ICH-GCP Guidelines Research Articles

Safety and immunogenicity study of a new purified chick embryo cell rabies vaccine Vaxirab-N (Pitman–Moore strain) manufactured in India

Zydus Cadila Health care, India developed a new purified chick embryo cell rabies vaccine (PCECV, Vaxirab-N; 1 mL) by adapting Pitman–Moore strain of virus on to the chick embryo fibroblast cell line in 2006. During 2007–10, a series of safety and immunogenicity studies were conducted as per ICH-GCP guidelines after obtaining permission from Drug Controller General of India. In the first study, Vaxirab-N was administered to 35 healthy adult volunteers by intramuscular (IM) route using pre exposure regimen. The geometric mean concentration (GMC) of rabies virus neutralizing antibody (RvnAb) of 7.5 IU/mL on day 35. In the second study, Vaxirab-N was administered to 35 healthy adult volunteers using simulated post- exposure prophylaxis regimen by IM route. A GMC of 6.3 IU/mL on day 14, 13.2 IU/mL on day 28 and 8.6 IU/mL on day 90 was obtained. In the third study, Vaxirab-N administered by intradermal (ID) route using Updated Thai Red Cross (TRC) regimen in 36 healthy adult volunteers showed GMC of 7.8 IU/mL on day 14, 11.5 IU/mL on day 28 and 6.0 IU/mL on day 90. The 4th study was multi centric and Vaxirab-N was administered to 129 animal bite cases by IM route using post-exposure Essen regimen. The GMC following this schedule was 8.2 IU/mL on day 14, 13.01 IU/mL on day 28, 7.92 IU/mL on day 90 and 3.72 IU/mL on day 180. Mild to moderate adverse events were reported to Vaxirab-N but no serious adverse events were reported in any of these studies. In conclusion, Vaxirab-N developed by Zydus Cadila was found to be safe and immunogenic by both intramuscular and intradermal route and is recommended for rabies prophylaxis (CTRI No. 2010/091/000055 and 2010/091/000509).

Informed Consent Document (ICD) as Educational Tool for Medical School

Background: India is fast becoming a hub for clinical research. A lot of clinical research is being done at all levels of the health care system and Physician assumes a central role in it. There is even shift of focus about imparting clinical research training to medical students, as at some stage of their practice they will be involved in clinical research. Informed Consent Document forms a central basis of ethical clinical research and is considered a priority as per Schedule Y, ICH-GCP guidelines and Declaration of Helsinki. Therefore it was considered worthwhile to assess the awareness of medical students about Informed consent document before and after imparting training to the medical students. Materials and Methods: This prospective study was conducted in the Department of Pharmacology, Gian Sagar Medical College, Patiala. 95 medical students in the final year of their MBBS course were enrolled in the study and were given a questionnaire before and after imparting training about informed consent document as per Schedule Y, ICH-GCP guidelines and Declaration of Helsinki. Results: The students were assessed on their knowledge and attitude about informed consent document. After the training, the students were significantly (p < 0.05) more aware about the role of the Informed consent document as per guidelines. Also, there was a significant difference (p < 0.05) in the pattern, behaviour and outlook of students after training was imparted to them. Conclusion: Training medical students about informed consent document significantly increased their knowledge, understanding and attitude.

FDA abandons the Declaration of Helsinki: The effect on the ethical aspects of clinical trial conduct in South Africa and other developing countries

Four years ago, the US Food and Drug Administration (FDA) ceased compliance with the Declaration of Helsinki (DoH) (2000 revision and all subsequent revisions) for conduct of clinical trials outside its borders. It instead ruled that compliance with the Good Clinical Practices (GCP) of the International Conference of Harmonization (ICH) is sufficient. However, the ICH-GCP guidelines do not address certain ethical requirements stipulated in the DoH, such as the use of placebos v. standard therapy, post-trial access to treatment and other benefits for participants; public disclosure of trial design; publication of trial results; and disclosure of conflicts of interest.

Ethical Considerations in Clinical Trials: A Critique of theICH‐GCP Guideline

This article examines issues relating to ethics decision-making in clinical trials. The overriding concern is to ensure that the well being and the interests of human subjects are adequately safeguarded. In this respect, this article will embark on a critical analysis of the ICH-GCP Guideline. The purpose of such an undertaking is to highlight areas of concern and the shortcomings of the existing ICH-GCP Guideline. Particular emphasis is made on how ethics committees perform their duties and responsibilities in line with the principles outlined in the ICH-GCP Guideline. This article will draw attention to the need for a new approach to addressing the weaknesses of the ICH-GCP Guideline in its present form.

Phase IIa Study of the Anti-CXCL12/SDF-1 Spiegelmer® Nox-A12 Alone and Combined with Bendamustine/Rituximab in Patients with Relapsed Chronic Lymphocytic Leukemia (CLL)

AbstractAbstract 4593 BackgroundNOX-A12 is a novel, potent, L-aptamer inhibitor of CXCL12/SDF-1, a chemokine which attracts and activates immune- and non-immune cells. The signaling of CXCL12 has been shown to play an important role in the pathophysiology of chronic lymphocytic leukemia (CLL), especially in the interaction of leukemic cells with their tissue microenvironment. The therapeutic concept of NOX-A12 is to inhibit such tumor-supporting pathways and thereby sensitizing the CLL cells towards chemotherapy. MethodsThe purpose of this phase IIa study is to evaluate the safety and efficacy of NOX-A12 in combination with background chemo-immunotherapy of bendamustine and rituximab (BR) in patients with relapsed CLL. The described study is being performed in compliance with ethical principles based on the Declaration of Helsinki and ICH-GCP guidelines. The study population was split into a pilot and expansion group. In the pilot group, 3 cohorts of 3 patients each received escalating doses of single agent NOX-A12 two weeks prior to the combined treatment of NOX-A12 and BR. Interim data from these patients are reported. Based on previous Phase I studies in healthy volunteers, pilot patients received a dose of 1, 2 or 4 mg/kg body weight (BW) single agent NOX-A12 on day -14, followed by a 2-weeks period of safety, PK and PD assessments prior to the combined treatment with NOX-A12 and BR. To date, the first cohort of the pilot group already progressed to the 2nd cycle of combined treatment. Evaluation criteria included adverse events according to CTCAE V4, flow cytometry of peripheral blood CD34+ cells and CLL cells, pharmacokinetics of NOX-A12, plasma concentration of CXCL12 and tumor response (NCI-WG 1996 criteria, updated 2008). ResultsTo date 3 patients (age range: 58 – 65 years) have been enrolled in the pilot group of this study. They had received 1 or 2 prior therapies, but no bendamustine. Single i.v. doses of 1 mg/kg BW NOX-A12 had no clinically relevant effects on vital signs, 12-lead ECG parameters and laboratory parameters. One patient reported grade 1 pain in the lower limbs two days after treatment with NOX-A12. This event was not dose-limiting and resolved spontaneously on the same day. Flow cytometry of CD34+ cells and CLL cells (CD19+/CD5+high) showed a rapid mobilization of these cells into the peripheral blood on day 1. Interestingly, return to baseline was not complete at the last assessment on day 3 (for details see Figure 1). The NOX-A12 pharmacokinetics in these 3 patients (for concentration-time profile see Figure 2) is very comparable to healthy volunteers receiving i.v. NOX-A12, with a maximum plasma concentration of 1.52 ± 0.14 μM after 1 h (tmax) and a plasma elimination half-life of about 50 h. As seen in healthy volunteers the plasma concentration of CXCL12 increased upon NOX-A12 treatment and reached a maximum of 0.434 ± 0.076 μM at 24 to 72 h p.a. without ever approaching the plasma concentration of NOX-A12 (Figure 2). ConclusionSingle i.v. doses of NOX-A12 at 1 mg/kg BW were safe and well tolerated; the maximum tolerated dose was not reached. NOX-A12 induced a long-lasting mobilization of CD34+ cells and leukemic cells in patients with relapsed CLL, consistent with a mechanism of action based on CXCL12 inhibition. Patient accrual and identification of an optimal chemosensitization regimen of NOX-A12 combined with BR is being continued. [Display omitted] [Display omitted] Disclosures:Vauléon:NOXXON Pharma AG: Employment. Zöllner:NOXXON Pharma AG: Employment. Dümmler:NOXXON Pharma AG: Employment. Kruschinski:NOXXON Pharma AG: Employment. Fliegert:NOXXON Pharma AG: Employment.

Experimental testing of skin reactions to insulin detemir in diabetes patients naïve to insulin detemir

Sporadic reports on immediate and delayed cutaneous reactions to insulin detemir, a modern insulin analogue, have raised unsupported claims of allergy of type I, III and IV. The purpose of this experimental study using a provocative design was to elucidate the potential mechanisms behind such skin reactions. A total of 40 patients with type 1 diabetes or insulin-requiring type 2 diabetes, all naïve to insulin detemir, were injected on the thigh with 0.l mL of insulin detemir (Levemir(®)) administered with an 8 mm needle at three different depths, i.e. intradermal, subdermal and subcutaneously. Saline was injected as control. Any cutaneous reactions were assessed after 10 and 30 min, after 24 and 48 h and after 7 days. Histopathology of positive reactions on day 7 was obtained. The study was randomized, controlled, double-blinded, and conducted in accordance with ICH-GCP guidelines. Blood flow was recorded with the Periflux PF5010, and skin colour (a*) with the DSMII colorimeter. Clinical reading, flowmetry and colorimetry consistently showed delayed reactions after intradermal insulin injection (35 of 40 patients reacted with mainly weak reactions, P<0.05), peaking after 48 h, contrasting no special reaction immediately after injection, except for reactions attributed to needle trauma. A total of 22 patients reacted on subdermal injection and 21 on subcutaneous injection. Histopathology on day 7 from 22 reactions in 15 patients showed a consistent pattern of inflammation with eosinophilia as typically observed in adverse skin reactions to a variety of medicines. Reactions were interpreted as non-specific biologic responses to the insulin different from direct toxic actions and classical allergic reaction patterns. Only one person registered itch/discomfort. A prick test vs. histamine reference excluded insulin detemir to be a pharmacological histamine releaser. Thus, provocative testing with insulin detemir produced delayed skin reaction but no immediate reaction. Measurement of circulating insulin detemir-specific antibodies by RIA before and after 3 months showed no increase. Non-allergic delayed skin reactions from intradermal and, to a minor degree, subdermal and subcutaneous injections of insulin detemir were frequent in this experimental study and showed a consistent histology pattern of inflammation with eosinophilia. Immediate reactions were not produced. The reactions are unlikely to be specific for insulin detemir, and other insulins should be studied in a similar provocative design.

Developing an international network for clinical research in ophthalmology: the European Vision Institute Clinical Research Network (EVICR.net)

There is a well-identified need for patient-oriented clinical research and this can only be achieved by creating active collaboration between academic centers with competence for clinical research, following GCP guidelines and supported by an infrastructure that provides appropriate management of clinical trials at a realistic cost. The European Vision Institute Clinical Research Network (EVICR.net) is a legal entity established as an independent European Economic Interest Grouping in accordance with the Council Regulation (EEC) #2137/85 and was built and developed to function as the necessary structure to perform clinical research in ophthalmology in the EU according to ICH GCP Guidelines and European Directives.

Postpartum blue is common in socially and economically insecure mothers

A survey was carried out among mothers within 2 weeks of delivery at a referral hospital in Bangalore after obtaining the approval from hospital authorities and ethical committee. Mothers within 2 weeks of delivery and in good health were included from the maternity ward and from outpatient department after obtaining the written consent. Women with debilitating illness, disabling mental disorders, alcohol dependence, and narcotic drug dependence were excluded from the study. Based on ICH-GCP guidelines, 130 subjects in the age group of 18–45 years were randomly screened.Two questionnaires were used in this study. Subjects were encouraged to complete the questionnaires on their own with minimum assistance to avoid bias. First questionnaire was the Edinburgh Postnatal Depression Scale (EPDS), used to diagnose the PPB. The EPDS included 10 questions and each one is valued on a four-point scale with maximum possible score of 30.

Laboratory testing in clinical trials under consideration of the ICH-GCP guideline1

Abstract Clinical trials are a prerequisite for the launch and registration of new drugs. During recent years the regulations have become more strict worldwide including Germany. The German law governing the manufacture and prescription of drugs (German Drugs Act, AMG) has adopted the contents of the guideline for Good Clinical Practice (GCP) which was harmonised by the International Conference on Harmonisation (ICH) and makes binding recommendations with respect to ethics and quality of clinical trials. Since laboratory investigations form an integral part of most clinical trials it is beyond doubt that these recommendations and laws do also apply to laboratory testing. In consideration of these rules it is a demand that laboratories and laboratory physicians be involved early in the planning of clinical trials. In addition, laboratories must be informed of ongoing trials before they are initiated in a trial site of a hospital. Optimally, a separate laboratory contract has been signed and laboratory testing is reimbursed according to the German fee regulations for physicians (GOÄ). In the authors' opinion, the dissemination of proficiency testing documents and reference values to the sponsor after a trial has been completed is insufficient to fulfil legal requirements and to comprehensively exclude legal liability of the laboratory personnel.

The Procalcitonin And Survival Study (PASS) – A Randomised multi-center investigator-initiated trial to investigate whether daily measurements biomarker Procalcitoninand pro-active diagnostic and therapeutic responses to abnormal Procalcitonin levels, can improve survival in intensive care unit patients. Calculated sample size (target population): 1000 patients

BackgroundSepsis and complications to sepsis are major causes of mortality in critically ill patients. Rapid treatment of sepsis is of crucial importance for survival of patients. The infectious status of the critically ill patient is often difficult to assess because symptoms cannot be expressed and signs may present atypically. The established biological markers of inflammation (leucocytes, C-reactive protein) may often be influenced by other parameters than infection, and may be unacceptably slowly released after progression of an infection. At the same time, lack of a relevant antimicrobial therapy in an early course of infection may be fatal for the patient. Specific and rapid markers of bacterial infection have been sought for use in these patients.MethodsMulti-centre randomized controlled interventional trial. Powered for superiority and non-inferiority on all measured end points. Complies with, "Good Clinical Practice" (ICH-GCP Guideline (CPMP/ICH/135/95, Directive 2001/20/EC)). Inclusion: 1) Age ≥ 18 years of age, 2) Admitted to the participating intensive care units, 3) Signed written informed consent.Exclusion: 1) Known hyper-bilirubinaemia. or hypertriglyceridaemia, 2) Likely that safety is compromised by blood sampling, 3) Pregnant or breast feeding.Computerized Randomisation: Two arms (1:1), n = 500 per arm: Arm 1: standard of care. Arm 2: standard of care and Procalcitonin guided diagnostics and treatment of infection.Primary Trial Objective: To address whether daily Procalcitonin measurements and immediate diagnostic and therapeutic response on day-to-day changes in procalcitonin can reduce the mortality of critically ill patients.DiscussionFor the first time ever, a mortality-endpoint, large scale randomized controlled trial with a biomarker-guided strategy compared to the best standard of care, is conducted in an Intensive care setting. Results will, with a high statistical power answer the question: Can the survival of critically ill patients be improved by actively using biomarker procalcitonin in the treatment of infections? 700 critically ill patients are currently included of 1000 planned (June 2008). Two interim analyses have been passed without any safety or futility issues, and the third interim analysis is soon to take place. Trial registration number at clinicaltrials.gov: Id. nr.: NCT00271752).

The importance of Good Clinical Practice guidelines and its role in clinical trials

Good Clinical Practice (GCP) is an international ethical and scientific quality standard for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials. It also serves to protect the rights, integrity and confidentiality of trial subjects. It is very important to understand the background of the formation of the ICH-GCP guidelines as this, in itself, explains the reasons and the need for doing so. In this paper, we address the historical background and the events that led up to the formation of these guidelines. Today, the ICH-GCP guidelines are used in clinical trials throughout the globe with the main aim of protecting and preserving human rights.

Wirksamkeit von Arnica bei Varizenoperation: Ergebnisse einer randomisierten, doppelblinden, Placebo-kontrollierten Pilot-Studie

Efficacy of Arnica in Varicose Vein Surgery: Results of a Randomized, Double-Blind, Placebo-Controlled Pilot Trial Introduction: In homeopathy Arnica is widely used as a woundhealing medication and for the treatment of hematomas. Objective: In this pilot study the efficacy and safety of Arnica D12 in patients following varicose vein surgery were investigated. Design: Prospective, randomized, double-blind, placebo-controlled pilot trial according to ICH GCP guidelines. Setting: The study was conducted by a surgeon at the Angiosurgical Clinic, Berlin- Buch. Intervention: After randomized allocation, 60 patients received either Arnica D12 or placebo. Start of medication occurred the evening before operation with 5 globules. On the operation day one preoperative and hourly postoperative dosages after awakening were given. On days 2–14 of the study 5 globules 3 times a day were given. Outcome Criteria: Surface (in cm² and using a three-point verbal rating scale) and intensity of hematomas induced by operation, complications of wound healing, and intensity of pain (five-point verbal rating scale) as well as efficacy and safety of the study medication were assessed. Results: Hematoma surface was reduced (from day 7 to day 14) under Arnica by 75.5% and under placebo by 71.5% (p = 0.4726). The comparison of hematoma surface (small, medium, large) using the verbal rating scale yielded a value of p = 0.1260. Pain score decreased by 1.0 ± 2.2 points under Arnica and 0.3 ± 0.8 points under placebo (p = 0.1977). Remission or improvement of pain was observed in 43.3% of patients in the Arnica group and in 27.6% of patients in the placebo group. Tolerability was rated as very good in all cases. Conclusion: The results of this pilot study showed a trend towards a beneficial effect of Arnica D12 with regard to reduction of hematoma and pain during the postoperative course. For a statistically significant proof of efficacy of Arnica D12 in patients following varicose vein surgery a larger sample size is necessary.

The World Medical Association revises the Declaration of Helsinki

The most comprehensive revision of the ubiquitous Declaration of Helsinki since its inception in 1964 was adopted in October in Edinburgh at the 52nd WMA General Assembly. Thankfully, this revision is nothing like as radical as the Faculty feared when it reviewed earlier drafts. What has emerged is a document with which pharmaceutical physicians – as doctors first and foremost – can be at ease. The Declaration has been largely rewritten in terms which are less archaic than the original, but retaining some of the turns of phrase with which those regularly referring to the declaration are very familiar. The principal changes include a much clearer reference to the role of research ethics committees (clause 13) – compatible with the details in chapter 3 of the ICH GCP guidelines, which is the chapter devoted to such committees. There is a new call to cease any investigation when there is conclusive proof of positive and beneficial results (17) as well as when risks are found to outweigh the potential benefits had a subtle revision. Importantly, with indirect reference to developing countries – and quite contrary to the way in which some of the earlier drafts could have been interpreted – clause 19 states that research is only justified if there is a reasonable likelihood that the population where the research is carried out stands to benefit from the results of such research. Consent has been toughened, and now has to be written or witnessed (22–26) and there is no place for the statement in the earlier versions allowing the physician who considered it essential not to obtain consent to be allowed to go ahead. Finally, clause 26 advocates a stong publication policy and exhorts that negative as well as positive results should be published. Not every pharmaceutical physician – even if at ease – will necessarily agree with every aspect of this revision. However, the WMA has clearly demonstrated its awareness of the importance of therapeutic research whilst safeguarding even more strongly the interests of humans offering themselves as research subjects.

Clinical pharmacologists and drug regulation--future perspective in Japan.

1. The Japanese pharmaceutical administration system, and recommendations for the improvement of clinical trial methodology following the implementation of GCP guidelines in Japan are described with special reference to three recent developments in Japanese drug regulation. 2. The implementation of GCP guidelines has not been fully satisfactory and clinical trials in Japan still run into problems. The Ministry of Health and Welfare has recently established a Committee on Safety of Medicines after serious trouble with a new drug was experienced. The Committee released an interim report on the reform of clinical trials supervision and the system for examination of New Drug Applications. 3. ICH-GCP guidelines will be implemented in Japan in the next few years. The principal differences between Japanese GCP and ICH-GCP guidelines, and their effects on clinical trials in Japan with reference to the acceptability of ICH-GCP, are discussed. 4. The final proposals on the National Health Insurance drug pricing method and the appropriate use of drugs by the Central Social Insurance Medical Council are anticipated to have a significant impact on the drug market. The changes in pricing system, especially premiums for innovative drugs, and the implications for the drug market are considered. 5. In these changed circumstances, the importance of the role of clinical pharmacologists in the framework of the new drug regulations in Japan is reviewed.