The Indian Council of Medical Research (ICMR) has issued the consensus document for management of non-Hodgkin’s lymphoma (high grade) which will provide guidance to practicing doctors and researchers for the management of patients suffering from non- Hodgkin’s lymphoma – high grade and also focusing their research efforts in Indian context.
Lymphoma is a type of cancer that develops in the lymphatic system, the body’s disease fighting network. It is estimated that around 1,000 people worldwide are diagnosed with lymphoma every day. Globally the incidence of disease is 385741 cases with mortality of 199650 cases. India accounts for 23801 cases with a mortality of 16597 cases.
This document will help practicing doctors, clinicians, researchers and patients in complex decision making process in management of the disease. It represents the current thinking of national experts on subject based on available evidence.
The ICMR had earlier constituted sub-committees to prepare consensus document for management of various cancer sites. This document is the result of the hard work of various experts across the country working in the area of oncology. This consensus document on management of non- Hodgkin’s lymphoma – high grade summarizes the modalities of treatment including the site-specific anti-cancer therapies, supportive and palliative care and molecular markers and research questions. It also interweaves clinical, biochemical and epidemiological studies.
The purpose of this document is to revamp recommendations for evaluation, staging and response assessment of patients with non-Hodgkin’s lymphoma. The availability of more effective therapies for lymphoma and the increasingly sensitive and specific technologies has made this consensus the need of hour. However, good clinical judgement, a careful history and physical examination are the cornerstones of patient follow up. The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with Non Hodgkin Lymphoma – High Grade. The guidance may not be appropriate for all patients with NHL but this compilation of Indian Data gives us an insight to best practice. This disease strata is currently undergoing extensive investigations and it is likely that paradigms will shift over the next several years.
Lymphomas are a very complex group of diseases with differing behaviours and treatment options. It is typically classified into two groups, Hodgkins lymphoma (HL) and non-Hodgkins lymphoma (NHL). NHL’S are subclassfied as low grade (indolent) and high grade. The high grade NHL is generally curable with cytotoxic therapy while the low grade lymphomas are controllable for long periods.
While lymphoma is potentially fatal, some forms are curable and a patient’s survival may be greatly enhanced by early diagnosis. Almost all lymphoma types can be cured or managed as a chronic disease, but its complexity and variation do not allow for a one-size-fits-all treatment approach. Instead, it necessitates highly specialized and individualized approaches. The cause of the majority of lymphoma cases is unknown, however, there could be several factors that may influence one’s risk of developing lymphoma. The relative effects of these factors in any given case of cancer vary and are very difficult to determine with accuracy at present.
In another bid to give momentum to research and clinical trials in the country, the centre eased regulations governing the import and export of human biological samples for commercial purposes. The Directorate General of Foreign Trade issued a notification, August 4, saying that the import and export of such samples “should be permitted by Customs authorities at the port of entry / exit without prior approvals (import licence / export permit) from any other Government agency.”
As long as “the concerned Indian company/agency submits an undertaking that they are following and will follow all the applicable rules, regulations and procedures for safe transfer and disposal of the biological samples being imported/exported as per the related norms/regulations” to the Customs authority at the port of entry or exit, any other approval is no longer required. Prior to this change, such a company or agency had to submit an application to the Indian Council of Medical Research, which then made decisions case-by-case.
In 2011, ICMR had formed a committee of experts, chaired by the director general of the Council, to scrutinise and, only then, clear every sample going in and out of India. Among the documents that had to be submitted to the committee was a copy of the informed consent of the individual patient agreeing to their sample being used for a particular study.
The debate over the ethics of the commercial use of the biological samples has been around for over a decade now. A November 2002 article from the British Medical Journal notes the objection raised by Indian scientists to a genetic study done by British and German scientists on people from coastal Kerala. The article says the concern was that India’s diverse genetic information could be mined for commercial purposes without regulations.
This notification comes on the heels of two circulars issued by the Central Drugs Standard Control Organisation that also made getting approvals for and the logistics of clinical trials and research easier for companies. All three steps have been taken at the same time as the ICMR bringing out its draft National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, which set standards for ethical practices and consent, and safeguard participants.
One circular removed the cap of three trials per investigator. The other says that trial sites no longer need to have at least 50 beds. Both circulars hand over the decision making powers to the ethics committee presiding over each trial. It was also felt that since India has too few principal investigators, restricting them to only three trials at a time was not feasible.
The Indian Council of Medical Research (ICMR) issued guidelines for diagnosis and management of celiac disease, which is a chronic immune-mediated enteropathy caused in genetically susceptible individuals by ingestion of gluten proteins present in wheat, barley and rye.
There has been an increase in reporting of celiac disease (CeD) in India, which may be due to increased recognition (due to newer diagnostic techniques) or increased incidence or both. Survey of the published literature indicates that there is a steady increase in the number of published papers dealing with CeD in India.
This could be due to an increase in interest in the disease amongst physicians, an increase in recognition of the disease, or due to true increase in the incidence of the disease. In the absence of previous baseline data on the incidence and prevalence of the disease, the latter possibility is difficult to prove. However, the opinion of the expert group was that in addition to increased recognition, there was likely to have been an increase in true prevalence of the disease in recent years. Similar phenomena have been reported from other countries, particularly in the Asia-Pacific region.
Earlier, the ICMR had created a Task Force on CeD in 2008, recognizing the need to focus on a disease that was beginning to be reported in sizeable sections of the population in several states of northern India. As recommended by the Task Force, data were collected on the prevalence of CeD in three regions of India through a population-based study carried out in three regions of the country.
The Task Force also recommended that ICMR develop guidelines for the diagnosis and management of CeD in India. While several international groups have generated guidelines for the diagnosis and management of CeD, these were largely rooted in the experience of western countries. There has been considerable skepticism over the applicability of these guidelines in a country like India where tropical enteropathy or environmental enteropathy is so widely prevalent, and where the incidence of parasitic and other infections of the small intestine is significant.
Celiac disease was originally described as a disease causing chronic diarrhoea and malabsorption. Flattening of the villi, inflammatory cell infiltration in the mucosa and loss of surface area were the major reasons for the clinical manifestations. The understanding that this is an immune process in which the intestinal epithelium is damaged is now well accepted. Following from the original descriptions by Willem Karel Dicke relating wheat consumption to CeD, a large number of studies have now established the central role played by proteins from wheat, barley and rye. The disease occurs only in individuals with a certain genetic predisposition, but at the same time it does not necessarily occur in all such individuals.
ICMR issues “National Ethical Guidelines for Biomedical and Health Research involving Human Participants, 2016”
The Indian Council of Medical Research (ICMR) has issued the draft “National Ethical Guidelines for Biomedical and Health Research involving Human Participants, 2016” which will make specific provisions to meet ethical challenges posed by newer scientific advances. The guidelines are divided in various sections to cover a range of topics and attempts to address the emerging ethical concerns related to biomedical and health research.
The guidelines have been drafted by Expert Subcommittees working under the dynamic leadership of an Advisory Committee chaired by Dr Vasantha Muthuswamy. The ICMR has invited suggestions/feedback from all interested stakeholders till 15th September, 2016.
These guidelines are applicable to all biomedical, socio-behavioural and health research conducted in India involving human participants, their biological material and data. The purpose of such research should be directed towards enhancing knowledge about the human condition in relation to its social and natural environment. It should be conducted under conditions that no person or persons become a mere means for the betterment of others and that human beings who are subjected to any medical research or scientific experimentation are dealt with in a manner conducive to and consistent with their dignity and well being, under conditions of professional fair treatment and transparency. It must be subjected to a regime of evaluation at all stages of the proposal i.e., research design and conduct with the objectives in mind, the means by which they are sought to be achieved, the anticipated benefits and harms, declaration of results and use of the results thereof.
As per the new guidelines, research pertains to a broad range of scientific enquiry on human participants for developing generalisable knowledge that improves health, increases understanding of disease and is justified ethically by its social value. Every research has some inherent risk and probabilities of harm to participants/community. Therefore, protection of participants should be built in to the design of study. Do no harm (non maleficence) has been the underlying universal principle in all systems of medicine around the world for guiding healthcare. While conducting biomedical and health research, the four basic principles namely; Respect for Persons (Autonomy), Beneficence, Non Maleficence and Justice have been enunciated to govern research. These four basic principles have been expanded into 12 general principles, which are to be applied to all biomedical and health research involving human participants or research using their biological material or data.
The 12 general principles include principle of biomedical and health research, principle of essentiality, principle of voluntariness, principle of non-exploitation, principle of ensuring privacy and confidentiality, principle of risk minimization, principle of professional competence, principle of accountability, principle of the maximization of benefit, principle of institutional arrangements, principle of transparency and principle of totality of responsibility.
The new guidelines have adapted important guidance points from some of the International guidelines in accordance with the socio-cultural milieu of our country. The socio-cultural ethos in India and its varying standards of health care today pose unique challenges to the application of universal ethical principles to biomedical and health research. The last decade has seen emerging ethical issues necessitating further revision as ‘National Ethical Guidelines for Biomedical and Health Research on Human Participants 2016’. These guidelines have covered some newer areas like social and behavioural sciences, responsible conduct of research and new technologies, while a few other specialised areas like informed consent process, biological materials and data sets, vulnerability, international collaboration, research during humanitarian emergencies and disasters have been expanded.
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Clinical Trial Registry – India
Clinical Trial Registry – India (CTRI) is a repository for information regarding the clinical trials that are conducted in India. The Clinical Trials Registry- India (CTRI), hosted at the ICMR’s National Institute of Medical Statistics (http://nims-icmr.nic.in), is a free and online public record system for registration of clinical trials being conducted in India that was launched on 20th July 2007 (www.ctri.nic.in). Initiated as a voluntary measure, since 15th June 2009, trial registration in the CTRI has been made mandatory by the Drugs Controller General (India) (DCGI) (www.cdsco.nic.in).
Today, any researcher who plans to conduct a trial involving human participants, of any intervention such as drugs, surgical procedures, preventive measures, lifestyle modifications, devices, educational or behavioral treatment, rehabilitation strategies as well as trials being conducted in the purview of the Department of AYUSH (http://indianmedicine.nic.in/) is expected to register the trial in the CTRI before enrollment of the first participant. Trial registration involves public declaration and identification of trial investigators, sponsors, interventions, patient population etc before the enrollment of the first patient. Submission of Ethics approval and DCGI approval (if applicable) is essential for trial registration in the CTRI. Multi-country trials, where India is a participating country, which have been registered in an international registry, are also expected to be registered in the CTRI. In the CTRI, details of Indian investigators, trial sites, Indian target sample size and date of enrollment are captured. After a trial is registered, trialists are expected to regularly update the trial status or other aspects as the case may be. After a trial is registered, all updates and changes will be recorded and available for public display.
Being a Primary Register of the International Clinical Trials Registry Platform (ICTRP) (http://www.who.int/ictrp/search/en/), registered trials are freely searchable both from the WHO’s search portal, the ICTRP as well as from the CTRI (www.ctri.nic.in).
Trials registered in CTRI will be monitored to ensure increasing voluntary disclosure of all items in the register. These items have been selected in order to:
Improve transparency and accountability: By disclosing all required details of the protocol of trials, public confidence in clinical trials is likely to be enhanced.
Improve the internal validity of trials: Empirical research has shown that some aspect of the methods of the trial are particularly important to produce reliable results by minimizing biases, confounders and the effects of chance or coincidence. These include the method of random sequence generation, adequate concealment of allocation of participants to interventions, adequate blinding of participants, investigators and outcome assessors, and inclusion of all participants’ results. The CTRI hopes that these items, though not mandatory at present, will be disclosed by all registrants, as incorporating such elements at the protocol stage is likely to increase the internal validity of the trial and also increase the chances of publication in a high impact journal that endorses the ICMJE requirement of reporting trials in accordance with the CONSORT statement.
Conform to accepted ethical standards: The Indian Council of Medical Research through its Bio-ethics initiative has developed ethical guidelines for the conduct of trials and for ethics committees. Clearance by local ethics committees is mandatory for all clinical trials and the CTRI hopes that making disclosure of ethical clearance a mandatory field for registration, it will lead to better links with the ICMR’s bio-ethics initiative.
Reporting of all relevant results of registered trials: The CTRI is working with the WHO ICTRP to ensure that results of all trials registered with the CTRI are adequately reported and publicly available.