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.

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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.

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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.

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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.

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The signed informed consent form provides documentary evidence that the patient has given informed consent to participate in a clinical trial and that the patient has been given the requisite information. However, this document must not only provide the necessary information, it must also be provided in a way that can be understood by the patient. Non conclusive information suggests that research participants frequently may not understand the information presented during the informed consent procedure. Comprehension requires that the patient be able to understand the information presented and have the time and opportunity to read, evaluate and consider the information presented. A shortened Informed Consent Form, with information that a reasonable person would want to understand along with specific information that the person wants in particular would be a good option to improve understanding or comprehensibility. Additional informational meetings with a qualified person like a counselor could help in comprehension. Questionnaires designed to test comprehension of patient, peer review, patient writing the salient features could help evaluate the comprehensibility of the Informed Consent Form.

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Randomized controlled trials often suffer from two major complications, i.e., 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.

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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.

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The past few years have seen a tremendous rise in the number of clinical trials conducted in India. This is been attributed to the huge patient population, genetic diversity, and rich technical pool in our country. However, the economical upsurge in the clinical trial industry has also caused concerns pertaining to the efficiency of the Regulatory Agencies and Ethics Committees (EC). The EC plays an important role in the regulation of clinical research at the local level. However, it is seen that many ECs are oblivious to their roles and responsibilities. It is reported that ECs lack standard operating procedures, do not have a proper composition or adequate representation, thus affecting their functions in regulating clinical research. Moreover, ECs seem to function in isolation, as self-sufficient bodies, having no communication with the regulatory agency or other ECs. This brings forth the need for ECs to come together and share their experiences and observations, with the aim of updating themselves and refining their functions. Efforts also need to be focused on capacity building, centralized registration of ECs, and bringing an oversight mechanism in place. The Ethics Committees in India need to work in close association with forums such as the Forum for Ethics Review Committees in India and the Forum for Ethical Review Committees in Asia Pacific, in an effort towards empowering themselves.

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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.

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The development of fixed-dose combinations (FDCs) is becoming increasingly important from a public health perspective. FDCs have advantages when there is an identifiable patient population for whom treatment with a particular combination of actives in a fixed ratio is safe and effective and when all of the actives contribute to the overall therapeutic effect. Such combinations of drugs are particularly useful in the management of chronic diseases. In addition, there can be real clinical benefits in the form of increased efficacy and/or a reduced incidence of adverse effects. Additional advantages of FDCs are potentially lower costs of manufacturing compared to the costs of producing separate products administered concurrently, simpler logistics of distribution and reduced development of resistance in the case of antimicrobials. Above all, FDC therapy reduces pill burden and improves medication compliance. Although, FDCs seem to be ideal under certain pre-defined circumstances, if a dosing adjustment is warranted, there may not be an FDC available in the most appropriate strength for the patient and if an adverse drug reaction occurs from using an FDC, it may be difficult to identify the active ingredient responsible for causing the reaction. Appendix VI of Schedule Y (Drugs & Cosmetics Rules 1945, India) states the requirements for marketing approval of various types of FDCs. The same is further elaborated in this article to provide a detailed guidance including the clinical trial requirements. However, the heterogeneity of the therapeutic field makes it difficult to develop a standard guidance document.

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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 R&D pipeline; 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.

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Data generated in all clinical trial are recorded on the data collection instrument Case report Form / Electronic Case Report Form by investigators located at various sites in various countries. In multicentric clinical trials since different investigator or medically qualified experts are from different sites / centers recording the medical term(s) uniformly is a big challenge. Medical coders from clinical data management team process these terms and perform medical coding. Medical coding is performed to categorize the medical terms reported appropriately so that they can be analyzed/reviewed. This article describes process which is used for medical coding in clinical data management and two most commonly used medical dictionaries MedDRA and WHO-DDE in brief. It is expected to help medical coders to understand the process of medical coding in clinical data management. Few common issues which the medical coder faces while performing medical coding, are also highlighted.

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The evolution of clinical research traverses a long and fascinating journey. From the first recorded trial of legumes in biblical times to the first randomized controlled of trial of streptomycin in 1946, the history of clinical trial covers a wide variety of challenges - scientific, ethical and regulatory. The famous 1747 scurvy trial conducted by James Lind contained most elements of a controlled trial. The UK Medical Research Council's (MRC) trial of patulin for common cold in 1943 was the first double blind controlled trial. This paved the way for the first randomized control trial of streptomycin in pulmonary tuberculosis carried out in 1946 by MRC of the UK. This landmark trial was a model of meticulousness in design and implementation, with systematic enrolment criteria and data collection compared with the ad hoc nature of other contemporary research. Over the years, as the discipline of controlled trials grew in sophistication and influence, the streptomycin trial continues to be referred to as ground breaking. The ethical advances in human protection include several milestones - Nuremberg Code, Declaration of Helsinki, Belmont Report, and 1996, International Conference on Harmonization Good Clinical Practice guidance. In parallel to ethical guidelines, clinical trials started to become embodied in regulation as government authorities began recognizing a need for controlling medical therapies in the early 20th century. As the scientific advances continue to occur, there will be new ethical and regulatory challenges requiring dynamic updates in ethical and legal framework of clinical trials.

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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.

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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.

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The process of informed consent is an ethical mandate for all clinical trials. The principles of ethics in research involving human beings decrees the conduct of a process where the prospective research subjects should be informed of all aspects of the research study and after complete comprehension of all the features involved, should express willingness to be a part of the study, and the same should be duly documented. The consent should be fully informed and autonomous. However, with subject populations that are mostly medically naοve and for whom the whole concept of clinical research and the umpteen terms and concepts associated with it are alien; the true essence of an "informed" and "autonomous" decision is largely lost. The consent process thus gets reduced to mainly a "narration-followed-by-signature" process. Over the last few years, this gap in principles and practices of ethics and consent has been acknowledged and innovative concepts and attempts are being fostered, to make the informed consent process more "ethical". The article discusses the loopholes associated with the informed consent process and the innovative concepts to make it more authentic.

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Currently there is considerable interest in the legislative debate around generic biological drugs or "biosimilars" in the EU and US due to the large, lucrative market that it offers to the industry. While some countries have issued a few regulatory guidelines as well as product specific requirements, there is no general consensus as to a single, simple mechanism similar to the bioequivalence determination that leads to approval of generic small molecules all over the world. The inherent complex nature of the molecules, along with complicated manufacturing and analytical techniques to characterize them make it difficult to rely on a single human pharmacokinetic study for assurance of safety and efficacy. In general, the concept of comparability has been used for evaluation of the currently approved "similar" biological where a step by step assessment on the quality, preclinical and clinical aspects is made. In India, the focus is primarily on the availability and affordability of life-saving drugs. In this context every product needs to be evaluated on its own merit irrespective of the innovator brand. The formation of the National Biotechnology Regulatory Authority may provide a step in the right direction for regulation of these complex molecules. However, in order to have an efficient machinery for initial approval and ongoing oversight with a country-specific focus, cooperation with international authorities for granting approvals and continuous risk-benefit review is essential. Several steps are still needed for India to be perceived as a country that leads the world in providing quality biological products.

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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.

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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.

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Obtaining informed consent in psychiatry clinical research involving subjects with diminished mental abilities and impaired consent capacity has been a challenge for researchers, posing many ethical concerns and procedural hurdles due to participants' cognitive deficits and impaired ability to judge reality. Regulations seem inadequate and provide limited guidance, not sufficient to address all the ethical issues inherent in different situations related to obtaining consent from decisionally impaired persons. Researchers are struggling to find a balance between risk-benefit ratio, research advancement, and autonomy of study subjects. Inspired to improve the consent process in psychiatry clinical research, many studies have been conducted focusing on various informed consent-related ethical concerns, with the aim of developing appropriate strategies and optimizing the informed consent procedure in psychiatry clinical research, overcoming the ethical concerns. This article critically reviews the various ethical issues and consent challenges, their underlying reasons, and investigates the appropriate strategies and practices needed to be adopted while obtaining informed consent from subjects with impaired consent capacity, participating in psychiatry clinical research.

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Clinical research is a relatively new field in our country that has seen very rapid growth in the last few years. Availability of personnel appropriately trained to the specific requirements of the role they will perform in clinical research is critical for capacity expansion. Our study attempts to understand the specific areas of knowledge and skills that are important for the role of a clinical research associate. The survey was conducted among clinical research professionals from industry and academia who had more than five years of clinical research experience and held important decision making positions in clinical research (stakeholders). The survey questionnaire was designed as a matrix of various clinical research roles on the y-axis and six knowledge modules and eight skills on the x-axis. Respondents were asked to rate the importance of the knowledge /skills to the role of clinical research associates on a three point scale. In discussing results, a significant response was considered to be 50% or greater positive response from the total group. The significant findings were that general, ethics and clinical trial execution modules were rated as critical for the role of clinical research associate. Regulatory module was rated as important for the role. The other significant responses were that three of the sub-topics in the methodology module - framing a research proposal/protocol and experimental design, designing case report forms and EDCs and conducting PK studies - were rated as important and one sub topic in the data management and statistics module was rated as not important. All the skills except leadership skills were rated as critical for the role. The findings of our survey were in general on the lines of expectations of performance of the role. The general, ethics and clinical trial execution modules are critical knowledge areas for the role of a clinical research associate. No clear trends emerged for some of the other modules. Leadership skills were not rated as critical to the role. This kind of a survey gives a good direction when training curriculum has to be designed for specific roles in clinical research. However, there is a need to expand the sample size to fine-tune the knowledge and skills areas.

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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.

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The growing emphasis on off-site and off-shore clinical data management activities mandates a paramount need for adequate solutions geared toward on-time, quality deliverables. The author has been leading large teams that have been involved in successful global clinical data management endeavors. While each study scenario is unique and has to be approached as such, there are several elements in defining strategy and team structure in global clinical data management that can be applied universally. In this article, key roles, practices, and high-level procedures are laid out as a road map to ensure success with the model.

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Personalized medicine has the potential of revolutionizing patient care. This treatment modality prescribes therapies specific to individual patients based on pharmacogenetic and pharmacogenomic information. The mapping of the human genome has been an important milestone in understanding the interindividual differences in response to therapy. These differences are attributed to genotypic differences, with consequent phenotypic expression. It is important to note that targeted therapies should ideally be accompanied by a diagnostic marker. However, most efforts are being directed toward developing both these separately; the former by pharmaceutical companies and the later by diagnostic companies. Further, this companion strategy will be successful only when the biomarkers assayed are differentiated on a value-based approach rather than a cost-based approach, especially in countries that reimburse disease management costs. The advantages of using personalized therapies are manifold: targeted patient population; avoidance of drug-related toxicities and optimization of costs in nonresponder patients; reduction in drug development costs, and fewer patients to be tested in clinical trials. The success of personalized therapy in future will depend on a better understanding of pharmacogenomics and the extension of these scientific advances to all countries.

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