Gx Inhalers: how many in vivo studies does it take to achieve BE?

Gx Inhalers: how many in vivo studies does it take to achieve BE?

January 26, 2016

In the last 8 years, 26 BE studies for fluticasone DPI have been carried out (as listed on clinicaltrials.gov), equivalent to 10,698 patients reported to have been treated; assuming a price of USD 3,000 to USD 10,000 per patient, that’s a whopping USD 32 Millions to USD 107 Millions that might have been spent on Gx Advair only! And only one company has managed to file a dossier in the US: Mylan.

  • Mylan conducted the largest PD study reported with 2,725 patients, for a price of likely to be in excess of USD 10 millions for one strength and one study only. It listed only one PK study, with 40 patients, which is a very unlikely number.
  • The second largest in vivo study carried out on a Gx Advair was by Roxane/Vectura on 1,430 patients, again on only one product strength. Vectura and Roxane recently reported that this study had been successful.
  • Actavis recently launched the 3rd largest PD study on Gx Advair, which will recruit up to 1,053 patients; it is due to read out in December 2016. It is interesting to note that this study, along with Mylan’s and Roxane/Vectura’s, only lists the lower of the 3 Advair Diskus strengths: a consensus seems to have developed that only one strength may need to be studied to convince the FDA of a valid PD BE success.
  • TEVA in the mean time conducted 6 in vivo studies for the same product, treated 2,731 patients, and still did not managed to file its Gx of Advair Diskus.

Developing a Gx for Symbicort DPI is no easier: 22 in vivo studies are listed for that product, with 10 of those attributed to Orion alone! And still no generic product on the market in the US.

Why are developers failing?
There are a number of reasons why it may be so difficult to achieve in vivo BE for inhaled products.

  • The first one is that the reference product is so variable that it would not be equivalent to itself if it were put to the tests. Developers fail to appreciate that fact and do not know how to work with the variability of the reference product.
  • The in vitro-in vivo correlation for inhaled dosage forms is not reliable. There is little published data to enable the drafting of meaningful theoretical models. It takes time and money to explore the formulation space of inhaled dosage forms. Developers are reluctant to invest in what could prove salvific for their projects. Front loading is very much the operative word for inhaled dosage forms: it pays off in the end.
  • Developers are very naïve about the costs and time needed to develop inhaler products. On the strength of successful bio-studies on solid dosage forms, they assume that a similar success awaits them in the inhalation field, only to discover they have widely underestimated the effort and expertise needed.
  • Developers have wrongly interpreted regulators’ guidelines and have ended up in dead-ends. European regulations suggest that in vitro BE must be established first, if it fails PK BE is needed, and that failing PD BE is required. US regulations are more nebulous and suggest “a weight of evidence approach” of combined in-vitro BE, PK and PD BE. This has resulted in developers wanting to achieve in vitro BE first before moving on to attempt PK studies, and later PD studies. The lack of correlation between in vitro and in-vivo PK data means that this approach has condemned developers to the infernal circle of in-vitro and PK failures.

How many studies does it take to achieve in vivo BE?
In Europe it is theoretically possible to file a product with in vitro data only, this would still require an in-vivo PIF (peak inspiratory flow) studies.
If PK data is required, 2 studies might be needed with and without charcoal, and in the case of pMDIs, a study with spacers might be demanded.
In the US, and in Europe in some cases, a PD study is required. To be on the safe side, it is wise to conduct pilot studies before pivotal studies. This means that developing a Gx inhaler might require a minimum of 2 PK studies and 2 PD studies.

PARs (public assessment record) are a good mine of information for planning Gx Inhaled project.

  • Orion filed 7 PK studies (5 with charcoal and 2 without) and one PIF study in support of its budesonide/formoterol EasyHaler application.
  • Cipla filed 2 PK studies (with and without spacer) in support of its fluticasone pMDI application, and 3 PK studies and one PD for fluticasone+salmeterol pMDI (2 strengths).
  • Elpen filed 1 pilot PK, 2 pivotal PK and one device acceptance study in support of its budesonide+formoterol DPI application.
  • Sandoz filed 3 PK, 2 PD and a PIF studies.
  • Teva however mentions 9 PK studies, 2 PD studies and one PIF study in support of its application for formoterol+budesonide DPI.

PARs are only the tip of the iceberg. Teva and Orion's dossiers are the most truthful picture of the efforts needed to achieve BE. One can expect that many more studies were carried out. It is safe to assume that between 6 to 10 PK studies might be required to map a meaningful in-vitro in-vivo correlation.

What’s next?
Inhaled products, despite their maturity are by and large not genericized. Developing Gx inhaled products is expensive but is high in rewards. Don’t underestimate how much effort will be needed: you won’t be able to do it on the cheap, but be smart and it can be achieved. Aedestra can help you achieve that goal. Get in touch know to find out how.

Aedestra is a product development company in the field of inhaled drug product.  We make developing inhaled products easy, so you can focus on delivery. We drive initiatives; you realise opportunities. We can help you develop the right product in the right way by providing strategic and technical expertise: reducing cost, time and risk. Be in touch now to expand and develop your inhaled portfolio.