Healthy Volunteers Studies Phase 1

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Regulatory Strategy

NUVISAN has in-depth experience with various types of first in human (FiH) and dose escalation studies (e.g., single and multiple ascending dose, dose finding) following parallel or crossover designs. We are able to enroll both healthy volunteers, special populations and patients. We are familiar with the regulatory requirements and expectations of authorities in Germany and can provide useful input during protocol development. If requested we can support you with starting dose calculations, dose increment, dose escalation method, number of subjects per dose group, specification of dose limiting tolerability/toxicity, definition of the maximum tolerated dose, and selection of recommended dose for further patient cohorts or studies.

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.

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