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 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 a revision of Schedule Y of the Drug & Cosmetics act, 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 healthcare 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 the death of the subjects. Moreover, no independent enquiry committee was set up to ascertain if the death of the 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 years

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 the 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 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 the 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 the Ethics committee (EC).¹¹

Highlights of the New Drugs and Clinical Trial Rules, 201911	Updated rules and regulations11
Approval timeline for clinical trials	90 working days from receipt of an application for drugs discovered outside India and 30 working days for new drugs or IND in India
Manufacturing of new drugs or IND, BE & BA studies or test analysis or examination	Permission is required from the Central Licensing Authority (CLA)
Waiver of local clinical trials	· If CLA has approved the marketing of the new drug in other countries or has granted permission to conduct global clinical trials for the new drug in India · No evidence of a difference in metabolism, safety, or efficacy owing to the difference in the genetic profile of the Indian population
Period of validity of a clinical trial	2 years from the date of issue by CLA
Post-trial access to IND or new drug	In unique circumstances, the drug is to be distributed free of cost to trial subjects per the direction of CLA, but no liability lies with the sponsor for the use of the drug after trial.
Pre-submission and post-submission meetings	To seek guidance with respect to law and procedures that governs the process of manufacturing and licensing or granting permission.
Approval for trials conducted by EC and registration of EC	· Approval to be obtained from the EC of another trial site if a trial site does not have an EC, and the EC should be within 50 km of the trial site.· CLA-approved registration of EC remains valid for five years from the date of issue.
Conditions to be fulfilled for the conduct of a clinical trial	· Submission of status report on a quarterly basis or depending on the duration of the trial to track subject enrolment· Online reporting of the status of the clinical trial every six months via the SUGHAM portal to know if the trial is ongoing or completed or has been terminated.
Fee for procuring a license, certificate of registration, and permission for trial	Different fee structures depending upon the purpose of the trial. Fee ranging from INR 50,000 to 5,00,000.

Bridging the Gap

The challenges of dealing with clinical trials are multi-faceted and involve abiding by 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 patient’s 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 workforce 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 a qualified workforce 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 healthcare 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.

Disclaimer:

The information contained in this article is intended solely to provide general guidance on matters of interest for the personal use of the reader, who accepts full responsibility for its use. Accordingly, the information in this article is provided with the understanding that the author(s) and publisher(s) are not herein engaged in rendering professional advice or services.

As such, it should not be used as a substitute for consultation with a competent adviser. Before making any decision or taking any action, the reader should always consult a professional adviser relating to the relevant article posting.

While every attempt has been made to ensure that the information contained in 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 in 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 in this article or for any consequential, special, or similar damages, even if advised of the possibility of such damages.

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Phone: +91-79-3001-3000
Fax: +91-79-3001-3010
Email: info@veedacr.com

Introduction

With patents expiring for many successful biologic drugs, researchers are focusing on developing drugs that are competitive in pricing and affordable to patients who require critical medications for managing chronic diseases.

A biosimilars medicinal product is a replica of the innovator medicinal product with similar safety and efficacy profiles.^1,2. Some of the popular biosimilars are monoclonal antibodies biosimilars for cancer therapeutics, erythropoietin biosimilars, insulin biosimilars, interferon biosimilars, granulocyte colony-stimulating factor biosimilars, and human growth hormone biosimilars.

Small Molecules Versus Large Molecules

Small molecules are chemically synthesized and are simple, well-defined molecules. They can be characterized fully and have highly predictable functions.

On the other hand, biologics are large molecules that are protein-based and synthesized from highly complex biological sources. As living systems are used in the manufacturing of biologics, the process requires sound technological expertise.

Despite large molecules posing problems such as extreme sensitivity to process and handling as well as immunogenicity, their proven efficacy and precision in targeted therapy is making biologics popular in the treatment of many non-communicable and chronic diseases such as blood disorders, cancer, inflammatory diseases, and diabetes.⁴

Current Scenario of Biosimilars

Approximately 32 biologics will lose patent rights by the year 2019, the combined sales of which are estimated to be around $ 51 billion.⁶ However, developing biologics is a tedious and complicated process, with many of the products taking approximately 10 to 15 years to come into the market.⁷

Studies have indicated that the market will continue to grow at a rate greater than 20% due an to increase in the incidence of chronic conditions leading to increased utilization of biologics.

Patent expiration of a number of best-selling biologicals opens the door for the approval of biosimilar versions of the original products. These biosimilars are usually 20-30% cheaper than the innovator product. The European Union (EU) has approved more than 20 biosimilars since they provided their consent to use the first biosimilar, somatropin, in 2006.¹⁰

It is anticipated that the global biosimilars market will cross $35 billion by the year 2025 with a compound annual growth rate (CAGR) of 33%.

Challenges in Developing Biosimilars

➔ Difference in Regulatory Approval Processes Between Countries:

In the EU, the interchangeability of biosimilars does not require additional regulatory evaluation if the biosimilars demonstrate similar activity as the original product with no additional risk to the patient.

However, this is not acceptable by the US regulatory body that mandates complex and costly trials to demonstrate the interchangeability of biosimilars.

In addition, USFDA limits the use of extrapolation of data. The additional regulatory requirement not only increases the timeline for biosimilars development but also increases the cost and impedes the manufacturer’s enthusiasm in pursuing biosimilars in the long run.^3,13,14

➔ Development and Timelines Challenges:

It is estimated that the cost of developing biosimilars can go up to $ 100 million with a development time of 5-9 years, excluding the cost of failure.15 The Pharmaceutical Research and Manufacturers of America (PhRMA) estimated the cost of developing a biosimilar to be approximately $ 375 million as compared to $1.2 billion to develop a new biologic.

However, the development timelines for biosimilars are relatively shorter than that of biologics. The Phase I and Phase III stages for biosimilars can be shortened, while the phase II stage can be skipped due to the established therapeutic efficacy and safety of the biologic.¹⁶

➔ Clinical Challenges:

Immunogenicity is a potential risk with biosimilars. Hence, stringent risk management plans and post-marketing surveillance of the drug should be in place to monitor any adverse events.^13,17

Another challenge is patient acceptance of biosimilars due to limited knowledge or awareness about such products. Concerted efforts have to be made to ensure that the patient understands the basic principles of biosimilars and their ability to exert therapeutic efficacy at much lower costs than their biological counterparts.¹⁸

➔ Analytical Challenges:

The physiochemical and structural comparability of biosimilars with the original product is difficult due to their inherent heterogeneity. Analytic techniques such as mass spectroscopy, chromatography, or electrophoresis can be used to address some of the hurdles by: ^13,17,19

☉ Comparing biosimilars lots against a reference product to assess the pharmacokinetics and pharmacodynamics of the biosimilars.
☉ Understanding multiple mechanisms of actions involved by in vitro characterization
☉ Choosing of bioassay should be a case-by-case decision depending upon the specificity and sensitivity of the biosimilars.

➔ Commercialization and Marketing Challenges:

Major pharmaceutical companies sometimes block other small players from producing biosimilars by creating restricted distribution agreements leading to the unavailability of the innovator product sample.

In addition, patents are abused to prolong the monopoly of a brand name, thereby delaying patient access to more affordable and life-saving biosimilars.¹³

➔ Establishing Concrete Guidelines for Market Approval:

The USFDA and regulatory bodies of other countries are yet to establish streamlined guidelines for marketing approval of biosimilars.^3,13,14

The Way Forward

➔ Biosimilars manufacturers can promote optimization by:⁵
☉ Building trust and confidence between the payers and providers by reimbursement for biosimilars and providing cost-saving alternative solutions for long-term treatment.
☉ Engage with the regulatory authorities during the early stages of the development of biosimilars to capture their interest.

➔ Enabling extrapolation of data by regulatory authorities of the country is one of the crucial steps that can push the development of biosimilars. This, in turn, helps establish fair market trade.⁵

➔ Contract research organizations (CROs) can lend expertise to sponsor companies:²⁰
☉ To develop a holistic, tailor-made, and optimal clinical development plan (CDP) without losing focus on the commercial aspect of the business

☉ By using therapeutic and regulatory expertise, real-world data, and market access strategies to influence access to biosimilars and to establish competitive pricing.

➔ By forging strategic global alliances and enhancing their expertise in biosimilars development.

Conclusion

Advanced manufacturing processes, limiting of patent litigations, and change in physicians’ and patients’ perception towards biosimilars can mitigate the current level of complexity and ambiguity involved in promoting biosimilars.¹⁰ 

In addition, the overall cost of biosimilars can also be reduced by involving more number of players, these measures will allow for safer and wider access of biosimilars products to patients around the globe.

Sources

• 1. Weise M, Bielsky MC, De Smet K et al. Biosimilars—why terminology matters. Nature Biotechnology. 2011 Aug;29:690-3. https://www.nature.com/articles/nbt.1936
• 2. https://bioprocessintl.com/manufacturing/biosimilarss/opportunities-challenges-biosimilars-development/ Accessed on March 13, 2019.
• 3.Rozek RP. Economic Aspects of Small and Large Molecule Pharmaceutical Technologies. Advances in Economics and Business. 2013;1(3): 258-69.
• 4.CN Chan J and TC Chan A. Biologics and biosimilars: what, why, and how? ESMO Open. BMJ Journals. 2017;2(1):e000180.
• 5.Oo Charles and Kalbag SS. Leveraging the attributes of biologics and small molecules, and releasing the bottlenecks: a new wave of revolution in drug development. Expert Review of Clinical Pharmacology. 2016 Mar;9(6):747-9.
• 6.Blackstone EAn and Joseph JR PF. The Economics of Biosimilars. Am Health Drug Benefits. 2013 Sep-Oct; 6(8): 469–478. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031732/
• 7.Blackstone EA and Joseph JR PF. Biologics and Biosimilars. The possibility of encouraging innovation and competition. The SciTech Lawyer. American Bar Association. 2015;11(3).https://pdfs.semanticscholar.org/bf63/c072c5019dbb294f85c8f865adbcc0bd698a.pdf

• 8.Bressler B and Dingermann T. Establishing a new marketplace for biologic therapy with biosimilar agents: importance of extrapolation of data. Biosimilars. 2015;5:41-8.
• 9.http://www.gabionline.net/Biosimilarss/General/US-67-billion-worth-of-biosimilars-patents-expiring-before-2020 Accessed on March 13, 2019.
• 10.Gupta SK, Chaudhari P, and Nath R. Opportunities and Challenges in Biosimilars Development. Bioproces international. https://bioprocessintl.com/manufacturing/biosimilarss/opportunities-challenges-biosimilars-development/ Accessed on March 13, 2019.
• 11.https://www.variantmarketresearch.com/report-categories/pharmaceuticals/biosimilarss-market Accessed on March13, 2019.
• 12.http://www.mabxience.com/products/biosimilars/global-biosimilars-market/ Accessed on March 13, 2019.
• 13.Breaking through on biosimilars. The Biosimilars Council. http://biosimilarsscouncil.org/wp-content/uploads/2018/05/Breaking-Through-on-Biosimilarss-Biosimilarss-Council-White-Paper.pdf Accessed on March 13, 2019.
• 14.Misra M. Biosimilars: Current perspectives and future implications. Indian Journal of Pharmacology. 2012 Jan-Feb;44(1):12-4.
• 15.https://www.pfizerbiosimilarss.com/biosimilarss-development Accessed on March 13, 2019.
• 16.http://www.pharmtech.com/clinical-and-cost-considerations-developing-biosimilars Accessed on March 13, 2019.
• 17.Cai XY, Wake A, and Gouty D. Analytical and bioanalytical assay challenges to support comparability studies for biosimilar drug development. Bioanalysis 2013 Feb;5(5). https://www.future-science.com/doi/full/10.4155/bio.13.1
• 18.http://ascopubs.org/doi/full/10.1200/JOP.2017.025734?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed Accessed on March 13, 2019.
• 19.https://www.biosimilarsdevelopment.com/doc/analytical-challenges-in-biosimilars-development-0001 Accessed on March 13, 2019.
• 20.https://www.iqvia.com/-/media/library/white-papers/integrated-approach-to-biosimilars-dev-and-commerc.pdf?la=en Accessed on March 13, 2019.

Disclaimer:

The information contained on this article is intended solely to provide general guidance on matters of interest for the personal use of the reader, who accepts full responsibility for its use. Accordingly, the information on this article is provided with the understanding that the author(s) and publisher(s) are not herein engaged in rendering professional advice or services.

As such, it should not be used as a substitute for consultation with a competent adviser. Before making any decision or taking any action, the reader should always consult a professional adviser relating to the relevant article posting.

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.

For information, contact us at:

Veeda Clinical Research Private Limited

Vedant Complex, Beside YMCA Club, S. G. Highway,
Vejalpur, Ahmedabad – 380 051,
Gujarat India.
Phone: +91-79-3001-3000
Fax: +91-79-3001-3010
Email: info@veedacr.com