1 Large Research and Medical Databases Clinical Trial Registry and National Medical Database : Indian Initiatives Dr. Vijay Kumar Scientist F and Head,

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Large Research and Medical Databases

Clinical Trial Registry and

National Medical Database

: Indian Initiatives

Dr. Vijay KumarScientist F and Head,

Division of Basic Medical SciencesIndian Council of Medical Research (ICMR)

New Delhi.

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Biomedical ResearchStrength India

1.5lac sub-centres, 23,000 primary health centres, 4000 community health centres 1,600 urban family welfare centres

Heterogeneous Population >1.2 billon Different Ethnic Groups Endogamous tribal population (conserved gene pool)

above 270 Medical Colleges > 400 Research Institutes > 370 Universities 11,500 hospitals and 14,000 diagnostic laboratories 50 R&D labs in the public sector & 200 in Govt. Sector

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Indian Council of Medical Research

(ICMR)

The apex body in India for the formulation, coordination and promotion of biomedical research under Department of Health Research, Ministry of Health and Family Welfare, Government of India

Established in 1911, as Indian Research Fund Association (IRFA)

Re-designated in 1949 as the Indian Council of Medical Research (ICMR) with considerably expanded scope of functions.

Intramural research is carried out through the Council's theme oriented 33 permanent research institutes/centers and including 6 regional centers addressing to regional health problems

Extramural research is done through center for advanced research, task force projects, ad hoc research schemes and fellowships in different universities, medical colleges in the country.

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The Mandate of ICMR

To undertake and support basic, epidemiological, applied and operational research in the areas of national public health importance using tools including those of modern biology.

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Fundamental Strategic Product development and evaluation

Operational Research

Communicable diseases

Non-communicable diseases

Reproductive health

Nutrition

Basic sciences

Medicinal plants, Traditional Medicine

Ethics, IPR, socio-behaviour sciences

Thrust Areas

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Clinical TrialRegulated under Schedule Y of Drugs and

Cosmetic Act 1940

Human clinical trials are conducted

To demonstrate the efficacy and safety of a new drug

To explore new indication, New route of administration New combination of old drugs.

Clinical trials form the basis for therapeutic decisions by all physicians, therefore, it is essential that they be able to evaluate the results and conclusions of such trials critically.

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New Drug DevelopmentClinical Evaluation-Good Clinical Practices

Phase I(Safety / tolerance) Pharmacokinetic-Healthy

volunteers/exceptions

Phase II(Efficacy and dose range studies conducted on

patients)

Phase III(Clinical trials on large number of patients)

Phase IV(Post marketing surveillance)

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Need for Clinical Trials Registry

Clinical trials hold enormous potential for benefiting patients, improving therapeutic regimens and ensuring advancement in medical practice that is evidence based. Unfortunately, the data and reports of various trials are often difficult to find and in some cases do not even exist as many trials abandoned or are not published due to "negative" or equivocal results. However, this tendency for availability of only selective information from the myriad clinical trials conducted is not commensurate with the practice of "evidence-based medicine“.Today, world over, a need has been felt on the imperative for transparency, accountability and accessibility in order to re-establish public trust in clinical trial data. And this would be feasible only if all clinical trials conducted are registered in a centralized clinical trials registry. Registration of trials will ensure transparency, accountability and accessibility of clinical trials

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Interactive workshop on Building and managing clinical trial capacity in India : Challenges in Ethics, Equity and Efficiency held on October 21-22, 2005

Recommendations

A registry for all Clinical trials should be created with multiple stakeholders be part of the design process of such a registry for it to be meaningful.

Such a registry should have a public and a confidential element. Some key items may need to be blocked from the public view (such as raw data pertaining to SAEs and proprietary information) but necessary for regulatory enforcement purposes and scientific research

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Clinical Trials Registry

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Clinical Trials Registry-India (CTRI) launched on 20th July,2007

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Clinical Trials Registry of India

The Clinical Trials Registry- India (CTRI), hosted at the ICMR’s National Institute of Medical Statistics (NIMS), 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). Moreover, Editors of Biomedical Journals of 11 major journals of India declared that only registered trials would be considered for publication1, 2.

Clinical Trials Registry of India

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.

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MissionEncourage all clinical trials to be prospectively registered before enrolment of first patientTo comply with ICMJE and WHO-ICTRP requirements

Vision To ensure that every clinical trial conducted in the region is prospectively registered with full disclosure of the trial data set items. While this register is meant primarily for trials conducted in India, the CTRI will also accept registration of trials conducted in other countries in the region, which do not have a Primary Registry of its own.

To improve transparencyTo improve internal validity of trials Conform to accepted ethical standards Reporting of all relevant results of registered trials

Mission and Vision

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To establish a public record system by registering all clinical trials on health products that are drugs, devices, vaccines, herbal drugs and made available to both public and healthcare professionals in an unbiased, scientific and timely manner

To create a more complete, authentic, and readily available data of all ongoing and completed clinical trials

Increase awareness and accountability of all the participants of the clinical trials and also for public access.

Objectives

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Web based access from any computer with internet connectivity

Scalable to cover more countries

Designed and developed on Open Technologies

Three levels of AccessUser (Authorized to submit Trials)Administrator (Responsible for administering

the Registry)Public (Facility to search information)

Features of Registry

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The information collected is available to the general public at no cost.

The Registry would be a searchable Primary register, which is to be linked to the WHO’s ICTRP.

Registration is voluntary

To register a study, trialists need to submit information on the Data Set items before enrolment of the first patient

Features of Registry

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All interventional clinical trials conducted in India and involving Indian participants need to be registered.

An interventional clinical trial is any research study that prospectively assigns people to one or more health-related interventions to evaluate their effects on health-related outcomes. Examples include but are not limited to:Preventive care, Drugs (including herbal), Surgical procedures, Behavioral treatments, Medical devices etc.

Thus, early and late trials, trials of marketed or non-marketed products, randomized or non-randomized trials -- all should be registered.

If in doubt about whether to register or not, registration is recommended.

Trial Registration Criteria

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Registration Data Set

UTRN WHO * CTRI No WHO * Trial Registration Date WHO * Title of study WHO * Scientific Title of Study WHO * Secondary IDs, if any WHO

Principal Investigator’s Name and Address Contact Person (Scientific Query) WHO

Contact Person (Public Query) WHO

Source/s of Monetary or Material SupportWHO

Primary Sponsor WHO

Secondary Sponsor WHO

Countries of Recruitment WHO

Site/s of study Name of Ethics Committee and approval

status* Regulatory Clearance obtained from DCGI*

Health Condition/Problem studied WHO

Study Type WHO

Intervention & Comparator agent WHO

Key inclusion /Exclusion Criteria WHO

Method of generating randomization sequence

Method of allocation concealment Blinding and masking Primary Outcome/s WHO

Secondary Outcome/s WHO

Target sample size WHO

Phase of Trial * Date of first enrollment WHO

Estimated duration of trial Status of Trial WHO * Brief Summary

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Some fields are mandatory for registration to proceed.All WHO fields [marked] need to be completed if the

trial is to receive a registration number and fulfill WHO/ICMJE requirements.

Both date of submission and date of registration are recorded.

Trialists are encouraged to include subsequent protocol amendments and give regular updates on the status of trial.

All amendments and original entries will be recorded (audit trail)

Trial Registration Requirements

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Voluntary – ensuring compliance

Improving quality of clinical trials

Scaling up

Sustainability

Challenges

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www.ctri.in

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National Medical Research Database

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Clinical Research Database

A Clinical Research Database is a tool used as part of the data collection process.

A database allows you to store your research data collected in the field in an organized fashion so that it can be easily analyzed in statistical programs.

The steps involve the initial process of collecting corresponding clinical information in a database

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National Medical Research Database ICMR initiative : Commissioning National Centre for Disease

Informatics (NCDIR), Bangalore in March 2011

The new centre was the outcome of the sustained and successful run of the National Cancer Registry Programme since December 1981.

The main objective of the NCDIR is To sustain and develop a national research data-base on

cancer, diabetes, CVD and stroke

through recent advances in electronic information technology with a national collaborative network, so as to undertake aetiological, epidemiological, clinical and control research in these areas.

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National Centre for Disease Informatics (NCDIR)

Current thrust areas of NCDIR: Cancer Registries - National Cancer Registry Programme

(NCRP) Patterns of Cancer Patient Care and Survival Development of Software Applications Programmes The NCRP, as of now, has a network of - 27 population based, - 9 hospital based cancer registries and - 17 centres collaborating in the study on

Patterns of Care and Survival Studies

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National Centre for Disease Informatics (NCDIR)

Major achievements Collection of disease data in a systematic way providing actual

incidence (not estimates) as per international standards and quoted. Sustained programme for over 25 years providing valid estimates of the

burden and patterns of cancer. The cancer atlas project helped map patterns of cancer in a cost effective

way using recent advances in Electronic Information Technology. This gave a new concept in data collection and broadened the field of

disease informatics. It identified many researchable areas; motivated pathologists and

clinical oncologists across country to collaborate and participate in cancer research; with minimum effort provided critical base line information at district level.

Finally it opened the entire North Eastern states for cancer registration and research

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Other contributions of NCDIR

Overall the contributions of the NCRP are the following: Towards Epidemiological and other Research Identification of geographic areas for site specific

research; Identification of variation in sites of tobacco related

cancers vis-à-vis geographic areas; laid a foundation for studies in molecular epidemiology

Towards Cancer Control Identified especially through the cancer atlas different

sites for priority towards cancer control; Provide an idea of the magnitude and trends over time

in different sites of cancer; Provided information for doing evidence based cancer

control activities through specific indicators.

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Other contributions of NCDIR

Towards Patient Care Identification of deficiencies in cancer patient care in

the Indian setting in terms of standardised recording of clinical information, compliance to treatment and follow-up;

Identification of proportion of patients presenting at late stage;

Laid a framework towards clinical evaluation and multi-centric trials.

The NCRP through its network of cancer registries has several national and international publications in Descriptive and Analytical Epidemiology that are of national relevance and importance.

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Creation of Genetic disease registry, DNA banking and EBV transformed cell lines from informative families of rare genetic disorders” at Department of Medical Genetics, SGPGI, Lucknow

Under this project DNA samples of 3531 individuals have been collected and DNA has been / is being extracted and stored at - 800 C.

This includes samples from 1299 probands with various genetic disorders and clinical presentations with possibly genetic etiology.

The number of samples from family members of the patients with genetic disorders is 1392. The clinical data including clinical presentation and detailed investigation reports is stored.

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Ethics provisions adopted

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Ethical Guidelines on Biomedical Research (1980/2000/2006)

Modifications Ethics committee review

procedures Informed consent – re-consent

, vulnerable populations & waiver

Post – trial access Disaster & emergency

research Clinical research including

herbal/traditional drugs Stored tissue research Stem cell research

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Ethical Guidelines on Biomedical Research on Human Participants 2006

General StatementMedical and related research using human beings as research participants must necessarily ensure that –

(i) The PURPOSE, of such research is that it should be directed towards:

The increase of knowledge about the human condition in relation to its social and natural environment

Mindful that the human species is one of the many species in a planet in which the well being of all species is under threat,

No less from the human species as any other, and that such research is for the betterment of all,

Especially the least advantaged.

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Ethical Guidelines on Biomedical Research on Human Participants 2006

(ii) Such research is CONDUCTED under conditions thatNo person or persons become a mere means for the betterment of others and that human beings who are subject 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; and After ensuring that the participant is placed at no greater risk other than such risk commensurate with the well being of the participant in question in the light of the object to be achieved.

Such research must be subjected to a regime of EVALUATION at all stages of the proposal i.e. research design and experimentation, declaration of results and use of results thereof.

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Ethical Guidelines on Biomedical Research on Human Participants 2006

These 12 principles laid down under Statement on General Principles are common to all areas of biomedical research

Essentiality Voluntariness, informed

consent and community agreement

Non-exploitation Privacy and

confidentiality Precaution and risk

minimisation Professional competence

Accountability and transparency

Maximisation of the public interest

Institutional arrangements

Public domain Totality of

responsibility Compliance

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Ethical Guidelines on Biomedical Research on Human Participants 2006

Principles of privacy and confidentiality whereby the identity and records of the human participants of the research or experiment are as far as possible kept confidential; -and that no details about identity of said human participants which would result in the disclosure of their identity, are disclosed without valid scientific and legal reasons which may be essential for the purposes of therapeutics or other interventions, without the specific consent in writing of the human participant concerned, or someone authorised on their behalf; -and after ensuring that the said human participant does not suffer from any form of hardship, discrimination or stigmatisation as a consequence of having participated in the research or experiment

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Ethical Guidelines on Biomedical Research on Human Participants 2006

Principles of accountability and transparency whereby the research or experiment will be conducted in a fair, honest, impartial and transparent manner after full disclosure is made by those associated with the research or experiment of each aspect of their interest in the research, and any conflict of interest that may exist; and whereby, subject to the principles of privacy and confidentiality and the rights of the researcher, full and complete records of the research inclusive of data and notes are retained for such reasonable period as may be prescribed or considered necessary for the purposes of post-research monitoring, evaluation of the research, conducting further research (whether by the initial or otherwise) and in order to make such records available for scrutiny by the appropriate legal and administrative authority, if necessary

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Ethical Guidelines on Biomedical Research on Human Participants 2006

Principles of public domain whereby the research and any further research, experimentation or evaluation in response to, and emanating from such research is brought into the public domain so that its results are generally made known through scientific and other publications subject to such rights as are available to the researcher and those associated with the research under the law in force at that time.

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Specific Principles

Clinical Trials of Drugs, Devices, Vaccines, Diagnostic agents, Herbal Drugs : Approval of DCGI is required.

Epidemiological Studies Human Genetics Research Transplantation Research

including Fetal tissue transplantation

Assisted Reproductive Technologies

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Expectation

All institutions in the country which carry out any form of biomedical research involving human beings should follow these guidelines in letter and spirit to protect safety and well being of all individuals.

Guidelines available at : http://www.icmr.nic.in

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References

Pandey A, Aggarwal AR, Seth SD, Maulik, M, Bano R. Juneja A. Clinical Trials Registry � India: Redefining the conduct of clinical trials. Indian J Cancer 2008; 45 (3): 79-82.

Pandey A, Aggarwal A, Maulik, M, Seth SD. Clinical trial registration gains momentum in India. Indian J Med Res [Letter to Editor] 2009; 130: 85-86.

Pandey A, Aggarwal AR, Seth SD, Maulik, M. Clinical Trials Registry � India: Raising the veil. Natl Med J India [Letter to Editor]2010; 23 (3):187 -188.

Schulz KF, Chalmers I, Hayes RJ, Altman D. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled clinical trials. JAMA 1995; 273:408-12.

J�ni P, Altman DG, Egger M. Assessing the quality of controlled clinical trials. BMJ 2001; 323: 42-6.

Altman DG, Schulz KF, Moher D for the CONSORT Group. The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med 2001; 134: 663-94.

International Committee of Medical Journal Editors (ICMJE). Uniform Requirements for Manuscripts Submitted to Biomedical Journals. Available at http://www.icmje.org.

Indian Council of Medical Research. Ethical Guidelines for Biomedical Research on Human Subjects. New Delhi: Indian Council of Medical Research, 2000, 2006.

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Acknowledgement

Dr. Arvind Pandey, Scientist G and Director, National Institute of Medical Statistics, New Delhi. India

Dr. Nanda Kumar, Scientist G and Director –in-Charge, National Centre for Disease Informatics (NCDIR), Bangalore. India

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THANK YOU