Drug Companies Reveal Shortcomings in FDA Draft Guidance on Generic Topical Patches

Regulatory NewsRegulatory News | 18 August 2016 |  By 

Mylan, Perrigo, AstraZeneca and Apotex are seeking more clarity and raising questions with the shortcomings of US Food and Drug Administration (FDA) draft guidance aiming to improve the way adhesion data is used for abbreviated new drug application (ANDA) submissions of transdermal delivery systems and topical patches.

The draft guidance, released in May, describes the recommended approach for an adhesion clinical study design and, once finalized, the guidance will supersede FDA’s prior recommendations on adhesion studies in individual product-specific guidance documents.


Pennsylvania-based Mylan, which says it appreciates FDA's new approach for evaluating comparative adhesion, notes that although FDA improves upon its present methods for evaluating adhesion, Mylan believes “it can be further improved to treat all products alike across the adhesion scale.”

For instance, in the draft guidance, “FDA proposes the use of a constant margin of 0.15 across all possible mean RLD [reference listed drug] scores. This method addresses the shortcomings with the previous approach for products with low adhesion scores on FDA's scoring scale by no longer requiring a generic applicant to demonstrate superior adhesion compared to the RLD when mean scores are <0.6. However, for mean RLD scores >0.6, the proposed constant margin could become too restrictive on a relative basis as the RLD scores increase. As a result, a generic product may now have to prove superior adhesion, instead of noninferiority, as RLD scores increase.”


In addition, Perrigo takes issue with the FDA request for photographic documentation, saying, “It is not clear what qualitative issues of an adhesion study photographic documentation would assess other than to confirm that the patch was applied flat against the skin to the correct application site. Quantitatively, photographic documentation [is] inferior to a visual measurement/assessment of patch adhesion. Light, camera angle, focus, resolution, depth of field, and skin and patch color are variables that have the potential to negatively affect the quality of the photographic documentation.”

Perrigo also says that if it is anticipated that four or more photographs are required to assess all of the edges of a patch, and study enrollment is 200 patients, approximately 7,200 photographs may be required to document the assessment.

“This volume of data to document a qualitative secondary measurement to collaborate a superior visual measurement appears to be unnecessary and an excessive burden on the study execution,” the Michigan-based drugmaker notes.

Meanwhile, the draft guidance also recommends that study subjects should be allowed to freely conduct daily activities and simulate real-world conditions, but the draft guidance also recommends patches to be worn between 12 and 24 hours and assessed every four hours, and patches with a 9-hour wear period to be assessed at least hourly.

Therefore, Perrigo recommends that FDA “add language to clarify that adhesion assessment studies may be run in a clinical setting and where feasible allow subjects to freely conduct daily activities and to simulate real-world conditions.”


AstraZeneca calls on FDA to clarify what products are covered under the guidance, including whether second- and third-generation transdermal systems are intended to be covered (i.e. iontophoresis, microneedles, poration, ablation etc.) or if there will be other standards/guidance to be considered for these.

“For example, only considering simple adhesion of a microneedle patch during a clinical study does not guarantee that (a) the needle penetrated in the first place, and (b) that the needles stayed in the skin long enough to deliver the drug,” AstraZeneca says. “Further clarification is requested from the Agency on whether there will be separate, specific guidance on these more complex systems or whether this guidance is intended to cover them.”


And Canadian generic drugmaker Apotex is requesting further clarification on the acceptability of the adhesion studies that have already been designed and conducted based on the existing individual product-specific guidance documents that were released before this draft became available.

Industry Comments on Assessing Adhesion with Transdermal Delivery Systems and Topical Patches for ANDAs


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