Issue link: https://www.e-digitaleditions.com/i/1524818
26 August 2024 Inhalation ANDA regulatory pathway recommendations Generic MDIs did not exist during the propellant switch programs of the mid-1990's and as a result there was no concern, consideration or allowance for them in technical and regulatory requirements at that time. Because generics rely so heavily on the refer- ence listed drug, it is in the best interest of the public health to develop rational and sustainable guidance and policy that accounts for this interdependent rela- tionship. I suggest that the benefits for patient health would be enhanced if the PAS approach were to be implemented without undermining, or worse obvi- ating, currently approved ANDA MDIs, or those in development (or to be developed) against currently approved NDA MDIs. Furthermore, it is possible that if new NDAs are required for already approved MDIs, then any approved generic, as well as any future such generic product(s) to the already approved NDA, could be jeopardized in a number of ways. ese include: • If the NDA is withdrawn for reasons of safety and efficacy, then ANDAs referencing that NDA can no longer be marketed. • e ANDA is at a dead end in terms of complying with a propellant change if the ANDA applicant cannot change the propellant of their own volition. • Necessary supplies of the drug product are likely to become rapidly unavailable for the ANDA applicant to use, if the original NDA is no lon- ger marketed and the company wanting to use the ANDA route wishes to continue development. is problem is worsened if the NDA applicant withdraws the already approved NDA (even if not for reasons of safety and efficacy). It is appreciated that the FDA could allow for substitution with a new RLD or reference product. However, this pro- cess would likely take an undetermined (lengthy) amount time to complete and is therefore a risky and uncertain process [20]. If all approved MDI products (NDA and ANDA) are required to refor- mulate under new applications, the point will likely become moot for years because generics would need a new RLD to become "off-patent" in order to apply for an ANDA. Potential consequences for inhaled product development and availability linked to the transition to low GWP propellants In the United States alone, COPD affects 6.5 per- cent of adults and asthma affects about 7.7 percent of adults and children [21, 22]. e chronic nature of these diseases, that children are also affected, and the known sequalae if left untreated or under- treated clearly point to a public health need to Furthermore, based on contemporary knowledge and methods, I also believe that the PAS approach poses no greater risk with respect to safety and effi- cacy for those MDI products than requiring a new NDA. e need for clinical data is greatly reduced by virtue of in vitro/in vivo correlations (IVIVC), in vitro/in vivo relationships (IVIVR), modeling/ in silico simulations and predictions compared to that available in the 1990's [6-9]. If limited patient- derived data are required, it may also be submitted via the PAS pathway to NDAs [19]; as discussed in the following excerpt: From: 2004 FDA GUIDANCE: SUBMITTING SEPARATE MARKETING APPLICATIONS... USER FEES STATES 2. Other Changes to Approved Products A change to an approved product based on chem- istry, manufacturing, or controls data and bio- equivalence, or other studies (e.g., safety and immunogenicity), that changes (1) the strength or concentration; (2) the manufacturing process, equipment, or facility; or (3) the formulation (e.g., different excipients) can be submitted as a supple- ment to an approved application. It seems reasonable to expect a thorough justification from the FDA if they were to require new NDAs for approved MDI products undergoing a propel- lant change only (i.e., no new indications, etc.). e PAS scenario would be more feasible and less costly, while providing a timelier FDA assessment (and a less burdensome FDA workload) and would have lower overall risk than existed in the 1990's. is sce- nario would be particularly so when all the necessary data can be submitted via the PAS route, without the additional encumberments to generic MDIs (dis- cussed later in this paper) that requiring new NDAs would bring. Requiring entirely new NDAs for approved MDI drug products may go beyond an abundance of caution to an extreme position. In contrast, a PAS change program for switching to the next generation of propellants would be: • less likely to result in approved product discon- tinuation/withdrawal with corresponding drug shortages and loss of therapeutic options; • less costly and a timelier response to the environ- mental considerations for propellant change; • both acceptable and of comparatively low risk (as all necessary data may be submitted via PAS); and • structured to allow approved generic MDIs to more feasibly persist because the corresponding NDA would be retained.