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 contribute 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 the 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 on 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 unaware by challenges that crop up during the 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 the 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 onboarding 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 know-how 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 onboarding 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 documented 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.

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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.