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

PURPOSE: While 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. METHODS: Two 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. RESULTS: The 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. CONCLUSION: Although 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

A Systematic Database Approach to Identify Companion Diagnostic Testing in Clinical Trials under the New In Vitro Diagnostic Medical Devices Regulation

The European Union In Vitro Diagnostic Medical Devices Regulation (EU) 2017/746 (IVDR) introduces companion diagnostics (CDx) as a new legal term. CDx are applied in combination with a medicinal product to identify patient subgroups most likely to benefit from a treatment or who are at increased risk. This new regulation came into full effect on 26 May 2022 and represents the current development in personalized medicine. The implementation of IVDR and CDx is a regulatory challenge in the EU, requiring re-assessment of in vitro diagnostic medical devices (IVD) in terms of their CDx designation. To retrospectively identify IVD biomarker testing applied in clinical trials, a systematic search in the German PharmNet Clinical Trials database was developed. In total 3643 clinical trials conducted between 2004 and 2022 were identified. The results were analyzed in terms of medicinal products, biomarkers, and IVDs. Patient stratification based on biomarker testing mainly takes place in oncology-related trials, and the biomarkers most frequently tested are PD-L1 and HER2. Furthermore, there is a significant overlap between the collected data and non-European national authorities that have already implemented the CDx concept. This analysis could be indicatory of the medicinal products and corresponding IVD tests that could be CDx candidates under the IVDR

Ethics committees in clinical trials involving medicinal products

Over the years, the role of ethics committees (ECs) in the review process of clinical trial applications (CTAs) has changed from being acollegial advisory body to apatient protection organisation with an authority character. While the law governing the medical profession in Germany only provides for an obligation for physicians to ask for an EC review in biomedical research on human beings, anegative opinion on the CTA does not lead to the inadmissibility of the research project from alegal point of view. In contrast, the German Medicinal Product Act (Arzneimittelgesetz, AMG) requires afavourable opinion as an approving assessment by the competent EC.The AMG defines both the elements of aclinical trial application to be reviewed by the EC as well as the principle grounds of non-acceptance to reject afavourable opinion. ECs that assess CTAs must be constituted in accordance with the state law and must be composed of interdisciplinary medical specialists, lawyers and methodologists. The main assessment criteria are amedically acceptable risk-benefit ratio, the appropriateness of the methods used, including biometric aspects, the requirements to be met by the study participants, such as their ability to give consent, the suitability of the investigators and trial facilities as well as the appropriateness of the written information with which the study participants are to be informed and give their consent.In spite of the already high degree of regulation, the applicability of the European Clinical Trial Regulation will result in even more detailed legal requirements for the composition and working procedures of an EC with the aim of further harmonising the assessment of CTAs in the EU

Lifibrol as a Model Compound for a Novel Lipid-Lowering Mechanism of Action

Lifibrol is a potent lipid-lowering drug with an unknown mechanism of action We investigated its effects on lipoprotein and sterol metabolism in normocholesterolemic male participants Seven participants were treated for 4 weeks with 600 mg/d lifibrol and 9 with 40 mg/d pravastatin in a double-blind randomized parallel-group trial Kinetic studies were performed at baseline and under acute and chronic treatment. Turnover of apolipoprotein B-100 was investigated with endogenous stable-isotope labeling, and kinetic parameters were derived by multicompartmental modeling Lathosterol and cholesterol metabolism were investigated using mass isotopomer distribution analysis (MIDA) after [I -(13)C]acetate labeling Carbon metabolism was investigated by calculating the total isotope incorporation into newly formed sterols and measuring the disposal of acetate by (13)CO(2) breath analysis Total- and low-density lipoprotein (LDL) cholesterol decreased by 18% and 27% under lifibrol and by 17% and 28% under pravastatin, respectively, whereas very-low-density lipoprotein (VLDL) cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol did not change Very-low-density lipoprotein apoB fractional synthesis and production increased under lifibrol but remained unchanged under pravastatin Low-density lipoprotein apoB fractional synthesis and production increased under pravastatin but remained unchanged under lifibrol Mass isotopomer distribution analysis indicated that both drugs decrease endogenous sterol synthesis after acute administration but pravastatin had more powerful effects Carbon-13 appearance in breath was higher during pravastatin than during lifibrol treatment. Mass isotopomer distribution analysis and carbon metabolism analysis indicated compartmentalization at the site of sterol synthesis, thus suggesting differential effects of the 2 drugs Although having comparable lipid-lowering properties lifibrol seems to have a mechanism of action distinct from that of statins Lifibrol could serve as a model compound for the development of new lipid-lowering agent