Many respiratory diseases have been historically treated using inhalation drugs as this route of administration allows for a higher drug concentration to reach the target organ thereby reducing systemic effects. Apart from respiratory disorders, trials are ongoing to determine the efficacy of inhaled insulin in diabetes management.1,2 Although pulmonary delivery of insulin is a valuable option with the advantage of ease of administration compared to injections, further research is ongoing to study its safety through the oral route.1,2

An ideal inhalation device is the one that delivers a reproducible and fixed dose of the drug to the lung, is patient-friendly, and not cumbersome. The commonly prescribed inhalation devices are pressurized metered-dose inhalers (MDIs), nebulizers, and dry-powder inhalers. All inhalation devices undergo stringent invivo and invitro testing to determine the safety and efficacy of the drug through these devices.3 However, inhalation clinical trials bring forth a number of challenges.

Device-drug compatibility

There are hiccups that investigators and sponsors face while conducting inhalation trials such as the need to use cumbersome and costly devices as well as the probability of bronchospasm due to the drug or non-drug component(s). In addition, some inhalation drugs can cause withdrawal symptoms. Other factors that influences the trial results are the difference in drug bioavailability in each patient due to varied breathing patterns or the presence of a comorbidity that affects drug absorption. For instance, epoprostenol has a short half-life of 3 to 5 minutes requiring continuous nebulization for long periods making it difficult to administer or prescribe on a long-term basis.3

Safety issues

A number of inhalation trials were terminated in the initial phases due to issues such as poor drug solubility and bioavailability leading to dangerous levels of undissolved drug in the systemic circulation.4

Patient training and adaptability

For effective therapy, the patient should be able to use the device correctly. Inhalation drugs and devices are viewed as complex by many patients and thus would require practical demonstration as well as repeated follow-up by medical staff to ensure that the patient is using the device as intended for optimal drug delivery. The patient should also be encouraged to use e-technologies that help in self-monitoring to look out for symptoms that may require medical intervention and help raise awareness about the respiratory disease.5 many studies have observed that inappropriate use of inhalers is a cause for improper management of respiratory diseases. A study in a university hospital in Northwest Ethiopia by Mebrahtom M et al demonstrated that approximately 71% of the subjects were handling inhalation devices incorrectly due to lack of awareness about MDIs consequently leading to poor asthma control.6 Another study by Arora P et al reported approximately 95% error in subjects using MDI and approximately 82% error in subjects using dry powder inhalers.7

Regulatory laws in India

There are no specific regulatory guidelines laid down by the legislative body, Central Drugs Standard Control Organization (CDSCO) and Drug Controller General of India (DCGI) for inhaled products. As applicable to all trials in India, inhalation clinical trials should also adhere to Schedule Y and Rule 122A to E of the Drugs and Cosmetics Act, 1945, Good Clinical Practices (GCP), and ethical guidelines for biomedical research on human subjects. The guidelines followed for bioavailability and bioequivalence studies are also applied to inhalation trials. However, bioequivalence studies for inhaled drugs are still in its nascent stages in India. Although pharmacokinetic (PK) bioequivalence studies alone are being accepted worldwide to establish equivalence of inhalation products, India is yet to approve second entry orally inhaled drugs with data from PK bioequivalence studies alone.8

Creating a conducive environment for inhalation clinical trials

To build India’s competence in inhalation trials, the recruited staff should have expertise in handling phase I/bioequivalence studies. The DCGI and CDSCO can also come up with specific study timelines as well as suggest appropriate study designs for inhalation trials in consultation with the technical committee. As the comparison of clinical efficacy endpoints between two orally inhaled products provides shallow dose response curves, equal weightage should be given to invitro bioequivalence assessments.8

Emphasis cannot be laid enough about the need for the investigator to share all medical decisions with the patient to improve patient compliance rates in clinical trials.5 Human factor (HF) studies can be designed to include strategies that mitigate errors caused due to improper device use. HF studies also help in understanding the effect of interaction between the patient and device on the safety and efficacy of the inhalation drug. HF studies are gradually showing their presence globally especially in clinical trials that involve the use of devices.9

With companies increasingly seeking alternative solutions, the route of inhalation delivery will continue to grow. This makes it critical for the scientific community to fill the existing gaps for conducting successful inhalation trials.

Sources

1.Cavaiola TS and Edelman S. Inhaled Insulin: A Breath of Fresh Air? A Review of Inhaled Insulin. Clinical Therapeutics. 2014;36(8):1275-89.

2.Oleck J, Kassam S, and Goldman JD. Commentary: Why Was Inhaled Insulin a Failure in the Market. Diabetes Spectrum. American Diabetes Association. 2016;29(3):180-4. https://doi.org/10.2337/diaspect.29.3.180

3.Holgate ST, Bousquet J, Chung KF et al. Summary of recommendations for the design of clinical trials and the registration of drugs used in the treatment of asthma. Respiratory Medicine, 2004;98(6):479–487.

4.Forbes B, O’Lone R, Allen PP et al. Challenges for inhaled drug discovery and development: Induced alveolar macrophage responses. Advanced Drug Delivery Reviews. 2014;71:15-33.

5.Shakshuki A and Agu RU. Improving the Efficiency of Respiratory Drug Delivery: A Review of Current Treatment Trends and Future Strategies for Asthma and Chronic Obstructive Pulmonary Disease. Pulmonary therapy. 2017;3:267-81.

6.Mebrahtom M, Mesfin N, Gebreyesus H et al. Status of metered dose inhaler technique among patients with asthma and its effect on asthma control in Northwest Ethiopia. BMC research notes. 2019;12:15.

7.Arora P, Kumar L, Vohra V et al. Evaluating the technique of using inhalation device in COPD and bronchial asthma patients. Respiratory Medicine. 2014;108(7):992-8.

8.Lee SL, Saluja B, Garcia-Arieta A et al. Regulatory Considerations for Approval of Generic Inhalation Drug Products in the US, EU, Brazil, China, and India. AAPS Journal. 2015;17(5):1285-1304.

9.Vaidya A. Learnings and Challenges of Conducting Human Factors Studies on Inhaler Devices. Clinical Trials Arena. 2017.https://www.clinicaltrialsarena.com/news/case-study-learnings-and-challenges-of-conducting-human-factor-studies-on-inhaler-devices-5852797-2/ Accessed on June 21st, 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.

In the clinical research industry, safety norms and processes should be applied to every aspect, starting from drug development to post-marketing use of approved drugs, keep in mind patient safety and data credibility at every stage of clinical development.

Patient safety requires collaborative effort of the regulatory system, healthcare system, and the sponsor. Equally important is the need for effective communication to patients by the regulatory bodies and health care systems to maintain transparency. Such communication also help in instilling confidence in patients about the scientific credibility of the trial. For instance, the Central Drugs Standard Control Organization (CDSCO), India uses information technology to keep the public aware about ongoing and completed trials. All data starting from filing of application to the trial results are available on the website. Sponsors, clinical research organizations, as well as ethics committees are required to furnish their details on the website. Data safety and monitoring boards (DSMB) are also formed to monitor trials, especially large trials, for safety and reliability of data. DSMBs play a significant role in letting the public know if the investigational drug poses any threat as well as to ensure that the sponsor does not purport the results to be unbelievably beneficial to the targeted patient population.

Emphasis should also be laid on novel and practical-oriented training programs for students in the health care profession to expose them to real-world situations. Students should understand the importance of having risk assessment, risk management, and risk mitigation plans in place to improve patient safety. Periodic assessment and continuing medical education programs for medical professionals are also pivotal in ensuring that they remain competent in their respective fields and prioritize patient safety and moral ethics in their profession.
The successful implementation of patient safety and data integrity is a multidisciplinary approach that requires sincere and diligent effort of each individual and organization involved in the conduct of clinical trials.

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.

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Phone: +91-79-3001-3000
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India is rapidly gaining acceptance globally as the go-to destination for clinical research. The country offers the advantages of having experienced personnel, good infrastructure such as well-equipped hospitals and laboratories, and a diverse patient pool. Moreover, the increase in life expectancy rate to 65 years and above gives rise to a host of lifestyle diseases such as diabetes, hypertension, neurodegenerative diseases and more, paving way for many multinational pharmaceutical companies to invest in clinical trials in India. Apart from this, cost effectiveness is an important factor that drives outsourcing of clinical trials to India.

The recent amendment made by the Ministry of Health and Family Welfare, Government of India, to the regulatory laws (New Drugs and Clinical Trials Rules, 2019) was with the aim of increasing the percentage of clinical trials conducted in India that hit an all-time low in the period between 2011 and 2013. In a bid to streamline approval processes, well-defined timelines have been introduced. The new rules have shortened the approval timeline for clinical trials of drugs manufactured outside India to 90 days. For drugs manufactured in India, the clinical approval timeline is 30 days. Pre-submission and post-submission meetings between the sponsor and the Drugs Controller General of India (DCGI) are attempts to increase transparency in all dealings related to the clinical trial. In addition, the non-refundability clause of the compensation package was removed as this was seen as a major deterrent for international companies, especially if a death/injury was proved to be unrelated to the trial at later stages. Apart from clinical trials, there has been a boom in the field of data management and medical writing with a number of homegrown clinical research organizations (CROs) demonstrating expertise to handle end-to-end services for sponsor companies.

Last but not the least, concerted efforts and joint participation of the Indian government and Indian pharmaceutical companies in policy-making decisions and prioritization of patient’s safety and health will build confidence in international companies about India’s capability in contributing to the clinical research industry.

Shaping of a Regulatory Framework Specific to the Indian Clinical Market

As India emerges as one of the leaders in the production of generic pharmaceuticals, contributing to approximately 20% of the global market¹, it is necessary to have regulatory authorities approve of more number of drugs or clinical trials to address the burden of diseases prevalent in India.

However, to safeguard public health, it is equally important to ensure that national and international pharmaceutical companies comply with stringent regulatory processes laid down for the approval of drugs.

Changes in the Indian Regulatory Scenario

Revision of Schedule Y of the Drugs and Cosmetics act 1945 in 2005 helped in aligning the Indian regulatory framework with internationally accepted definitions and procedures.

In addition, the Indian Good Clinical Practices (GCP) guidelines that were drafted by the expert committee of the Central Drugs Standard Control Organization (CDSCO) helped in ensuring uniformity in the conduct and quality of clinical research across the country.

With the recent introduction of the New Drugs and Clinical Trial Rules by the Ministry of Health and Family Welfare of India in 2019, the government is focusing on fast-tracking the approval of new drugs with equal weightage given to bio-equivalence or bioavailability studies.2

The government has also ensured further strengthening of the regulatory sector by allocating a higher budget of approximately 65 million US dollars at the central and state level.

This has helped in improving the infrastructure, such as setting up of an E-governance portal (SUGHAM) to bring in transparency, accountability, and ease of business.

A good initiative by the CDSCO was the setting up of a pharmacovigilance program in 2010 to have robust systems in place for adverse event reporting.1

The New Regulatory Rules

Some of the regulatory rules that have become effective following the New Drugs and Clinical Trials Rules 2019 are:

• Timelines have been revised for approval of global clinical trial applications to 90 days and 30 days for domestic trials from the previous duration of 6 months.³
• Phase III clinical trials are not required for any new drugs that have been approved for sale in the United States, Canada, Australia, or the United Kingdom.³
• Post-marketing surveillance studies are to be conducted in India to monitor for idiosyncrasies or unexpected adverse events.³
• Orphan drugs have been exempted from phase III and phase IV clinical trials.³
• Participant has access to free drug post-trial if no suitable alternative is available in the market. However, the Sponsor would not be responsible for any complications that occur post the study duration.⁴
• The approval obtained for a clinical trial is valid for 2 years.⁴
• Compensation for death/injury/disability that is related to the trial will be decided by the Drug Controller General of India (DCGI).⁴

 Conclusion

To head towards India’s goal of becoming a competent clinical trial destination, it is important to not only speed up the approval of drugs or clinical trials but also to keep allegiance to the Ethics committee and to the Indian Council of Medical Research’s (ICMR) National Ethical Guidelines for Biomedical and Health Research involving Human Participants, to prevent exploitation of trial participants.⁵ 

Transparency in the drug approval process, and stringent laws with penalties for unethical conduct of trials can become game changers with respect to maintaining high standards of quality for drugs and reliability of data from clinical trials.

The regulatory environment can also see an improvement in the implementation of regulatory laws by increasing the number of skilled staff such as drug inspectors, regulatory specialists, and so on. Equal emphasis should be laid on standard operating procedures (SOPs) and updating guidance documents to help staff understand the current regulatory environment.

Exchange programs with other countries that have sound regulatory processes can be beneficial for the Indian regulatory personnel to appreciate the importance of a well-defined regulatory framework and how some aspects can be practically implemented in the Indian regulatory environment.⁶

Of utmost priority should be a patient’s safety and rights. Having a representative from patient advocacy groups in important decision-making meetings held by the DCGI allows for a patient-centric approach with respect to the review of policies and laws.⁶

To conclude, high-quality drugs and ethical clinical trials are the joint responsibility of sponsors, clinical investigators, and regulatory bodies. Periodically updating the Indian regulations can address loopholes and instill confidence in international pharmaceutical companies to continue investing in India. This will, in turn, propel India’s economic growth.

Sources

1. Medicines regulation. Regulatory systems in India. WHO Drug Information. 2017;31(3). https://www.who.int/medicines/publications/druginformation/issues/WHO_DI_31-3_RegSystemIndia.pdf?ua=1
2. 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
3. Vaidyanathan G. India’s clinical-trial rules to speed up drug approvals. Nature. April 2019. https://www.nature.com/articles/d41586-019-01054-4. Accessed on June 11, 2019.
4. https://www.turacoz.com/2019/04/15/new-drug-and-clinical-trial-rules-2019-india-what-they-bring-to-the-table/ Accessed on June 11, 2019.
5. Jesani A and Srinivasan S. New Drugs and Clinical Trials Rules, 2019: The market trumps ethics and participant rights. Indian Journal of Medical Ethics. 2019. https://doi.org/10.20529/IJME.2019.020. https://ijme.in/articles/new-drugs-and-clinical-trials-rules-2019-the-market-trumps-ethics-and-participant-rights/?galley=print

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 in 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

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

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