Harmonization Good Clinical Practice Research Articles

Recent Progress and Challenges in Investigator-driven Clinical Development of Novel Drugs and Medical Devices at The University of Tokyo Hospital

At the University of Tokyo Hospital, investigator-driven clinical development of novel drugs and medical devices is mainly supported by the Translational Research Center and Clinical Research Support Center. The former supports non-clinical research and the preparation of test materials and the latter supports clinical trials. The Clinical Research Support Center was established in 2010 by the reorganization of the former Clinical Research Center, which was established in 2001. The center adopted International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) as a standard guideline for clinical trials and prepared standard operation procedures and templates for protocols and informed consent documents in 2001 and, thereafter, provided consultation services to researchers for protocol development. In 2010, the service was extended to project management, data management and monitoring to support the credibility of clinical trials. In 2011, The University of Tokyo Hospital was selected by the government as a base for the early and exploratory clinical development of drugs in the fields of psychological and neurological diseases. For this purpose, a phase 1 unit for early phase clinical pharmacology trials is now being built. The center provides training courses for clinical research coordinators and hold seminars for clinical researchers; however, the biggest challenge remains the education and training of medical students who will lead clinical trials in the future.

A systematic review of on-site monitoring methods for health-care randomised controlled trials

Monitoring the conduct of clinical trials is recommended by International Conference of Harmonisation Good Clinical Practice (ICH GCP) guidelines and is integral to trial quality assurance. On-site monitoring, that is, visiting trial sites, is one part of this process but little is known about the procedures that are performed in practice. To examine and summarise published on-site monitoring methods for health-care clinical trials, including evaluations of their benefits and costs to trials. A systematic literature review identified all articles reporting the methods and practices of on-site monitoring of randomised controlled trials (RCTs). Articles were categorised into (1) reports from research groups and organisations, (2) reports from individual RCTs, (3) randomised trials of on-site monitoring interventions, (4) cost simulations, or (5) surveys of trial staff and monitors. Data were extracted on the characteristics of the trials and groups reporting on-site monitoring (e.g., geographical origin, sponsor, and trial focus). Information from articles in categories (1)-(3) was summarised on the frequency and scope of site monitoring visits, monitoring team size and composition, activities during site visits, and reporting structures. Evaluations of the benefits and disadvantages of on-site monitoring were examined for all included articles. In total, 57 articles were identified, comprising 21 articles about the on-site monitoring practices of 16 research groups, 30 articles from 26 RCTs, 1 on-site monitoring intervention RCT, 2 cost simulations, and 3 surveys. Publications in categories (1)-(3), mostly originated from the United States (33/52, 63%) or Europe (15/52, 29%), were predominantly describing non-commercial organisations or trials (45/52, 87%), with heart disease (9/26, 35%) or cancer (5/26, 19%) the commonest focus of individual RCTs. The frequency of visits ranged from every 6-8 weeks up to once every 3 years, with mostly all trial sites visited. The number of monitors visiting a site varied between 1 and 8. The most common on-site monitoring activity was verifying source data and consent forms, with a focus on data accuracy. Only six articles evaluated their on-site monitoring process, with improvements observed in recruitment rates and protocol adherence but with direct costs and staff time viewed as the major disadvantages. The on-site monitoring RCT ended prematurely so preventing full assessment. Trialists and organisations may utilise additional unpublished on-site monitoring systems. The varied terminology used to describe monitoring may have limited identification of some relevant articles. This review demonstrated that on-site monitoring is utilised in trials worldwide but systems vary considerably with little evidence to support practice. These on-site monitoring practices need to be evaluated empirically, including costs, to provide robust evidence for the contribution of site visits to trial performance and quality.

An insight into the emerging role of regional medical advisor in the pharmaceutical industry

The position of regional medical advisor (RMA) is relatively new in the pharmaceutical industry and its roles and responsibility are still evolving. The RMA is a field based position whose main mission is to foster collaborative relationships with the key opinion leaders (KOLs) and to facilitate the exchange of unbiased scientific information between the medical community and the company. Field-based medical liaison teams are expanding world-wide as part of the pharmaceutical industry's increased focus on global operations including emerging markets. Now, the position of the RMA has evolved into comprehensive, complex, highly interactive, targeted, highly strategic, innovative, and independent role since its inception by the Upjohn Company in 1967. The major objective of the RMA is to develop the professional relationships with the health-care community, particularly KOLs, through peer-to-peer contact. The RMA can facilitate investigator-initiated clinical research proposals from approval until completion, presentation, and publication. It is possible for a RMA to have valuable access to KOLs through his expertise in the clinical research. The RMA can assist in the development, review, and follow-up of the clinical studies initiated within the relevant therapeutic area at the regional/local level. The RMA can lead regional/local clinical projects to ensure that all clinical trials are conducted in compliance with the International Conference of Harmonisation Good Clinical Practice (ICH GCP) guidelines.

A Randomized, Double-Blind, Placebo-Controlled, Phase-2B Study to Evaluate the Safety and Efficacy of Recombinant Human Soluble Thrombomodulin, ART-123, in Patients with Sepsis and Suspected Disseminated Intravascular Coagulation

Abstract 24 IntroductionSevere sepsis remains the most common cause of death in critically ill patients (1) and new therapeutic approaches are urgently needed. DIC is also a frequent complication of severe sepsis (3), and when present is associated with increased mortality in these patients (4, 5). Current management of DIC is primarily focused on treating any associated underlying medical condition, although use of supplemental clotting factors or platelets, or anticoagulant therapy may occasionally be required (6). ART-123 (Artisan Pharma, Waltham, MA, USA) is a soluble recombinant human thrombomodulin that acts by reducing thrombin-mediated clotting and enhancing protein C activation at the site of clotting. We sought to determine the safety and efficacy of ART-123 when combined with standard care in patients with sepsis-associated DIC. Study DesignThis study was a Phase 2b, multicenter, international double-blind, randomized, placebo-controlled, parallel group trial, conducted in compliance with the ethical principles of the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. Two hundred and thirty intensive care units (ICUs) in seventeen countries enrolled 750 adult patients with sepsis and suspected DIC as assessed using a modified international society of hemostasis and thrombosis score. Patients were randomized to receive intravenous ART-123 (0.06 mg/kg/day) for 6 days or placebo, in addition to standard of care. The primary endpoint was reduction in mortality. Secondary endpoints included reversal of overt DIC and reduction in disease severity. Patients were randomized to receive intravenous ART-123 (0.06 mg/kg/day) for 6 days or placebo, in addition to standard of care. Blood samples were also obtained at different time points to measure various coagulation and inflammatory biomarkers. The primary endpoint was reduction in mortality. Secondary endpoints included reversal of overt DIC and reduction in disease severity. ResultsA total of 750 patients were randomized, 9 of whom did not receive the allocated treatment so that 371 patients received ART-123 and 370 received placebo. There were no meaningful differences between groups in any of the baseline variables. Twenty-eight-day mortality was 17.8% in the ART-123 group and 21.6% in the placebo group (Cochran-Mantel-Haenszel two-sided p-value of 0.273 in favor of ART-123, which met the predefined statistical test for evidence suggestive of efficacy). There were no statistically significant differences in event free and alive days between groups. D-dimer, F1.2 and TATc concentrations were lower in the ART-123 group than in the placebo group. There were no differences between groups in bleeding or thrombotic events or in the development of new infections. In post hoc analyses, greatest benefit from ART-123 was seen in patients with at least one organ system dysfunction and an international normalized ratio >1.4 at baseline. ConclusionsAdministration of ART-123 at a dose of 0.06 mg/kg/day for a 6-day treatment period was associated with clear pharmacologic effects (lower D-dimer, F1.2 and TATc levels) and plausible probability of efficacy. ART-123 was found to be a safe intervention in critically ill patients with coagulopathy due to sepsis, even in settings where patients are administered prophylactic doses of heparin, with no difference in bleeding complications between ART-123 and placebo-treated patients. These findings provide support for undertaking a phase III study, based on the population identified from the post hoc analyses, to extend these observations. Future trials using ART-123 should also be designed to better characterize the complex interactions present within the coagulation cascade in septic patients and to enable a description of the interactions between ART-123 and other anticoagulant modalities in these patients. Disclosures:Kaul:Asahi Kasei Pharma America Corporation: Employment. Tsuruta:Asahi Kasei Pharma America Corporation: Employment. Gorelick:Asahi Kasei Pharma America Corporation: Employment. Osawa:Asahi Kasei Pharma America Corporation: Employment. Vincent:Asahi Kasei Pharma America Corporation: Employment.

The FIB-PPH trial: fibrinogen concentrate as initial treatment for postpartum haemorrhage: study protocol for a randomised controlled trial

BackgroundPostpartum haemorrhage (PPH) remains a leading cause of maternal mortality worldwide. In Denmark 2% of parturients receive blood transfusion. During the course of bleeding fibrinogen (coagulation factor I) may be depleted and fall to critically low levels, impairing haemostasis and thus worsening the ongoing bleeding. A plasma level of fibrinogen below 2 g/L in the early phase of postpartum haemorrhage is associated with subsequent development of severe haemorrhage. Use of fibrinogen concentrate allows high-dose substitution without the need for blood type crossmatch. So far no publications of randomised controlled trials involving acutely bleeding patients in the obstetrical setting have been published. This trial aims to investigate if early treatment with fibrinogen concentrate reduces the need for blood transfusion in women suffering severe PPH.Methods/DesignIn this randomised placebo-controlled double-blind multicentre trial, parturients with primary PPH are eligible following vaginal delivery in case of: manual removal of placenta (blood loss ≥ 500 ml) or manual exploration of the uterus after the birth of placenta (blood loss ≥ 1000 ml). Caesarean sections are also eligible in case of perioperative blood loss ≥ 1000 ml. The exclusion criteria are known inherited haemostatic deficiencies, prepartum treatment with antithrombotics, pre-pregnancy weight <45 kg or refusal to receive blood transfusion. Following informed consent, patients are randomly allocated to either early treatment with 2 g fibrinogen concentrate or 100 ml isotonic saline (placebo). Haemostatic monitoring with standard laboratory coagulation tests and thromboelastography (TEG, functional fibrinogen and Rapid TEG) is performed during the initial 24 hours.Primary outcome is the need for blood transfusion. To investigate a 33% reduction in the need for blood transfusion, a total of 245 patients will be included. Four university-affiliated public tertiary care hospitals will include patients during a two-year period. Adverse events including thrombosis are assessed in accordance with International Conference on Harmonisation (ICH) good clinical practice (GCP).DiscussionA widespread belief in the benefits of early fibrinogen substitution in cases of PPH has led to increased off-label use. The FIB-PPH trial is investigator-initiated and aims to provide an evidence-based platform for the recommendations of the early use of fibrinogen concentrate in PPH.Trial registrationClincialTrials.gov NCT01359878.

CPI™ Certification as Predictor of Clinical Investigators’ Regulatory Compliance

Hospitals, research sponsors, institutional review boards, and other stakeholders do not have data to support a universal “test” to ensure that a clinical investigator is not only adequately trained in the International Conference on Harmonization Good Clinical Practices but can implement those principles into practice. Many stakeholders have created their own training programs of vastly different content and quality with little to no reciprocity. This has led to waste in the industry as well as qualified investigators having to retake basic courses because of the lack of reciprocity or globally accepted mark. In addition, investigators who may not be as well versed as they should be often are left to continue in their role because of the lack of efficacy evaluation of what training they received. The Certified Physician Investigator (CPI™) certification put forth by the Academy of Pharmaceutical Physicians and Investigators is poised to be that standard yet is not widely accepted as it is relatively new,...

A key risk indicator approach to central statistical monitoring in multicentre clinical trials: method development in the context of an ongoing large-scale randomized trial

Background Monitoring in randomized trials is recommended as part of International Conference on Harmonisation Good Clinical Practice standards. On-site monitoring in multicentre trials is common but is costly and can be inefficient. Central statistical monitoring can be used to detect unusual data patterns, identify intentional or unintentional trial misconduct, and to prioritise on-site visits and additional training. Motivated by an ongoing international multicentre clinical trial of over 25,000 randomized participants with electronic data capture, we developed key risk indicator (KRI) methods for central statistical monitoring in multicentre trials.

Barriers to conducting clinical research in reproductive medicine: India

Research in India is evolving at a rapid pace. Ergo, we need faster approval processes and review timelines. Improvement in the quality of institutional review boards would also contribute to good research practices. Clinical research should be included as a part of the undergraduate medical and pharmacy curriculum, and leading hospitals and practitioners should openly endorse research.

Framework for Activity of Ethics Committees in Ukraine

Ethics committee supervision is an essential part of conducting clinical trials and is required to ensure compliance with the international recommendations including the Declaration of Helsinki, International Conference on Harmonisation Good Clinical Practice (ICH GCP), Directive 2001/20/EC of the European Parliament and Council and WHO recommendations etc. No clinical trial can be initiated without prior review and approval from an ethics committee. In addition to expert evaluation of planned clinical trials, ethics committees are responsible for providing regular monitoring of clinical trial compliance with the international and national ethic, moral and legal aspects throughout the whole process of the trial conduct. Copyright © 2011 John Wiley & Sons, Ltd.

Spontaneous Bacterial Peritonitis in Alcoholic Cirrhosis: An Indian Perspective

Background: Spontaneous bacterial peritonitis (SBP) iscommonly associated with cirrhosis of liver, and has beenassociated with high mortality. Model for end-stage liver disease(MELD) scoring system has been applied as a marker ofdisease severity and predictor of mortality in patients withalcoholic cirrhosis. Recent studies have estimated a prevalenceof 10 to 30% SBP in cirrhotic patients with ascites admitted tohospitals but the data is lacking on Indian population. Hence,the present study was designed to evaluate the profile of SBPin patients with alcoholic cirrhosis in North India according toMELD score.Materials and methods: The prospective study was conductedin patients admitted in the department of medicine. A total of100 patients suffering from alcoholic cirrhosis with ascites wereenrolled in the study. All subjects underwent the following testfor biochemical parameters, abdominal ultrasonography, chestX-ray, endoscopic findings and paracentesis was performedand analyzed. MELD score was calculated for all the patients.Results: Out of total patients, 24% reported with SBP. Patientssuffering from SBP had statistically significant (p < 0.05) higherMELD score, International normalized ratio (INR) and serumcreatinine levels. Also, the patients with SBP had significantly(p < 0.05) lower platelet count as compared to patients withoutSBP. All the other parameters were comparable in both thegroups.Conclusion: SBP is a common complication of alcoholiccirrhosis of Indian patients and measures should be taken fortheir containment.Abbreviations: SBP: Spontaneous bacterial peritonitis; MELD:Model for end-stage liver disease; INR: International normalizedratio; TIPS: Transjugular intrahepatic portosystemic shunt; ICHGCP:International conference on harmonization-good clinicalpractice; AFB: Acid fast bacilli; CNNA: Culture negativeneutrocytic ascites; MNB: Monobacterial bacterascites; AST:Aspartate transaminase; ALT: Alanine transaminase; SAAG:Serum ascites albumin-gradient.

Current state of clinical trials in Korea

The number of clinical trials sponsored by global pharmaceutical companies performed in countries other than the U.S. and Western Europe has been steadily increasing over the past decade. Among those emerging countries, Korea deserves attention for its rapid growth in the number of trials and sites. As of 2009, Korea was ranked the tenth country in the number of clinical trials registered at http://clinicaltrials.gov. This is remarkable growth given that it was not included in the top 30 countries in 2005. High population density, qualified medical professionals, regulatory changes including Investigational New Drug-New Drug Application (IND/NDA) separation, acceptance of International Conferences on Harmonization-Good Clinical Practices (ICHGCP) by Korea Food&Drug Administration (KFDA), and governmental policies to boost clinical trials were the most influential factors that caused such an outstanding achievement. The Korean National Enterprise for Clinical Trials (KoNECT), an organization founded to lead initiatives to improve the milieu for clinical trials, has been playing a pivotal role in the steering of 15 regional clinical centers designated by the government. Based upon improvements in infrastructure so far, diversity in therapeutic areas and the proportion of early phase trials are expected to grow. Korea has grown to be one of the major countries in the clinical trial market, which was made possible by the cooperation of industry, academia and government. Further investment and efforts to solve current challenges will allow such growth to continue into the next decade.

A randomized, 36-month, post-marketing efficacy and tolerability study in Sweden and Finland of latanoprost versus non-prostaglandin therapy in patients with glaucoma or ocular hypertension

To compare the effect of time on therapy, efficacy, tolerability and resource utilization of latanoprost or non-prostaglandin analogues (non-PGs) in patients who required a change in intraocular pressure (IOP)-lowering monotherapy. This open-label, multicentre study (Sweden, 19 sites; Finland, seven sites) included adults with glaucoma or ocular hypertension with mean diurnal IOP > or = 21 mmHg on ocular hypotensive monotherapy. Patients were randomized to latanoprost monotherapy or non-PG therapy (commercially available therapy other than a PG) and followed for 36 months. End-points included: time to treatment failure (baseline to visit with a change in/addition to treatment); diurnal IOP (mean of 08.00, 12.00 and 16:00 hr measurements) at months 6, 12, 24 and 36; tolerability; and resource utilization, where analyses used Swedish and Finnish 2006 unit costs. Three hundred and twenty-six patients received >or = 1 dose of latanoprost (n = 162) or non-PGs (n = 164). Median time to treatment failure was longer for latanoprost (36 months) than for non-PGs (12 months; p < 0.001); 51% and 24% of patients remained on randomized therapy after 36 months, respectively (p < 0.001). Decreases in mean diurnal IOP from baseline were significantly greater for latanoprost than for non-PGs at months 6 and 12 (p < 0.01). No serious adverse events were judged to be treatment-related. Mean total 36-month direct costs were similar in patients initiated with latanoprost and non-PGs. Patients who failed previous monotherapy remained on therapy longer when switched to latanoprost. Latanoprost's IOP-reducing effect and tolerability were sustained over the long term. Resource utilization and costs were generally similar in those initiating latanoprost or non-PG therapy.

Circles of Hell: researchers' nightmare or laps of the regulatory pentathlon?

I doubt that personal spats between foot-soldiers will further solutions to the research governance problems unmasked by Paul Stewart and myself in the BMJ last year [1]. Almost 1 year on, I believe progress is unlikely until the monarchs with the money at grant foundations concede that their largesse is being wasted and take sanctions against the robber barons among regulators. What follows therefore is a mere exhibition joust, aimed mainly at our common and worst foe, RD their incompetence and intimidation were not fully manifest at the time of my article [2], but were exposed by the unanimous obloquy directed at them during the meeting of National Institute of Health Research Senior Investigators in April at the Wellcome Trust (http://www.nihr.ac.uk/files/pdfs/DismantlingBarriersWorkshop.pdf).

Surviving a Site Audit: Tips for Good Clinical Practice in an Implant Trial

The number of clinical trials involving implants for trauma and orthopedic surgery is increasing. The International Conference on Harmonization-Good Clinical Practice (ICH-GCP) guideline has been developed in order to assure that the rights, safety, and well-being of trial subjects (i.e., patients) are protected. Not performing a trial according to legal requirements including this guideline is no longer acceptable, and trial audits are increasingly being performed as an independent quality check for data validity and credibility. This manuscript provides an overview of the guideline for Good Clinical Practice (GCP) in the context of conducting an implant trial in trauma and orthopedic surgery. As long as all guidelines are adequately adhered to and all paperwork is in order, there is no reason to fear a trial audit.

Investigator‐initiated pragmatic trials in developing countries – much needed but much ignored

The last decade has witnessed clinicians in developing countries gaining recognition as investigators for many sponsor initiated multicentre rials. This is indeed a welcome change as it has provided an impetus for investigators in these countries to gear up and meet world standards. This is exemplified by the fact that the Ethics Committees across countries are increasingly becoming compliant with International Conference on Harmonization-Good Clinical Practice (ICH-GCP) guidelines, laboratories are making efforts for Good Laboratory Practice (GLP) accreditation, indigenous clinical trial registries have been set up [1] and programmes to train clinical research co-ordinators/monitors and investigators are being undertaken at various levels. Contributions have also been made by generating informed consent templates [2] and by producing teaching materials for clinical trial participants [3]. However, with the recent upsurge of sponsor initiated clinical trials, investigator initiated clinical trials have taken a back seat. High on the agenda for pharmaceutical company-sponsored clinical trials are new drug development or expanding the indication profile of their drugs. Questions such as comparative efficacy of one drug over another or a medical management with surgical/interventional management, strategies to ease drug dosage schedules, quality of life issues, exploration of alternative systems of medicines are not frequently explored in these trials. These are objectives of concern in investigator-initiated trials and the findings of these trials have important bearing for practice and for making health related policies [4]. Many investigators have the keenness and also the know-how for initiating and conducting such trials. However, the task is not easy if GCP standards are to be maintained. Funds are a major crunch. Government funding agencies/research groups/associations in the west have from a long time realized this need and have sponsored such investigator-initiated trials which have contributed significantly to furthering medical knowledge. Key examples would be the Diabetes Control and Complication Trial (DCCT), the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and Clinical Antipsychotic Trials of Intervention Effectiveness. There are some examples from the developing countries as well such as Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) [5], the SPEAR trial to compare chloramphenicol vs ampicillin plus gentamicin for community acquired very severe pneumonia in children in low resource settings [6], the ongoing CORONIS trial to compare various surgical techniques for Caesarean section. Interestingly the funding for such studies has come from agencies such as the World Health Organization, the Fogarty International Center of the National Institute of Health, Center of International Health and Development of Boston University and Johns Hopkins Bloomberg School of Public Health to name a few. This is indeed one of the options for investigators in developing countries but self-reliance should be the ultimate goal. All this would need a great deal of commitment from government aided agencies not only for providing funds for the conduct of the studies, but also for establishing systems for overseeing and ensuring GCP-compliant conduct of these trials. A government agency or scientific societies could play a constructive role in this regard. To start with, investigators who have published pilot trials could be encouraged to evolve their studies into adequately sized (if need be multi-centre) studies. A list of unanswered questions addressing the indigenous needs could be prepared and a list of investigators with proven credentials could be drawn up. For this, investigators with a past track record of conducting and publishing their trials should be chosen. Furthermore, these investigators could be helped to develop final protocols with inputs even from various experts the world over. The trial registration should be ensured. Evaluation of reports of the monitors, data safety monitoring board and audit of the trial could help in paving the way for the conduct of GCP compliant trials. Some problems are indeed expected. There could be concerns about the legal issues such as compensation to the participants in case of injury, insurance of the investigators, staff for ensuring quality control and quality assurance, inter-departmental and inter-institutional collaborations. However, none of these is insurmountable. Successful models are available [7, 8] and benefits could be derived from them to suit the needs of our country. Over a period of time sponsor-initiated trials conducted in developing countries have forayed into the medical literature and created their impact on medical practice. There is no reason why investigator-initiated pragmatic trials should lag behind.

American Society of Clinical Oncology Statement on Minimum Standards and Exemplary Attributes of Clinical Trial Sites

To describe both minimum requirements for a site conducting quality clinical trials and attributes of an exemplary site. Minimum requirements and exemplary attributes were selected based on literature review, prevailing regulatory requirements, and consensus among a group of community and academic clinical researchers. To provide guidance to oncologists who wish to conduct patient-oriented research, recommendations are made to assist in the development and implementation of high-quality research programs with the priority of protecting the welfare and rights of trial participants. A quality research site complies with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, the accepted international ethical and scientific quality standards for designing, conducting, recording, and reporting trials involving human participants. Recognizing that many research sites conduct clinical trials in compliance with accepted GCP standards, supplemental attributes of an exemplary research site that exceed the GCP criteria are also described. These attributes include diversification of clinical trial mix, high accrual activity, participation in the trial development process, maintenance of high educational standards, quality assurance, multidisciplinary involvement in the clinical trial process, and promotion of clinical trial awareness programs. Meeting the minimum criteria ensures conduct of quality clinical trials; however, some sites may wish to incorporate value-added attributes to exceed GCP compliance. These attributes are proposed as performance goals rather than requirements, recognizing that all sites conducting research will not necessarily meet each attribute but may still conduct high-quality clinical trials.

Quantitative evaluation of sebum lipid components with nuclear magnetic resonance

A NMR spectroscopic method is described that enables the quantitation of specific lipid classes and components, independent of fatty acid composition. We demonstrate this method for measuring cholesterol, squalene, and pools of sterol esters, wax esters (WEs), and triglyceride (TG) components in sebum and meibum. When 600 MHz NMR equipment is used in conjunction with highly sensitive cryogenically cooled probes, this method has adequate sensitivity, and for some applications, advantages over commonly used HPLC-evaporative light-scattering detection and mass spectrometry-based approaches. This method is shown to be useful for preclinical and clinical monitoring of the efficacy of sebum-reducing agents in animals and humans. In Syrian hamsters, 3% topical flutamide and 20 mg/kg oral isotretinoin reduced sterol esters by 18.7% and 30.0%, respectively, and reduced WEs by 32.9% and 31.8%, respectively, as measured in a punch biopsy of the ear. In a 72 patient clinical methodology study, the assay delivered reproducible and noninvasive measurements of WEs, cholesteryl esters, TGs, and squalene from Sebutape skin blots. The quantitative results of sebum analysis obtained by the NMR method correlate well with those obtained with HPLC-based approaches. This approach may be broadly applicable to cases in which fatty acid-independent quantification of lipid classes is desired.

The JSQA guideline for GCP auditing

AbstractThe International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) has been adopted by three regions USA, Europe and Japan and implemented since 1996. Details of GCP auditing are not provided in ICH GCP. The Japan Society of Quality Assurance (JSQA) has prepared ‘The JSQA GCP Guideline for GCP Auditing’ to promote the global discussion on GCP auditing and expects to establish a global guideline on GCP auditing along with ICH GCP.The guideline will include the mission and the organization of a sponsor's auditing department and establish the principles for planning, performing, and reporting audits. The guideline is expected to be a basic principle along with ICH GCP for not only sponsor's auditors, but also independent auditors and auditors of Contract Research Organizations (CROs) to conduct an audit in the various situations of each country and sponsor. Copyright © 2007 John Wiley &amp; Sons, Ltd.

Resolution of issues in clinical trials that sponsors entrusted to Contract Research Organizations in and outside Japan

AbstractThe difficulties Japanese sponsors experienced with Contract Research Organizations (CROs) (including Site Management Organizations (SMOs)) inside and outside Japan were analyzed to explore preventive measures from the viewpoint of the Japanese sponsor's quality assurance. The results of the analysis were grouped into four major service categories: monitoring, data management (DM), clinical laboratories and phase I sites. Characteristic issues were found in each category and there was also an indication of difficulties related to the difference in the interpretation of International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines between Japan and other countries. The corrective and preventive measures formulated in response to these issues were also discussed. Copyright © 2004 John Wiley &amp; Sons, Ltd.

Review of procedures for protecting human subjects in recent clinical studies of pesticides

Arguments have been made for and against the regulatory use of data from human subjects on both scientific and ethical grounds. One argument against the use of data from human clinical studies involving pesticides asserts that such data are obtained from studies that do not follow the Common Rule (40 CFR 26), which provides procedures for protecting human subjects in studies funded by federal agencies, including the U.S. Environmental Protection Agency (U.S. EPA). Although privately conducted studies using human subjects are not legally subject to or required to comply with the Common Rule, the protections of the Declaration of Helsinki and the International Conference on Harmonisation (ICH) Good Clinical Practice are commonly followed. We sought to answer the question of whether recent human clinical studies with insecticides performed according to Good Clinical Practice provided volunteers with the same protections as the Common Rule. All three sets of guidance have in common the intent to protect volunteer human subjects by providing standards for the conduct of studies in which they participate. This analysis compares the elements of the Common Rule with comparable elements from the Declaration of Helsinki and Good Clinical Practice to evaluate similarities and differences in procedural requirements. It then evaluates the documentation from 15 recent human studies of twelve insecticides conducted at four clinical laboratories in order to determine whether the conduct of those studies is consistent with the protections of the Common Rule. There were some cases for which we could not verify compliance with certain Common Rule elements; however, based on our evaluation it is apparent that the studies we reviewed were conducted in a manner substantially consistent with the fundamental protections of the Common Rule—voluntary participation, informed consent, and review by an ethical committee or institutional review board.