cohort of two subjects is dosed (1 active drug, 1 placebo) before the remainder of the cohort is dosed two days later. Our staff is trained in emergency procedures on a regular basis and all necessary emergency equipment is available on all floors of the clinic. General precautions include those related to drug-induced anaphylactic reactions of single individuals, which require emergency interventions by a physician including application of high dose corticosteroids, anti-histaminic drugs, volume resuscitation and catecholamine therapy as well as O2-insufflation or general resuscitation in rare cases. In addition, study-specific rescue medication may be made available (insulin, magnesium etc.) Furthermore, we routinely have an emergency physician present for several hours after dosing.

BioAvailability & PK

Absolute And Relative Bioavailability

NUVISAN can support these studies end-to-end, including support regarding regulatory, statistical and bioanalytical requirements. For new chemical entities often absolute bioavailability of a dosage form compared to that following IV administration is assessed and in the course of development bridging studies may be required when formulation changes are necessary and formulations need to be compared. In the latter case the comparative bioavailability study aims to show that two products are equivalent in terms of safety and efficacy, typically by demonstrating pharmacokinetic equivalence. Waivers of a clinical study may be possible depending on BCS class or if an in vivo/in vitro correlation has been established. We have worked with a wide range of APIs, formulations and routes of administration. Products in these studies may be pharmaceutically equivalent or pharmaceutical alternatives.

BE Studies

These studies are used to demonstrate bioequivalence of a test drug to an already approved reference drug. Usually the reference drug chosen must have been granted marketing authorization based on a full dossier. Whenever possible a 2-way cross-over is chosen. Most often bioequivalence is assessed after single dosing, in some cases however under steady state conditions. Usually the parent drug must be analysed unless this proves to be impractical. In some cases the metabolites must be measured as well. Bioequivalence has been established if the 90 % confidence intervals for the log-transformed ratios of the geometric means of AUC and Cmax lie within the prescribed range. For highly variable drugs fully or partially replicated designs can be implemented. In case of highly variable drugs FDA guidance permits one to define new limits for the ratio of both AUC and Cmax, the EMA guideline however only permits an adjustment of the range for Cmax. For drugs with a narrow therapeutic index, it may be required to narrow the range for AUC and possibly also for Cmax. Our statistical department can support with estimation of sample size, ANOVA and can also help to plan a two-stage approach with an interim-analysis between the two stages.

DDI Studies

NUVISAN has conducted studies with various FDA index substrates, inhibitors and inducers. In these studies, midazolam has been administered as a sensitive index substrate for CYP3A (at least five-fold increase in AUC with a strong index inhibitor), warfarin as a moderately sensitive substrate for CYP2C9 (at least two-fold but less than 5-fold increase in AUC with a strong index inhibitor), omeprazole as a sensitive substrate for CYP2C19 and both clopidogrel as well as fexofenadine as substrates for the transporter P-gp. If requested, subjects can be genotyped prior to inclusion in such a study. By example, in the study with warfarin subjects were genotyped for a number of polymorphisms of CYP2C9 and VKORC1. We also performed a study with a mixture of 7 substrates for CYP enzymes and the transporter P-gp (Geneva cocktail). Itraconazole has been given as a strong inhibitor of CYP3A and fluconazole as a moderate inhibitor of CYP3A (and CYP2C9). Carvedilol was administered to inhibit the transporter P-gp. Competitive and non-competitive inhibition of enzymes is observed immediately, i.e. typically after single-dosing, and does not change over time. Mechanism-based inhibition is time-dependent and increases after multiple dosing (Deodahr M. et al. (2020). Mechanisms of CYP450 Inhibition: Understanding Drug-Drug Interactions Due to Mechanism-Based Inhibition in Clinical Practice. Pharmaceutics 2020, 12, 846; doi:10.3390/pharmaceutics12090846).  Similarly, induction of CYP enzymes usually requires the perpetrator drug to be given over a period of time. In our clinic we used multiple doses of rifampicin as a strong inducer of CYP2C19 and CYP3A. Another important consideration is the mode of administration. Oral administration of a drug can be used to look at pre-systemic inhibition. When choosing which interactions to study the intended clinical use of a drug also needs to be considered. For example, in one interaction study, multiple doses of diltiazem and atenolol were administered to investigate the potential of diltiazem and atenolol, respectively as concomitant medication to potentiate the heart-rate lowering effect of an S1P receptor modulator. Furthermore, we conducted an equally large number of DDI studies to study the pharmacokinetics of drugs in combination products. Our bioanalytical department has supported most of these studies with proprietary as well as non-proprietary assays; in part single assays and in part combined assays measuring several analytes in the same probe.

FE Studies

Food effect sometimes is already evaluated in one of the cohorts of the SAD portion of our FIH trials, however, usually a dedicated study is performed later on particularly if the formulation to be marketed is different.  Modified-release drugs generally require investigation of a food effect. Our set-up in the clinic fully supports the conduct of food effect bioavailability and fed bioequivalence studies. Our own canteen prepares the high fat high calorie breakfast as defined by the FDA and other standardized meals. If needed, a meal plan can be prepared by a dietician. For studies investigating a food effect there is meal oversight to ensure that the breakfast is eaten in its entirety and within the prescribed time. Furthermore, there are bag checks on admission and video surveillance of yard and hallways to ensure subjects comply with fasting times and other restrictions.

Cardiac Safety Studies

Drug-induced QTc prolongation may, in rare cases, lead to Torsade de pointes, a polymorphic ventricular tachycardia. Known risk factors include: bradycardia, hypokalemia, hypomagnesemia, base-line QT prolongation, and female gender (Kallergis E.M. et al. Mechanisms, Risk Factors, and Management of Acquired Long QT Syndrome: A Comprehensive Review. The Scientific World Journal 2012, Article ID 212178, 8 pages, doi:10.1100/2012/212178.) Thus a drug’s tendency to cause QTc prolongation has been required to be investigated by regulators. In the past based on ICH E14 of 2005 it often was necessary to conduct a TQT trial (dependent upon ability to conduct the study, how the drug is used, and nonclinical data).

NUVISAN has successfully conducted such TQT trials which investigate the potential of a drug to cause QTc interval prolongation using a supra-therapeutic dose and a positive control. (Lissy M, Demmel V, Sachse R, Ammer N, Kelepouris N, Ostrow V. Thorough QT/QTc Study Evaluating the Effect of Macimorelin on Cardiac Safety Parameters in Healthy Participants. Clin Pharmacol Drug Dev. 2020 Sep 22. doi: 10.1002/cpdd.872. Epub ahead of print. PMID: 32961034.)

A study initiated by the Cardiac Safety Research Consortium demonstrated that exposure response analysis correlating intense ECG monitoring with PK data from early clinical trials was able to correctly predict QT effects of positive drugs and exclude such an effect for a negative drug. This has led to a revision of the guidance by the ICH E14 Implementation Working Group in 2016 and opened the path to obtain a waiver for a TQT study. Such intense monitoring correlating the change in QTc interval of subjects receiving active drug relative to that of the placebo subjects, as a function of the drug concentrations, is frequently implemented in our early clinical trials. In particular, the SAD and MAD of a FIH trial when a wide range of doses is administered and as such are a useful for conducting such an evaluation.

The key to conducting either a TQT study or exposure response modelling is to obtain high quality recordings. For the conduct of such a trial subjects remain in our intensive assessment unit for the hours following dosing. Mobile partition walls separating the beds are set up to ensure a quiet atmosphere. Staff dedicated to such a study are experienced in using the Holter devices Getemed and CardioMen, and uploading the recordings to a server. Recordings typically are reviewed by the collaborating Holter provider and a consulting cardiologist.

Special Populations

Our patient populations include type 2 diabetes patients, pre-diabetics, patients with hyperhydrosis, and patients with restless leg syndrome. Currently we are conducting an interaction study in women with relapsing multiple sclerosis in collaboration with several neurological clinics.  We have also been recruiting postmenopausal women and tubal ligated women on a regular basis. Upcoming is a vaccination study that includes elderly subjects.

Implementation Of Special Assessments

We cooperate closely with specialists. Specialized investigations, whenever possible, are conducted in our clinic. To this end, assessment rooms for these investigations are set up in our clinic.

For example, we have conducted a large number of studies in the area of women’s health. For most of these studies screening gynecological assessments including PAP are performed in-house. In some studies ovulatory status was followed closely by trans-vaginal ultrasound. We have also placed IUDs and obtained endometrial biopsies during the course of some studies. There is a long-standing collaboration with gynecologists, some of whom have worked directly for NUVISAN in the past and who now continue the collaboration.

Assessments of the CNS have been implemented as part of trials testing neurological drugs and as part of other trials. Assessments include EEG (placement of electrodes and recordings by experienced NUVISAN staff in-house, evaluation of transmitted EEGs by cooperating neurologists), Mini mental status exam, implementation of tests from Vienna test battery: Critical Flicker Fusion Threshold, Choice Reaction Time (pure reaction time, motor time, total reaction time), and use of questionnaires such as Addiction Center Research Inventory (ARCI49), Columbia Suicide Severity Rating Scale (C-SSRS), and Buss & Perry Aggression Questionnaire.

We also cooperate closely with several ophthalmological practices in the Neu-Ulm and Ulm area. Most ophthalmological assessments are performed in our clinic. We conduct studies testing eye drops in healthy volunteers and proof of concept trials testing oral drugs e.g. in non-proliferative diabetic retinopathy patients. Furthermore ophthalmological assessments often need to be carried out in other trials (as a PD parameter or as a safety assessment). Tests include BCVA, tonometry, slit lamp anterior and posterior segment examinations of the eye including funduscopy, corneal esthesiometry, tear film break-up time (TFBUT), fluorescein staining of the cornea and conjunctiva, Schirmer test, pupillometry, and DRSS 7-field fundus photography. Our conciliar ophthalmologists also perform fluorescein angiography and more recently also spectral domain OCT and OCT angiography.

Cardiac Safety Studies

Drug-induced QTc prolongation may, in rare cases, lead to Torsade de pointes, a polymorphic ventricular tachycardia. Known risk factors include: bradycardia, hypokalemia, hypomagnesemia, base-line QT prolongation, and female gender (Kallergis E.M. et al. Mechanisms, Risk Factors, and Management of Acquired Long QT Syndrome: A Comprehensive Review. The Scientific World Journal 2012, Article ID 212178, 8 pages, doi:10.1100/2012/212178.) Thus, a drug’s tendency to cause QTc prolongation has been required to be investigated by regulators. In the past based on ICH E14 of 2005 it often was necessary to conduct a TQT trial (dependent upon ability to conduct the study, how the drug is used and nonclinical data).

NUVISAN has successfully conducted such TQT trials which investigate the potential of a drug to cause QTc interval prolongation using a supra-therapeutic dose and a positive control. (Lissy M, Demmel V, Sachse R, Ammer N, Kelepouris N, Ostrow V. Thorough QT/QTc Study Evaluating the Effect of Macimorelin on Cardiac Safety Parameters in Healthy Participants. Clin Pharmacol Drug Dev. 2020 Sep 22. doi: 10.1002/cpdd.872. Epub ahead of print. PMID: 32961034.)

A study initiated by the Cardiac Safety Research Consortium demonstrated that exposure response analysis correlating intense ECG monitoring with PK data from early clinical trials was able to correctly predict QT effects of positive drugs and exclude such an effect for a negative drug. This has led to a revision of the guidance by the ICH E14 Implementation Working Group in 2016 and opened the path to obtain a waiver for a TQT study. Such intense monitoring correlating the change in QTc interval of subjects receiving active drug relative to that of the placebo subjects as a function of the drug concentrations is frequently implemented in our early clinical trials.  In particular, the SAD and MAD of a FIH trial when a wide range of doses is administered and as such are a useful for conducting such an evaluation.

The key to conducting either a TQT study or exposure response modelling is to obtain high quality recordings. For the conduct of such a trial subjects remain in our intensive assessment unit for several hours following dosing. Mobile partition walls separating the beds are set up to ensure a quiet atmosphere.

Surrogate Markers For Efficacy

NUVISAN has conducted numerous trials that aim to establish biosimilarity to reference drugs (e.g. several trials with large numbers of healthy volunteers to evaluate Neupogen, Neulasta, Humira, Zomacton, Nutropin and Stelara biosimilarity). Such studies follow the analytical, functional and preclinical characterisation of both products and are often followed by Phase III studies in patients to demonstrate similar efficacy and safety. The overarching biosimilar guideline of the EMA in 2014 stated that confirmatory PK/PD studies might be sufficient to establish biosimilarity if an accepted surrogate marker for efficacy was available and referenced, I.e. for the efficacy of G-CSF absolute neutrophil count (ANC) as such a biomarker. We conducted two studies, with the Clintrials.gov Identifiers NCT02912377 and NCT02629562 respectively, that demonstrated pharmacokinetic and pharmacodynamic similarity of a biosimilar with the reference drug Neulasta. The trials demonstrated that the pharmacokinetic parameter AUC remained within the standard bioequivalence margins. Furthermore, based on the fact that the efficacy marker absolute neutrophil count also satisfied the standard requirements for bioequivalence, a Phase III study in patients was waived and the product was approved. Following this approval, the product specific guideline for G-CSF was revised now explicitly stating that trials in patients are not necessary. (Lehnick, D., Wessels, H., Höfler, J., Roth, K., Scholz, U. Pelmeg®, a biosimilar pegfilgrastim developed in the context of evolving regulatory guidelines. Generics and Biosimilars Initiative Journal. 2020; 9 (3): 125-31. DOI: 10.5639/gabij.2020.0903.021).  An important consideration when planning this trial was the consideration that the dose should be in the steep part of the dose-response curve to ensure that the study would permit one to detect differences in efficacy between the products.

When planning a biosimilar trial, we suggest to collaborate closely with regulatory authorities to discuss such opportunities so as to replace a Phase III trial in patients with a trial investigating PK and PD in healthy volunteers. Our experience is that regulatory authorities are quite open to respond to scientific advances and NUVISAN may be able to facilitate the process.

Patient Specific Studies

For your respiratory studies, we can support you with our 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, and 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.

Monitoring Services

Clinical Management and Monitoring Late Phase Oncology Studies in Latin America

Our geographic footprint facilitates a significant presence in the leading Latin American market, combined with well-established affiliate operations, thereby covering a total of 10 countries with dedicated staff.
NUVISAN has 20 years of oncology drug development expertise in the region. Our project approach and processes are tailored to the specific needs of oncological studies.

Rare Diseases

NUVISAN offers tailored concepts across all key therapeutic areas with particular expertise not only in pivotal Phase II/III studies, but also in late-phase approaches such as observational studies, as well as regional and national projects.

Monitoring Services

We ensure that our clinical monitors are always up to date with local and international standards and we, as the majority of our partners, are members of local clinical research associations in their respective regions.
The clinical monitoring team is designed to closely work with the project management team in order to ensure that your study is executed precisely. Monitors are the representatives of NUVISAN and your study towards the investigators. To follow the recruitment plan as scheduled, we assure best communication skills and perform quality checks on the investigator site frequently.

Clinical Support

Our suite of services includes clinical management and monitoring solutions, regulatory affairs expertise, support with clinical development planning, statistics and data management, corporate project management, and consultancy services. With a team of highly skilled professionals and a commitment to excellence, we help our clients achieve their goals and bring innovative new treatments to market efficiently and effectively.

Regulatory Affairs

Scientific writing of IMPDs

An Investigational Medicinal Product Dossier (IMPD) is required to support the Clinical Trial Application in the European Union. NUVISAN is experienced in scientific writing of IMPDs, in updating IMPDs to incorporate progress in pharmaceutical development, and in analyzing possible gaps in the dossier. NUVISAN can also provide support in answering requests from Competent Authorities.

Support with the Clinical Development Plan

A clinical development plan (CDP) summarizes clinical studies which are required during the development of an active substance and corresponding medicinal product for submitting the results from the clinical trials in an application for marketing authorisation. NVISAN can support your product development, elaborating such a CDP tailored to your product.

Statistics & Data Management

The key to excellent data management is flexibility. We respond smartly and straight forward to minimize any influence on timelines. This ability is the true mark of a valuable CRO partner —but NUVISAN surpasses that basic function by applying strong cost-effective measures, quality assurances, as well as therapeutic and regulatory expertise.

Since the data of any clinical investigation is of utmost value NUVISAN’s philosophy is not to separate data management from the study team, but involve the data management department already in the proposal process. We believe integration from the start is the ideal way to efficiently clean and organize data.

You can work with us for full-trial build or select from our suite of Data Management Services:

• CDASH Case report form (CRF) design, electronic or paper
• Data Mangement Plan and Data Validation Plan Development
• Database set-up and validation
• Electronic data capture (EDC) systems implementation and training
• Double data entry for paper CRF–based studies
• In-depth, thorough quality assessments: checking for errors or trends and querying data through final database lock
• Generation and Delivery of CDISC SDTM submission package

Validation of all system components throughout the study period is performed as modifications are introduced

We also adhere to the benchmarks set by SCDM and CDISC.

Use of familiar systems improves efficiency because it frees sites to focus on the protocol requirements rather than technology. We work with ORACLE’S INFORM, Oracle’s CLINTRIAL and CLINSPARK to afford industry recognized programs in the performance of data management activities.

Corporate Project Management

Since many years, NUVISAN has successfully managed projects in numerous therapeutic areas. Over time, we adapted to different types of projects and became a partner of choice for the management of your projects.

With over 15 years of experience in project management, our team offers full-service capabilities allowing us to handle an entire program or specific services, from strategy definition to regulatory submission. Fully dedicated to your project, we work proactively to mitigate the risk in order to proactively anticipate all challenges that could be faced, rather than being reactive in nature.

Our project managers will only aim to complete every project on time and on budget, while maintaining a high quality of service.

Our Corporate Project Managers (CPM) collaborate with you from the start to ensure every aspect of a project is planned and executed the best way possible. The CPM are the primary interface between you and the project team members and will ensure a close and efficient communication.

Our project management responsibilities:

• Establish a strong relationship of trust with our clients and communicate transparently with them throughout the project
• Get full commitment from cross-functional teams & align with your goals
• Manage dynamic development teams & set-up strategic leadership
• Set up a proactive risk identification and management plan
• Provide expertise & continuous support for all of your projects

Medical Writing

Our Corporate Project Managers (CPM) collaborate with you from the start to ensure every aspect of a project is planned and executed the best way possible. The CPM are the primary interface between you and the project team members and will ensure a close and efficient communication.

Our project management responsibilities:

• Establish a strong relationship of trust with our clients and communicate transparently with them throughout the project
• Get full commitment from cross-functional teams & align with your goals
• Manage dynamic development teams & set-up strategic leadership
• Set up a proactive risk identification and management plan
• Provide expertise & continuous support for all of your projects

Consultancy

NUVISAN offers pharmaceutical consultancy services from drug discovery to registration, provided by seasoned pharma industry professionals. Spreading from Germany to all over Europe, we have satisfied new and returning clients in various areas of drug development. We recognized that the demands of the modern healthcare industry require tailored approaches to bring compounds as fast as possible and with appropriate quality into the next phase, and that the ‘one-solution-fits-all’ paradigm is no longer relevant.

At present, our consultancy services comprise the following (but may not be limited to)

• Impurity profiling with safety evaluations
• Design of DMPK/ADME in vitro and in vivo studies (with unlabeled or radiolabeled test materials)
• Human PK predictions
• Drug-drug interaction assessments
• Due diligences
• Project development plan reviews with strategic directions
• Project management and DMPK representation (as external member of your project team)
• Clinical monitoring
• Regulatory affairs
• Scientific writing (study reports, IB, IMPD, IND, briefing books)
• Dossier analyses including proposals to close gaps with assessments and/or conduct of new non-clinical or clinical studies