SubscribeThe world market for asthma treatment was valued at $11.5 billion in 2003, a figure which is expected to almost double to $20.9 billion by 2010. Within the same timeframe the global market for chronic obstructive pulmonary disease (COPD) is expected to more than treble from $2.3 billion to $7.4 billion.
Treatment for these respiratory conditions can be inhaled (such as inhaled beta agonists, corticosteroids and combinations) or taken orally (such as Leukotriene antagonists). The former is most widely used and, with the exception of Merck’s Singulair (oral), accounts for almost all of the market-leading therapies for asthma and COPD.
To support registration and marketing claims, new entrants to the asthma and COPD markets must run comparative trials against market leading products. When aiming to eliminate bias and ensure that the results of these trials are statistically valid, it would be preferable to perform these trials in a double-blind manner.
However, how can blinding for products be achieved where physical differences are so extreme? Modification of the inhalation device or using the same device for both treatments is not feasible because the inhaler plays such a critical role in the dispersal and subsequent action of the active ingredient in the airways. This article will look at ways in which blinding of inhalers for double-blind trials can be achieved.
Clinical Study Design
For oral solid dosage forms, companies often use a double-blind, double-dummy design to enable them to use their product in its planned market form. This approach also means that they do not need to ‘blind’ their own product and perform all of the associated analytical work. The company is already producing the active, and can readily produce placebo using the same/similar formulation minus the active ingredient.
Active comparator can be readily purchased from the open market; placebo comparator units, however, are by and large difficult to purchase. Producing a straight placebo copy of the commercial comparator product, complete with identification markings and trademarks, is not possible for legal and ethical reasons.
As a result, the comparator product usually has to be blinded using techniques such as over-encapsulation or over-coating. The blinded product still appears different from the trial drug. However, since it is now encapsulated/over-coated, a matching placebo can be easily produced. This allows a double-dummy design to be used, as described below.
In a trial comparing Product A with Product B, for each dose the patient takes the following units, depending on how the comparator was blinded (see Figure 1).
| Figure 1 | |
| Double-Blind = | Encapsulated A OR Encapsulated B |
| Double-Dummy = | Active A tablet and Placebo B capsule OR Placebo A tablet and Active B Capsule |
This strategy can also be applied to products delivered by inhaler. Wile the developer of the innovator product can easily provide an active and placebo of their own inhaler, it is not possible to do this for the comparator. However, in the same way as an active solid dose can be purchased from the open market, a similar approach can be used to acquire active comparator.
The key difference is that it is not possible to simply encapsulate and then manufacture a matching placebo. Placebo units must be produced by converting active inhaler units by removing and replacing their active ingredients and insert materials.
For legal and ethical reasons, it is important that the comparator units used in a clinical trial are distinct from the commercial product. In basic terms, the commercial product is what it is supposed to be. A trial inhaler could contain active product or could be a placebo, so should appear different from the commercial product. This adds work to the production of clinical trial supplies because both the active and placebo product have to be changed in some way.
Blinding Metered Dose Inhalers (MDIs)
These inhalers consist of a plastic body (the actuator) into which an aerosol canister is inserted. The aerosol contains the active ingredient and propellants, and it is generally labelled according to the country from which it was sourced. The base of the aerosol may be embossed with a trade name, batch number or an instruction (such as ‘shake before use’ in the local language). Additional markings specific to the product (embossed markings, labels, inkjet printing) may also be present on the actuator body.
In clinical trials where an MDI is the comparator, there are two basic approaches to blinding these units. A double-blind design can be used if both the innovator product and the comparator are MDIs with similar size, shape and dimensions. Both products can be encased by a masking device.
This is usually a large plastic actuator that covers the entire MDI, while still allowing it to function normally. Generally, however, this approach can be used on very few occasions because it is rare to find two MDIs close enough in size and dimensions. This approach has been used successfully before, it could be argued that it was too easy for the patient to remove the masking device, exposing the identity of each MDI and unblinding the study.
A double-blind, double-dummy design is most commonly used. Contract manufacturers and generics companies who are involved in MDI manufacture are willing to sell aerosol canisters containing a propellant only. If the company sponsoring the trial has aerosol-filling capabilities, it is possible that propellant-only units could be produced in-house. In most instances, it is possible to match exactly the size and appearance of the commercial MDI aerosol by identifying the parts used in its manufacture and sourcing identical parts off-the-shelf.
Occasionally, the design of specific parts may be covered by a patent or may be produced on a ‘customer-specific’ basis by the manufacturer. If this is the case, parts that are close in appearance but not identical can be used. While the blind may not be perfect, the likelihood of a patient or investigator actually having two different units side-by-side and making a direct comparison should be taken into account. If such a scenario is unlikely, a slight difference may not be an issue.
If sourcing placebo aerosols from a third party, careful planning is recommended in order to minimise costs and avoid delays to clinical trials. First, allow time to obtain these units as they will be subject to the schedule of your chosen manufacturer. Secondly, order as many units as possible each time by taking future trial requirements into consideration. Set up and changeover costs and times for an aerosol line are significant, so minimising the number of these substantially reduces the unit cost of each placebo aerosol.
The result of the above process is that we now have a placebo aerosol that can be substituted for those found in commercial units. Further work is required to ensure that the active and placebo units match.
As mentioned above, commercial units may also have text embossed on their base. This can form part of the product identification and therefore should not be copied on placebo units. Placebo units, therefore, have blank bases, differentiating them from commercially-sourced actives. To eliminate this difference, it is necessary to cover the bases of both units in the same way. Various methods are available to achieve this.
Commercial aerosols are labelled. It is not possible to copy labels for obvious reasons, thus active aerosols should be de-labelled so that they match the unlabelled placebo units.
It is also necessary to change the appearance of actuators on active and placebo units so that they are different from those on the commercial product. This generally requires the removal of labels or embossed markings. Alternatively, over-labelling can be used, though we rarely see this approach because labels can be removed by patients.
Since actuator designs are protected, it is not possible to simply copy these. The only way to obtain these for placeblo units is to purchase additional commercial units, remove the active aerosol and replace it with a placebo aerosol. One way of emitting cost that can be utilised is to supply patients with a single actuator and multiple aerosols for a clinical trial.
Dry-Powder Inhalers (DPIs)
Many of the new generation of inhalers do not use aerosol technology, and involve patients drawing powder into their airways themselves. This approach is believed to improve dispersal of the drug in the airways. Examples of leading DPIs include GSK’s diskhaler/accuhaler (Advair/Seretide), AstraZeneca’s Pulmicort, Boehringer Ingelheim’s Spiriva and Novartis/Astrazeneca’s Foradil/Oxis. Each company’s DPI is based on a unique design, so different blinding strategies are required for each.
Capsule-based DPIs
Active powders for Boehringer’s Spiriva and Novartis’s Foradil are provided in hard gelatine capsules. In order to take a dose of these products, patients remove a capsule from a blister pack insert it into the inhaler unit, depress a button to pierce the capsule and inhale the contents through a mouthpiece. Converting the inhaler unit itself for use in a trial is fairly straight forward, and involves removing or obscuring commercial labels or printing on the inhaler body. The difficult part of the process is producing placebo capsules and blisters that match the active commercial product.
While plain capsule shells that match those used in these products can be readily sourced, these lack the printing that appears on the commercial product. For the reasons mentioned above, it is not possible to simply copy this. As a result, it is necessary to remove printing from commercial capsules, obscure it or print something similar in appearance onto the placebo capsules.
Patient instructions (such as ‘remove capsule only at time of use’), and the fact that capsules are contained in individual blisters in high-barrier films, suggest that any approach that involves removing product from its original packaging may affect its stability. Analytical support for the process is therefore essential, and it may also be necessary to perform this work several times to identify environmental conditions that minimise risks to stability.
Producing the capsules themselves involves selecting an inert filler that has similar appearance, density and behaviour to the active blend contained in commercial capsules. Particle size analysis can help in the selection of a closely matching powder. It is also necessary to choose the correct technology to fill the capsules with an appropriate weight of powder. Fill weights for these products are generally very low, and the accuracy and nature of fill are incompatible with most high-throughput capsule machines used by clinical supplies departments.
Packaging the placebo capsules in a manner that matches that of the active commercial product can also create problems. Blister packs are branded, and as such cannot be copied. It is also possible that blister packaging technology not available to most clinical supplies departments was used to produce the blisters (such as tropicalised blister packs). Again, this can make it difficult to produce matching packs.
Therefore, the options are to remove or obscure branding from commercial packs, while ensuring that the approach used does not affect product integrity. Repacking the active and packing the placebo in plain packaging is also an option. As discussed above, there may be stability issues with such an approach, so analytical support for repackaging is essential.
Reservoir-based DPIs
Some DPIs, such as AstraZeneca’s turbohaler design, contain a reservoir of powder containing the active ingredient. In principle, it should be possible to convert these units to placebo simply by breaking them open, removing the active powder and then reclosing the units. However, there are complications in this process:
- Opening the units without damaging them can be problematic, and special tooling needs to be developed.
- Special wash methods need to be developed to remove all traces of the active ingredient from all parts of the inhaler unit; rinse methods need to be developed to ensure that solvents used in this process are also removed.
- Containment and extraction units are required to remove active dust and solvent from the atmosphere during the process.
- Analytical tests have to be developed to prove that active ingredient has been removed.
- Specialised equipment and tooling is required to re-assemble the units, again without damaging them.
It is possible to replace the active powder in the reservoir with an inert placebo powder, but this approach is not always used. Powder doses delivered by this device are so low that they are believed to be undetectable to the patient, so replacing powder simply adds additional complexity and cost to the conversion process. Replacing the powder is easy enough, but it is a manual process and adds to the cost of conversion.
As with other inhalers, commercial labels and markings need to be removed or obscured on each unit so that clinical trial turbohalers appear different from commercial units.
Blister-Based DPIs
In the therapeutic area of asthma and COPD, the best known inhaler unit employing blister strips to deliver active powder for each dose is GSK’s accuhaler/diskhaler. This unit employs a 60-dose blister strip, with a specific dose of drug in each blister pocket.
Each time a patient takes a dose they pull a trigger, which advances the blister strip to the next full pocket and the dose counter to the next number. Disassembly and reassembly of this DPI is highly complex, and therefore the most difficult DPI to convert to placebo.
GSK have invested millions of dollars in a robotic line for filling blister strips and assembling these units. Replicating this technology in a typical clinical supplies unit for a few hundred, or indeed thousand, placebo units for clinical trials is not feasible. While alternative approaches can be developed, these still involve significant time, cost and complexity that may exceed the resources and funds available to an in-house clinical supplies unit.
Conclusions
Use of a double-blind, double-dummy design will enable companies developing new inhalation products to perform unbiased comparative trials against market leading products. However, significant engineering and analytical work is required to convert commercial inhalers to placebos. As a result, it is essential that planning for this type of project begins well in advance of any proposed clinical trial start date. Even if time is available, the cost of automating such a process for a one-off comparative study is huge.
If a trial requires only a few thousand comparator inhaler units to be converted to placebo, this can result in very high costs for each unit produced. It is worth bearing in mind that while this cost may be a barrier to an in-house clinical supplies department working on a limited number of trials, it may be less of a barrier to a contractor working with several companies with several trials each.
By spreading the cost of developing and equipping this process across several clients and trials, a contractor may be more willing to invest in developing one of these conversion processes. From the industry’s perspective, outsourcing production of placebo units could bring double-blind inhaler studies within reach.
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