Investigator's Brochure Research Articles

Review of the European Union Clinical Trials Regulation: Key Early Learnings from the United Kingdom Drug Information Association Medical Writing Committee.

The European Union Clinical Trials Regulation (EU CTR) provides new regulatory requirements for the preparation and submission of clinical trial documents. The United Kingdom Drug Information Association Medical Writing (UK DIA MW) Committee, with members from across the pharmaceutical industry, have reviewed the EU CTR and in this report, provide expert guidance on writing documents for submission in the EU CTR Clinical Trials Information System (CTIS) portal. Medical writers should be aware that the Investigator's Brochure containing the Reference Safety Information (RSI) must align with the annual safety report, and the RSI format must comply closely with the EU CTR. For clinical study protocols, medical writers should prepare a single integrated EU protocol that receives consolidated approvals from all participating EU member states, with different versions of a protocol for different EU member states no longer permitted. This report also provides details of experiences and recommendations on protocol synopses from the UK DIA MW Committee. In addition, plain language summaries are new EU CTR documents required for each study presenting summaries of clinical trial results for laypersons. Some of these documents will be published in the publicly accessible CTIS portal which has created concerns amongst many companies who are keen to protect commercially confidential information (CCI). Medical writers may help reduce CCI through lean writing, but specifically identifying CCI may require specialist legal evaluation. This report by the UK DIA MW Committee highlights the key processes for medical writers to ensure compliance with the EU CTR when preparing documents for submission to the CTIS portal.

Enhancement of anti-PD-L1 antibody plus anlotinib efficacy due to downregulation of PD-L1 in the micro-conduit endothelium within the tumor: a randomized double-blind trial.

The possible enhancing effect of anlotinib on programmed death receptor ligand (PD-L1) antibody and the efficacy-predicting power of PD-L1 in micro-conduit endothelium, including lymphatic endothelial cells (LECs) and blood endothelial cells (BECs), were determined to identify patients who would benefit from this treatment. PD-L1 positivity in LECs, BECs, and tumor cells (TCs) was assessed using paraffin sections with multicolor immunofluorescence in an investigator's brochure clinical trial of TQB2450 (PD-L1 antibody) alone or in combination with anlotinib in patients with non-small cell lung cancer. Progression-free survival (PFS) with different levels of PD-L1 expression was compared between the two groups. Among 75 patients, the median PFS (mPFS) was longer in patients who received TQB2450 with anlotinib [10 and 12 mg (161 and 194 days, respectively)] than patients receiving TQB2450 alone (61 days) [hazard ratio (HR)10 mg = 0.390 (95% confidence interval {CI}, 0.201-0.756), P = 0.005; HR12 mg = 0.397 (0.208-0.756), P = 0.005]. The results were similar among 58 patients with high PD-L1 expression in LECs and TCs [159 and 209 vs. 82 days, HR10 mg = 0.445 (0.210-0.939), P = 0.034; HR12 mg = 0.369 (0.174-0.784), P = 0.009], and 53 patients with high PD-L1 expression in BECs and TCs [161 and 209 vs. 41 days, HR10 mg = 0.340 (0.156-0.742), P = 0.007; HR12 mg = 0.340 (0.159-0.727), P = 0.005]. No differences were detected in the mPFS between the TQB2450 and combination therapy groups in 13 low/no LEC-expressing and 18 low/no BEC-expressing PD-L1 cases. Mono-immunotherapy is not effective in patients with high PD-L1 expression in LECs and/or BECs. Anlotinib may increase efficacy by downregulating PD-L1 expression in LECs and/or BECs, which is presumed to be a feasible marker for screening the optimal immune patient population undergoing anti-angiogenic therapy.

Impact of Fine-Tuned Machine Translation on Medical Documentation Translation and Client Satisfaction

Aim: The aim of this study was to assess the impact of Fine-Tuned Machine Translation (FTMT) models, followed by Machine Translation Post-Editing (MTPE), on the translation quality and client satisfaction in medical documentation. Materials and Methods: The research analyzed 733,632 words across 317 projects completed in 2023 by Lingrowth, a medical and life science translation service provider. These projects involved translations from 16 source languages to 34 target languages. Document types included Instructions for Use (IFU), Investigator Brochures (IB), Summary of Product Characteristics (SmPC), Clinical Study Reports (CSR), and Informed Consent Forms (ICF). The projects were categorized into two groups for comparison: translations performed by human translators using Translation Memory (TM) and those processed by FTMT followed by MTPE. The primary metrics for evaluation were the number of post-project finalization requests and instances of severe negative feedback from clients. Results: It was observed that human-translated projects had a higher frequency of post-project finalization requests, whereas MTPE projects after FTMT exhibited a marginally higher rate of severe negative feedback. However, statistical analysis indicated that these differences were not significant, suggesting that the introduction of FTMT models with subsequent MTPE does not adversely affect the overall quality of medical document translations. Conclusion: The study concludes that FTMT models, when supplemented by MTPE, are com-parable in effectiveness to traditional human translations in the context of medical documentation. This highlights the potential of integrating FTMT in translation workflows without compromising translation quality or client satisfaction.

Exploration of pharmacokinetic differences between East Asians and Caucasians: insights from pharmacokinetic studies in healthy subjects.

Interethnic differences in the pharmacokinetics of drugs result from a complex interplay of environmental, genetic, and demographic factors. Identifying ethnic differences in pharmacokinetics is challenging due to the multifaceted contributions of the underlying factors. To address these challenges, this paper reviews 9 pharmacokinetic studies meeting the following criteria: (A) Conducted at Seoul National University Hospital from 2013 to 2022 as a single-center study. (B) Pharmacokinetic studies involving both East Asians (Korean, Japanese, or Chinese) and Caucasians. (C) Study drugs were administered orally. (D) Raw data was provided for reanalysis. This retrospective analysis aimed to investigate the existence of ethnic differences in drug exposure and understand the possible factors contributing to these variabilities. Pharmacokinetic, demographic, and clinical laboratory test data were analyzed to assess potential pharmacokinetic differences between East Asians and Caucasians. This assessment involved calculating the geometric mean ratio of dose-normalized area under the time-concentration curve (AUC) and dose- and weight-normalized AUC, along with their 90% confidence intervals. Additionally, pharmacological information, including metabolic pathways, was gathered from the investigational brochure or the respective country's drug label. Among 9 studies, 4 studies demonstrated approximately 1.3 to 1.8 times higher drug exposure in East Asians compared to Caucasians. These drugs were primarily eliminated through hepatic metabolism, with less than 5% excreted unchanged in the urine. Two drugs were metabolized by hepatic cytochrome P450 3A4, one by glutathione S-transferase, and specific metabolic pathways for another drug were not identified. Further research is needed to assess the causes of ethnic variability in these drugs.

Impact of Medication Reconciliation in Oncology Early Phase Studies: A Drug-Drug Interaction Retrospective Study.

This study aims to investigate the impact of medication reconciliation (MR) conducted by pharmacists before patient enrollment and the initiation of investigational treatments. By implementing MR, the primary objective is to evaluate the extent to which the inclusion of patients with prohibited or not recommended concomitant medications in clinical trials can be significantly reduced. The study included all patients who participated in clinical trials and underwent MR between September 1, 2015, and September 1, 2020. To identify prohibited or monitored drugs, protocols and investigator's brochures provided by the sponsor were meticulously reviewed and taken into consideration. MR was performed for 501 patients, uncovering 35% of the medications they were currently taking. Through the pharmaceutical analysis, a total of 346 drug-drug interactions (DDIs) were identified, of which 188 required monitoring and 158 were strictly prohibited. More than half of the prohibited medications were herbal drugs. A significant portion of these prohibited drugs were discontinued, with only 6% being replaced by suitable alternatives. The implementation of MR played a crucial role in the identification of 51% of the prohibited or monitored drugs that were initially overlooked by oncologists. MR is a highly effective measure aimed at reducing the risk of DDIs with investigational drugs, thereby minimizing protocol deviations and enhancing patient care. Sponsors of clinical trials value its implementation and recognize the substantial benefits it brings to the entire trial process. Consequently, many sponsors willingly provide funding to investigational sites that adopt MR as part of their standard practice, acknowledging its critical role in ensuring patient safety and maintaining data integrity throughout the course of clinical research studies.

Real-World Venetoclax-Obinutuzumab in 232 Treatment Naive CLL Patients: Feasibility and Tolerability

Fixed duration venetoclax-obinutuzumab (VO) is approved in treatment naïve (TN) chronic lymphocytic leukemia (CLL), based on CLL14 study addressed to patients (pts) with coexisting conditions. The combinations showed also to be effective and well tolerated in the younger population enrolled in the randomized CLL13 trial. The aim of this retrospective, multicenter Italian study is to evaluate the feasibility and tolerability of this combination in TN CLL in common clinical practice as well as reasons for choosing fixed-duration VO instead of continuous BTKi. Consecutive pts receiving first-line therapy after VO approval/reimbursement in Italy (May 2022) were considered. Reasons for choosing the fixed duration treatment were recorded. The impact of clinical, biological, and demographic characteristics on VO feasibility (definitive treatment discontinuation and/or schedule modifications due to toxicity) and tolerability were analyzed. Debulking (Deb) phase (D1-D56) was separately evaluated to better understand its influence on treatment management. From May 2022 to June 2023, 790 treatment naïve continuous pts were treated with targeted agents in 49 centers. Treatment choice consisted of: continuous BTKi in 558 pts and fixed-duration VO in 232 (the latter representing the population of our analysis). The main reasons given by physicians for choosing VO instead of BTKi were: disease biology 46% (mutated IgHV status), fixed duration 33%, comorbidities 15%, patient choice 6%. Pts' characteristics are shown in Table 1. When considering Deb-phase (232 pts), VO was regularly administered according to the investigator brochure in 150 (64.7%). In 22 cases (9.5%) the schedule was a priori modified by clinicians: 12 pts started with V led-in and postponed O infusion at C2D1; in 10 planned O D8 and D15 infusions were omitted. Overall, 12 pts (5.2%) permanently discontinued VO due to toxicity. 3 of them dying due to: COVID pneumonia, invasive aspergillosis, VO-unrelated cachexia. In the remaining 48 (20.7%) schedule was adjusted due to AEs. Treatment modifications, overlapping in some cases were: 42 extended the Deb-phase (median days to completion 63, range 59-130); 14, never reached the full V dose; 31 did not perform the planned 5 O infusions (median 3 infusions, range 1-4). No age, neither coexisting conditions influenced treatment feasibility. The only parameters having an impact on Deb-phase discontinuation or schedule modifications due to toxicity were: baseline ANC<1500/mmc (OR 3.1, p=.035), hypogammaglobulinemia (OR 2.2, p=.018), concomitant use of anticoagulants (3.13, p=.029). Overall 23 pts (9.9%), including 7 categorized as high risk TLS, were hospitalized for treatment initiation. During Deb-phase grade 3-4 AEs occurred in 69 pts (30%): neutropenia (18%); thrombocytopenia (14%); infections (5%); IRR (5%). Development of any severe AE was influenced by: upper GI disorder, baseline neutropenia or thrombocytopenia. TLS was recorded in 13 pts (6%): 11 O-related and 4 V-related. All 4 clinical TLS were considered as secondary to O. Only high CLL-CI risk was associated with TLS. None of the baseline factors nor type of steroids premedication predicted IRR. At the present follow-up of the 232 pts considered: 142 completed the 6 cycles of combinations treatment, 75 are still ongoing, 15 definitively discontinued treatment for AEs. Overall, 42 pts received VO with an adjusted schedule for toxicities: 22 are receiving V at reduced dose, 39 pts did not complete the planned O infusions (treatment modifications overlapping in some cases). G 3-4 toxicity developed in 78 pts being neutropenia and infections the most common reported. At univariate analysis factors affecting treatment feasibility were: presence of endocrine comorbidity; intermediate/high CLL-CI and hypogammaglobulinemia. To our knowledge this is the first real-world study on clinical factors that may influence VO feasibility. Despite this setting of unselected population, most clinicians were adherent to VO schedule. A low rate of pts permanently discontinued therapy during Deb-phase with no impact of age or comorbidities on feasibility. Furthermore, TLS and IRR were in line with clinical trials. Longer follow-up data will be reported at the meeting allowing by multivariate analysis to better clarify the role of comorbidities on treatment management and the reproducibility of VO tolerability in common clinical practice.

Preclinical efficacy in investigator's brochures: Stakeholders' views on measures to improve completeness and robustness.

Research ethics committees and regulatory agencies assess whether the benefits of a proposed early-stage clinical trial outweigh the risks based on preclinical studies reported in investigator's brochures (IBs). Recent studies have indicated that the reporting of preclinical evidence presented in IBs does not enable proper risk-benefit assessment. We interviewed different stakeholders (regulators, research ethics committee members, preclinical and clinical researchers, ethicists, and metaresearchers) about their views on measures to increase the completeness and robustness of preclinical evidence reporting in IBs. This study was preregistered (https://osf.io/nvzwy/). We used purposive sampling and invited stakeholders to participate in an online semistructured interview between March and June 2021. Themes were derived using inductive content analysis. We used a strengths, weaknesses, opportunities and threats matrix to categorize our findings. Twenty-seven international stakeholders participated. The interviewees pointed to several strengths and opportunities to improve completeness and robustness, mainly more transparent and systematic justifications for the included studies. However, weaknesses and threats were mentioned that could undermine efforts to enable a more thorough assessment: The interviewees stressed that current review practices are sufficient to ensure the safe conduct of first-in-human trials. They feared that changes to the IB structure or review process could overburden stakeholders and slow drug development. In principle, more robust decision-making processes align with the interests of all stakeholders and with many current initiatives to increase the translatability of preclinical research and limit uninformative or ill-justified trials early in the development process. Further research should investigate measures that could be implemented to benefit all stakeholders.

The Innovator's Credo: Fail Early and Often

Editorial| June 2021 The Innovator's Credo: Fail Early and Often Steven L. Shafer, MD Steven L. Shafer, MD Search for other works by this author on: This Site PubMed Google Scholar ASA Monitor June 2021, Vol. 85, 5. https://doi.org/10.1097/01.ASM.0000754184.26241.a4 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Cite Icon Cite Get Permissions Search Site Citation Steven L. Shafer; The Innovator's Credo: Fail Early and Often. ASA Monitor 2021; 85:5 doi: https://doi.org/10.1097/01.ASM.0000754184.26241.a4 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search nav search search input Search input auto suggest search filter All ContentAll PublicationsASA Monitor Search Advanced Search Topics: sharks, surgical procedures, operative, swimming, propofol, fospropofol, entrepreneurs, software, prodrugs I was in tears laughing as I read the investigator's brochure for fospropofol on a flight to Baltimore. Fospropofol was a water-soluble prodrug of propofol, rapidly metabolized into phosphate and propofol. Fospropofol was being developed, in part, to eliminate propofol pain on injection. Unfortunately, phosphate makes your genitals burn, as every anesthesiologist who has given a bolus of I.V. dexamethasone phosphate or codeine phosphate to an awake patient knows (no anesthesiologist ever does this twice). It struck me as an uneven trade. What, exactly, is one supposed to tell the patient before inducing with fospropofol? During the presentation I had been asked to give, I explained that the perceived benefits (slower onset and offset) were not benefits at all. I also shared my view that genital burning was a showstopper. To my amazement, and against both the available evidence and scientific first principles, the company leadership was convinced that fospropofol... You do not currently have access to this content.

Stakeholders’ recommendations for revising Good Clinical Practice

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is revising ICH E6 Good Clinical Practice (GCP). The Clinical Trials Transformation Initiative (CTTI) initiated a project to identify and provide ICH with stakeholders’ priority areas and suggestions for revising ICH E6 GCP. We conducted a global online survey to identify areas of ICH E6 GCP that are and are not in need of revision. A total of 327 stakeholders completed the survey. Stakeholders represent many research roles and types of organizations, are employed in 39 countries, and conduct research in 153 countries. The ICH E6 GCP principles mentioned most often (range, 25%–29%) in need of revision were implementing systems that assure quality, providing medical care by qualified physicians/dentists, protecting confidentiality and privacy, obtaining informed consent, and documenting and storing information. The Investigator section (n = 244, 75%) and Sponsor section (n = 242, 74%) of ICH E6 GCP were identified as needing the most revision and the Investigator Brochure section (n = 166, 51%) as needing the least revision. The topic most frequently mentioned as needing revision is Monitoring (n = 146; 45%) in the Sponsor section. Although none of the principles or topics in ICH E6 GCP were identified as needing revision by the majority of stakeholders, a meaningful percentage of stakeholders identified areas that they believe need revision. These findings, which represent the views of a wide variety of stakeholders, may be useful to ICH for identifying where specifically to focus their revision efforts. CTTI provided the final report to ICH with the project findings for their consideration.

Commentary on "Investigator brochures for phase I/II trials lack information on the robustness of preclinical safety studies" by Sievers et al.

Commentary on "Investigator brochures for phase I/II trials lack information on the robustness of preclinical safety studies" by Sievers et al.

Abstract OT-14-01: Adaption of the EORTC quality of life breast cancer module for male breast cancer - phase I

Abstract Background: Approximately 1% of all new cases of breast cancer (BC) occur in men. Care of male BC is largely based on extrapolation from treatment strategies and management of symptoms in women. The impact of BC diagnosis and therapy on Quality of Life (QoL) in women with BC is well documented. Comprehensive, prospective data about QoL in men treated for BC are sparse. Due to the lack of a validated male BC QoL questionnaire, we previously evaluated the QoL of the male BC using the original EORTC QLQ-C30 and breast module QLQ BR23 with “female” items replaced by male-specific items from the EORTC QoL prostate module (EORTC QLQ-PR25). The development of a validated worldwide questionnaire for male BC is sponsored by EORTC QoL Group and will be completed in cooperation with EORTC Breast Group and the International Male BC Program (a cooperation between EORTC-BCG, TBCRC, within the BIG and NABCG networks) Trial design: The evaluation of the QoL issues relevant for male BC, as well as the translation of issues into items to build the tool for QoL assessment in male BC will be carried out through four phases: 1. A systematic Literature review 2. Interviews with patients 3. Interviews with Health Care Professionals (HCP) 4. Consultation of experts in Oncology and QoL Inclusion criteria: • Histologically proven early BC or metastatic BC in male patients • Age ≥ 18 years • Ability to understand and fill out questionnaires • Written informed consent Exclusion criteria: • Other cancer in the past 5 years except non-melanotic skin cancer • Patients participating in interventional clinical studies with QoL as primary endpoint • Any condition potentially hampering compliance with the study protocol Aims: The study proposes to carry out an evaluation of the QoL issues relevant for male patients with BC, and translating the issues into questions to build the tool for an adequate QoL assessment in these patients. The specific aims are: 1) To carry out an evaluation of the existing EORTC QLQ-BR 45 (adapting for male BC) and for suitability of use in male BC patients 2) To carry out an evaluation of the EORTC QLQ-PR25 (adapting for male BC) for suitability of use in male BC patients 3) To provide recommendations to the EORTC on a suitable assessment approach to assess QOL in male BC Statistical methods: A systematic literature review to assess what factors are unique to male BC patients in influencing their QoL and what QoL measures exist for them will be performed. This will be conducted by reviewing all studies with male BC participants and including investigator brochures describing side effects in male BC patients, as well as by evaluating issues captured by other existing EORTC modules. The final list of potential QoL issues relevant to the male BC will be tested for relevance and importance in semi-structured qualitative interviews with patients and HCP. A total of 2-5 patients per year will be recruited from collaborating hospitals/countries. At least 40 in total will be interviewed before, during, or after treatment for male BC. At least 2 experts/country from the all collaborating centres will be included in the interview to discuss and consider the potential issues. Finally, the issue list will be translated into questions to build the tool for a QoL assessment in male BC patients. Present accrual and target accrual This study started in October 2019. A systematic literature review has been completed. Seventeen centres from worldwide are participating in the study. New centers may still join. Contact information for people with a specific interest in the trial Vesna Bjelic-Radisic E-Mail: Vesna.Bjelic-Radisic@helios-gesundheit.de Fatima Cardoso e-mail: fatimacardoso@fundacaochampalimaud.pt Citation Format: Vesna Bjelic-Radisic, Fatima Cardoso, Joachim Weis, Eveline Bleiker, David Cameron, Galina Velikova, Karatzyna Pogoda, Samantha Serpentini, Kevin Punie, Rinat Yerushalmi, Erika Matos, Birgit Carly, Ivana Bozovic-Spasojevic, Markus Fleisch, Zoe Luisa Probst, Sina Maria Schafer, Nicola Russell, Sofie Tombeur, Joanna Vermeij, Heidi Roelstraete, Kathryn Ruddy, Juan I Arraras, Andrew Bottomley. Adaption of the EORTC quality of life breast cancer module for male breast cancer - phase I [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-14-01.

Nonclinical & clinical interface - extrapolation of nonclinical data to support Phase I clinical studies

A review of the Investigator's Brochure and Clinical Study Reports for 58 non-oncology small molecule and biopharmaceutical drug candidates tested in a healthy volunteer subject population was conducted. Key findings were (1) a vital role for nonclinical pharmacology and toxicology testing was confirmed to allow setting of clinical starting dose and supporting use of highest dose based on No Observed Adverse Effect Levels (NOAELs), Pharmacologically Active Doses (PADs) and other approaches, (2) for clinical starting dose calculation, reference to the NOAEL was key, whether in calculation of a Maximum Recommended Starting Dose (MRSD), or by supporting PAD approaches (small molecules); or, through pharmacokinetic/pharmacodynamic (PK/PD) data modelling (biopharmaceuticals), (3) starting dose for small molecules was very conservative with human exposure >100- to 100-fold (46%) lower or between 10- and 100-fold (41%) lower than that seen at the NOAEL; high margins over exposure seen at NOAELs were also seen for biopharmaceuticals, (4) at the highest doses used, about 25% of studies for small molecules and 12% of studies for biopharmaceuticals showed exposure greater than that seen at the NOAEL and (5) adverse event evaluation showed that our current paradigm of moving from nonclinical testing into SAD/MAD Phase I testing is remarkably safe.

Investigator brochures for phase I/II trials lack information on the robustness of preclinical safety studies.

Meaningful and ethical phase I/II trials can only be conducted with supportive prospective risk-benefit assessment. This relies largely on preclinical animal studies addressing the safety and efficacy of treatments. These studies are reported in an Investigator's Brochure (IB) to inform ethics review boards and regulatory authorities. Our study investigated the extent, reporting quality and accessibility of preclinical safety studies (PCSSs) compiled in IBs. We analysed a sample of 46 IBs for phase I/II trials approved at a leading German university medical centre from 2010 to 2016. We extracted all PCSSs presented in the 46 IBs and assessed them for reporting on methodological measures to reduce validity threats. The 46 IBs included 777 PCSSs. Blinded outcome assessment, randomization and sample size calculation were reported for fewer than 1% of studies. Only 5% of the PCSSs provided a reference to published data. Compliance with Good Laboratory Practice (GLP) guidance was reported for 52% of PCSSs, but the GLP document itself does not include any relevant methodological requirements for the reduction of validity threats. Scarce reporting in IBs and the very limited publicly available data on PCSSs make it almost impossible for investigators to critically evaluate the robustness of preclinical evidence of drug safety. Combined with recent findings on the presentation of preclinical efficacy studies in IBs, we conclude that the current reporting patterns in IBs strongly limit the independent review of evidential support for early human trials. Regulatory authorities and IRBs should require better reporting in IBs.

Reporting of prior clinical studies in Investigator's Brochures did not adhere to the basic principles of evidence synthesis: a cross-sectional study

ObjectivesInternational regulations require Investigator's Brochures (IBs) to compile all available evidence that inform the risk-benefit assessment for the newly planned clinical trial. This study examined the adherence of IBs to the basic principles of evidence synthesis when compiling prior clinical studies. Study Design and SettingFor 97 IBs for phase I/II trials reviewed at one German research ethics committee we assessed the reporting on search, appraisal, and synthesis procedures for prior clinical studies. For a random subsample of 30 IBs, we evaluated the quality of reporting of the compiled 247 prior clinical studies. ResultsOnly 2% of all 97 IBs reported a comprehensive search strategy, provided a critical appraisal of the compiled prior clinical studies or presented respective study results in a structured manner. For the 247 prior clinical studies compiled in 30 IBs, the information required to appraise their risk of bias (eg, sample size calculation or baseline characteristics) was rarely reported. ConclusionWhen compiling all available evidence supporting the rationale for the proposed clinical study IBs do not acknowledge the broadly established principles for reviewing and reporting evidence. This may impact negatively on the trustworthiness and efficiency of risk-benefit assessment.

Standardizing Safety Assessment and Reporting for Neonatal Clinical Trials

Standardizing Safety Assessment and Reporting for Neonatal Clinical Trials

Survey of Safety Information in the Investigator's Brochure: Inconsistencies and Recommendations.

A survey was undertaken to gain an understanding of current industry practices in the preparation of the safety information for the Investigator's Brochure (IB). Sixteen of a potential 25 respondents completed a survey (64% response rate). Five respondents represented pharmaceutical and biotech companies, and 11 were consultants or worked at contract research organizations for such companies. The results showed a lack of uniformity of practices. This may be due to the lack of harmonized regulations and guidelines, the lack of standardized terminology and definitions, and the lack of clarity regarding the purpose and content of the various safety-related sections of the IB. These sections, although interrelated, have different purposes, and the criteria and methodology used have to be appropriate for these purposes. It is recommended that regulations, guidelines, and terminology be harmonized worldwide to enable consistent reporting to regulatory authorities across regions, minimize duplication of work for companies that operate in different regions, and to provide meaningful safety information both to the investigator and regulatory authorities. Recently published information regarding the format and the content of a "Reference Safety Information" section provides clarity for this element of the IB, which can hopefully be adopted globally. Until further regulatory clarity is provided for other safety sections, recommended approaches are provided.

Automated SPE-based synthesis of 16α-[18F]fluoroestradiol without HPLC purification step

[18F]fluoroestradiol ([18F]FES) is well-established PET radiotracer for diagnosing and monitoring treatment of estrogen-positive breast cancer. The radiotracer is produced via one-pot two steps synthesis using cyclic sulfate precursor and is usually purified by semi-preparative HPLC. Here we suggested simple SPE purification procedure using OASIS WAX 3cc and Sep-Pak QMA light cartridges that afforded [18F]FES in typically 15% RCY (corrected for decay) within 45 min formulated in 5% EtOH/saline. All purity parameters were well within specifications recommended in the Investigator's Brochure for [18F]Fluoroestradiol.

Integrating data from the Investigational Medicinal Product Dossier/investigator's brochure. A new tool for translational integration of preclinical effects.

Integrating data from the Investigational Medicinal Product Dossier/investigator's brochure. A new tool for translational integration of preclinical effects.

Preclinical efficacy studies in investigator brochures: Do they enable risk-benefit assessment?

Human protection policies require favorable risk–benefit judgments prior to launch of clinical trials. For phase I and II trials, evidence for such judgment often stems from preclinical efficacy studies (PCESs). We undertook a systematic investigation of application materials (investigator brochures [IBs]) presented for ethics review for phase I and II trials to assess the content and properties of PCESs contained in them. Using a sample of 109 IBs most recently approved at 3 institutional review boards based at German Medical Faculties between the years 2010–2016, we identified 708 unique PCESs. We then rated all identified PCESs for their reporting on study elements that help to address validity threats, whether they referenced published reports, and the direction of their results. Altogether, the 109 IBs reported on 708 PCESs. Less than 5% of all PCESs described elements essential for reducing validity threats such as randomization, sample size calculation, and blinded outcome assessment. For most PCESs (89%), no reference to a published report was provided. Only 6% of all PCESs reported an outcome demonstrating no effect. For the majority of IBs (82%), all PCESs were described as reporting positive findings. Our results show that most IBs for phase I/II studies did not allow evaluators to systematically appraise the strength of the supporting preclinical findings. The very rare reporting of PCESs that demonstrated no effect raises concerns about potential design or reporting biases. Poor PCES design and reporting thwart risk–benefit evaluation during ethical review of phase I/II studies.

Validation of Instruments for Assessing Drug Safety Management During the Conduction of Clinical Trials

Background: The management of drug safety with the collection of reliable safety data during the conduction of clinical trials conduct is essential for the registry and marketing of products. The systematic evaluation of this process, based on objective measures, requires the application of quality instruments. This study was aimed to design and validate eight instruments through the components of quality (structure, process, and results), for characterizing and assessing the process of drug safety management, during the conduction of clinical trials. Methods: The eight instruments were designed according to the international recommendations for Good Clinical Practice (GCP) and comprise a knowledge survey for professionals at the investigational sites, a satisfaction scale of internal and external clients and a satisfaction survey for patients with the treatment of the adverse events. The instruments also include a checklist to evaluate the safety management infrastructure (human, material and organizational resources) in the sponsoring center, a checklist to evaluate the same criterion at the investigational sites and three checklists that evaluate adherence to regulatory requirements of essential documents (investigator’s brochure, protocol, and informed consent form). The content validity was evaluated by Delphi method and the reliability was determined by Cronbach α test. Results: All the items were valued as very adequate after the second round of the expert panel. The instruments were deemed as appropriate and understandable in the pre-test performed. All responders agreed with the options given and the accessibility of the application. Only 10% of professionals at the research sites suggested that the knowledge survey was too long. Cronbach α values between .66 and .93 were obtained. Conclusion: The structure, process, and outcome framework allowed for the characterization of drug safety management during clinical trials, providing a useful approach for the promoter to systematically measure and evaluate the process. The eight instruments were deemed as reliable, feasible and easy to be used for examining drug safety management while carrying out clinical trials.