Bioequivalence: Interpreting the FDA Guidances for a Nasal Spray

In our blog introducing bioequivalence, we described how studies establishing bioequivalence can be a way to avoid expensive clinical trials without compromising on the safety or efficacy of a drug product. In particular, this applies for generic versions of already approved drugs, or for different dosage routes for those drugs. In these cases, bioequivalence studies can replace a traditional clinical trial in approving the product under an Abbreviated New Drug Application (ANDA), dramatically decreasing the cost of bringing a drug product to market. The FDA issue guidances for a large variety of drugs and delivery methods outlining what is required of a bioequivalence study for an ANDA to be successful. In this series, we give an overview of these guidances for a range of different drug delivery methods to highlight key requirements, as well as where statistical input can be of most impact. Here, we focus on demonstrating bioequivalence for a nasal spray.

We have discussed detailed ideas about bioequivalence previously, but some key definitions are listed here:

Bioequivalence

Two drug products are considered to be bioequivalent if there is no significant difference in the rate or extent at which equal doses of an active ingredient becomes available at its site of action under similar conditions.

Average Bioequivalance (ABE)

A measure of bioequivalence which is concerned only with the average of important parameters across a study population without considering their variability. This method is emphasised by European regulators.

Population Bioequivalence (PBE)

A more complex bioequivalence methodology which establishes that the variability of important properties is equivalent between drug products along with their average of those parameters. This is given more weight by US regulators, such as the FDA.

Lifestage

The different phases of the intended usage cycle of the product. Often categorised as Beginning (B), when the product is new; Middle (M), about halfway through the intended lifespan of the product; and End (E), when the product is nearing the end of its intended usage.

To highlight key insights into what is required by the FDA guidances for establishing bioequivalence for inhaled drug products, we will take a look the guidance provided for a specific product: inhaled Fluticasone Propionate (FP). FP is a steroid with a wide range of uses, but in its inhaled form it is typically used to treat respiratory conditions such as COPD, asthma, and allergies.

The specific guidance we will examine is for FP delivered as a suspension nasal spray. When actuated, the device emits a spray of tiny fluid droplets containing a suspension of solid FP particles. When these droplets impact the walls of the nasal passages, the fluid evaporates, leaving the solid particles to be absorbed into the bloodstream.

Recall that the purpose of a bioequivalence study is to establish that key properties of a new product are not significantly different than an already licensed product. In the guidance, the former is designated the Test (T) product and the latter the Reference (R) product. In the case of a nasal spray, these key properties include both the physical delivery of the drug by the device, and the physiological behaviour of the active ingredient.

If the formulation of the T product is equivalent to the R product – i.e., it has the same active and inactive ingredients in similar amounts – only the former of these properties need be tested to prove bioequivalence. The guidance list eight in vitro assays suitable for proving equivalence for the physical delivery of the drug. These are:

1. Single Actuation Content (SAC)

This is the amount of FP present in a single actuation of the nasal spray. The guidance recommends this is tested at both the beginning and end lifestages to ensure that the dosage continues to be consistent throughout. A PBE assessment should be performed on the SAC.

2. Droplet size distribution

Droplet size distribution is a test which checks that the range of sizes of droplets in the nasal spray is correct. Typically, smaller droplets travel farther into the respiratory tract and are absorbed faster. It is important to ensure, therefore, that the droplet size is correct for the intended behaviour of the product. The equivalence for droplet size is assessed using a PBE analysis comparing the average 50^th percentile droplet mass, known as the D₅₀, and the range of particle masses.

3. Drug in Small Particles (DISP)

DISP is a check on the amount of FP carried by small droplets of fluid – those less than 9 micrometres in diameter. This is vital for ensuring that the dose delivered by the device is correct as the smallest particles are those which travel furthest into the respiratory tract. DISP is tested by measuring the mass of solid FP deposited downrange of the device shortly after a series of actuations. The fewest actuations possible for the sensitivity of the assay are used to mimic a single actuation as closely as possible.

DISP is assessed using a PBE analysis but, uniquely among the assays listed, it is a one-sided measure. Indeed, the FP guidance contains the example for a one-sided PBE calculation and is referenced by other guidances which require such analyses. We aren’t particularly concerned if there are too few small particles as many often reach unintended parts of the body. As a result, the T device is determined to be equivalent if its DISP is similar to or smaller than that of R.

4. Spray Pattern

The spray pattern characterises the cross-section of the spray plume. It is defined by the longest (D_max) and shortest (D_min) diameters of the plume, as well as their ratio (D_max/D_min) known as the ovality. The closer the ovality is to one, the closer the cross-section of the plume is to being a perfect circle. The spray pattern affects where the active ingredient is absorbed, meaning it is critical that it is under control. The guidance recommends that the spray pattern is evaluated qualitatively, and a PBE analysis is performed on the ovality ratio and area. These assessments should be made at two different distances from the testing device.

5. Plume Geometry

The plume geometry also defines characteristics of the spray produced by the spray, namely the width of the plume, and the angle of the spray cone. Similar to the spray pattern, it affects how and where the FP is absorbed. Unlike the spray pattern, the plume geometry does not require a PBE analysis, with the plume angle and width of T considered equivalent if they fall within 90%-111% of R.

6. Drug Particle Size Distribution (DPSD)

Alongside the size of the fluid droplets which carry the drug particles, it is also vital that the size of the drug particles themselves is tested. If the particles are too large, then they will be absorbed through the walls of the nasal passages too slowly, while if they’re too small then this process will happen too fast.  Similar to the droplet size distribution, DPSD is assessed using a PBE analysis on the D₅₀ and the span of particle masses.

7. Priming and Repriming

This test ensures that the nasal spray provides an appropriate dose of FP under circumstances likely to be encountered in real-world use, such as after a long period of inactivity or after being dropped. The FDA guidance recommends that this is also evaluated using a PBE analysis.

8. Dissolution

The final in vitro assay listed in the guidance is a test of how easily the particles of FP dissolve using particles of similar size to those emitted by the device and a justified combination of media, media volume, agitation/stirring, etc. This metric is not assessed by a BE analysis, but rather by comparative analysis of the dissolution profiles of the T and R products.

For T products which have a different formulation, then an alternative approach is recommended in the guidance. This requires in vitro assays 1-6 be completed, alongside two in vivo studies to test the physiological and clinical behaviour of the T product.

The first of these is a study which checks that the pharmacokinetic (PK) properties of the two products are equivalent. We’ve discussed these in detail in our previous blogs, but, in short, PK describes how a drug product is absorbed and transported to its site of action by the body. In this case, the guidance recommends that equivalence be established for the overall exposure to the drug (described by the AUC) and the maximum observed concentration of the drug in the bloodstream (the C_max). To be classified as equivalent on these properties, the 90% confidence interval on their T/R ratio must fall within the range 80%-125%.

Once equivalence on PK has been established, the final step is to prove equivalence on the efficacy of the product. This is done by conducting what amounts to a mini-clinical trial where the T and R products are compared against placebo. In this case, patients suffering from seasonal allergic rhinitis (i.e. hayfever) are assessed on how effective the treatment is for treating a set of their symptoms, namely runny nose, sneezing, nasal itching, and congestion.

Participants score the severity of their symptoms from 0 (absent) to 3 (severe) regularly both prior to and after a dose of the product. The primary endpoint of the study is the difference in the total symptom score after treatment and a baseline score taken over a 7-day placebo run-in period before the start of the study. If the T product behaves similarly to the R product in the study, then the two can be considered equivalent on this clinical endpoint.

If equivalence can be established for the physical, PK, and clinical endpoints, then the T product can be declared bioequivalent to the R product, which is often sufficient for it to be approved for market under an ANDA. We can clearly see that this is a far swifter and less complex process when compared to the traditional three-phase clinical trial process, meaning the final product is likely to be cheaper and more accessible for the end user.

The study requirements for a Fluticasone Propionate nasal spray are typical for such products, but other drug delivery methods will need to show equivalence in other properties to demonstrate bioequivalence. In the remaining parts of this series, we will examine the FDA guidance for some other common classes of drug product.

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