Investigator's Brochure Research Articles

Basic ADME in non-clinical drug discovery and development

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.

The Investigator's Brochure: A multidisciplinary document

The Investigator's Brochure (IB) is a multidisciplinary document that summarises the main elements of an entire development programme to date. Although the IB also serves other purposes, it is primarily written to enable investigators conducting clinical studies to assess the risks and benefits associated with an investigational product. The ICH E6 guideline specifies that an IB should include information on the investigational product itself as well as on its use in non-clinical and clinical studies, together with a section providing guidance for the investigator on the use of the drug. Beyond a need for good project management skills, the main challenge and responsibility for medical writers is to ensure that the information presented in an IB is as concise and focused as possible while remaining balanced and sufficiently complete to communicate what an investigator needs to know about using the investigational product.

Regulating Clinical Trials in Saudi Arabia

The rising needs for new clinical trials in different medicinal fields have paved the area to conduct numbers of clinical trial in Saudi Arabia. The article provides brief description of clinical trial regulations and further explores opportunities for development. The clinical trial administration was established in 2009 and is responsible for assessing all clinical trial applications from sponsors, Clinical Research Organizations and investigators to conduct clinical trial in Saudi Arabia. The functions of clinical trial administration include evaluation of clinical trial protocols and amendments, good clinical practice (GCP) inspection and maintaining Saudi Clinical Trials Registry. The main requirements to license clinical trial in Saudi Arabia include: trial protocol, inform consent form, the site IRB/EC approval to conduct the trial, confidentiality agreement between the sponsor and the principle investigator, investigator brochure, financial disclosure of principal investigator, certificate of analysis of study medicinal product, investigational medicinal product (IMP) labeling & packaging, Clinical trial agreement between the sponsor and the principle investigator and subjects Insurance. The administration had licensed 260 clinical trials to date. The future development of clinical trial environment in Saudi Arabia is promising. The Saudi Food and Drug Authority have created state of the art regulatory framework that support quick approval of clinical trial. Moreover, the presence of numerous world-class medical facilities and increasing numbers of western-trained investigators as well as rapidly growing pharmaceutical market and healthcare investments, contribute to enhancing Saudi Arabia’s attractiveness to conduct more clinical trial within the coming few years to come. Keywords: Clinical trials, Saudi Arabia, regulations, registry, SFDA, clinical practice, pharmaceuticals, CRO, IRB, investigator, inspection, healthcare, Middle East.

Serious Adverse Events Reporting and Follow-Up Requirements in the European and Developing Countries Clinical Trials Partnership-Funded Clinical Trials: Current Practice

Background: This study aimed to assess the current pharmacovigilance practice and compliance with the International Committee for Harmonization Good Clinical Practice (ICH-GCP) requirements within a range of clinical trials funded by the European and Developing Countries Clinical Trials Partnership (EDCTP). Methods: A combination of a retrospective desk review of projects documentation as of June 2014 and a prospective survey among EDCTP-funded clinical trials investigators were used. Results: The overall survey response rate was 64.3%. Among the 54 trial investigators who responded to the survey, 64% are sponsored by academic institutions, 25% by public research institutions, and 6% by Product Development Partnerships (PDPs). 77% of the Sponsors are based in Europe, 17% in Africa and 6% are globalbased institutions. 75% of the respondents confirmed occurrence and reporting of Serious Adverse Events (SAEs) in their trials. The primary reference document for SAEs reporting and follow up reported as % of clinical trials are clinical trial protocols (81.5%), SOPs for handling SAEs (50%) and investigator brochure (11%). The average SAE reporting time by 81% of respondents within 24 hours, 11% within 48 hours, 4% within 7 days and 2% between 7 and 15 days. Majority (79.6%) of investigators report SAEs directly to the their trial Sponsors, 62.3% to National Ethics Committees (NECs) and Institutional Review Boards (IRBs), 33.3% to the national regulatory authorities (NRAs), 22.2% to the safety monitors, and 3.7% to the Contract Research Organisations (CROs). Combinations of these recipients were reported by several respondents. Among the 41 respondents who reported SAEs occurrence in their trial, only 22 confirmed that they are required to report to their NECs and IRBs. 85% of respondents send SAEs reports by e-mail, 27.8% by Fax mail, 11.1% by telephone and 9.3% as printed hard copies. Conclusion: A majority of respondents (75%) confirmed that SAEs have occurred in their trials; in this group, 45% of respondents did not confirm the requirement of reporting SAEs to local oversight bodies. It is important that both NECs and NRAs in all countries where clinical trials are conducted clearly make available their reporting requirements to the investigators to ensure adequate compliance with local reporting requirements. Further studies are necessary to better understand the magnitude of this problem and to strengthen capacity of local trial oversight by NECs and NRAs.

Translating Drugs From Animals to Humans: Do We Need to Prove Efficacy?

Translating Drugs From Animals to Humans: Do We Need to Prove Efficacy?

Early targeted drug development: Pilot FDA review of PI3K inhibitor phase I studies using a knowledge management database.

3060 Background: Optimized phase 1 (ph1) clinical trials may increase the likelihood of successful oncology drug development. We developed a FDA knowledge management (KM) database that allows comprehensive assessment of ph1 trial features. Here we pilot whether the database can catalogue diversity in early phase studies of the PI3K inhibitor drug class. Methods: We evaluated the development programs of 6 PI3K inhibitors, including ph1 protocols, annual reports, and investigator brochures submitted to the FDA under the investigational new drug (IND). Key features of PI3K inhibitor ph1 trials were summarized in the KM database. Results: Of the 6 PI3K inhibitor ph1 trials surveyed, three agents (50%) targeted PI3K alone and 3 (50%) were dual PI3K and mTOR inhibitors. Four (66%) trials used a traditional 3+3 design, while two (33%) adopted a bayesian continual reassessment model. MTD was the primary endpoint of all trials. Three trials (50%) adopted an enrichment strategy for the expansion cohort, which varied from molecular enrichment (somatic alteration in PI3K, PTEN or EGFR) or clinical enrichment (Cowden syndrome). Pharmacodynamic (PD) assays included surrogate tissue (assessment of molecular changes in PBMCs, skin, and hair) and primary tissue (FDG-PET, flow cytometry of CLL, and tumor biopsy). Dose-limiting toxicities included hyperglycemia, anorexia, gastrointestinal, rash, mood alteration, uveitis, thrombocytopenia, elevated ALT, low phosphate, and ECG alteration. Two trials (33%) reported ≥ grade 3 hyperglycemia. Conclusions: FDA review of PI3K ph1 studies reveal a variety of designs, enrichment strategies based on molecular and clinical features, PD assays, tumor types, and toxicities. The KM database will assist in determining which features are important to successful development. Preliminary analysis of these trials (as well as prior experience with other targeted agents) indicate that early selection of an enriched population most likely to benefit, development of validated biomarker assays prior to pivotal trials, adoption of randomized ph2 designs, and exploration of combination strategies will accelerate the development programs and increase the likelihood of success.

Ensuring Quality of Regulatory Clinical Documents

AbstractA large number of clinical documents are generated during the clinical stage of drug development. These documents are used to obtain regulatory permission for clinical trial initiation, to execute clinical trials, and eventually to get regulatory approval for new products or indications. The types of clinical documents required are numerous and complex and include study protocols, informed consent forms, investigator brochures, investigational new drug annual reports, and clinical study reports. In addition, clinical documents that summarize clinical study results are part of a new drug application or biological license application. Because clinical documents are critical for drug development and business, they must be of the highest quality. Towards that end, we have developed a comprehensive QC program and implemented a QC step in the clinical document preparation process. This program is process driven with an SOP for QC review and a QC step is formalized in each document‐specific SOP. We also applied quality audit principles in the QC review. Independent reviewers perform each QC review using checklists to provide a consistent and objective evaluation of clinical documents. The document author addresses each QC finding and subsequent QC changes are verified. The scope of a QC review is tailored to each document. The QC review is an inherent step of the clinical document preparation process, providing necessary assurance that clinical documents generated are of the highest quality possible. Copyright © 2011 John Wiley & Sons, Ltd.

Carlecortemcel-l: an ex vivo expanded umbilical cord blood cell graft for allogeneic transplantation

Background: Success of umbilical cord blood transplantation (UCBT) is mostly affected by the cell dose infused and its application is limited by the size of the recipient. For most adults and older children it is not possible to find a single UCB unit large enough for reliable engraftment. One strategy to increase the number of progenitor cells available is ex vivo expansion of the unit. The main challenge of ex vivo expansion systems is how not to deplete the self-renewing cell population by driving them into differentiation into committed progenitors. Objective: Copper modulates basic cell functions, such as survival, proliferation, and differentiation. Reduction of cellular copper in ex vivo culture conditions enabled preferential proliferation of early progenitors and increased engraftment capabilities. The result of a Phase I study of carlecortemcel-l, a product derived from ex vivo expansion of UCB progenitors in the presence of a copper chelator and early-acting cytokines, and the study design for the current pivotal study are presented. Methods: A literature review using PubMed and the investigator's brochure from the manufacturer. Conclusions: Early results suggest that carlecortemcel-l infusion is safe and may be associated with favorable non-relapse mortality rates. A pivotal global study is currently being conducted to evaluate safety and efficacy of this product from centralized manufacturing facilities.

The safety of temozolomide in the treatment of malignancies

Background: Temozolomide (TMZ) has demonstrated clinical antitumor activity. In the US and the EU, TMZ is licensed for the treatment of glioblastoma multiforme concurrently with radiation followed by a maintenance treatment, and for refractory anaplastic astrocytoma or glioblastoma multiforme. TMZ is also approved for metastatic melanoma in > 20 countries worldwide. Objectives: To ascertain the safety profile of TMZ. Methods: Synthesis of evidence from published clinical trials and the investigator's brochure of the manufacture. Conclusion: For a cytotoxic cancer-treatment agent, TMZ has an acceptable safety profile. Lymphopenia is common in patients treated with all doses and schedules of TMZ. All patients receiving TMZ should be observed for lymphopenia and potential opportunistic infections, particularly when it is combined with other immune suppressive therapies.

Candidate HIV-1 Tat vaccine development: from basic science to clinical trials

Over the past 20 years most of the efforts in HIV vaccinedevelopment have focused on sterilizing immunity bytargeting the Envelope protein (Env). However, resultsfrom preclinical and clinical trials have been largelydisappointing [1–11]. Therefore, current vaccine strat-egies are not only aimed at preventing virus infection butalso at blocking virus replication and disease onset. Inparticular, the control of virus replication should provideprotection from disease development and reduce virustransmission, halting the HIV epidemic. This objectivemay be achieved by targeting virus regulatory genes,which are expressed early after infection, are essential forvirus replication and pathogenesis, and are moreconserved among HIV clades. This approach may beeffective for both preventive and therapeutic vaccinestrategies [12–68]. In this article we review thecharacteristics of Tat and why it was selected for use in avaccine.Wealsocitethelessonlearnedinthedevelopmentof this anti-Tat vaccine for use in human clinical trials.

Pemetrexed-induced edema of the eyelid

Pemetrexed is a novel antimetabolite that targets multiple enzymes in the folate pathway, and has exhibited clear antitumor activities in the treatment of malignant pleural mesothelioma and non-small cell lung cancer. Although many adverse events of pemetrexed, such as bone marrow suppression, have been reported, edema of the eyelid has been previously reported in only one case (0.2%, n=519), according to the Pemetrexed Clinical Investigator's Brochure, April 2005 version. We experienced a patient who developed the valuable edema of the eyelid. We believe that medical oncologists should be aware of this rare adverse event, although the mechanism responsible for it is not yet known.

Mass kinetics of apolipoprotein A-I in interstitial fluid after administration of intravenous apolipoprotein A-I/lecithin discs in humans

Apolipoprotein kinetics are customarily determined by modeling time curves of specific radioactivity or isotopic enrichment in plasma after intravenous infusion of radiolabeled lipoproteins or stable isotope-enriched amino acids. However, this provides no information on the fractional rate of transfer of the apolipoprotein from plasma to interstitial fluid (k(p-if)) or its mean residence time in interstitial fluid (MRT(if)). To determine these parameters for a pharmacologic dose of exogenous apolipoprotein A-I (apoA-I) given intravenously as apoA-I/lecithin discs, we measured apoA-I in plasma and prenodal leg lymph in five healthy men before, during, and after a 4 h infusion at 10 mg/kg/h. ApoA-I concentrations in plasma and lymph were modeled by linear compartmental models (SAAM II version 1.1), using lymph albumin to adjust for the effects of variations in lymph flow rate. k(p-if) averaged 0.75%/h (range, 0.33-1.32), and MRT(if) averaged 29.1 h (14.1-40.0). Neither parameter was correlated with the distribution volume (57-105 ml/kg) or the fractional elimination rate (1.44-2.91%/h) of apoA-I, determined by modeling plasma apoA-I concentration alone. Although used here to study the mass kinetics of apoA-I, if combined with infusion of a tracer, analysis of lymph could also expand the modeling of endogenous apolipoprotein kinetics.

日本人健常成人を対象としたＦｉｒｓｔ‐ｉｎ‐Ｈｕｍａｎ試験における初回投与量設定に関するレトロスペクティブな検討

Aims:In 2005, the U. S. Food and Drug Administration (FDA) published a guide estimating the safe starting dose based on body surface area for healthy volunteers. Toxicity should be avoided at the initial dose in healthy volunteers, but studies are also required to rapidly attain the objectives. This study was aimed to discuss the safety of the starting doses which had been determined based on body weight.Methods:Fifty investigational drugs which were administered systemically to healthy volunteers in first-in-human studies were investigated. The following were surveyed from the investigator's brochures and study reports:(1) drug category (2) rules of determining the starting dose (3) ratios between the starting dose and no observed adverse effect level (NOAEL), 50% effective dose (ED50) and estimated clinical dose, and (4) frequency of adverse events with dose escalation in placebo and experimental groups, and so on.Results:Rules of determining the starting dose were described in 33 drugs. The most frequent one was 1/60 of NOAEL (32 drugs). Drugs showing starting dose/NOAEL ratios of 1/100 or less and starting dose/ clinical dose ratios of 1/20 or less accounted for approximately 60%. The frequency of adverse events did not differ between placebo and experimental groups up to the 5th dose.Conclusions:It was suggested that the starting doses had been determined prudently in the first-inhuman studies. In order to estimate more reasonable starting doses, the approach based on body surface area proposed by FDA should be considered. But it is important to carefully consider the specific characteristics of each drug before determing the starting dose.

Toward protecting the safety of participants in clinical trials

It is a widely held belief that the current system of oversight of clinical research, particularly the means of assessing risks and minimizing harms to participants in clinical trials, could be improved. In particular, the system is inefficient with overemphasis on the monitoring ability of some groups such as research ethics review boards and investigators, underemphasis on others such as data monitoring committees (DMCs) and sponsors, confusion about responsibilities for safety and imperfect communication between these different groups. Research ethics review boards are not able to perform safety monitoring by review of individual adverse events and are often burdened by duplicative reviews of large multicenter studies. There are no standards for DMCs to ensure they can reliably identify safety issues. Sponsors may be overreliant on data audits and slow to disseminate safety data in a coherent summary. Investigators, their staffs and clinical sites may not fully appreciate all the nuances of good clinical practice or may be inattentive to the daily conduct of studies. Regulators, particularly those in the United States, have failed to completely harmonize their policies with each other or with international regulatory agencies. We recommend well-designed monitoring plans for all studies that are appropriate to their scope and risk, more centralized review of large multisite studies and closer local scrutiny of single-institution studies. In addition, sponsors should pay greater attention to monitoring adverse events and keeping up-to-date databases or investigator's brochures emphasizing safety issues. A minimal standard of education or expertise in good clinical practice should be established for investigators, their staffs and research ethics review board members. DMC composition and functions should be standardized and regulations should be harmonized nationally and internationally. Finally, there should be a concerted effort to study the efficacy of various components of the system.

Galantamine for Alzheimer's disease.

Galantamine (also called galanthamine, marketed as Reminyl (Janssen)) can be isolated from several plants, including daffodil bulbs, and now synthesized. Galantamine is a specific, competitive, and reversible acetylcholinesterase inhibitor. It is also an allosteric modulator at nicotinic cholinergic receptor sites potentiating cholinergic nicotinic neurotransmission. A small number of early studies showed mild cognitive and global benefits for patients with Alzheimer's disease, and recently several multicentre clinical trials have been published with positive findings. Galantamine has received regulatory approval in Sweden, is available in Austria, and awaits marketing approval in the United States, Europe, and other countries. The objective of this review is to assess the clinical effects of galantamine in patients with probable Alzheimer's disease, and to investigate potential moderators of an effect. The Cochrane Dementia Group specialized register of clinical trials was searched using the terms 'galantamine,' and 'galanthamine' (15 February 2000) as was the Cochrane Controlled Trials Register (2000, Issue 2). These terms were also used to search the following databases: EMBASE, MEDLINE, PsychLit; Combined Health Information Database, NRR (National Research Register), ADEAR (Alzheimer's Disease Education and Referral Centre clinical database, BIOMED (Biomedicine and Health), Glaxo-Wellcome Clinical Trials Register, National Institutes of Health Clinical Trials Databases, Current Controlled Trials, Dissertation Abstracts (mainly North American dissertations) 1961-1994, Index to UK Theses (British dissertations) 1970-1994. Published reviews were inspected for further sources. Additional information was collected from an unpublished investigational brochure for galantamine. Trials selected were randomized, double-blind, parallel-group, and unconfounded comparisons of galantamine with placebo for a treatment duration of greater than 4 weeks in people with Alzheimer's disease. Data were extracted independently by the reviewers and pooled where appropriate and possible. The pooled odds ratios (95%CI) or the average differences (95%CI) were estimated. Intention-to-treat and observed cases data were both reported, if the data were available to be reported. -Outcomes of interest include the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), clinical global impression of change (CIBIC-plus or CGIC), Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL), Disability Assessment for Dementia scale (DAD) and Neuropsychiatric Inventory (NPI). - Potential moderating variables of a treatment effect included trial duration and dose. Seven trials were identified that met criteria for entry, with 6 being Phase II or III industry-sponsored multicentre trials. One was of 12 weeks duration; one of 5 months; one of 29 weeks; and the rest of 6 months duration. Trials of 5 months or more were aggregated in the analyses as '6 months'. Overall, galantamine showed significant treatment effects at daily doses of 16-32 mg/d for trials of 3- to 6-months duration. For global ratings, trials of 3 months duration with doses of 24-32mg/d (Odds Ratio (OR) 2.2; 95%CI 1.4 to 3.7) and 36mg/d (OR 3.3; 95%CI 1.2 to 9.3) were statistically significant in favour of treatment. For trials of 6 months duration (5-months to 29 weeks), only doses of 8mg/d failed to be statistically significant (24mg: OR 2.0; 95%CI 1.5 to2.5; 32mg: OR 1.9; 95%CI 1.4 to 2.5). For cognitive function over 6 months duration: at a 24mg/d, improvements measured -3.5 points (k=3; 95%CI -4.3 to -2.8) on weighted mean difference on the ADAS-Cog scale, and -4.0 points at 32mg/d (k=2; 95%CI -5.0 to -3.0). Both observed cases (WMD 3.8; 95%CI 0.3 to 7.3) and intention to treat analyses using the Disability Assessment of Dementia gave statistically significant results in favour of treatment for daily doses of 32mg for 6 months duration. The small number of trials available for analysis, however, limited the power of analyses to detect differences. Galantamine consistently failed to show statistically significant treatment effects at doses of 8mg/day. Galantamine's adverse effects appear similar to those of other cholinesterase inhibitors, in that it tends to produce gastrointestinal effects acutely and with dosage increases. Overall, people treated with galantamine at doses of 24-32 mg/d were more likely to discontinue participation in most trials than were people treated with lower doses or placebo, but in the one trial with a slower rate of titration the discontinuation rate was not significantly greater than placebo for the 16 mg/day dose. (ABSTRACT TRUNCATED)

A Review and Analysis of Key Regulations and Guidelines Concerning the Safety Sections of the Investigator’s Brochure

Recent regulatory initiatives and consensus documents have altered the conventional approach to evaluating and communicating pharmacovigilance information. While these trends may initially seem to provide opportunities to combine certain aspects of the premarketing and postmarketing safety evaluation functions, they also have the potential to obscure the substantial differences between comprehensive risk assessment in investigational and postmarketing settings. Personnel involved in evaluation of safety data from clinical trials (including studies for new indications for currently marketed products) must give special consideration to those regulatory, legal, scientific, and ethical issues that are unique to the premarketing environment. In this paper, we approach this complex topic by contrasting the risk assessment of investigational products, as summarized in the investigator's brochure, with similar, well-described risk evaluation processes that are carried out for marketed products.

Standard operating procedures for clinical research personnel—part 6

AbstractThis is the sixth in a series of articles containing proposals for wording and content of standard operating procedures (SOPs) for clinical research activities conducted by sponsors and Contract Research Organisations (CROs). The procedures include those required by the International Conference on Harmonisation (ICH), the Food and Drug Administration (FDA), many other guidelines and regulations, and ‘best practice’ observed by the authors. The model forms require modification for actual use. In this article, three SOPs for the management of investigator brochures including preparation (SOP 301), review, approval and amendment (SOP 302) and distribution (SOP 303) are addressed. A sample of the format and contents of an investigator brochure is also included. (The full text of all 101 SOPs is available from the authors.) Copyright © 2001 John Wiley & Sons, Ltd.

Pearls and pitfalls of clinical trial investigation: should I get involved in the drug development process?

The revolution in neurological therapeutics means that an increasing number of neurologists will have the opportunity to participate in a drug development process that is long and complicated. The opportunity provides challenges as well as rewards, and should be undertaken only after thoughtful review of the Clinical Investigator's Brochure and protocol. Key questions that the neurologist should address prior to participation are reviewed herein.

FDA's role in anesthetic drug development.

FDA's role in anesthetic drug development.

An evaluation of non-clinical animal data from the point of view of a clinical pharmacologist

The development of a new chemical entity for human use is a stepwise process based on an assessment of both animal and human data on efficacy and safety of the drug. Clinical pharmacologists always refer to animal data through an Investigator's Brochure (IB) when planning and performing a clinical trial(s). The IB should provide the investigator(s) with useful information to select doses, dosing intervals, and safety monitoring procedures and also to support the clinical management of subjects during the trial(s). Non-clinical animal studies contained in the IB, however, lack a relationship to the pharmacological and toxicological findings of the investigated product(s). Most of the non-clinical animal studies address the methodology and the results obtained, but are lacking in a discussion of the relevance of the findings. The IB should include not only a summary of the findings in each field of animal study but also relationships of the findings through some indicator(s) such as blood and tissue concentrations of the parent drug and/or metabolites. I do hope Pharmaceutical Companies will provide much useful information about their product(s) through the improvement of their system of research and development.