REGULATORY STRATEGIES FOR ACCELERATED DRUG APPROVAL: A COMPREHENSIVE REVIEW OF FDA EXPEDITED PROGRAMS AND REGULATORY BEST PRACTICES WITH PEMBROLIZUMAB (KEYTRUDA®) CASE STUSY

ABSTRACT

The United States pharmaceutical market represents a significant center for global drug development and regulatory science. The U.S. Food and Drug Administration's (FDA) Center for Drug Evaluation and Research (CDER) has developed comprehensive frameworks for evaluating novel therapeutics, with submission volumes increasing from 139,322 in 2014 to over 310,000 in 2024. Understanding the strategic factors that influence FDA approval timelines provides valuable insights for regulatory science professionals and pharmaceutical developers worldwide seeking to optimize drug development processes and accelerate patient access to innovative therapies.

This review examines the systemic and strategic factors influencing FDA regulatory review timelines for new drug applications (NDAs), with emphasis on proactive regulatory strategy, expedited development pathways, and submission quality. We conducted a comprehensive analysis of FDA expedited programs, Common Technical Document (CTD) requirements, and case studies of successful regulatory strategies, including the accelerated approval of pembrolizumab (Keytruda®), a PD1 checkpoint inhibitor that revolutionized cancer immunotherapy. This drug has subsequently received regulatory approvals in multiple countries worldwide, demonstrating the global impact of effective regulatory strategies. The pembrolizumab case exemplifies how integrated use of expedited pathways can achieve approval within 6 months of BLA submission.

АННОТАЦИЯ

Фармацевтический рынок Соединенных Штатов является одним из ключевых центров мировой разработки лекарственных препаратов и регуляторной науки. Центр по оценке и исследованию лекарственных средств (CDER) Управления по санитарному надзору за качеством пищевых продуктов и медикаментов США (FDA) разработал комплексные подходы к оценке новых терапевтических средств, при этом объем подаваемых заявок увеличился с 139 322 в 2014 году до более чем 310 000 в 2024 году. Понимание факторов, определяющих сроки одобрения FDA, представляет значительную ценность для специалистов в области регуляторной науки и разработчиков лекарственных препаратов во всем мире, позволяя оптимизировать этапы разработки и ускорять доступ пациентов к инновационным методам терапии.

В данном обзоре рассматриваются системные и стратегические факторы, влияющие на сроки регуляторного рассмотрения заявок по одобрению новых лекарственных препаратов (NDA). Проведён комплексный анализ программ ускоренного рассмотрения FDA, структуры Общего технического документа (eCTD), а также практических кейсов эффективных регуляторных стратегий. В качестве ключевого примера приведено ускоренное одобрение пембролизумаба (Keytruda®) - ингибитора контрольной точки PD-1, который стал прорывом в области противоопухолевой иммунотерапии. Впоследствии препарат был одобрен в десятках стран, наглядно продемонстрировав глобальный эффект эффективной регуляторной стратегии. Этот кейс показывает, что грамотное использование ускоренных регуляторных механизмов позволяет получить одобрение в течение всего шести месяцев после подачи заявки на лицензию на биопрепарат (BLA).

Keywords: FDA approval, regulatory strategy, expedited programs, drug development, pembrolizumab

Ключевые слова: одобрение FDA, регуляторная стратегия, разработка лекарственных препаратов, пембролизумаб.

Introduction

The FDA's Center for Drug Evaluation and Research (CDER) serves as the regulatory gatekeeper for new therapeutic agents, evaluating their safety, efficacy, and manufacturing quality. The efficiency of this evaluation process directly determines when patients gain access to potentially life-saving medications. While the intrinsic scientific merit of a drug candidate remains paramount, the regulatory strategy employed and the quality of the regulatory submission represent critical non-clinical determinants that can either accelerate or significantly delay approval. The volume of submissions processed by CDER has grown substantially over the past decade.

According to FDA Electronic Submissions Gateway (ESG) statistics, CDER handled over 2.8 million total submissions from 2014 to 2024, with annual volumes rising from 139,322 submissions in 2014 to 310,433 in 2024 [1]. This represents a 123% increase over the ten-year period, creating an increasingly competitive environment where operational excellence in regulatory affairs is not merely advantageous but essential. Within this high-volume context, only a small fraction of submissions represent original NDAs or Biologics License Applications (BLAs) seeking approval for novel drugs. In 2024, CDER approved 50 novel drugs, with 26 having received orphan drug designation for rare diseases [2]. Notably, 68% of these approvals (34 of 50) were granted in the United States before approval in other countries, underscoring the efficiency potential of the U.S. regulatory system when properly navigated.

Methods and Materials

This article examines two interconnected pillars that influence approval timelines: the strategic framework for FDA interaction and utilization of expedited development programs, and the technical quality and completeness of regulatory submissions. We conclude with an analysis of pembrolizumab's accelerated approval pathway as a paradigm for regulatory excellence.

Total submissions to CDER have more than doubled over the past decade, rising from 139,322 in 2014 to 310,433 in 2024. This 123% increase reflects growing global pharmaceutical research and development activity and expanding regulatory requirements. The dramatic increase in submission volume creates several implications for drug sponsors. First, it intensifies competition for reviewer attention and agency resources. Second, it elevates the importance of submission quality, as deficient applications face longer delays in an already crowded review queue. Third, it emphasizes the value of strategic early engagement with FDA to differentiate promising candidates and secure expedited pathways.

Figure 1. FDA CDER Submission Volume Trends (2014-2024)

Data source: FDA Electronic Submissions Gateway

Despite the massive total submission volume, CDER approved 50 novel drugs in 2024, consistent with historical averages ranging from approximately 20 to 60 novel approvals annually over the past 15 years [3]. The relatively stable number of novel approvals amid growing total submissions underscores the selective nature of successful drug development and the critical importance of regulatory strategy.

Remarkably, 33 of the 50 novel drugs approved in 2024 (66%) utilized one or more of FDA's expedited development and review programs [2]. This high utilization rate demonstrates that expedited pathways have become the norm rather than the exception for innovative therapies addressing serious conditions.

Figure 2. Utilization of FDA Expedited Programs in 2024 Novel Drug Approvals. Data source: FDA CDER 2024 Annual Report

A passive, document-driven approach to FDA interaction represents a significant risk factor for regulatory delay. Successful sponsors employ a dynamic, strategic engagement model throughout the drug development lifecycle, viewing FDA not as an adversarial gatekeeper but as a collaborative partner in bringing safe and effective therapies to patients.

The FDA meeting management process provides sponsors with formal opportunities for alignment at critical development junctures. Type A meetings address disputes or issues requiring urgent FDA input, Type B meetings occur at predetermined milestones (pre-IND, End-of-Phase 2, pre-NDA/BLA), and Type C meetings provide general guidance on development programs. These meetings are not procedural formalities but strategic opportunities to secure FDA agreement on trial designs, endpoint selection (particularly for accelerated approval pathways), and the overall structure of the evidence package. Early alignment prevents costly missteps that could necessitate additional clinical studies or result in Complete Response Letters that extend timelines by 12-18 months or more.

The FDA offers four primary expedited programs designed to facilitate development and review of drugs for serious conditions: Fast Track designation, Breakthrough, Therapy designation, Accelerated Approval, and Priority Review [4]. These programs are not mutually exclusive and are frequently used in combination to achieve optimal timelines.

Table 1.

FDA Expedited Development and Review Programs: Eligibility, Benefits, and Timeline Impact. Data compiled from FDA guidance documents

The strategic value of expedited programs extends beyond the direct reduction in review clock time. Research analyzing 581 drug-indication pairs approved between 2008 and 2021 found that Priority Review was most frequently utilized (56.8%), followed by Fast Track (34.9%), Breakthrough Therapy (19.8%), and Accelerated Approval (14.1%) [6]. Importantly, these programs are commonly used in combination, with some products receiving three or four designations.

Analysis of review timelines demonstrates substantial benefits. Therapies with Priority Review had a mean review time of 9.4 months compared to 18.6 months for standard review, representing a time savings of 9.2 months on average [5]. The median development time for drugs with Accelerated Approval, Breakthrough Therapy, or Fast Track designation was 6.0 years versus 7.2 years for drugs without these designations - a 1.2 year reduction in total development time.

The International Council for Harmonization (ICH) Common Technical Document (CTD) format is the mandated structure for marketing applications submitted to FDA, as well as regulatory agencies in Europe, Japan, and other ICH regions. The CTD is organized into five modules: Administrative Information and Prescribing Information (region-specific), Common Technical Document Summaries, Quality (Chemistry, Manufacturing, and Controls), Nonclinical Study Reports, and final module - Clinical Study Reports.

While the CTD provides a standardized structure, it should not be viewed as a series of disconnected modules but rather as a coherent scientific and regulatory narrative.

Results and discussion

As part of the discussion, we refer to the case study of the FDA approval of pembrolizumab. The 2014 approval of pembrolizumab, a PD-1 inhibitor, for advanced melanoma represents a paradigm case of strategic regulatory excellence. Pembrolizumab achieved FDA approval on September 4, 2014, becoming the first anti-PD-1 therapy approved in the United States [9,10]. Merck's regulatory strategy for pembrolizumab exemplified proactive FDA engagement from the earliest stages of development. Key strategic elements included early FDA alignment on trial design and breakthrough therapy designation.

Merck engaged FDA early to secure agreement on using a single-arm trial design with objective response rate (ORR) and duration of response as endpoints suitable for Accelerated Approval. This eliminated the need for a randomized controlled trial with overall survival endpoints, which would have extended development by 2-3 years.  In January 2013, pembrolizumab received Breakthrough Therapy designation based on compelling early clinical evidence in patients with advanced melanoma refractory to ipilimumab [11]. This designation enabled intensive, ongoing collaborative dialogue with FDA throughout development, allowing real-time resolution of issues that might otherwise have delayed submission.

Leveraging its Breakthrough Therapy status, Merck utilized Rolling Review to submit completed portions of the BLA as data became available. This allowed FDA review of CMC and nonclinical sections to proceed while clinical trial follow-up continued, compressing the overall timeline from data completion to approval.

The regulatory approval was based on data from the KEYNOTE-001 Phase 1b trial, a multicenter, open-label, randomized, dose-comparative study. In the cohort supporting approval, 173 patients with unresectable or metastatic melanoma who had progressed following ipilimumab treatment were randomized to receive pembrolizumab at 2 mg/kg (n=89) or 10 mg/kg (n=84) every 3 weeks [9]. At the recommended 2 mg/kg dose, the overall response rate by blinded independent central review was 24% (95% CI: 15-34%), with 6 months of follow-up showing 86% of responses ongoing. The durability of response was a critical factor in FDA's benefit-risk assessment, as it suggested potential for long-term clinical benefit despite the relatively modest ORR.

Beyond strategic program utilization, Merck's operational execution was exemplary. The BLA dossier was meticulously prepared with comprehensive Module 2 summaries that proactively addressed anticipated reviewer questions. Narrative consistency across modules was rigorously maintained, and all clinical datasets conformed to CDISC standards, facilitating efficient FDA review. The approval came less than 4 years after IND submission, approximately half the typical 7-8 year development timeline for oncology drugs. This dramatic acceleration was achieved through the synergistic application of strategic regulatory programs and flawless execution, validating the principles outlined in this review.

Subsequently, pembrolizumab has achieved over 40 FDA approvals for various cancer indications, demonstrating the long-term value of early strategic investment in regulatory pathways [13].

Conclusion

Priority Review reduces median review time from 12 months to 8 months. In 2024, 66% of CDER`s 50 novel drug approvals utilized expedited programs. Strategic use of Breakthrough Therapy designation, combined with Rolling Review and rigorous dossier preparation, can compress development timelines by 1-2 years.

In the context of steadily rising submission volumes at CDER - from 139,322 submissions in 2014 to 310,433 in 2024, achieving timely drug approval is increasingly dependent on a sponsor's proactive regulatory intelligence and executional precision.  This review has demonstrated that optimal approval timelines result from the integration of two essential elements: sophisticated regulatory strategy and technical submission excellence.

A sophisticated regulatory strategy encompasses early and substantive FDA interaction, strategic utilization of expedited development programs (particularly Breakthrough Therapy designation and Rolling Review), and alignment on trial designs and endpoints that support efficient evidence generation. However, this strategy is only realized through the submission of a technically flawless CTD that presents a compelling, consistent, and complete scientific narrative.

The case of pembrolizumab illustrates that the integration of Breakthrough Therapy, Rolling Review, Priority Review, and Accelerated Approval - combined with exceptional submission quality - can compress development timelines by years and review timelines by months. With 66% of novel drugs approved in 2024 utilizing expedited programs, these pathways have become the standard approach for innovative therapies addressing serious conditions.

Future developments in regulatory science will likely involve greater use of artificial intelligence for dossier quality control, real-world evidence integration into regulatory submissions, and more sophisticated adaptive trial designs. The fundamental principle, however, will remain: sponsors that master both the strategic and technical dimensions of regulatory science will consistently navigate the approval pathway with the greatest speed and predictability, ultimately accelerating patient access to transformative new therapies.

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