Transdermal Drug Delivery Systems and 505(b)(2) / Hybrid Regulatory Pathways.

By Roberto Gabach – Director & New Projects Manager

Transdermal drug delivery systems, also named as “patches”, are controlled release dosage forms designed to deliver a therapeutically effective amount of drug through the skin during the time of application of the product, which may vary between 9 h (methylphenidate) to 148 h (buprenorphine).

 A systemic drug delivery from skin can be also achieved from a dosage form different than the patch, as occur with gels of testosterone, oxybutynin, and estradiol. In the case of semi-solids products the administration is usually once-a-day.

The development of a novel transdermal delivery system containing a marketed drug in another dosage form has the aim of improving the drug’s performance from the existing product (e.g. tablets) in terms of efficacy and/or safety, and also improves patient compliance and overall therapeutic benefit.

Another important objective of patches and semisolid forms with systemic effects is to deliver drugs from the skin towards the bloodstream with a minimal inter and intra patient variation.

Most of commercialized products in transdermal dosage forms (patch) have been previously approved in other pharmaceutical forms. An exception to this rule is rotigotine, a drug destined to the treatment of Parkinson disease and Restless Leg Syndrome, which is only commercialized by transdermal route (Neupro® patch). 

The most recent patch approved through the 505(b)(2) pathway is Secuado® (asenapine transdermal system) in October 2019, which is destined to the treatment of schizophrenia in adults. Asenapine had been previously approved in August 2009 a sublingual tablets (Saphris®). 

Is it possible to develop a transdermal product by referencing a previously approved drug in another dosage form (e.g. tablets) in order to reduce the number of clinical studies to be conducted and the cost of the new development? Clearly, the answer is yes. 

The 505(b)(2) approval pathway in the USA and a Hybrid application in Europe allow reducing the cost and time of clinical development of a new product compared to a conventional submission, and although the overall development cost is higher than that of a generic, it is associated with market advantages over the latter.

NDA 505(b)(2) and hybrid applications can be approved based at least partially on data from studies not conducted by the applicant/sponsor and for which the applicant has not obtained a right of reference, provided the proposed drug has characteristics in common with the approved drug. The application may include clinical and preclinical data from published literature, including previous regulatory submission data to support it.

Hybrid application and 505(b)(2) pathway are alike in their approval requirements. In both approval procedures the pre-submission meetings with regulatory authorities (FDA or EMA) are essential in order to establish the exact data sets required.

If the new developed formulation results bioequivalent to the reference product and the indications are the same, the amount of clinical information required by regulatory authorities is greatly reduced.

505(b)(2) application represents a hybrid between the FDA’s full NDA (505(b)(1) NDA) and the Abbreviated New Drug Application (505(j) Abbreviated NDA or ANDA). 

Changes that support a submission of a Hybrid medicine in the EU and a 505(b)(2) application in USA include, but are not limited to: a different dosage form (e.g. tablets to transdermal patches), a different strengths, a change in the route of administration (oral to transdermal), a change in the dosing regimen (twice daily to once-a-day), an API modification (new salt, enantiomer, etc.) of an off-patent molecule. 

While ANDAs are eligible for 180 days of market exclusivity in USA if it is the first generic to market, a NDA 505(b)(2) application may be granted with three to seven years of market exclusivity, depending on the extent of the change to the previously approved drug and the type of clinical data included in the NDA. A market exclusivity of 3 years could be granted if one or more of the clinical studies, other than bioavailability/bioequivalence studies, were conducted or sponsored by the applicant. 

Generic medicines are considered equivalent to their reference products and, as such, cannot be branded or marketed on their own features. Their product inserts are identical to that of the reference product.

Because hybrid medicines and products approved by 505(b)(2) pathway offer additional benefits compared to the reference product (a new delivery system, better patient compliance, amelioration of certain adverse effects, etc.), they can be branded and marketed with attention to the advancements they bring to previous treatment. 

Generics compete on price with the RLD while hybrid or 505(b)(2) products compete based on the improvements they offer.

Changes from the previously approved drug must be significant enough to give the new product (e.g. transdermal patch) a real value that is particularly attractive to prescribing physicians.

Transdermal technology can be applied to a number of drugs that are currently commercialized in other dosage forms. Certain chemical and pharmacological/therapeutic characteristics of drugs (molecular weight, aqueous and lipid solubility, daily dose, etc) must be analyzed to determine with the greatest accuracy the possibility that a drug may be a potential candidate for transdermal administration.

In summary, in case of pharmaceutical projects based on a change in the dosage form of drugs whose patents have expired, or prior to the expiration of their patents, the NDA 505(b)(2) approval pathway in USA and the hybrid application in Europe, are strategies that deserve to be analyzed, since they allow optimizing costs, duration and risks of a new pharmaceutical development.

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