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Inhalation clinical trials – Challenges and ways to overcome.

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.

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