Navigating Complex Challenges, Regulatory Requirements, and Design Considerations in Transdermal Drug Delivery System Clinical Trials

The design of clinical trials for transdermal drug delivery requires comprehensive consideration of multiple factors, including the characteristics of the skin and the drug, the complexity of the delivery system, technical challenges, regulatory requirements, patient compliance, safety evaluation, and the complexities inherent in multidisciplinary collaboration. Therefore, it is essential to meticulously design the clinical trial protocol, establish strict standard operating procedures (SOPs), and leverage the expertise of a professional technical team.

Recently, held in NanjingChina New Resources Conference for the Entire Pharmaceutical Industry ChainAt the Special Session of the Conference on R&D and Application Innovation Collaboration in Transdermal Technology, a group of renowned industry experts gathered to delve into the opportunities and challenges across the entire industrial chain of transdermal formulations.Professor Liu Yali, Deputy Director of the Institution and Director of the Phase I Clinical Trial Ward at the First Affiliated Hospital of Shantou University Medical College, delivered a keynote speech titled “Regulatory Requirements and Design Considerations for Clinical Trials of Transdermal Drug Delivery Systems.”

Professor Liu Yali is the founding director of the institution at Hunan Cancer Hospital, formerly serving as Deputy Director of the Institution and Director of the Phase I Clinical Trial Ward. He serves as Vice Chairman of the Clinical Evaluation Branch for Drug Innovation and R&D under the China Medical Education Association, a two-term Executive Committee Member of the Chinese Society of Clinical Oncology (CSCO), and one of the first national experts in Good Clinical Practice (GCP) inspections. Professor Liu has 26 years of experience working in hospitals, over ten years in the pharmaceutical industry, and prior experience at the Center for Drug Evaluation (CDE).

Key Points from Professor Liu Yali's Speech:

Transdermal drug delivery systems can exert systemic effects through local administration or achieve localized effects at the site of application. Today, transdermal delivery has become the third major route of drug administration, following oral and injectable routes. Transdermal delivery offers numerous advantages, such as: avoiding hepatic first-pass metabolism and gastrointestinal interference (e.g., pH, food, enzymes), thereby enhancing therapeutic efficacy; avoiding adverse effects of drugs on the gastrointestinal tract; maintaining stable blood drug concentrations over extended periods (avoiding peak-trough fluctuations); reducing dosing frequency and improving patient compliance, particularly for drugs with short half-lives that require frequent administration; and allowing immediate discontinuation of therapy in case of adverse reactions (simply by removing the patch).

However, topical formulations have certain limitations. For instance, many drugs cannot penetrate this barrier in sufficient quantities. Drugs unsuitable for transdermal delivery include those requiring high doses (>5 mg) or causing skin irritation. Additionally, there is significant variability among individuals and across administration sites. The molecular weight, polarity, and melting point of a drug all influence its transdermal absorption.

From the perspective of disease:Currently, there are more than 2,000 types of skin diseases in the global disease classification system, and topical preparations are relied upon for the treatment of 70% of these conditions.Therefore, pharmaceutical companies should prioritize a deep understanding of disease pathogenesis from a disease-centric perspective during project initiation. While intense competition has emerged among multiple drugs targeting the same indication, many diseases still lack effective treatments. Consequently, pharmaceutical companies should place greater emphasis on addressing current unmet clinical needs.

In addition to dermatological conditions, there is significant clinical demand for solutions addressing poor medication adherence, particularly in pediatric and geriatric populations. Furthermore, products bridging the gap between therapeutic treatment and medical aesthetics—such as those targeting dandruff, scalp pruritus, and seborrhea—also represent a substantial unmet clinical need.

Precautions for the Clinical Application of Transdermal Preparations: Considerations Throughout Project Initiation, Protocol Design, and Clinical Operations

First, the design principles for bioequivalence (BE) studies of transdermal patches are consistent with those for other conventional drugs, except that the site of administration is the skin. Therefore, there are numerous requirements and standards for the skin at the application site in study subjects, including excessive hairiness, presence of scars or tattoos, and the duration of patch application.

Additionally,Adhesion force testing can be conducted concurrently with bioequivalence (BE) studies.However, the sample sizes for the two trials may differ, with the adhesion trial typically having a larger sample size than the bioequivalence (BE) trial. The adhesion score is one of the primary endpoints for evaluating the efficacy of transdermal patches. Throughout the study period, the patch should not be covered or reinforced. Subjects’ daily activities should not be restricted, and any patch that detaches during the trial must not be reapplied.

Additionally,In clinical trials of transdermal patches, in addition to assessing drug bioequivalence and adhesive strength, it is also necessary to evaluate the potential for skin irritation and sensitization caused by the patch.A true irritation test requires continuous application for 21 days to assess the skin’s long-term response to the patch. The sensitization test involves a 48-hour continuous application following a 2-week interval after the initial 21-day continuous application period. According to FDA guidelines on irritation and sensitization testing, in addition to a positive control group, an inert placebo patch may be required as a negative control for certain drugs to meet specific study requirements. The selected dose may be the same as that used in bioequivalence (BE) studies, or it may need to be adjusted (e.g., reduced by half or to one-quarter). Although these assessments are not currently mandated by Chinese regulations, Professor Liu still recommends conducting such observations and evaluations in clinical trials to comprehensively understand the efficacy and safety of the patch.

Professor Liu emphasized that, as factors such as skin perspiration can affect the absorption of transdermal patches, attention should be paid to ambient temperature and humidity.

In the regulatory framework for clinical trial registration of transdermal drug delivery systems, the guidelines issued by the U.S. FDA are worthy of attention and study.# FDA Requirements for Clinical Trials of Transdermal Drug Delivery SystemsClinical trials conducted by pharmaceutical companies are categorized into three types: bioequivalence studies, adhesion studies, and skin irritation and sensitization studies.For some of these drugs, bioequivalence is assessed using clinical endpoints in randomized controlled trials. Furthermore, adhesion studies can be conducted concurrently with either bioequivalence trials or skin irritation and sensitization tests; however, regardless of the combination chosen, adhesion assessment is a mandatory endpoint in the clinical evaluation of transdermal patches.

According to Professor Liu, there are currently more than 300 transdermal drug products marketed in the United States. Among them, the FDA has issued guidance documents on bioequivalence studies for 28 patch and plaster products (covering 22 active ingredients). The guidelines for 23 transdermal patches and 3 topical patches all adopt pharmacokinetic endpoints for bioequivalence studies. For the other two topical patches (capsaicin and diclofenac epolamine), bioequivalence studies with clinical endpoints are required. Additionally, the diclofenac epolamine patch must also undergo a pharmacokinetic-based bioequivalence study to confirm its safety.

In China, the guideline for transdermal drug delivery pharmaceuticals, titled "Technical Guidelines for the Research and Development of Topical Chemical Generic Drugs," has been issued. For generic drugs in the form of topical true solutions: if the types (Q1) and amounts (Q2) of excipients are identical, and the critical quality attributes (CQAs) of at least three batches of the generic product are consistent, an application for waiver of clinical trials may be submitted. For suspensions and semi-solid formulations (such as creams, ointments, and gels): if Q1, Q2, and Q3 are consistent, studies may be conducted in accordance with the bioequivalence guidelines specific to the product; if a waiver is requested, justification and supporting evidence must be provided. It is generally recognized in pharmaceutical research technology that while complete consistency in Q1 and Q2 remains challenging, if Q3 is consistent, clinical equivalence trials should be conducted to demonstrate clinical equivalence between the generic drug and the reference listed drug.

The “Technical Guidelines for Clinical Trials of Drugs with Local Administration and Local Action” have also been issued. Many products submitted by domestic pharmaceutical companies fall into this category. Most of these generic drugs require randomized controlled clinical trials to demonstrate bioequivalence with the reference listed drug, implying a heavier burden on pharmaceutical companies in conducting clinical trials. Globally, the industry is conducting more in-depth and extensive exploration of pharmacokinetic (PK) methods for locally acting transdermal drug delivery systems to overcome this challenge.

Professor Liu added that the regulations governing clinical registration trials are of paramount importance. Numerous relevant regulations have been promulgated both domestically and internationally; among these, the U.S. regulatory framework is more robust, featuring numerous clinical guidelines for various drugs. Therefore, pharmaceutical companies should place greater emphasis on referencing international guidelines during drug research and development and project initiation.

Modified new drugs must demonstrate clear clinical advantages at the project initiation stage, such as significantly enhancing local efficacy; substantially reducing adverse reactions or medication-related risks; or markedly improving patient adherence. Taking the clinical advantages of modified transdermal patches in the United States as an example, the fentanyl transdermal patch is a modified new drug that reduces adverse reactions, provides long-lasting analgesic effects, and maintains prolonged duration of action compared with the oral formulation, all of which constitute its clinical advantages.

Currently, in the absence of true source innovation within the industry, greater attention should be paid to improved new drugs. Particularly when an improved new drug involves a change in indication, comprehensive clinical trials are required. For instance, when donepezil was reformulated from an oral preparation into a transdermal patch for the treatment of Alzheimer’s disease, Phase II and Phase III clinical trials remained unavoidable after the selection of the new therapeutic indication. However, it is worth noting that this drug underwent extensive bridging studies during Phase I. This approach has provided significant insights: if Phase I trials are well-designed and executed, they can potentially eliminate the need for many subsequent clinical trials, thereby accelerating the drug development process.

Nowadays, innovations in materials and technology have brought greater feasibility to the research and development of transdermal formulations, and it is hoped that transdermal technologies will continue to provide patients with better therapeutic options in the future.