Biologics have changed the way we treat diseases. Unlike small-molecule drugs, which are made from chemical compounds with clear structures, biologics are large and complex molecules that come from living organisms. This group includes monoclonal antibodies, recombinant proteins, and the growing area of cell and gene therapy. Biologics allow for better targeting of disease pathways, but they also present unique challenges. As a result, they require a different approach to clinical development.

This article looks at important aspects of designing, carrying out, and monitoring clinical trials for biological products. We will discuss the challenges of immunogenicity, the complexities involved in making biological products, and the changing rules that govern these processes. This includes the new guidelines from ICH E6(R3) and recent efforts to update the FDA. These factors all influence how these treatments are given to patients.

But first, let us understand what biologics are or how different they are from small molecules, as discussed in the section that follows:

Introduction to biologics development

The fundamental difference between biologics and small-molecule drugs lies in their origin and structure. Small molecules are typically chemically synthesized and generally have a molecular weight well under 500 Daltons. And possess a simple, well-defined structure. In contrast, biologics are derived from biological sources. Such as microorganisms, animal cells, or plant cells, which are orders of magnitude larger and more complex. This complexity means that even minor changes in manufacturing can alter the final product’s safety and efficacy profile.

Categories of biologics

Monoclonal Antibodies (mAbs): Designed to bind specific targets (e.g., PD-1 inhibitors for cancer).
Recombinant Proteins: Such as insulin, growth factors, and clotting factors.
Cytokines and Fusion Proteins: Immune modulators like interferons or etanercept.
Cell Therapies: Including CAR-T cells and mesenchymal stromal cells, which are living drugs.
Gene Therapies: Viral vectors (e.g., AAV) that deliver genetic material to correct or replace faulty genes.
Biosimilars: Highly similar versions of already approved biologics, with no clinically meaningful differences.

The regulatory landscape

In the United States, the regulatory pathway for biologics is primarily overseen by the Center for Biologics Evaluation and Research (CBER), whereas small molecules fall under the Center for Drug Evaluation and Research (CDER). While some therapeutic proteins are reviewed by CDER, CBER handles most Cell and Gene Therapies (CGTs), vaccines, and blood products.

The goal of the clinical development program is to support a Biologics License Application (BLA). Unlike an NDA for a small molecule, which emphasizes chemistry, the BLA requires extensive clinical data to demonstrate “purity, potency, and safety”. A failed BLA can result in a Complete Response Letter (CRL), and recent history shows that past alignment with the FDA does not guarantee future approval if scientific standards evolve.

Globally, the regulatory environment is harmonizing around principles of risk-based oversight. The ICH E6(R3) guideline, which emphasizes “Quality by Design” and risk-proportionate approaches to trial conduct, is being adopted by major regulatory bodies, including the EMA, which brought Annex 1 into effect in July 2025, as well as the NMPA (China), TGA (Australia), and Health Canada. This shift encourages sponsors to build quality into trials from the outset rather than merely inspecting for it at the end.

With the regulatory framework established, sponsors must then translate these requirements into concrete trial designs, as discussed below:

Special considerations in biologics trial design

The unique nature of biologics, particularly advanced therapies, often renders traditional randomized controlled trial (RCT) designs impractical or unethical. This is especially true for products targeting rare, genetic diseases with very small patient populations.

The challenge of small patient populations (rare diseases)

Many Cell and Gene Therapies (CGTs) are designed for ultra-rare conditions. For example, the FDA’s emphasis on mechanistic reasoning and biological plausibility, particularly in the context of accelerated approval and rare disease development programs, highlights the need for flexible development frameworks. But when only a handful of patients exist globally, enrolling a statistically robust control arm is impossible.

Innovative design strategies:

Single-arm trials: These are increasingly common for serious conditions. However, a company developing a treatment for a rare condition faced two refusals from the FDA. The first came due to manufacturing problems found during an inspection of a third-party facility. The second was more significant as the FDA reversed its earlier position and decided that the single-arm trial data, which had initially been accepted as proof of the drug’s effectiveness, were no longer sufficient to demonstrate efficacy. This highlights a key challenge. Which is with no control group for comparison, the FDA’s confidence in the evidence can shift over time. Thereby leaving companies vulnerable to changing regulatory standards even after initial acceptance.
Externally controlled studies: Using historical data or real-world evidence (RWE) to create a synthetic control arm. The FDA’s December 2025 guidance on “Use of Real-World Evidence to Support Regulatory Decision-Making” provides a framework for this approach.
Bayesian designs: In January 2026, the FDA published a draft guide on using Bayesian methods in clinical trials. This guide allows companies to use past data to support current control groups, which can help them lower the number of participants needed in their studies.
Adaptive designs: These allow for modifications like sample size reassessment or adaptive enrichment based on interim data, making trials more efficient.

Choosing control groups and endpoints in biologics trials:

Selecting control arms for biological trials poses ethical and practical questions: The FDA recently stressed the need to control placebo even in vaccine trials and highlighted that the “gold standard” still depends on the context.
Head-to-head comparisons: When a potentially curative therapy exists, randomizing patients to a placebo becomes unethical. In such cases, sponsors must engage in rigorous early dialogue with regulators.

Endpoint selection:

Surrogate endpoints and biomarkers: For accelerated approval, the FDA is increasingly open to biomarkers. For instance, Beam Therapeutics aligned with the FDA on an accelerated pathway for BEAM-302 based on AAT biomarker levels over 12 months. Similarly, the January 2026 draft guidance on “Minimal Residual Disease in Multiple Myeloma” outlines how such biomarkers can support accelerated approval.
Patient-reported outcomes (PROs): For chronic biologic therapies, PROs captured via digital health technologies are becoming critical for understanding the true clinical benefit.

Immunogenicity and safety assessment in biologics clinical trials

A primary concern with biologics is immunogenicity, the ability of the therapeutic protein to induce an unwanted immune response. This can lead to the production of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs), which can neutralize the drug’s effect or cross-react with endogenous proteins, causing severe safety issues.

Designing for immunogenicity:
Trial designs must incorporate serial sampling schedules to assess the incidence and impact of ADAs. Researchers now use modern approaches such as the MHC-associated peptide proteomics (MAPPs) assay to predict immunogenicity risk by identifying which peptides derived from the biologic are presented to T-cells, potentially driving an immune response.

Long-term safety:

Cell therapies: Pose risks such as graft-versus-host disease (GvHD) and cytokine release syndrome (CRS), making it essential for sites to train staff in specific management protocols.
Gene therapies: Risks include insertional mutagenesis (where the viral vector inserts into the host genome and activates an oncogene) and oncogenicity. This mandates long-term follow-up observational studies, often lasting 5 to 15 years, to monitor for late-onset adverse events.
Durability of response: In gene therapy, a key question is whether the treatment remains effective over time. Trials need to include plans for long-term follow-up to check how long the therapy works and how well it keeps producing the necessary gene.

However, addressing these safety demands in practice requires an operational infrastructure that goes well beyond what conventional small-molecule trials typically demand. Let’s take a look at them in the following section.

Trial conduct and operational complexity

The operational execution of a biologic trial is significantly more complex than that of a small molecule trial.

Manufacturing and the supply chain
The link between the clinic and the manufacturing suite is inseparable.

“Process equals product”: Manufacturing changes during a trial can affect comparability. The FDA has recently introduced flexibility, allowing minor manufacturing changes between Phase 1 and Phase 2 with supportive comparability data. However, sponsors must maintain rigorous oversight.
Product stability: Many biologics have short shelf-lives and strict cold chain requirements (e.g., -70°C for mRNA or viral vectors). For autologous cell therapies, teams must meticulously manage the “vein-to-vein” time, the duration from apheresis to infusion.
Supply chain visibility: With multiple vendors involved in specialized distribution, sponsors must ensure end-to-end oversight.

Site selection and investigator qualifications
Not every clinical site can handle a complex biologic.

Infrastructure needs: Sites administering cell therapies require apheresis centers and, in some cases, clean rooms for cell handling.
Training: Sponsors must train site staff on complex administration protocols (e.g., pre-conditioning chemotherapy for CAR-T) and the management of specific adverse events like CRS or immune effector cell-associated neurotoxicity syndrome (ICANS).

The role of decentralized clinical trials (dcts)
While DCTs are gaining traction, their suitability for biologics is mixed.

Suitable elements: Remote monitoring of stable patients on long-term subcutaneous biologics (e.g., for rheumatology) can be highly effective, utilizing digital health technologies for data collection.
Challenges: Administering IV biologics at home remains difficult due to the risk of infusion reactions and the need for immediate medical intervention. The FDA Final Guidance on DCTs (October 2025) and Health Canada’s Draft Guidance stress that the qualifications of local healthcare providers must be equivalent to those at a traditional site.

Oversight and regulatory compliance

Enhanced oversight of CMC (Chemistry, Manufacturing, and Controls)

Many clinical holds for biologic trials stem from manufacturing questions, not clinical ones. The integration of regulatory strategy with CMC is vital.

Potency assays: A critical part of the BLA is the potency assay, which measures the biological activity of the product. The FDA’s draft guidance on “Potency Assurance for Cellular and Gene Therapy Products” emphasizes that sponsors must develop and validate assays in tandem with clinical trials to ensure they measure the relevant mechanism of action.
Process validation: Recognizing the unique manufacturing challenges of CGTs, the FDA has moved away from applying the traditional expectation of three successful Process Performance Qualification (PPQ) lots. Instead allowing sponsors to demonstrate process understanding through flexible, risk-based approaches tailored to the specific product and manufacturing platform.

Safety reporting and pharmacovigilance

The final guidance on “Investigator Responsibilities-Safety Reporting for Investigational Drugs and Devices” (December 2025) clarifies sponsor and investigator roles in navigating FDA safety reporting rules. For biologics, aggregate safety data reviews are crucial for continuously assessing the benefit-risk profile, especially as long-term data on durability and late toxicity accumulates.

BIMO inspections

Preparing for FDA Bioresearch Monitoring (BIMO) inspections is critical. The focus is on data integrity and trial conduct. With the implementation of the new Quality Management System Regulation (QMSR) for combination products (e.g., a pre-filled biologic in a device), FDA investigators now have expanded access to internal records, including management reviews and supplier audits, which were previously shielded.

The impact of evolving regulatory standards

The current regulatory climate is one of rapid evolution and sometimes, uncertainty.

Learning from CRLs: Recent cases in 2025 and early 2026 show that getting approval from the FDA does not always stop the agency from issuing Complete Response Letters (CRLs). Some sponsors experienced unexpected changes in the FDA’s views on the adequacy of single-arm trials. These situations highlight the importance of having ongoing discussions with the FDA throughout the entire process, and not just at the beginning.
Importance of documentation: Sponsors must obtain clear, written confirmation from the FDA (e.g., meeting minutes) regarding trial design, endpoints, and control arms. This documentation is the only defense against shifting internal agency standards.
International harmonization: Navigating multi-regional clinical trials (MRCTs) requires balancing divergent views from the FDA, EMA, and NMPA. What one region accepts as a surrogate endpoint, another may reject.

Conclusion

The development of biological products is changing medicine and offers hope for conditions that were once thought untreatable. Success in this field requires a complete approach that covers many areas. Including the design of treatments for rare diseases, understanding how the immune system reacts, managing the logistics of delivering living drugs, and navigating the changing regulations.

Sponsors need to use innovative study designs, ensure strong oversight of manufacturing processes, and keep clear communication with regulators. As the FDA updates its methods and introduces flexible approval processes for rare diseases, those who can adjust to new standards while staying committed to patient safety and accurate data will succeed. In conclusion, the future of medicine lies in biological products. And the tests that develop these treatments must be precise and complex, just like the treatments themselves.

Are you planning a biologics clinical trial?

Designing a trial that meets FDA standards, selecting the optimal study design, and determining the evidence required for regulatory approval can be complex. Our team can help you develop a trial strategy that is scientifically rigorous, regulatory-ready, and tailored to your specific needs. Share your requirements with us, and we will work with you to build a trial strategy that is scientifically sound, operationally feasible, and fully compliant with regulatory expectations.