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India – An attractive hub for clinical research

Advancement in medical sciences has benefited humanity in many ways. However, in the process of conducting clinical trials, incidences of scientific, moral, and ethical misconduct have been unearthed that have shaken up the scientific community and public. This led to the formation of a formal organization in 1979 by the United States (US) namely the “International Ethical Guidelines for Biomedical Research Involving Human Subjects” to protect and safeguard the interests of trial subjects. Following this, many countries drafted their own guidelines for Good Clinical Practices (GCP). However, with increasing number of clinical trials being conducted at sites in multiple countries, it was necessary to have a uniform guideline for conducting clinical trials. This gave rise to the International Conference on Harmonization (ICH)-GCP guidelines in 1996 with the objective of providing a uniform standard that facilitates the acceptance of clinical trial data by the regulatory authorities of the respective countries. Over the course of time, many countries adapted the ICH-GCP guidelines to frame their own guidelines. India too followed suit with the Indian Council of Medical Research (ICMR) introducing the “Ethical Guidelines for Biomedical Research on Human Subjects” that is continuously revised and amended to ensure that clinical trials are conducted with utmost quality, giving priority to the welfare of the subjects involved.1

India – A global destination

India is emerging to be a favorite destination for clinical trials for many international companies due to several factors:

☉ Conducive Regulatory Environment: Internationally harmonized and favorable regulatory processes such as fast track approval of investigational new drugs making the Indian clinical research environment more amenable to conducting clinical trial. Market trends show a compound annual growth rate (CAGR) of approximately 12% (US dollars 987 million) in the Indian clinical trials industry from US dollars 500 million in 2017.1,2,3,4,5

☉ Trained Manpower: Availability of skilled healthcare professionals who are specialists in different therapy areas, well-versed in the English language and who ensure compliance to ICH-GCP guidelines.1,2,3

☉ Technology Infrastructure: World-class technologies in data management and information technology and related services.1,2,3

☉ Patient Pool: Large population who are treatment naïve and have a diverse genetic and ethnic makeup. With India becoming increasingly urbanized and with greater connectivity between the urban and rural areas, it becomes convenient to recruit patients from different geographical areas. In addition, there is a high incidence and prevalence of acute and chronic diseases due to lifestyle changes leading to diseases such as diabetes, cancer, and so on. Such lifestyle-related disorders open up the possibility of conducting more clinical trials in these disease areas.1,2,3,6

☉ Ease of recruitment: In countries such as the US, approximately 86% of the clinical trials fail to recruit the required number of subjects leading to delay of almost a year. This delay costs the sponsor company several million dollars. Some of the reasons for delayed recruitment are unwillingness of patient to participate, stringent safety requirements, and hefty compensation packages. India provides the possibility of recruitment of patients with relative ease with due to increased trial compliance and transparency especially with the recent release of the New Drugs and Clinical Trial Rules 2019 that consists of updated rules and regulations for fast tracking approval of clinical trials. Among countries with fast growing economies, it has been noted that India has a growth rate in recruitment sites of approximately 22.6% with the highest growth rate seen in China (≈36%).1,2,7,8

☉ Competitive costs – Cost effectiveness is a pushing factor for many trials being shifted to India. The cost to develop a new drug is estimated to be almost 50% less than what would be required in the US or in the European Union. 1,2,3

Future of clinical research in India

Specific guidelines are being worked upon by the Central Drugs Standard Control Organization (CDSCO) for stem cell research, biosimilars, and medical devices to protect patients as well as to encourage clinical research and development in the country. After a lull period in the Indian clinical industry before 2015 due to ethical and quality concerns, open communication between sponsor representatives and the regulatory team of CDSCO has helped in reconsidering India once again as a potential global destination for enrolling a diverse population in clinical trials that adhere strictly to ICH-GCP guidelines.6

Sources

1. Das NK and Sil A. Evolution of Ethics in Clinical Research and Ethics Committee. Indian Journal of Dermatology. 2017 Jul-Aug;62(4):373-9

2.Burt T, Sharma P, Dhillon S et al. Clinical Research Environment in India: Challenges and Proposed Solutions. Journal of Clinical Research and Bioethics. 2014;5(6):1-8.

3.Bajpai V. Rise of Clinical Trials Industry in India: An Analysis. Hindawi Publishing Corporation. Review Article. ISRN Public Health. 2013:http://dx.doi.org/10.1155/2013/167059

4.Melissa Fassbender. India poised to become ‘one of the largest clinical trial hub’ says CRO. (2018). https://www.outsourcing-pharma.com/Article/2018/08/13/India-poised-to-become-one-of-the-largest-clinical-trial-hubs-says-CRO?utm_source=copyright&utm_medium=OnSite&utm_campaign=copyright Accessed on May 12, 2015.

5.https://www.medgadget.com/2019/01/india-cro-market-growing-at-an-impressive-cagr-of-12-by-2023-says-recent-study.html Accessed on May 12, 2015.

6.Reconsidering India as a Clinical Trial Location. Pharm-Olam. https://cdn2.hubspot.net/hubfs/4238150/PharmOlam_March2018/PDF/pharm-olam_india_clinical_trials_white_paper_1.pdf?t=1524594556831 Accessed on May 14, 2019.

7.Pathan IK, Nuthakki S, Chandu B et al. Present Scenario Of Clinical Trials In India. International Journal Of Research In Pharmacy And Chemistry. 2012;2(2):ISSN: 2231-2781

8.Luo J, Wu M, & Chen W. Geographical Distribution and Trends of Clinical Trial Recruitment Sites in Developing and Developed Countries. Journal of Health Informatics in Developing Countries. 2017;11(1). http://www.jhidc.org/index.php/jhidc/article/download/157/211

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While every attempt has been made to ensure that the information contained on this article has been obtained from reliable sources, Veeda Clinical Research is not responsible for any errors or omissions, or for the results obtained from the use of this information. All information on this article is provided “as is”, with no guarantee of completeness, accuracy, timeliness or of the results obtained from the use of this information, and without warranty of any kind, express or implied, including, but not limited to warranties of performance, merchantability and fitness for a particular purpose. Nothing herein shall to any extent substitute for the independent investigations and the sound technical and business judgment of the reader. In no event will Veeda Clinical Research, or its partners, employees or agents, be liable to the reader or anyone else for any decision made or action taken in reliance on the information on this article or for any consequential, special or similar damages, even if advised of the possibility of such damages. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, mechanical, electronic, photocopying, recording or otherwise without the prior written permission of the publisher.

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veedacr1 · 3 years ago

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Evolving Clinical Development Regulatory Framework in India

India is emerging as a country with tremendous potential to contribute to the national and international clinical trial platforms. The Central Drugs Standard Control Organization (CDSCO) is the national regulatory authority of India managed by the Drug Controller General of India (DCGI).1,2,3 The DCGI is responsible for the coordination of inspections of the sponsors, manufacturing units, as well as the trail sites.3

Early years in clinical development

In 2000, the Indian Council of Medical Research (ICMR) set up ethical guidelines for conducting biomedical research on human subjects.4 The year 2005 saw revision of Schedule Y of the Drug & Cosmetics acts, 1945, to align Indian regulatory laws to definitions and procedures that are internationally accepted. The changes included:

•Defining Phase I to Phase IV of a trial

•Demarcated responsibilities of sponsor(s) and investigator(s)

•Options to record any deviation or changes to the approved study protocol

India also signed the trade related intellectual property rights (TRIPS) agreement in 2005 in order to open up the prospects for conducting more clinical trials in India.5 Apart from harmonizing the regulatory acts to international standards, India quickly became a favorable destination for clinical trials as it offered:6

•English-speaking professionals in health care

•technical expertise

•growing economy

•world-class technology

•large, diverse, and treatment-naïve population

Set Back for clinical trials

Despite changes in the regulations, many multinational pharmaceutical companies took advantage of the large population that had either inadequate knowledge about clinical trials or were illiterate. In addition, an ill-defined health care system added to the challenges of monitoring unethical practices. This led to conducting clinical trials with little supervision and no recording of patient informed consent either in written or as audio/visual content. Patients were administered investigational drugs or devices without disclosing known serious adverse effects, some leading to death of the subjects. Moreover, no independent enquiry committee was set up to ascertain if the death of patient was related/not related to the investigational product or device.4

The years 2010 to 2013 saw a trying phase in the Indian clinical trial scenario due to the accumulated ill effects of conducting unethical trials. However, with a better regulatory framework in place, the Clinical Trial Registry of India (CTRI) has recorded a steady rise in the number of trials being conducted as seen in Figure 1. It was also observed that most of the trials were phase III trials.7

Figure 1 Clinical trial trends over the years8 📷

Figure 2 presents the state-wise distribution of trials in India between 2007 and 2015. Approximately, 3330 trails were registered during this period. It was observed that maximum number of trials was conducted in Maharashtra and the least number of trials was conducted in the Northeastern state. Among the Northeastern states, no trials were conducted in Nagaland.7

Figure 2 State-wise distribution of clinical trials in India (2007-2015 data)7📷

Revival of the clinical and regulatory scenario

In 2014, the CDSCO has constituted 12 new drug advisory committees (NDAC) and 25 subject expert committees (SECs). These committees have a number of experts from eminent government colleges and institutions to expedite the approval timelines of a clinical trial to 6-7 months. The three-tier process consists of:9

📷

However, only the SEC reviews global clinical trial applications and no further approval is required from the Technical committee or the Apex committee. Investigational new drug (IND) applications are also reviewed independently by the IND committee and do not require the approval of the Apex committee. A Technical committee comes into picture only if the SEC has rejected a sponsor’s application and the sponsor feels aggrieved by the decision. In such an event, if the Technical committee disagrees with the decision of the SEC, it has the power to overrule the decision of the SEC.10

In March 2019, the Ministry of Health and Family Welfare, India released the New Drugs and Clinical Trial Rules 2019 with the intention to fast track the approval for clinical trials, new drugs, bio-equivalence (BE), or bio-availability (BA) studies. These rules have also addressed any ambiguity that existed with respect to the regulation of Ethics committee (EC).11

Bridging the gap

The challenges of dealing with clinical trials are multi-faceted and involve abiding of the regulatory framework in a responsible and ethical way by stakeholders, government, and judicial system alike.

Patient safety and protection should be of utmost importance laying strict rules for:12

•informed consent by audio-visual recording and in a language that the patient is comfortable with

•respect for the patients cultural, social, economic, and educational background

•timely reporting of SAEs

New ground rules that can open up the possibility of expanding medical research in India are:13

•approval of proposals submitted to the DCGI within 30 days of application, if there is no communication from the DCGI

•fast tracking of domestic approvals

•pre and post submission meetings with the expert committee to bring in more transparency to the process and to set a well-defined timeline for trial completion

•trial compensation in case the investigational drug led to SAEs/death.

Proficient work force and state-of-art infrastructure also play an important role in attracting sponsor companies. Research has demonstrated that though Phase III trials are being conducted in a big way in India, Phase I trials seem to be limited to the sponsor country. This could be attributed to the Sponsor’s apprehension in procuring qualified work force and technology. To enable indigenous research to happen in India, it is pivotal to provide appropriate exposure or continuing medical education to personnel and access to up-to-date technology to be recognized as a country competent enough to conduct any phase trials.9

Equally important is the need for skilled health care workers to be available throughout the country to account for the uneven distribution of clinical trials across states. Concentrating a trial on a particular state could lead to biased conclusions and oversimplify or exaggerate a disease burden or condition. By providing access to people in all states to join a clinical trial, we not only minimize bias but also include diverse, ethnic populations.9

The future

With positive, patient-friendly, fast track, and transparent regulatory laws, India will continue to grow as an international hub for testing and developing innovative medicines and medical devices.

Sources

1.Evangeline L, Mounica NVN, Reddy VS et al. Regulatory process and ethics for clinical trials in India (CDSCO). The Pharma Innovation Journal. 2017;6(4):165-9. http://www.thepharmajournal.com/archives/2017/vol6issue4/PartC/6-4-4-176.pdf

2.Lahiry S, Sinha R, Choudhary S et al. Paradigm Shift in Clinical Trial Regulations in India. Indian Journal of Rheumatology. 2018;13:51-5.

3.Gogtay NJ, Ravi R, and Thatte UM. Regulatory requirements for clinical trials in India: What academicians need to know. Indian Journal of Anaesthesia. 2017 Mar;61(3):192-9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372399/

4.Ramu B, Kumar M S, and Ramakrishna N. Current Regulatory Scenario for Conducting Clinical Trials in India. Pharmaceutical Regulatory Affairs. Open Access. 2015;4:2. https://www.researchgate.net/publication/281765214_Current_Regulatory_Scenario_for_Conducting_Clinical_Trials_in_India

5.Burt T, Sharma P, Dhillon S et al. Clinical Research Environment in India: Challenges and Proposed Solutions. Journal of Clinical Research Bioethics. 2014;5:6. DOI: 10.4172/2155-9627.1000201

6.Chaturvedi M, Gogtay NJ, Thatte UM. Do clinical trials conducted in India match its healthcare needs? An audit of the Clinical Trials Registry of India. Perspectives in Clinical Research. 2017;8(4):172-5.

7.http://ctri.nic.in/Clinicaltrials/news/CTRI_Newsbulletin_July-Dec_2017.pdf Accessed on April 23, 2019.

8.Bhave A and Menon S. Regulatory environment for clinical research: Recent past and expected future. Perspectives in Clinical Research. 2017;8:11.6.

9.Key Highlights of New Drugs & Clinical Trial Rules, 2019. Accessed on April 23, 2019

10.Dan S, Karmakar S, Ghosh B et al. Digitization of Clinical Trials in India: A New Step by CDSCO towards Ensuring the Data Credibility and Patient Safety. Pharmaceutical Regulatory Affairs: Open Access. 2015;4(3): DOI: 10.4172/2167-7689.1000149.

11.https://www.thehindubusinessline.com/news/new-rules-sweeten-the-deal-for-clinical-trials-by-indian-pharma-cos/article26283499.ece Accessed on April 23, 2019.