Impact of an Evolving Regulatory Landscape on Skin Cancer Drug Development in the U.S

Article and Authorship Details

Article type: This is a pre-print. This article is under review.

Authors: David M. Miller1* MD PhD, Sophia Z. Shalhout1 PhD, Denise Casey3 MD, Lola Fashoyin-Aje2 MD, Steven Lemery2 MD, Marc R. Theoret2 MD, Richard Pazdur2 MD

1Department of Medicine, Division of Hematology/Oncology and the Department of Dermatology, Massachusetts General Hospital, Boston, MA 2The Food and Drug Administration, Silver Spring, Maryland. 3DataRevive LLC, Rockville, MD 20850

*Corresponding author: David M. Miller MD PhD
Massachusetts General Hospital

Funding sources: None

Conflicts of interest: David M. Miller has received honoraria for work on advisory boards for Pfizer Inc., Merck Sharpe & Dohme, Sanofi Genzyme, Regeneron, EMD Serono, and Checkpoint Therapeutics. This article reflects the views of the authors and should not be construed to represent the views or policies of the FDA.

Manuscript word count: 2493
Abstract word count: 149
References: 12
Figures: 8
Tables: 2

Keywords: regulatory medicine, cutaneous oncology, melanoma, Merkel cell carcinoma, squamous cell carcinoma

Abbreviations: 2D Measurement: Sum of two dimensional tumor measurements, ACTG: AIDS Clinical Trials Group Oncology Committee of the National Institute of Allergy and Infectious Diseases criteria, AK: actinic keratosis, BCC: basal cell carcinoma, CCR: complete clearance rate, CTCL: cutaneous T-cell lymphoma, DESI: Drug Efficacy Study Implementation, DFSP: dermatofibrosarcoma protuberans, FDA: US Food and Drug administration, FDAAA: Food and Drug Administration Amendments Act, FDAMA: Food and Drug Administration Modernization Act, FDARA: Food and Drug Administration Reauthorization Act, FDASIA: Food and Drug Administration Safety and Innovation Act, GRS: global response criteria, HDAC: histone deacetylase, KS: Kaposi’s sarcoma, laBCC: locally advanced basal cell carcinoma, laCSCC: locally advanced cutaneous squamous cell carcinoma, lb95%CI: lower bound 95% confidence interval, mBCC: metastatic basal cell carcinoma, MANUF (CMC): Chemistry, Manufacturing and Controls, MCC: Merkel cell carcinoma, mCSCC: metastatic cutaneous squamous cell carcinoma, mRECIST: modified RECIST, mSWAT: modified SWAT, ORR: overall response rate, OS: overall survival, PFS: progression-free survival, PHBPA: Public Health and Bioterrorism Preparedness Act, PK: pharmacokinetic analysis, RECIST: Response Evaluation Criteria in Solid Tumors, r/mCSCC: recurrent or metastatic cutaneous squamous cell carcinoma, rCTCL: refractory cutaneous T-cell lymphoma, RFS: relapse-free survival, SCC: squamous cell carcinoma, SWAT: severity-weighted assessment tool, u/mMelanoma: unresectable or metastatic melanoma, U.S.: United States, WHO: world health organization; WSSI: weighted skin severity index.


Background: There has been a rapid proliferation of FDA-approved medications with labeled indications for skin cancer over the last decade, with particular growth over the last 5 years.
Objective: We aimed to evaluate the impact of an evolving U.S. regulatory framework on drug development programs to better understand current trends and regulatory considerations when adjudicating drug approvals for patients with skin cancer.
Methods: We reviewed publicly-available regulatory documents of all systemic medications with a labeled indication for skin cancer.
Results: We identified 130 FDA approvals that resulted in a unique indication, usage, formulation or dosage change in skin cancer since 1949.
Limitations: Publicly available data from the mid-to-late 20th century is limited.
Conclusions: The therapeutic landscape in skin cancer has changed greatly since the first approval in 1949. In concert, regulatory medicine has also evolved over the last 70 years with the aim of ensuring safe and effective medicines for a diverse array of patients.


Skin cancer is a heterogeneous group of malignancies that result from neoplasia of keratinocytes, melanocytes, adnexal structures, nervous tissue, stromal cells and effectors of the innate and adaptive immune system. In aggregate, new cases of skin cancer outnumber all other forms of cancer combined, with keratinocyte carcinoma alone accounting for 3-4 million cases in the US every year.1 In keeping with the diverse mechanisms that give rise to cutaneous malignancy, there are a heterogeneous group of drug therapies used to treat skin cancer, which includes cytotoxic agents, targeted therapies, and immunotherapies (Table 1). Analogous to the changing therapeutic landscape in cutaneous oncology, the field of regulatory medicine has also evolved substantially over the last century.

To understand how current trends and regulatory approaches to adjudicating drug approvals for skin cancer are influenced, it is useful to also recognize the evolution of regulatory medicine in general. For example, the FDA’s modern regulatory function commenced with the Pure Food and Drugs Act of 1906, which prohibited the manufacturing and distribution of misbranded products. Galvanized in large part by the Elixir of Sulfanilamide disaster, Congress passed the Federal Food, Drug, and Cosmetic (FD&C) Act in 1938. The FD&C Act contained provisions requiring new drugs to be shown safe before marketing. In 1962, the FD&C statute was amended to require proof of efficacy in addition to safety prior to granting marketing approval (Figure 1).

Figure 1. Landscape of Regulatory Medicine and Cutaneous Oncology Time_Series_Drug_Development_HTML.knit