Denise Conti, CDER Office of Generic Drugs, provides an overview on orally inhaled and nasal drug products
Thank you for the introduction um so this afternoon my talk will focus on current product specific guidances and common questions in pre-anti-communications when developing orally inhaled and nasal drug products so first i will provide an overview on oral inhalation and nasal products then i will present the current bioequivalence recommendations for this type
Of products then i will turn the focus of the talk on the current product specific guidances we have available and at the end i will present some typical questions we receive from generic industry when they are developing this type of complex products most of early inhaled and nasal drug products are used to treat diseases in the respiratory tract they are
Classified as drug device combination products meaning they have the drug component and the device component and according to the gadofa ii commitment ladder they are also classified as complex products they may have complex formulations or complex routes of delivery or complex dosage forms and in mainly many cases all these complexities together in one single
Product so the drug can be formulated as solution or suspension or a solid blend the site of action can be systemic or local there are different dosage forms according to nasal or inhalation routes of administration so we have for example nasal spray products and nasal aerosol products we also have inhalation sprays and inhalation aerosols and the same for
Powder formulations or nasal or inhalation administration there are multiple challenges that need to be considered when developing generics or local action oral inhalation and nasal drug products so first the performance of the product depends on the device characteristics then bioavailability of the drug depends on multiple factors for example how the patient
Uses the device to administer the medication and when the drug is in the local site of action all the processes that happen the solution permeability clearancy process in addition to that at this present moment there is no practical way to measure the amount of drug that is delivered to the lung or nasal cavity in the case of drugs that act systemically they are
Delivered to the blood and then distributed to the sites of action in the body in this case bioequivalence can be determined with typical pka studies for locally acting drugs pk is downstream to the therapeutic effect so in this case a typical pk study may not be sufficiently established bioequivalence currently the agency recommends the weight of evidence
Approach for establishing bioequivalence of orally inhalation and nasal direct problems according to this approach the generic product needs to demonstrate equivalence to the reference product in terms of in-vitro studies pk studies a comparative clinical endpoint or pharmacodynamic study in addition to formulation and device similarities meaning all these
Elements together a plus b plus c plus d this is a list of in vitro bioequivalency studies we recommend for dry pot inhalers meter dose inhalers and nasal suspension products i will not go over into detail of all these inventory studies in terms of design and and bioequivalence criteria due to the time limit we have at this presentation these are the current ev
Voice studies we recommend for this type of product so a comparative pharmacokinetic study for dpis mdis and nasal suspensions using healthy subjects this is a typical single dose two-way crossover study a comparative clinical endpoint or pharmacodynamic study for mdis and dpis using patients with asthma or copd depending on the indication in the rld label in
The case of nasal suspensions we recommend a comparative clinical endpoint study using patients with allergic urinitis for nasal solution products the bioequivalence recommendation depends on the activity if the drug will act systemically or local and the formulation characteristics of the generic product so if the product is intended for systemic action and the
Generic formulation is considered the same as reference formulation in this case in vitro studies only are sufficient but if the formulation is considered not q and q2 different from the reference formulation then we recommend an in vivo pk study or nasal solution products of local activity we recommend sameness in terms of formulation and in vitro studies only
As chris andrea presented you yesterday these are the four ways of communication between generic industry and the agency i will focus now on product specific guidances so we publish product specific guidances with specific objectives to facilitate generic drug product availability in the market to assist generic industry when developing these complex products and
To identify the current thinking methodology we believe it’s most appropriate to support generic applications the bio-equivalency recommendations in psgs are guided based on the principles in the cfr3224 which lists different types of ways to measure bioavailability or establish bioequivalence so uh considering all mdis and dpi products and also nasal products
We have in the market currently we have about 55 and 60 percent of product specific guidances for this product this is a complete list of all psgs we have available for mdis dpis nasal solution products as well as nasal suspension products you can go to the website and download all these product specific guidances now i will focus my presentation on typical
Questions we receive from generic industry when they are developing oral inhalation and nasal direct products so basically the questions are related to formulation development device development and bioequivalence in terms of specific questions sometimes asking clarifications on the product specific guidances or sometimes proposing alternative approaches to our
Current recommendations in terms of formulation this is the most common question we receive if the proposed formulation is q1 q2 the same as the reference formulation so the way we assess this type of question we look into the excipients in the generic proposed formulation if you are the same as the reference formulation and also the concentrations of excipients
If they are similar to the reference formulation within the plus minus five percent range so when submitting formulation related questions you can submit up to three proposed formulations for your generic product and please submit complete information about all excipients you plan in your generic product and the concentrations of excipients inside the container
Of your product for example if you are developing a generic meter dose inhaler the concentration of excipients inside the canister with respect to device the common question we receive is if a proposed test device is acceptable for in the submission as uh dr um whitsman presented you earlier currently we rely on the comparative analysis to access test devices
In comparison to the reference devices but the way we look into these comparisons is regarding to user interface so when submitting device related questions submit samples of your proposed test product in addition to the reference problem submit results of your comparative analysis and based on the results if you identify minor differences or more than minor
Differences or no differences then you formulate your question this will help us to with our assessment this is just a snapshot of the guidances that dr whitsman already presented sometimes we receive questions if a proposed clinical study protocol is acceptable so in this case i want to make the point that we do not pre-review clinical protocols and as chris
Andrea presented yesterday you should be submitting specific questions regarding to your clinical development program for example if the psg recommends a clinical study with formulation with a population a and you want to conduct your clinical study with a different patient population this would be a type of question you should submit in your control correspondence
If you have multiple questions in your clinical development program then we recommend you to submit a pre-end meeting request sometimes we receive this type of question if the product is eligible for by waiver of individual studies in this case i want to make point that inhalation in nasal drug products they are complex products in this case vivo bioavailability
Or bioequivalence may not be self evident in this in in that case just wave the in vivo studies based on the cfr 320 22 may not be appropriate so if you are developing your generic product and you believe you you don’t need to conduct in vivo studies as per the recommendations in the psg you should be submitting an alternative bioequivalence approach in lieu
Of the clinical study that is currently recommended in this case in addition to your proposed approach you should be submitting your rationale and justification and if you have preliminary data to support your proposal you can also submit that and as final uh comment many times we receive open and non-specific questions like is my ender acceptable for review or
Is the end acceptable for filing and then many times if the end can be approved so at the pre and the stage we cannot address this type of questions because they they are they need scientific review after the end is submitted uh so at the pre-ended stage we recommend you ask specific questions about your development program specific issues that you need help
From the agency through the pre and the meeting request mechanism so in conclusion um quarter inhalation and nasal direct products are complex to the device combination products we publish product specific guidances to help development of these products and the current recommendations in the guidances they identify the current thinking methodology we believe is
The most appropriate to support an application if there are questions clarifications that are needed regarding to the recommendations we have or if you consider propos submitting an alternative bio equivalency proposal you can do that but please clearly identify your questions focus on complex situations in your development program provide your rationale and
Justification and preliminary data if you have available so i’d like to thank you my co-workers and uh thank you audience for the attention
Transcribed from video
Guidances and FAQ for Orally Inhaled and Nasal Drug Products (32of39) Complex Generics 2018 By U.S. Food and Drug Administration
