Challenges to Navigating the Pharmaceutical Regulatory Landscape

Navneet Kaur
Senior manager of
regulatory affairs
Alkermes, Inc.

The pharmaceutical industry stands at a crossroads of innovation, science, and stringent compliance. Predicting the regulatory pathway for any newly developing drug has never been an exact science. Consequently, achieving approval into the pharmaceutical market has always been expensive, time-consuming, and stressful for all stakeholders. Navigating this intricate landscape presents challenges for stakeholders—from global corporations to emerging biotechs. These hurdles arise from varying regulations across regions, rapidly advancing technologies, and the need to balance safety with innovation. In the United States, the biomedical industry encounters numerous regulatory challenges in conducting nonclinical and clinical studies and managing chemistry, manufacturing, and controls (CMC) activities. While the industry faces several obstacles, drug manufacturers can adopt strategies to address them effectively.

Current regulatory affairs

As recognized gatekeepers to the global marketplace, the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) are the starting points for many drugs introduced today. According to the Centre for Innovation in Regulatory Science,¹ the FDA approves the highest number of new active substances among the world’s six major regulatory agencies, which, aside from FDA and EMA, include Canada’s Therapeutic Products Directorate, China’s National Medical Products Administration, Australia’s Therapeutic Goods Administration, and Japan’s Pharmaceuticals and Medical Devices Agency. This number continues to increase. In 2023, the FDA approved 55 new drugs, a 50 percent increase from the previous year (37 new drugs) and the second-highest number of new drugs approved over the past three decades. Despite the large caseload, FDA officials boast various efficiencies that highlight the overall success and validity of the administration’s review process, including a 76 percent rate of novel drug approvals by the administration’s Center for Drug Evaluation and Research on the first cycle. Furthermore, of the 37 novel drugs approved by the FDA in 2022, 25 (or 68 percent) were first approved for use in the United States, according to the FDA.

Nonclinical studies and regulatory challenges

While limited in early development, nonclinical studies provide critical insights into potential risks compared to the evaluation of safety, efficacy, dosage, and side effects that clinical studies can offer. There is no set number or specific typeofnonclinical studies required to satisfy safetyassessments. Flexibility exists for each new compound. The traditional approach is outlined in guidance documents from the FDA and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. These guidelines typically involve a combination of in vitro assays and whole-animal testing. Recent scientific advancements have introduced new approach methodologies for nonclinical testing,² which are currently used across various stages of drug development. While traditional nonclinical testing methods can predict clinical outcomes, there is ongoing encouragement for improvements to enhance their predictive capabilities.

Nonclinical studies, such as preclinical toxicology and pharmacology, must comply with FDA standards, including Good Laboratory Practice.³ Demonstrating safety through animal studies presents ethical and scientific challenges, as it is critical for these studies to strike a balance between ethical considerations and the scientific rigor required to meet regulatory standards. Companies face high costs and extended timelines when generating the necessary nonclinical data to support investigational new drug (IND) applications. The use of innovative approaches, such as in vitro methods and computational toxicology, introduces regulatory uncertainties, since these methodologies may not always align with established guidelines.

Regulatory challenges in clinical studies

Clinical trials are inherently intricate, demanding precise planning and execution. The evolving FDA guidelines have made this endeavor even more challenging. In June 2024, the FDA introduced draft guidance highlighting the significance of promoting inclusivity in clinical research. This guidance urges sponsors to establish diversity action plans to recruit participants from diverse racial and ethnic groups and other demographic categories, such as older adults and individuals with complex medical conditions. Fulfilling diversity objectives remains challenging due to the need to balance FDA requirements for demographic representation and the competitive landscape for participants in rare disease trials, which can lead to delays. Additionally, the FDA requires sponsors holding IND applications to include the initially planned and actual enrollment figures in annual reports, categorized by race, gender, and age. This requirement underscores a growing regulatory emphasis on demographic transparency.

In September 2024, the FDA released guidance⁴ advocating decentralized clinical trials (DCTs). These trials aim to enhance accessibility and efficiency by incorporating telehealth visits and remote assessments. Implementing DCTs presents obstacles, such as achieving regulatory compliance, ensuring robust infrastructure, and maintaining data quality from remote sources. Sponsors are also required to address complex requirements for IND submissions, safety protocols, and amendments, further increasing administrative burdens. The rising reliance on real-world evidence⁵ adds another layer of difficulty, as it demands meticulous data validation and interpretation. Ensuring compliance through HIPAA and other privacy laws, along with securely managing data from digital health devices, such as wearables, is crucial to maintaining data integrity.

With trial costs increasing and resources constrained—particularly for smaller sponsors—it has become essential to innovate trial designs, engage with the FDA proactively, and adopt advanced technologies. By focusing on ethical and patient-centered practices, sponsors can effectively navigate the challenges of modern clinical trials while meeting regulatory standards.

Regulatory issues in executing CMC strategies

Executing CMC strategies involves managing challenges to ensure compliance with evolving regulations. Organizations must stay vigilant and adapt proactively, updating filings, aligning compliance measures with new requirements, and revising testing protocols. Having systems in place to monitor regulatory updates, assess their impact, and implement changes quickly is critical. Non-compliance can lead to delays, rejections, or legal and financial consequences, underscoring the importance of responsive compliance strategies.

Transitioning to large-scale manufacturing can reveal gaps that need to be addressed to meet regulatory standards.Regulatory bodies require proof that processes consistently produce quality products.Extensive testing to confirm quality, safety, and efficacy is resource-intensive and can be difficult to meet consistently.

Variability in raw material quality or availability poses risks to production, requiring robust risk-mitigation strategies,⁶ including assessments and remediation plans. Regulatory bodies mandate the documentation and reporting of manufacturing deviations, with non-compliance potentially resulting in delays or recalls. It’s crucial for companies to also remain inspection-ready at every development stage to meet CMC requirements.

Maintaining data integrity is essential. This involves ensuring data accuracy and uniformity throughout the product lifecycle. Challenges arise from generating data across various development stages and managing complex systems with cross-functional teams. Any errors or gaps in data handling can undermine submissions that invite regulatory scrutiny or delays. Organizations can adopt robust data management systems to address this, adhere to best practices for maintaining data integrity, and conduct regular audits to ensure compliance with regulatory standards.

Mitigation strategies for meeting regulatory challenges

Creating a regulatory strategy that spans the entire drug lifecycle is crucial. Anticipating future issues and evaluating options early can determine product approval success. Early CMC focus ensures drug quality and supply. Mitigation strategies must align with the clinical development plan from a multidisciplinary perspective. These strategies cover pre-submission, regulatory approval, and post-market monitoring. Key baseline strategies include

• Engaging with health authorities.Collaboration is crucial to managing nonclinical, clinical, and CMC risks. This proactive engagement helps ensure compliance with regulatory standards, addresses safety concerns early, and aligns the development process with established guidelines. By maintaining open communication, companies can gain valuable insights into regulatory expectations, receive guidance on innovative approaches, and resolve potential challenges that may affect the advancement of drug development.
• Designing a regulatory strategy roadmap. Assess drug benefits versus risks and identify the most significant anticipated regulatory hurdles.
• Defining the patient population to be targeted. Collect and analyze data across various parameters, such as demographics and characteristics, disease profiles, environmental factors, and social determinants of health.
• Establishing a standard for trials. Create a standard adaptable to the constantly evolving regulatory environment and clinical healthcare landscape.
• Consulting with relevant experts. Conduct a complete review of all clinical development plan elements to identify potential areas for improvement.

Predicting the future of regulatory challenges is difficult because of today’s increasingly sophisticated advanced technology. All drug development efforts will face extraordinary hurdles as attempts are made to bring more drugs to market. By developing a comprehensive understanding of the existing regulatory bodies and what to look for when assessing new products for patient care, drug developers can be better prepared to meet regulatory trends and implement best practices in the manufacturing space.

Navneet Kaur is a senior manager of regulatory affairs at Alkermes, Inc., a global biopharmaceutical company.

Sources

1. New Drug Approvals in Six Major Authorities. Centre for Innovation in Regulatory Science. https://cirsci.org/wp-content/uploads/dlm_uploads/2024/07/CIRS-RD-Briefing-93-six-agency-briefing-v2.0.pdf
2. An FDA/CDER perspective on nonclinical testing strategies: Classical toxicology approaches and new approach methodologies (NAMs). ScienceDirect. July, 2020. https://www.sciencedirect.com/science/article/abs/pii/S027323002030088X
3. Nonclinical Laboratories Inspected under Good Laboratory Practices. FDA. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-references/nonclinical-laboratories-inspected-under-good-laboratory-practices
4. Conducting Clinical Trials with Decentralized Elements. FDA. https://www.fda.gov/media/167696/download
5. Real-World Evidence. FDA. https://www.fda.gov/science-research/science-and-research-special-topics/real-world-evidence
6. How to navigate chemistry, manufacturing, and controls (CMC ) challenges in breakthrough drug development. News Medical Life Sciences. October 21, 2024. https://www.news-medical.net/whitepaper/20241021/How-to-navigate-chemistry-manufacturing-and-controls-(CMC-)-challenges-in-breakthrough-drug-development.aspx