Application In Clinical Trials Research Articles

Limited availability of methods for the detection of xenotransplantation-relevant viruses in veterinary laboratories.

The German Xenotransplantation Consortium is in the process to prepare a clinical trial application (CTA) on xenotransplantation of genetically modified pig hearts. In the CTA documents to the central and national regulatory authorities, that is, the European Medicines Agency (EMA) and the Paul Ehrlich Institute (PEI), respectively, it is required to list the potential zoonotic or xenozoonotic porcine microorganisms including porcine viruses as well as to describe methods of detection in order to prevent their transmission. The donor animals should be tested using highly sensitive detection systems. I would like to define a detection system as the complex including the actual detection methods, either PCR-based, cell-based, or immunological methods and their sensitivity, as well as sample generation, sample preparation, sample origin, time of sampling, and the necessary negative and positive controls. Lessons learned from the identification of porcine cytomegalovirus/porcine roseolovirus (PCMV/PRV) in the xenotransplanted heart in the recipient in the Baltimore study underline how important such systems are. The question is whether veterinary laboratories can supply such assays. A total of 35 veterinary laboratories in Germany were surveyed for their ability to test for selected xenotransplantation-relevant viruses, including PCMV/PRV, hepatitis E virus, and porcine endogenous retrovirus-C (PERV-C). As comparison, data from Swiss laboratories and a laboratory in the USA were analyzed. Furthermore, we assessed which viruses were screened for in clinical and preclinical trials performed until now and during screening of pig populations. Of the nine laboratories that provided viral diagnostics, none of these included all potential viruses of concern, indeed, the most important assays confirmed in recent human trials, antibody detection of PCMV/PRV and screening for PERV-C were not available at all. The situation was similar in Swiss and US laboratories. Different viruses have been tested for in first clinical and preclinical trials performed in various countries. Based on these results it is necessary to establish special virological laboratories able to test for all xenotransplantation-relevant viruses using validated assays, optimally in the xenotransplantation centers.

Japanese Pharmaceutical Regulations of Engineered Viral Vectors for Medical Use Compared With Those in the United States and the European Union.

Japanese Pharmaceutical Regulations of Engineered Viral Vectors for Medical Use Compared With Those in the United States and the European Union.

Ethical Issues and Barriers for Multi-National Paediatric Clinical Trials: The Challenging Experience of the DEEP Project

Introduction: The procedures and requirements for the clinical trial application (CTA) to Ethics Committees (ECs) and/or Competent Authorities (CAs) are not fully harmonised, and this is even more evident when non-EU countries are involved. This lack of harmonisation makes more difficult the approach in the case of 'small populations', such as children and patients affected by rare diseases. A phase III efficacy-safety comparative trial (DEEP-2) involving paediatric patients affected by transfusion dependent haemoglobinopathies from seven European and non-European countries (Albania, Cyprus, Greece, Italy, United Kingdom, Egypt, Tunisia) was carried out in the context of a FP7 project (HEALTH-F4-2010-G.A. n. 261483) and included in an agreed Paediatric Investigation Plan. Aims: The aims of this paper are to describe in a complex multi-national/multi-ethnic framework the different provisions and procedures to authorise a paediatric trial in EU/non-EU countries and to evaluate the possible impact of the following key indicators on the timing of ECs approval and CAs authorisation: complexity of the national/local provisions and procedures to authorise a paediatric trial, including the number of ECs and CAs to be addressed; number and type of additional local/national documentation; number of queries from CAs and ECs; geographic setting (EU and non-EU). Methods: The following information was collected from official websites and through a survey addressed to Principal Investigators: The regulatory and legal frameworks in force at the time of the submission of DEEP-2 in each involved country;The procedures required at local/national level (i.e. number of ECs and CAs to be addressed, parallel or subsequent submission to the CA and the EC, preparation of the CTA form and documents required from CAs and ECs);The timing of ECs approval and CAs authorisation, including number and types of queries, were collected from DEEP-2 Trial Master File. Descriptive analysis, Wilcoxon Rank-Sum test and General Linear Model (GLM) analysis were used to describe results and to analyse significance of the considered indicators. Results: In the EU countries, relevant legislative acts apply and include GCP and specific procedures for paediatric trials, in non-EU countries GCP guidelines apply but have not been implemented in the national laws regulating clinical trials. Moreover, within the 4 EU Member States a different approach was in place, even if under the same rules (i.e. Directive 2001/20/EC as implemented in the national law) with distinctive documents required for the CTA in almost all the EU countries compared with the EC provisions. The CTAs were performed in the period June 2012 - September 2015 in 23 trial sites. The EC approvals and CA authorisations were issued between January 2013 - September 2015. In the EU countries, the authorisation process was completed within 7,3 to 33,8 months (median = 15 months), while in non-EU countries, the authorisation process was completed by 7 months (median = 4 months) (figure 1). In particular, the comparison of the CA time authorisation shows a significant difference between EU and non-EU clusters (p = 0.001); however, if the statistical model is adjusted for the number of EC requests as covariate, the difference is not significant. Thus, it seems that the main factor influencing the time for EC approval is the number of requests for changes/clarifications (mainly on informed consent/assent, study protocol, insurance) (figure 2). Conclusion: Delays in completion of the authorisation phase in many countries seems to be a relevant issue and the timeframes for the authorisation in EU countries are not compliant with the European requirements (60 days for single opinion release and 30 days for its acceptance, as stated in Directive 2001/20/EC). The main reasons for delay is the complexity of the procedures and the requests from the ECs/CAs. In non-EU countries, procedures are different and faster with less requests from ECs and CAs. The upcoming application of a stronger set of rules, CT-Regulation (EU) 536/2014, is expected to harmonise practices in Europe and possibly outside Europe. The final aim of this change should be to assure a good balance between a timely approval and a high-level of children protection. Disclosures Reggiardo: CVBF: Consultancy. Tricta:ApoPharma: Employment.

Die Rolle von Ethikkommissionen bei der Bewertung klinischer Arzneimittelpr\xfcfungen

ZusammenfassungDie Rolle von Ethikkommissionen bei der Bewertung klinischer Arzneimittelprüfungen hat sich im Laufe der Jahre gewandelt. Aus den kollegialen Beratungsgremien wurden Patientenschutzorganisationen mit Behördencharakter. Während das ärztliche Berufsrecht in Deutschland bei biomedizinischer Forschung am Menschen lediglich eine Beratungspflicht für Ärzte vorsieht, bei der eine ablehnende Stellungnahme in rechtlicher Hinsicht nicht zu einer Unzulässigkeit des Forschungsvorhabens führt, verlangt das Arzneimittelgesetz (AMG) eine zustimmende Bewertung durch die zuständige Ethikkommission.Das AMG definiert sowohl die durch die Ethikkommission zu prüfenden Elemente eines Antrages für eine klinische Arzneimittelprüfung als auch abschließend die Gründe, anhand derer die zustimmende Bewertung versagt werden kann. Ethikkommissionen, die Anträge gemäß AMG bewerten, müssen nach Landesrecht gebildet sein und sind interdisziplinär mit Fachärzten, Juristen und Methodikern besetzt. Wesentliche Bewertungsinhalte sind ein ärztlich vertretbares Nutzen-Risiko-Verhältnis, die Angemessenheit der verwendeten Methoden einschließlich biometrischer Aspekte, die Anforderungen an die Studienteilnehmer, wie z. B. Einwilligungsfähigkeit, die Eignung der Prüfer und Prüfeinrichtungen sowie die Angemessenheit der schriftlichen Informationen, mit denen Studienteilnehmer informiert werden und sie ihre Einwilligung erteilen sollen.Trotz der bereits jetzt hohen Regelungsdichte werden zukünftig mit der Anwendbarkeit der Verordnung (EU) Nr. 536/2014 die Anforderungen an Zusammensetzung und Arbeitsweise von Ethikkommissionen noch detaillierter gesetzlich festgelegt mit dem Ziel, die Bewertung klinischer Arzneimittelprüfungen in der EU weiter zu harmonisieren.

Recommendations for Regulating the Environmental Risk of Shedding for Gene Therapy and Oncolytic Viruses in Canada.

Canadian academic and industry stakeholders are concerned about the inclusion of “virus-like particles or sub-viral particles” in the definition of New Substances Notification Regulations for Organisms (NSNR(O)) which impacts clinical cell and gene therapy and commercialization. The requirement of an independent 120 days Environment and Climate Change Canada (ECCC) review preceding a Health Canada review on quality and environmental concerns places an additional burden on Sponsors submitting clinical trial applications (CTA) and/or New Drug Submissions (NDS). A workshop initiated by CellCAN and BIOTECanada with participants from Environment and Climate Change Canada, Health Canada, the Public Health Agency of Canada and Innovation, Science and Economic Development (Ottawa, March 19, 2018) with invited stakeholders discussed approaches to streamline the environmental review process. The following main recommendations were the focus of the workshop: A regulatory policy to clarify Canadian Environmental Protection Act (CEPA)'s definition of “living organism.” This is currently defined as “a substance that is an animate product of biotechnology.” A regulatory policy could potentially exempt “human cells touched by biotechnology for use in human medicinal products” from this definition to clarify any unintended overreach of CEPA, particularly as it applies to non-genetically modified cell therapies.A guidance document to better interpret NSNR(O) Schedule 1 requirements by CTA/NDS sponsors to satisfy the environmental review process.An amendment at the level of regulations, to the NSNR (O) to create a deferment to postpone environmental assessment of micro-organisms used in the manufacturing during investigational clinical trials (pre-market stage). The regulations would apply at the time of market authorization evaluation and review, when sufficient clinical data on vector shedding has been collected, as part of the investigational clinical trials.Amendment to Schedule 4 of the CEPA to include the Food and Drugs Act and Regulations (Food and Drugs Act /FDR) as an exclusion to the application of CEPA. This would remove the current dual regulation of cell and gene therapies by both CEPA and Food and Drugs Act /FDR.These recommendations and other options were discussed at the workshop. These recommendations if adopted will significantly streamline the current regulatory burden and harmonize environmental assessment requirements with other jurisdictions.

Ready for Germany's revised radiation rules?

The assessment of the benefit-risk ratio of investigational medicinal products (IMPs) and the approval of clinical trial applications (CTAs) conducted in the European Union (EU) is a remit of national competent authorities (NCAs) of the 28 member states. The aim of this article is to shed light on clinical studies for oncology drugs carried out in Germany which involve diagnostic radiation tests. The authorisation process surrounding diagnostic radiology accompanying clinical investigations and used for measuring IMP related treatment effects is not well understood. The procedure appears to be complicated because the scientific evaluation of the application is carried out by an independent agency, the Federal Office for Radiation Protection (Bundesamt für Strahlenschutz, BfS). To avoid delays and failures in conducting studies in Germany knowledge of the scope, procedural steps and associated timelines is crucial for project management purposes. Reliable planning is a pre-requisite for timely study initiation. Novelties of the recently implemented law and key aspects relevant to CTAs should facilitate obtaining BfS clearance. Integrating this additional regional requirement in drug development plans is of importance for timely commencement of multi-national clinical trials.

Analysis of integrated clinical trial protocols in early phases of medicinal product development

PurposeWhile in the past, most clinical trial applications (CTAs) following non-integrated (standard) protocols were used to investigate one primary objective concerning a (new) drug, nowadays, the use of integrated protocols investigating multiple objectives within the same CTA becomes more and more popular. The aims of the present study were to investigate the usage and the impact of integrated protocols on regulatory activities and to find the motivation for their increasing use.MethodsTwo thousand nine hundred sixty-nine phase I and I/II CTAs submitted to the German Federal Institute for Drugs and Medical Devices (BfArM) during the time period from August 1, 2004, until August 31, 2014, were analysed with regard to protocol and sponsor status, duration until initial authorisation and the number of substantial amendments and their respective approval times. Additionally, applicants who submitted integrated protocols to BfArM were interviewed with respect to their opinion on integrated protocols in an online survey.ResultsThe percentage of integrated protocols has constantly increased by approximately 10% within the last 10 years from 17.9% in 2004 to 28.2% in 2014. It could be shown that authorisation procedures with single integrated protocols take significantly longer until initial authorisation (58 vs. 53 days) requires more substantial amendments (1.9 vs. 1.2 amendments per CTA) and the approval of the entirety of amendments takes longer to process as compared to standard protocols (22 vs. 14 days). Nevertheless, applicants prefer the use of integrated protocols due to higher time and cost economy for the entire phase I development process.ConclusionAlthough clinical trials (CTs) following integrated protocols are partly more time-consuming and costly, still, time and/or money may be saved during drug development due to the fact that overall, fewer CTs are needed than with standard protocols. Hence, the main reason for the increasing use of integrated protocols is improved time and cost efficiencies when conducting CTs.

How to Deal with Regulation EU 536/2014 on Clinical Trials? A View from the Hospital Clínic Barcelona Research Ethics Committee

A new legal development came into action on January 2016 to align the tasks and workflow of Research Ethics Committees (REC) with the Regulation EU 536/2014. We will show how our Hospital and our REC has adapted to the new rules. There are 125 REC in Spain. For each study, only one REC is responsible for issuing an opinion on the clinical trial (CT) application dossier. The RECs of other centres involved in the study are not entitled to contribute to the evaluation. This new paradigm implies that the REC responsible of the evaluation has to deal with local issues of each centre like investigator and facilities suitability. This new system requires a considerable harmonisation effort in order to secure that a reasonable consistent approach is adopted and that criteria for the evaluation of CT do not substantially differ between RECs. In early 2015 AEMPS set up a Clinical Trial Coordination Group (CTCG) chaired by the Head of Human Drugs Sector of the AEMPS and one member of each of approximately 25 RECs with higher experience in the evaluation of CT applications. Monthly meetings are held. We have created a Thecnical Secretary for Supporting the Research (TSSR) which includes a multidisciplinary working group in charge of:−Supporting the signature of the facilities suitability form of our centre.−Hospital Clínic research activity register.−Methodology, regulatory and ethical support to the investigators.−Supporting to the Technical Secretary of the REC.−Accelerating contract signature and other administrative procedures. The TSRS will allow us:−To know about the research activity in the Hospital, although our REC is not the one that evaluated the dossier.−To speed up bureaucratic procedures.−Keep the budget for the REC activities.

Lentivector Iterations and Pre-Clinical Scale-Up/Toxicity Testing: Targeting Mobilized CD34+ Cells for Correction of Fabry Disease

Fabry disease is a rare lysosomal storage disorder (LSD). We designed multiple recombinant lentivirus vectors (LVs) and tested their ability to engineer expression of human α-galactosidase A (α-gal A) in transduced Fabry patient CD34+ hematopoietic cells. We further investigated the safety and efficacy of a clinically directed vector, LV/AGA, in both ex vivo cell culture studies and animal models. Fabry mice transplanted with LV/AGA-transduced hematopoietic cells demonstrated α-gal A activity increases and lipid reductions in multiple tissues at 6 months after transplantation. Next we found that LV/AGA-transduced Fabry patient CD34+ hematopoietic cells produced even higher levels of α-gal A activity than normal CD34+ hematopoietic cells. We successfully transduced Fabry patient CD34+ hematopoietic cells with “near-clinical grade” LV/AGA in small-scale cultures and then validated a clinically directed scale-up transduction process in a GMP-compliant cell processing facility. LV-transduced Fabry patient CD34+ hematopoietic cells were subsequently infused into NOD/SCID/Fabry (NSF) mice; α-gal A activity corrections and lipid reductions were observed in several tissues 12 weeks after the xenotransplantation. Additional toxicology studies employing NSF mice xenotransplanted with the therapeutic cell product demonstrated minimal untoward effects. These data supported our successful clinical trial application (CTA) to Health Canada and opening of a “first-in-the-world” gene therapy trial for Fabry disease.

Preclinical validation: LV/IL-12 transduction of patient leukemia cells for immunotherapy of AML

Interleukin-12 (IL-12) is a potent cytokine that may be harnessed to treat cancer. To date, nearly 100 IL-12-based clinical trials have been initiated worldwide. Yet systemic administration of IL-12 is toxic. Different strategies are being developed to reduce such toxicities by restricting IL-12 distribution. Our previous studies employed lentivector-mediated expression of murine IL-12 in tumor cells and demonstrated effective protection in both mouse leukemia and solid tumor challenge models. In this study, we carried out preclinical validation studies using a novel lentivector to engineer expression of human IL-12 in acute myeloid leukemia blast cells isolated from 21 patients. Acute myeloid leukemia cells were transduced with a bicistronic lentivector that encodes the human IL-12 cDNA as a fusion, as well as a LNGFR (ΔLNGFR)/mutant thymidylate kinase cassette as a marking and cell-fate control element. A range of 20–70% functional transduction efficiencies was achieved. Transduced acute myeloid leukemia cells produced bioactive IL-12 protein and displayed dose-dependent sensitivity to the prodrug 3′-azido-3′-deoxythymidine. In vitro immortalization assays using transduced mouse hematopoietic stem cells demonstrated minimal genotoxic risk from our IL-12 vector. Scale-up transduction and cell processing was subsequently validated in a GMP facility to support our (now approved) Clinical Trial Application (CTA).

Regulatory Forum Opinion Piece*

In the context of monoclonal antibody drug development, tissue cross-reactivity (TCR) studies are immunohistochemical (IHC) studies conducted on a broad panel of normal body tissues, using the antibody therapeutic as the primary reagent. The ICH S6 guidance states that these studies are performed to support investigational new drug (IND) or clinical trial applications (CTAs) for the initial dosing of human subjects for all antibody-based therapeutics. The purpose of TCR studies is, ostensibly, to inform investigators and regulators of potential target organs of toxicity based upon the binding of the therapeutic agent to tissue components. The value of TCR studies in predicting toxicity that would not otherwise have been detected in in vivo pharmacology and toxicology studies in pharmacologically relevant animal models has been a subject of debate for more than a decade. The history, challenges, and proper and improper uses of TCR studies were reviewed in this forum by Leach et al. in 2010. Coincident with this publication, a cross-industry survey on the utility of TCR assays in predicting human toxicity was separately published by a working group of the preclinical safety committee of the Biotechnology Industry Organization

Impact assessment of the European Clinical Trials Directive: a longitudinal, prospective, observational study analyzing patterns and trends in clinical drug trial applications submitted since 2001 to regulatory agencies in six EU countries.

BackgroundShifts in clinical trial application rates over time indicate if the attractiveness of a country or region for the conduct of clinical trials is growing or decreasing. The purpose of this observational study was to track changes in drug trial application patterns across several EU countries in order to analyze the medium-term impact of the EU Clinical Trials Directive 2001/20/EC on the conduct of drug trials.MethodsRates of Clinical Trial Applications (CTA) for studies with medicinal products in those six countries in the EU, which authorize on average more than 500 trials per year, were analyzed. Publicly available figures on the number of annually submitted CTA, the distribution of trials per phase and the type of sponsorship were tracked; missing data were provided by national drug agencies.ResultsSince 2001, the number of CTA in Italy and Spain increased significantly (5.0 and 2.5% average annual growth). For Italy, the gain was driven by a strong increase of applications from academic trial sponsors; Spain's growth was due to a rise in trials run by commercial sponsors. The Netherlands, Germany, France and the UK saw a decline (1.9, 2.3, 3.0 and 5.3% average annual diminution; significant (P < 0.05) except for Germany) in clinical drug trials. The decrease in the UK was caused by a sharp fall in academic trial activities. Across the six analyzed countries, no EU-wide trial-phase-specific patterns or trends were observed.ConclusionsThe EU Clinical Trials Directive 2001/20/EC did not achieve the harmonization of clinical trial requirements across Europe. Rather, it resulted in the leveling of clinical trial activities caused by a continuing decrease in CTA rates in the Netherlands, Germany, France and the UK. Southern European countries, Italy and Spain, benefited to some extent from policy changes introduced by the Directive. In Italy's case, national funding measures helped to considerably promote the conduct of non-commercial trials. On the other hand, the EU Directive-driven transition from liberal policy environments, based on non-explicit trial approval through notifications, towards red-taped processes of trial authorization, contributed to the decreases in trial numbers in Germany and the UK. In the latter case, national research governance concerns had a share in the country's marked decline. However, different EU member states successfully developed best practices, which a new European legislation should take into consideration to resume Europe's attractiveness and international competitiveness for the conduct of clinical trials.

Evolution of indicators of activity related to the management of investigational drugs in a pharmacy service over a period of 10 years

BackgroundIn the last years there has been an increase in clinical trials (CT) developed in the hospital as well as in their complexity.PurposeDescribe the evolution of the indicators of activity...

Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

Innovative Early Development Regulatory Approaches: expIND, expCTA, Microdosing

The Food and Drug Administration (FDA) Critical Path Initiative as well as the European Medicines Agency Road Map to 2010 (ref. 2) call for opportunities for more efficient drug development. One of the initiatives that has emerged in this context is the elaboration through guidance of exploratory investigational new drugs (INDs)/clinical trial applications (CTAs). This article reviews the history of these emerging guidances as well as the experience to date in their use by the industry.

Strategies to improve minority patient accrual to cancer clinical trials

6017 Background: Clinical trials (CT) provide the basis for standards of care. However, the rate of accrual to adult cancer CT is 3% and even lower for minorities. The lack of minority patients on CT results in difficulty ascribing standards to these groups. Proposed obstacles for inadequate accrual for ethnic minority participation are speculated to be socio-economic such as an unwillingness to participate in research and a fear of experimentation. We hypothesized that obstacles to accrual on CT for minority populations are predominantly disease-related and not socio-economic. Methods: An NCI funded CT shared resource was established between a comprehensive cancer center and a public hospital serving ethnic minority and economically disadvantaged patients. Over a 3-year period, all patients were screened to determine eligibility for a cooperative or institutional CT. A dedicated team, including nurses experienced in CT, undertook extensive interaction with all patients to facilitate accrual. Results: 462 patients were screened with 134 (29%) having an identified study available. Screened patients included 238 (56%) African Americans (AA), 165 (39%) Caucasians (C), and 20 (5%) Hispanics (H). 73 subjects, 54% of eligible and 16% of all patients, were accrued to a CT. Ethnicity on CT was: AA = 61%, C = 37%, and H = 2%. These accrual rates far exceed the national norm. Reasons eligible patients did not enter a CT were: medical co-morbidities (25%), not meeting eligibility criteria (21%) and inadequate performance status (10%). Only three patients (5%) indicated they did not wish to participate in research. Conclusion: This experience documents how a dedicated research team can enter ethnic minority and low-income patients onto CT. The largest group of patients not entered was due to a study not being available. All ethnic groups were proportionately accrued to CT. Strategies to improve applicability of CT may require design of studies for patients with co-morbidities or advanced disease. No significant financial relationships to disclose.