Showing papers in "Perspectives in Clinical Research in 2011"

Intention-to-treat concept: A review.

Abstract: Randomized controlled trials often suffer from two major complications, ie, noncompliance and missing outcomes One potential solution to this problem is a statistical concept called intention-to-treat (ITT) analysis ITT analysis includes every subject who is randomized according to randomized treatment assignment It ignores noncompliance, protocol deviations, withdrawal, and anything that happens after randomization ITT analysis maintains prognostic balance generated from the original random treatment allocation In ITT analysis, estimate of treatment effect is generally conservative A better application of the ITT approach is possible if complete outcome data are available for all randomized subjects Per-protocol population is defined as a subset of the ITT population who completed the study without any major protocol violations

Patient-reported outcomes: A new era in clinical research

Abstract: Now-a-days there is significant discussion about patient-reported outcomes (PRO) in medical world. The following article covers almost all the areas of PRO including-their importance, important concepts for understanding of PRO, significance, ideal properties, types, development and evaluation of PRO instruments. It is useful for physicians, pharmacists and patients for the assessment and improvement of the therapy.

An evaluation of knowledge, attitude, and practice of adverse drug reaction reporting among prescribers at a tertiary care hospital

Abstract: Objectives: Spontaneous reporting is an important tool in pharmacovigilance. However, its success depends on cooperative and motivated prescribers. Under-reporting of adverse drug reactions (ADRs) by prescribers is a common problem. The present study was undertaken to evaluate the knowledge, attitude, and practices (KAP) regarding ADR reporting among prescribers at the Civil Hospital, Ahmedabad, to get an insight into the causes of under-reporting of ADRs. Materials and Methods: A pretested KAP questionnaire comprising of 15 questions (knowledge 6, attitude 5, and practice 4) was administered to 436 prescribers. The questionnaires were assessed for their completeness (maximum score 20) and the type of responses regarding ADR reporting. Microsoft Excel worksheet (Microsoft Office 2007) and Chi-Square test were used for statistical analysis. Results: A total of 260 (61%) prescribers completed the questionnaire (mean score of completion 18.04). The response rate of resident doctors (70.7%) was better than consultants (34.5%) (P < 0.001). ADR reporting was considered important by 97.3% of the respondents; primarily for improving patient safety (28.8%) and identifying new ADRs (24.6%). A majority of the respondents opined that they would like to report serious ADRs (56%). However, only 15% of the prescribers had reported ADRs previously. The reasons cited for this were lack of information on where (70%) and how (68%) to report and the lack of access to reporting forms (49.2%). Preferred methods for reporting were e-mail (56%) and personal communication (42%). Conclusion: The prescribers are aware of the ADRs and the importance of their reporting. However, under reporting and lack of knowledge about the reporting system are clearly evident. Creating awareness about ADR reporting and devising means to make it easy and convenient may aid in improving spontaneous reporting.

Survival analysis in clinical trials: Basics and must know areas

Abstract: Many clinical trials involve following patients for a long time. The primary event of interest in those studies is death, relapse, adverse drug reaction or development of a new disease. The follow-up time for the study may range from few weeks to many years. A different set of statistical procedures are employed to analyze the data, which involves time to event an analysis. It is a very useful tool in clinical research and provides invaluable information about an intervention. This article introduces the researcher to the different tools of survival analysis.

Quality assurance: Importance of systems and standard operating procedures

Abstract: It is mandatory for sponsors of clinical trials and contract research organizations alike to establish, manage and monitor their quality control and quality assurance systems and their integral standard operating procedures and other quality documents to provide high-quality products and services to fully satisfy customer needs and expectations. Quality control and quality assurance systems together constitute the key quality systems. Quality control and quality assurance are parts of quality management. Quality control is focused on fulfilling quality requirements, whereas quality assurance is focused on providing confidence that quality requirements are fulfilled. The quality systems must be commensurate with the Company business objectives and business model. Top management commitment and its active involvement are critical in order to ensure at all times the adequacy, suitability, effectiveness and efficiency of the quality systems. Effective and efficient quality systems can promote timely registration of drugs by eliminating waste and the need for rework with overall financial and social benefits to the Company.

Plagiarism: Why is it such a big issue for medical writers?

Abstract: Plagiarism is the wrongful presentation of somebody else's work or idea as one's own without adequately attributing it to the source Most authors know that plagiarism is an unethical publication practice Yet, it is a serious problem in the medical writing arena Plagiarism is perhaps the commonest ethical issue plaguing medical writing In this article, we highlight the different types of plagiarism and address the issues of plagiarism of text, plagiarism of ideas, mosaic plagiarism, self-plagiarism, and duplicate publication An act of plagiarism can have several repercussions for the author, the journal in question and the publication house as a whole Sometimes, strict disciplinary action is also taken against the plagiarist The article cites examples of retraction of articles, suspension of authors, apology letters from journal editors, and other such actions against plagiarism

Quality of clinical trials: A moving target.

Abstract: Quality of clinical trials depends on data integrity and subject protection. Globalization, outsourcing and increasing complexicity of clinical trials have made the target of achieving global quality challenging. The quality, as judged by regulatory inspections of the investigator sites, sponsors/contract research organizations and Institutional Review Board, has been of concern to the US Food and Drug Administration, as there has been hardly any change in frequency and nature of common deficiencies. To meet the regulatory expectations, the sponsors need to improve quality by developing systems with specific standards for each clinical trial process. The quality systems include: personnel roles and responsibilities, training, policies and procedures, quality assurance and auditing, document management, record retention, and reporting and corrective and preventive action. With an objective to improve quality, the FDA has planned new inspection approaches such as risk-based inspections, surveillance inspections, real-time oversight, and audit of sponsor quality systems. The FDA has partnered with Duke University for Clinical Trials Transformation Initiative, which will conduct research projects on design principles, data quality and quantity including monitoring, study start-up, and adverse event reporting. These recent initiatives will go a long way in improving quality of clinical trials.

Regulations and guidelines governing stem cell based products: Clinical considerations.

Abstract: The use of stem cells as medicines is a promising and upcoming area of research as they may be able to help the body to regenerate damaged or lost tissue in a host of diseases like Parkinson's, multiple sclerosis, heart disease, liver disease, spinal cord damage, cancer and many more. Translating basic stem cell research into routine therapies is a complex multi-step process which entails the challenge related to managing the expected therapeutic benefits with the potential risks while complying with the existing regulations and guidelines. While in the United States (US) and European Union (EU) regulations are in place, in India, we do not have a well-defined regulatory framework for "stem cell based products (SCBP)". There are several areas that need to be addressed as it is quite different from that of pharmaceuticals. These range from establishing batch consistency, product stability to product safety and efficacy through pre-clinical, clinical studies and marketing authorization. This review summarizes the existing regulations/guidelines in US, EU, India, and the associated challenges in developing SCBP with emphasis on clinical aspects.

The Nuremberg Code-A critique

Abstract: The Nuremberg Code drafted at the end of the Doctor's trial in Nuremberg 1947 has been hailed as a landmark document in medical and research ethics. Close examination of this code reveals that it was based on the Guidelines for Human Experimentation of 1931. The resemblance between these documents is uncanny. It is unfortunate that the authors of the Nuremberg Code passed it off as their original work. There is evidence that the defendants at the trial did request that their actions be judged on the basis of the 1931 Guidelines, in force in Germany. The prosecutors, however, ignored the request and tried the defendants for crimes against humanity, and the judges included the Nuremberg Code as a part of the judgment. Six of ten principles in Nuremberg Code are derived from the 1931 Guidelines, and two of four newly inserted principles are open to misinterpretation. There is little doubt that the Code was prepared after studying the Guidelines, but no reference was made to the Guidelines, for reasons that are not known. Using the Guidelines as a base document without giving due credit is plagiarism; as per our understanding of ethics today, this would be considered unethical. The Nuremberg Code has fallen by the wayside; since unlike the Declaration of Helsinki, it is not regularly reviewed and updated. The regular updating of some ethics codes is evidence of the evolving nature of human ethics.

Good documentation practice in clinical research.

Abstract: One of the most common inspection findings in investigator site inspections is lack of reliable, accurate and adequate source documentation. This also happens to be the most common pitfall identified during sponsor audits. The importance of good documentation practice needs to be emphasized to investigator sites to ensure that the study results are built on the foundation of credible and valid data. This article focuses on the key principles of good documentation practice and offers suggestions for improvement.

Hybrid approaches to clinical trial monitoring: Practical alternatives to 100% source data verification.

Abstract: For years, a vast majority of clinical trial industry has followed the tenet of 100% source data verification (SDV). This has been driven partly by the overcautious approach to linking quality of data to the extent of monitoring and SDV and partly by being on the safer side of regulations. The regulations however, do not state any upper or lower limits of SDV. What it expects from researchers and the sponsors is methodologies which ensure data quality. How the industry does it is open to innovation and application of statistical methods, targeted and remote monitoring, real time reporting, adaptive monitoring schedules, etc. In short, hybrid approaches to monitoring. Coupled with concepts of optimum monitoring and SDV at site and off-site monitoring techniques, it should be possible to save time required to conduct SDV leading to more available time for other productive activities. Organizations stand to gain directly or indirectly from such savings, whether by diverting the funds back to the RD investing more in technology infrastructure to support large trials; or simply increasing sample size of trials. Whether it also affects the work-life balance of monitors who may then need to travel with a less hectic schedule for the same level of quality and productivity can be predicted only when there is more evidence from field.

Phase 0 clinical trials in oncology new drug development

Abstract: Research focus of pharmaceutical industry has expanded to a larger extent in last few decades putting many more new molecules, particularly targeted agents, for the clinical development. On the other hand, researchers are facing serious challenges due to high failure rates of new molecules in clinical studies. The United States Food and Drug Administration (FDA) in combination with academia and industry experts identified many factors responsible for failures of new molecules, and with a vision of taking traditional drug development model toward an innovative paradigm shift, issued regulatory guidance on conduct of exploratory investigational new drug (exploratory IND) studies, often called as phase 0 clinical trials, requiring reduced preclinical testing, which has special relevance to life-threatening diseases such as cancer. Phase 0 trials, utilizing much lower drug doses, provide an opportunity to explore the clinical behavior of new molecules very early in the drug development pathway, helping to identify the promising candidates and eliminating non-promising molecules, thus improving the efficiency of overall drug development with significant savings of resources. Being non-therapeutic in nature, these studies, however, pose certain ethical challenges requiring careful study designing and informed consent process. This article reviews the insights and perspectives for the feasibility, utility, planning, designing and conduct of phase 0 clinical trials, in addition to ethical issues and industrial perspective focused at oncology new drug development.

Implications of ICH-E5: Assessment of drug's sensitivity to ethnic factors and necessity of a bridging study for global drug development

Abstract: The ICH-E5 guideline provides a general framework for evaluating the potential impact of ethnic factors on the acceptability of foreign clinical data, with the underlying objective of minimizing duplication of clinical data, and it also describes the requirement of bridging studies for extrapolation of foreign clinical data to a new region. The ICH-E5 guideline brought great change in concept and strategy of global drug development for pharmaceutical companies. The procedures described in the ICH-E5 guideline have proved useful in the assessment of the ethnic sensitivity of a medicinal product that is to be introduced to a foreign region for registration purpose. Many companies are now developing various products based on ICH-E5 strategies and many successful cases will continuously appear within coming years.

Adaptive designs in clinical trials.

Abstract: In addition to the expensive and lengthy process of developing a new medicine, the attrition rate in clinical research was on the rise, resulting in stagnation in the development of new compounds As a consequence to this, the US Food and Drug Administration released a critical path initiative document in 2004, highlighting the need for developing innovative trial designs One of the innovations suggested the use of adaptive designs for clinical trials Thus, post critical path initiative, there is a growing interest in using adaptive designs for the development of pharmaceutical products Adaptive designs are expected to have great potential to reduce the number of patients and duration of trial and to have relatively less exposure to new drug Adaptive designs are not new in the sense that the task of interim analysis (IA)/review of the accumulated data used in adaptive designs existed in the past too However, such reviews/analyses of accumulated data were not necessarily planned at the stage of planning clinical trial and the methods used were not necessarily compliant with clinical trial process The Bayesian approach commonly used in adaptive designs was developed by Thomas Bayes in the 18th century, about hundred years prior to the development of modern statistical methods by the father of modern statistics, Sir Ronald A Fisher, but the complexity involved in Bayesian approach prevented its use in real life practice The advances in the field of computer and information technology over the last three to four decades has changed the scenario and the Bayesian techniques are being used in adaptive designs in addition to other sequential methods used in IA This paper attempts to describe the various adaptive designs in clinical trial and views of stakeholders about feasibility of using them, without going into mathematical complexities

Pharmacovigilance for clinical trials in India: Current practice and areas for reform.

Abstract: Keeping in mind India's increasing participation in multinational trials, this article explores potential areas of Indian pharmacovigilance, requiring reform and provides recommendations for building a robust safety reporting system. Internal discrepancies exist between Schedule Y and Central Drugs Standard Control Organisation approval letter regarding what to report. Schedule Y's silence on expedited reporting requirements creates confusion for Indian sites that are part of multinational trial. Not allowing waiver for serious adverse events that are protocol specified or are study endpoints, along with lack of emphasis on causality as reporting criteria, adds substantial burden of uninformative cases for regulatory review. Despite global focus on Development Safety Update Report, Indian regulators are not yet insistent on real-time update of a drug's cumulative safety profile. Issues like reporting requirements for generic trials, pregnancy reporting and lenient timeline for death/life-threatening events need attention. Finally, the need to formulate an all-encompassing pharmacovigilance guideline for India, in sync with global practice cannot be overemphasized.

Patient advocacy groups: Need and opportunity in India

Abstract: With an increasing number of corporate hospitals, healthcare related issues, research trials and undue attention by media in India, there is a need to focus more on patient's rights and protection. In India, multiple agencies like regulatory bodies, scientific review committees, ethics committees, NGOs, etc. work toward patient rights and protection. However, these agencies are inadequate to cater to the general issues related to patient's rights. There's a need to have a separate group of people who provide advocacy to the patient, or simply, a patient advocacy group which will work explicitly in these areas to increase transparency and credibility of healthcare system in India. This group will provide special attention to patient care and protection of rights from the planning stage rather than at the troubleshooting stage.

Trend of clinical drug trials in type 2 diabetes mellitus over last decade

Abstract: Background: Type 2 diabetes mellitus (Type 2 DM) has been recognized as the recent pandemic; India and China competing each other for the title--Diabetes Capital of the World. A number of new drugs have been recently available and has lead to a boom in the clinical drug trial industry. We intend to evaluate the trend of clinical drug trials in Type 2 DM over last one decade. Materials and Methods: Clinical drug trial registry of USA was used for getting the data regarding number of drug trials conducted in each country over last decade. India, China, and USA being the countries with highest prevalence of diabetes were included in the analysis. The percentage share of each country in clinical drug trials in Type 2 DM was compared with their percentage share in prevalence of Type 2 DM. Discussion: A significant growth in the drug trials in Type 2 DM was observed during 2005 to 2008, after which there has been a plateau. It was also recognized that India and China which contribute to around 30% of diabetic population of the world contributed in only 9.73% and 5.15% of drug trials in Type 2 DM during 2010, respectively. USA comprising of 15.15% of diabetic population of world was seen to have contributed in 38.36% of clinical drug trials in Type 2 DM. This raises a question of skewing in the data generated from various drug trials conducted in Type 2 DM.

Plagiarism: Pre-submission screening.

Abstract: Sir, The recently published paper by Chitra Bargaje on \"good documentation practice in clinical research\"[1] motivated me to discuss this not often discussed aspect of documents versus facts. I completely agree with the statement – \"What is not documented is not done!\". But there are situations where certain activities are performed by the subject and they can be documented and endorsed only by the principal investigators.

Integrated monitoring: setting new standards for the next decade of clinical trial practice

Abstract: The new age clinical research professional is now geared toward an "integrated monitoring" approach. A number of critical activities at the site level and at the sponsor's organization need convergence to harness rich dividends in early study start and quick close of the study. The field monitor needs full integration to ensure standard of care, train the site in protocol, select the right site, ensure regulatory support, ensure excellent project management skills, coach, support the logistics team, manage the vendor, ensure good documentation practices, develop patient recruitment and retention, lean the applicable process, as well as ensure effective site management amongst the myriad activities assigned toward developing the drug in the clinic.

Negotiation skills for clinical research professionals.

Abstract: Negotiation as a skill is a key requirement for each and every job profile where dealing with multiple parties is involved. The important focus while negotiating should be on the interest then position. Key to every successful negotiation is advance planning, preparation, and patience as the objective is to create value and establish the terms on which parties with differing and often conflicting aims will co-operate. While preparing one should collect facts, know priorities, principles, identify common ground, decide on walk-away position, and try and identify the next best alternative. Negotiation is a set of skills that can be learned and practiced so that your ability to utilize relationship, knowledge, money, power, time, and personality to negotiate improves with each negotiation. In a successful negotiation, all parties win. Important thing to note is that not every negotiation involves money. Anytime you want something from someone else and anytime someone wants something from you, you are negotiating. Everything is negotiable and every day you negotiate with customers, suppliers, colleagues, your wife, and even your children. Negotiation is a game, and like any game it has its rules and tactics. Clinical Research professionals deal with various parties for different purposes at the same time; hence, they require excellent negotiation skills. Project Mangers and Clinical Research Associates are the two most important roles in clinical research industry who require negotiation skills as they deal with various internal and external customers and vendors.

Challenges in conducting psychiatry studies in India.

Abstract: A large number of psychiatry studies are conducted in India. Psychiatry studies are complex and present unique challenges in the Indian setting. Ethical issues pertaining to the risk of worsening of illness, use of placebo and validity of informed consents are commonly faced. Site selection can be difficult due to the relative paucity of ICH-GCP (International Conference on Harmonisation - Good Clinical Practice) trained psychiatry investigators in India. Recruitment can be challenging due to issues such as strict eligibility criteria, (lack of) availability of caregiver, illness-related considerations, etc. Assessment of the consent capacity of patients is not simple, while structured assessments are not commonly employed. As the illness fluctuates, the consent capacity may change, thus requiring continued assessment of consent capacity. Study patients run the risk of worsening of illness and suicide due to exposure to inactive treatments; this risk is counterbalanced by use of appropriate study designs, as well as the indirect psychotherapeutic support received. Psychiatry studies are associated with a high placebo response. This necessitates conduct of placebo-controlled studies despite the attendant difficulties. Also, the high placebo response is often the cause of failed trials. Rating scales are essential for assessment of drug response. Some rating instruments as well as some rater training procedures may not be suitable for the Indian setting. Technological advancements may increase the procedural complexity but improve the quality of ratings. Psychiatry studies present monitors and auditors with unique scenarios too. Utilization of psychiatry specific training and expertise is recommended to ensure successful conduct of these studies in India.

Perception of various stakeholders regarding clinical drug trial industry in India.

Abstract: Context: Though India has been thought to be an ideal destination for conduct of clinical drug trials, other smaller countries seem to be doing better. The pace of growth observed during 2005-2009 seems to be plateaued in 2010. Aims: There is an urgent need for introspection and corrective actions. Materials and Methods: An online survey was conducted among various stakeholders from clinical drug trial industry in India regarding their perception about clinical drug trial industry in India. Respondents were requested to rate training of investigator sites, industry, performance of regulatory, etc. Results: Majority of respondent felt that the clinical drug trial industry in India is growing, though India is not utilizing its full potential. Lack of trained investigators and delay in regulatory approvals came out as biggest hurdles. Conclusions: Urgent steps need to be taken in terms of proper training of all stakeholders. Regulatory bodies ought to bring about some radical changes in the system so as to match the other competing nations.

Trends in food and drug administration inspection: A warning for the industry!

Abstract: 10.4103/2229-3485.83220 In recent years, US Food and Drug administration (FDA) has been ramping up its enforcement efforts by increasing the number of inspections within and outside the United States. The FDA has also been collaborating with different regulatory authorities to conduct these inspections. Along with this, these recent warning letters also show some trends in inspection findings, which suggest a change in the inspection focus of FDA and probably hint at major reforms that may happen in regulatory policies for inspection.[1,2]

Use, abuse and misuse of notes to file.

Abstract: A quick and easy solution to the absence of adequate documentation during clinical trial conduct is the use of notes to file. Over the years, the use of notes to file has evolved from a last resort solution to a common working practice amongst clinical teams, bordering on misuse and abuse of this tool. This article explores this evolution from the perspective of an independent observer.

Strategies for ensuring quality data from Indian investigational sites.

Abstract: The topic of ensuring quality and compliance is and must be a top priority in the conduct of clinical trials, as warranted by regulatory guidelines as well as the inherent responsibility of the professionals conducting such research. Fast-growing emerging clinical geographies such as India demand special attention due to rapid growth and associated factors that may put study quality at risk. In this paper, we used the basic principle of PDCA (Plan, Do, Check, and Adjust) to structure the processes of a clinical trial from protocol to final analysis in order to highlight the interactive nature of involved people and processes required to ensure quality of data and site functioning.