BE Studies of Inhaled Drug Products - Challenges and Strategies
06 Mar 2018
In the recent disease management scenario, inhaled drug products are playing a significant role in therapeutics. Inhalational route of drug delivery has several advantages like drug delivery directly at the site of action, faster onset of action, and lower systemic concentration which precludes adverse events to a certain extent. These products also avoid first pass metabolism, hence a lower dose is required.
The inhaled drug products can be administered by either oral route or nasal route, and can be broadly classified as:
- Orally inhaled drug products (OIPs): Inhaler, metered dose inhaler (MDI), pressurized MDI (pMDI, the most common type of inhaler). In MDIs, medication is typically stored as a solution in a pressurized canister that contains a propellant, although it may also be a suspension. The MDI canister is attached to a plastic, hand-operated actuator. On activation, the metered-dose inhaler releases a fixed dose of medication in aerosol form. Examples are Rotacaps (single dose) inhaler, Diskus inhaler (multiple dose), Turbuhaler etc.
- Nasal inhaled drug products: Nasal spray, single dose nebulizers, multiple dose nebulizers etc.
Many organizations are trying to formulate their generic drugs at a reduced cost to compete with the innovator drugs. To conclude that the new generic formulation is equivalent to the marketed drug, a bioequivalence study has to be performed in healthy human volunteers. The results of such clinical studies form a part of the dossier that needs to be submitted to the regulatory authorities for approval.
Being a clinical research organization, there are various challenges to perform clinical studies with inhaled drug products:
- Method of administration of such products is quite different and requires more precautions as study participants play a significant role for arriving at the correct dosage.
- There may be differences in the participant’s ability to inhale, which can lead to dosing noncompliance in BE studies. Volunteers should be screened for respiratory diseases with detailed medical history including smoking history, physical examination, chest x-rays and pulmonary function testing (PFT), as those with a history of smoking or respiratory diseases usually have poor stamina to inhale. Spirometry for lung function assessment and Oximetry to detect oxygen saturation of hemoglobin should also be performed.
- In MDI, study participants need to coordinate between inhalation and actuation. In such cases, if the dosing is performed by the clinical personnel, there may be chances of inappropriate coordination between inhalation and actuation. On the other hand, if the dosing is performed by the participant himself, the pattern of drug actuation may vary from participant to participant. This may lead to nonequivalence of the drug in the body even if the generic drug is well formulated.
- Dry powder inhalers (DPI): DPIs do not require timing and coordination, but do demand that the inspiration produces a certain inspiratory flow rate (IFR) or peak inspiratory flow (PIF). Here, the energy for propelling and inhaling the drug is provided by the individual, that is, they are breath actuated. Hence, the inhalation attempt has to be rapid and deep with quick acceleration over 3–4 seconds. After this, the participant has to hold the breath for 5–10 seconds and then breathe out normally through the nose. The most common mistake while using a DPI is not completely exhaling before the beginning of inhalation, followed by not holding the breath adequately.
- Use of a spacer with an MDI: Using a spacer, an MDI obviates the need for coordination between inhalation and actuation, and also decreases the deposition of the drug particles in the oropharynx.
- Nasal Spray: Before dosing, study staff should wear hand gloves, nose mask, gown (white apron), cap and shoe cover. Study staff should discard the used ones and wear a new set of hand gloves and nose mask for each participant. It is important that the participant knows the correct use of nasal spray. After screening, trained study staff will in-turn train the participants on how to use the nasal spray correctly, and evaluate tolerance of the participant to receive the drug without reactions, which, generally, result in sneezing. Study staff will train the participants to handle the spray correctly and independently. Prior to dosing, participants should also be instructed to inhale air through the nose and exhale only through the mouth which minimizes spillage of the drug from the nose.
Precautions to assure maximum absorption and minimize intra and inter-participant variation are as follows:
- Air-conditioning of the room where drugs will be administered must be off during all procedures.
- All study participants should wear gowns, caps, masks, and gloves, prior to dosing.
- Following administration, the study participant must leave the room, safely remove the gown, caps, masks, and gloves, fold or roll them into a bundle and discard in a waste container, wash his hands and face, and go to the blood collection room with a new mask.
- Blood samples must be processed (centrifuged) in a room that is separate from the administration and collection rooms, minimizing cross-contamination.
- After last actuation, participant must receive 200 ml of water at ambient temperature to push the drug particles that may have remained in the oral cavity to the gastrointestinal tract. Glass containing water will be sealed in order to avoid any contamination with particles of the drug in the study environment, and should be opened by the study staff just prior to dosing.
- Dose selection/method of assay: Since the inhalational route delivers the drug at the site of action, the systemic concentration required is very low, sometimes too low to be detected by the standard bioanalytical methods. Increasing the dose could endanger the safety of the participant; for example, increased incidence of tremors, palpitations and hypokalemia are seen with a higher dose of salbutamol. Therefore, developing more sensitive methods of drug assay is required.
For all aerosol based OIPs, priming is also required. This can be done within 24 hours before the first actuation of the study drug being administered; each bottle should be primed by shaking well and then making 10 actuations until a fine spray appears. The priming of the study drug should be done in a different room, away from the place where study participants are housed or may come into contact with the spray. After each bottle has been primed, it should be weighed and recorded as the pre-dose weight.
Additionally, post-dose weight can also be recorded to ensure that the correct amount of the drug is actuated.
Incorrect dosing of inhalers by study participants may reduce/increase/vary amongst the recruited sample size of the clinical study. This may jeopardize the study result. Hence, it is crucial that the study personnel who educate the participants with the inhaler technique are able to perform it correctly themselves; however, a recent study showed that 93% of those tested were unable to demonstrate the various stages of inhaler use and correct IFR. Therefore, it is recommended that study participants are carefully taught how to administer the drug to confirm a synchronized dosing.
There are various training devices available in the market for the proper method of administration. Some are described below:
- In-Check Dial: The In-Check Dial is an inhalation airflow meter that can help educate and assess patients who use inhaler devices. The In-Check Dial simulates the internal resistance of several common inhaler devices and measures inspiratory flow. These measurements encourage study participants to modify their inspiratory technique (by inhaling with more or less effort) in order to achieve an optimum inspiratory flow.
- Trainhaler: Trainhaler is a training device to be used with Flo-Tone to improve pMDI technique in 3 ways: correct flow, co-ordinate signal and inhalation duration.
By evaluating the air flow of the participants during screening, and by providing a proper training to participants before initiation of a BE study, such challenges can be overcome and variations minimized.