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Approach for Rescue Trials

Conducting a clinical trial is a complex and challenging task and involves robust scientific understanding and logistics planning. Although there are international guidelines for good clinical practices, the standard approach may not work for all clinical trials especially in the case of trials that use orphan drugs, terminally ill patients, epidemiological trials, and so on.

Factors that plague clinical trials

It has been reported that approximately 50% of phase III clinical trials do not achieve their objective or fail to demonstrate the desired results. Some of the major issues that pharmaceutical companies face while conducting large-scale trials are:

Meeting regulatory deadlines: Inadequate or poor patient recruitment, poor execution, or complicated study design are some reasons that contributed to the inability of a company to meet timelines. Approximately, 80% of trials are behind schedule. Analysis shows patient recruitment to be one of the prime reasons for study delay.

Data quality: A flawed study design and complacency in following the patient eligibility criteria required for enrolment also affect the data quality and ethics of a trial. In addition, lack of patient informed consent or breach of confidentiality are other serious unethical practices that affect final data quality.

Infrastructure and resources: While accounting for infrastructure and resources, sponsor companies sometimes underestimate the requirement of trained staff at each step of a trial. A sponsor may need to recruit more number of clinical trial associates, study coordinators as well as other trained personnel depending upon the number of trial sites and targeted cohort size. At times, the importance of site inspection is also overlooked. Site inspections help in evaluating the technical capability of the staff and confirm if the site is well equipped to handle additional responsibilities.

Unexpected challenges: Sponsor companies are sometimes caught unawares by challenges that crop up during execution of a trial. Without a risk management plan (RMP), it is impossible to identify warning signs and can also bring the trial to an abrupt halt.

All the above factors require the sponsor to look for remediation measures and this is where rescue trials come into picture.

Rescue trials

There are different approaches that pharmaceutical companies employ for rescue support. For specific issues, the company may choose to bring on board a third party with expertise in a specific function or completely outsource study management and control to a contract research organization (CRO).

Integrating into an ongoing study requires the on boarding team to have the flexibility as well as the insight to identify problem areas that have led to the failure of the Sponsor’s trial. Therefore, it is necessary for the CRO to have demonstrated expertise in handling a particular therapeutic area or to have the technical knowhow of running rescue studies. This will help in seamless knowledge transition and identification of bottlenecks that have caused the trial to fail.

In case the trial is being transferred from another CRO, there should be a clear communication and handover plan from the outgoing CRO to the on boarding CRO and the Sponsor Company. This communication should include strategic details such as current study status, vendors involved, database migration, documentation and quality control, current risk management plan, to name some of them.

Key takeaway

For a successful rescue study, there should be document compliance and effective documented communication between the sponsor and CRO. Corrective action and preventive action (CAPA) at each stage of the trial is necessary, especially in the case of rescue studies, to meet study milestones and to avoid any further delay in trial execution

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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V-KONNECT with Dr. Arun Bhatt

Veeda through its V-Konnect series interacted with Dr. Arun Bhatt and discussed about “Clinical Trials in India and its regulatory perspective with New CT rules”

About the V- Konnect

V-Konnect interview series, is a program to get in touch with specialized industry experts to know their views on opinions on current relevant subject matters.

About Dr. Arun Bhatt – Consultant – Clinical Research & Development

Dr. Bhatt is currently working as a consultant in pharmaceutical medicine and clinical pharmacology. He is Editor-in-Chief of ISCR journal- Perspectives in Clinical Research. Dr. Bhatt has extensive three decades in the Indian pharmaceutical industry in clinical research, drug development and regulatory affairs. He was former President of ISCR, President at Clininvent, CEO of CMI (India experience of) and Medical Director at Novartis. He is been awarded with ISCR Special Award in 2017 for his contribution to Research Fraternity, Outstanding Service award by Drug Information Association in 2012, Honorary Fellowship by Clinical Research UK in 2009. He is also a qualified assessor of NABH Accreditation for Clinical Trials sites and have more than 150 publications in national and international journals.

Transcript.

1. What are the challenges you see in the Indian clinical trial sector today? Can you please mention how to overcome this challenges?

A:

• Quality of trial conduct

• Gaps in Knowledge of Regulations, Ethics and Science

• Challenges can be tackled if all stakeholders participate passionately in training and development of their teams and strive for quality in conduct of clinical trials. Some of the actions are discussed below.

2. Despite professional competence and large patient pool availability, India is yet to reach its potential in clinical trials. How this can be improved?

A:

• Professional competence is not in clinical research but in clinical diagnosis. We need investigators who are trained and passionate about academic clinical research and who are willing to get trained in clinical trial regulations, ethics and science and are willing to devote time to conduct good clinical research of internationally accepted standards. This is essential to build quality in clinical trials.

• Large patient pool is not organized or classified. The sites should develop detailed database of patients including demography, disease and drug information. This would help in quick screening and fast recruitment of subjects.

• Government should create awareness about 1) the need for new drug development and clinical trials and 2) regulatory efforts to ensure protection of rights, safety and well being of patients.

•Ethics committees should receive support, guidance and training from government bodies – ICMR – and hospital administration to ensure that they can fulfill their primary responsibility of protection of rights, safety and well-being of patients.

• Industry sponsors should invest in supporting all the above efforts and encouraging academic investigator-initiated trials.

3. With the recent changes in new CT rules, what can be the benefits and shortcomings for clinical trials conducted in India?

A:

• Benefits

• Time bound approvals for clinical trials in 90 working days

• Advantages to Indian R & D discovery for initiation of Phase I in 30 working days

• Accelerated approval / trial waivers for serious and rare diseases

• Challenges:

• Investigators: Academic trials to comply with ICMR guidelines  Ethics committees (EC):

• Dual registration from DCGI office and Dept of Health Research  Composition: 50% non-affiliated members

• Short comings

• Independent Non-institutional ECs, which may not be competent in ethical oversight, permitted to oversee clinical trials

• Sponsor concerns about delays in approval because irrelevant queries

• Lack of clarity / transparency in regulatory inspection process

• No change / improvement in SEC review process

• Approval requirements for non-interventional Phase IV studies

• Some of the criteria for accelerated approval / waivers are unclear and are as per discretion of regulatory authorities

4. What are the industry expectations from Indian regulatory going forward?

A:

• Transparency and clarity in accelerated / waiver criteria / pathways

• Professional regulatory inspection with graded regulatory actions along the lines of FDA and EMA

5. Where do you see Indian Clinical trials industry in next 5 years?

A:

• Depends on how the new regulations improve the quality and conduct of Indian trials, and how the society and media react to the favorable regulatory environment for new drugs and clinical trials

• All stake holders should learn from past deviations and watchfully conduct clinical trials in compliance with regulations.

• Over next 5 years all stake holders should strive for ensuring human protection and data integrity and to establish image of India as a quality innovation R & D hub.

• Focus should be on quality and Quantity will follow.

6. What are the current issues surrounding clinical trial data integrity and what can be done to improve it?

A:

• Attitudinal shift by sponsors to reject data whose integrity is suspect

• Strengthen QA and monitoring process

• Reward sponsor team member who discover data integrity issue and whistle blowers

• Action – suspension of contract, blacklisting, regulatory notification, information sharing with industry – against responsible parties – in-house staff, CROs, investigator sites

• Training in documentation, monitoring and QA sponsor and investigator site staff

• Training of ECs in oversight and monitoring to detect data integrity issue and to take appropriate actions

7. What measures should industry take to ensure clinical trials are carried out safely?

A:

• Training of in-house staff – monitors, project managers, medical monitors, auditors and site staff in pharmacovigilance, assessment of causality and clinical trial relationship of SAE, regulatory reporting and compensation

• Train the site personnel thoroughly in protocol procedures especially selection criteria, follow-ups and safety assessments
• Project team should promptly detect important protocol deviations, which can impact safety of subjects, and take appropriate actions e.g. exclude patients, stop recruitment and inform EC etc.

• Medical monitor and project team should verify the assessment of causality and clinical trial relationship of SAE by the investigator considering company safety information and medical condition

• Ensure that the investigator complies with regulatory requirements of free medical management

8. How do you position Indian ethics committees with respect to functioning and competence in current global scenario? What is your view on steps to be taken to further improvise functions of ethics committee?

A:

• Barring a few empowered ECs in major academic institutions, most ECs lack competence in fulfilling their vital responsibility of ensuring protection of rights, safety and wellbeing of clinical trial participants.

• Department of Health Reasearch should provide training and conduct ongoing monitor/review of functioning of ECs.

On a Closing remarks Dr. Arun Bhatt mentioned that, “As a country, we should remember those who forget history are condemned to repeat it and conduct clinical trial balancing the twin requirements of human protection and data integrity. We should comply with regulations and guidelines both in letter and spirit!”

Disclaimer:

The opinions expressed in this publication are those of the Interviewee and are not intended to malign any ethic group, club, organization, company, individual or anyone or anything. Examples of analysis performed within this publication are only examples. They should not be utilized in real-world analytic products as they are based only on personal views of the Interviewee. They do not purport to reflect the opinions or views of the VEEDA CRO or its management. Veeda CRO does not guarantee the accuracy or reliability of the information provided herein.

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.