Clinical Trial Regulatory Requirements: An Overview

Clinical trials are governed by a layered system of regulatory requirements that vary by jurisdiction, product type, and trial phase. For researchers and life-science professionals, understanding these requirements is essential before enrolling the first participant. This article explains the core regulatory frameworks for clinical trials in the United States and European Union, including Investigational New Drug (IND) applications, Investigational Device Exemption (IDE) applications, Good Clinical Practice (GCP) guidelines, and the pathways that differ for drugs, biologics, devices, and advanced therapies.

The regulatory pathway for a clinical trial depends on what is being studied and where the study will take place. A small academic study of an existing approved drug for a new use follows a different path than a first-in-human trial of a novel biologic. A medical device trial requires an IDE instead of an IND. A trial conducted in the European Union operates under the Clinical Trials Regulation instead of the FDA framework. Each pathway carries specific documentation, oversight, and reporting obligations that sponsors must satisfy before and during the study.

At a Glance: Regulatory Pathways by Product Type

The table above summarizes the main routes, but the actual requirements depend on the specific product, its risk classification, and the intended use. The sections below explain each pathway in detail.

The Purpose of Clinical Trial Regulation

Regulatory oversight of clinical trials exists to protect study participants and to ensure that the data generated are reliable enough to support marketing decisions. The core documents that define these expectations are the International Council for Harmonisation (ICH) guidelines, particularly ICH E6 for Good Clinical Practice. These guidelines describe the responsibilities of sponsors, investigators, and institutional review boards, and they set standards for protocol design, data recording, adverse event reporting, and informed consent.

The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) both follow ICH guidelines as the foundation of their clinical trial requirements. However, each agency implements these standards through its own regulations and processes. The FDA operates under Title 21 of the Code of Federal Regulations, while the EMA operates under the EU Clinical Trials Regulation 536/2014, which replaced the earlier Clinical Trials Directive in 2022.

A key principle across all regulatory systems is that the level of oversight should match the level of risk. Early phase trials that expose participants to unproven interventions receive the most scrutiny. Later phase trials that confirm safety and efficacy in larger populations also face rigorous review, but the questions asked are different. Regulators want to know whether the product works, for whom it works, and what harms might occur.

The FDA Investigational New Drug Application

The IND application is the mechanism by which a sponsor obtains FDA authorization to ship and administer an investigational drug in humans. The FDA has 30 days to review an IND after submission. If the agency does not place the trial on clinical hold, the sponsor may begin enrolling participants. A clinical hold is an order to delay or suspend a trial, and it is issued when the FDA identifies significant safety concerns, deficiencies in the protocol, or inadequate manufacturing information.

The IND application must contain three broad categories of information. First, the sponsor must provide animal pharmacology and toxicology data from preclinical studies. These studies establish the starting dose for humans and identify potential toxicities that require monitoring. Second, the sponsor must include manufacturing information that demonstrates the drug can be produced consistently and at adequate purity. Third, the sponsor must submit the clinical protocol and investigator information, including the qualifications of the study team and the commitments to obtain informed consent and institutional review board approval.

The preparation of a preclinical dossier to support an IND application requires careful integration of pharmacology, toxicology, and pharmacokinetic data. The dossier must justify the proposed starting dose, the dosing schedule, and the route of administration in humans. It must also address the species relevance of the animal models used and the translational limitations of those models. Sponsors typically conduct good laboratory practice compliant toxicology studies in two species, one rodent and one nonrodent, before submitting an IND.

The IND pathway applies to drugs and biologics that have not been approved for marketing. It also applies to approved drugs being studied for new indications, new dosing regimens, or new patient populations. A sponsor who wishes to study an approved drug for a new use must submit an IND unless the study qualifies for an exemption. The FDA provides guidance on when an IND is not required, such as for certain studies of approved drugs that do not involve a route of administration, dose, or patient population that significantly increases risk.

The FDA Investigational Device Exemption

Medical devices follow a different regulatory path than drugs. A sponsor who wishes to conduct a clinical study of a significant risk device must obtain an Investigational Device Exemption from the FDA. The IDE allows the sponsor to ship the device across state lines for the purpose of conducting the investigation. The IDE application must include a report of prior investigations, including bench testing and animal studies, a description of the device, the proposed protocol, and the qualifications of the investigators.

The FDA classifies devices into two categories for clinical trial purposes. A significant risk device is one that presents a potential for serious risk to the health, safety, or welfare of a subject. Examples include implants, devices that support or sustain human life, and devices that are substantially important in diagnosing, curing, mitigating, or treating disease. A nonsignificant risk device does not meet these criteria. Studies of nonsignificant risk devices require only institutional review board approval, not an IDE application to the FDA.

The IDE process has been clarified over time through FDA guidance and manual updates. The agency has issued manuals that explain the policies and procedures for IDE submissions, including the information required for different device types and the criteria for approval. Sponsors of device trials must also comply with the same GCP standards that apply to drug trials, including informed consent, adverse event reporting, and data integrity requirements.

The IDE pathway has been used for a wide range of devices, from cardiovascular implants to diagnostic tools. For example, the ACURATE IDE trial evaluated valve underexpansion and clinical outcomes with a transcatheter aortic valve replacement system. The Amulet IDE trial characterized device-related thrombus in patients receiving a left atrial appendage closure device. These trials demonstrate the breadth of device studies that operate under the IDE framework and the importance of collecting detailed safety and effectiveness data.

The EU Clinical Trials Regulation

The European Union operates its clinical trial oversight under Regulation 536/2014, which became fully applicable in January 2022. This regulation replaced the previous Clinical Trials Directive and introduced a centralized portal and database for clinical trial applications. Sponsors submit a single application through the Clinical Trials Information System, which is assessed by the national competent authorities of the member states where the trial will be conducted.

The regulation introduced a coordinated assessment procedure. For a trial conducted in multiple member states, one member state serves as the reporting member state and leads the assessment of the application. The other member states, known as concerned member states, assess specific aspects of the application, particularly site-specific and patient-safety considerations. The reporting member state has 45 days to complete the initial assessment, with an additional 50 days if the sponsor is asked for further information.

The EU regulation places strong emphasis on transparency. Trial results must be submitted to the EU database within one year of the end of the trial, or within six months for pediatric trials. This requirement aligns with the broader movement toward clinical trial registration and results reporting that has developed over the past two decades.

The transition to the new regulation has been challenging for academic sponsors. A report from an Italian cancer research institute described the impact of Regulation 536/2014 on academic studies involving therapeutic radiopharmaceuticals. The institute conducted 16 clinical trials under the previous directive and is currently promoting five studies under the new regulation. The transition required staff training in quality documentation, the establishment of a contract research organization to ensure data quality, careful budget planning, and the evaluation of innovative business models. The report noted that the new regulation's Good Manufacturing Practice requirements for investigational medicinal products created particular challenges for academic centers that previously relied on hospital pharmacies for product preparation.

Good Clinical Practice Guidelines

Good Clinical Practice is the international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve human participants. Compliance with GCP provides public assurance that the rights, safety, and well-being of trial participants are protected and that the data from the trial are credible.

The ICH E6 guideline is the primary GCP reference used by regulatory authorities in the United States, the European Union, Japan, and many other countries. The guideline describes the responsibilities of institutional review boards, investigators, and sponsors. It also establishes standards for essential documents, which are the records that individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced.

Key GCP requirements include the following. Informed consent must be obtained from each participant before any trial-related procedure. The consent form must explain the purpose of the trial, the procedures involved, the potential risks and benefits, and the participant's right to withdraw at any time. Adverse events must be documented and reported according to the protocol and regulatory requirements. Serious adverse events must be reported to the sponsor and the relevant regulatory authorities within specified timelines. Data must be recorded accurately and completely, and corrections must be made in a way that preserves the original entry.

GCP also requires that trial sites be monitored. The sponsor must ensure that the trial is conducted according to the protocol, that the data are accurate and complete, and that the rights and well-being of participants are protected. Monitoring may be conducted on-site, remotely, or through a combination of both approaches. The level of monitoring should be proportionate to the risks of the trial.

Clinical Trial Registration and Results Reporting

Clinical trial registration and results reporting have become legal requirements in many jurisdictions. The FDA Amendments Act of 2007 mandated that certain clinical trials be registered on ClinicalTrials.gov and that results be submitted to the registry within specified timelines. The law applies to trials of drugs, biologics, and devices that are subject to FDA regulation, with some exceptions for early phase trials.

Research on the impact of the FDA Amendments Act has shown that the law was associated with improvements in trial transparency. A study of efficacy trials supporting FDA approval of new drugs for cardiovascular disease and diabetes between 2005 and 2014 found that, compared with the period before the law, post-law studies were more likely to be registered, more likely to be published, and more likely to present findings concordant with the FDA reviewer's interpretation. The study examined 183 trials supporting 30 drugs approved for 32 indications.

However, compliance with registration and reporting requirements remains incomplete. A cross-sectional analysis of clinical trials submitted to the FDA for drugs approved in 2012 found that, per drug, a median of 57 percent of trials were registered, 20 percent reported results in ClinicalTrials.gov, and 56 percent were published. Almost half of all reviewed drugs had at least one undisclosed phase II or III trial. The study also found that 68 percent of research participants were enrolled in trials subject to the FDA Amendments Act, and 51 percent of those participants were enrolled in trials that were not compliant with the law.

These findings have important implications for sponsors. Registration and results reporting are not optional administrative tasks. They are legal obligations that affect the public record of a product's development and the scientific community's ability to assess the evidence base. Sponsors should build registration and reporting timelines into their trial planning from the outset.

Accelerated Approval and Postapproval Requirements

The FDA's accelerated approval pathway allows approval of investigational drugs that treat serious conditions and fill an unmet medical need, based on changes to surrogate measures that are reasonably likely to predict clinical benefit. Postapproval clinical trials are then required to confirm whether these drugs offer clinical benefit.

A cohort study of cancer drugs granted accelerated approval from 2013 to 2023 found that, among 46 indications with more than five years of follow-up, approximately two-thirds were converted to regular approval, 22 percent were withdrawn, and 15 percent remained ongoing after a median of 6.3 years. Fewer than half of the indications demonstrated a clinical benefit in confirmatory trials. The time to withdrawal decreased from 9.9 years to 3.6 years, and the time to regular approval increased from 1.6 years to 3.6 years.

These findings illustrate the risks and uncertainties of the accelerated approval pathway. Sponsors who pursue accelerated approval must be prepared to conduct confirmatory trials that may take years to complete. They must also be prepared for the possibility that the confirmatory trials will not demonstrate clinical benefit, which can lead to withdrawal of the approval.

The accelerated approval pathway is one example of how regulatory requirements extend beyond the initial clinical development program. Sponsors must consider the full lifecycle of a product, including postapproval commitments, when planning their regulatory strategy.

Biosimilar Development and Regulatory Requirements

Biosimilars are biological products that are highly similar to an already approved biological product, with no clinically meaningful differences in safety, purity, and potency. The development of biosimilars follows a distinct regulatory pathway that emphasizes comparability with the reference product.

The EMA began issuing guidelines for the development of biosimilars almost two decades ago and has approved numerous biosimilars. The FDA has issued draft guidances providing stepwise considerations for the nonclinical and clinical development of biosimilars. Clinical trials for biosimilars aim to resolve uncertainties that may remain following nonclinical development regarding the similarity of the proposed biosimilar with the reference product.

Pharmacokinetic and pharmacodynamic studies form the backbone of early clinical development for biosimilars and serve to inform phase 3 clinical development. Factors to be considered in clinical development include study population, design, end points, sample size, duration, and analytical methods. The goal is to demonstrate that any differences between the biosimilar and the reference product are not clinically meaningful.

The regulatory requirements for biosimilars differ from those for novel biologics. A biosimilar sponsor does not need to repeat the full clinical development program of the reference product. Instead, the sponsor must demonstrate similarity through a stepwise approach that includes analytical studies, animal studies, and clinical studies. The extent of clinical testing depends on the residual uncertainty after the analytical and animal studies are complete.

Advanced Therapy Medicinal Products

Advanced therapy medicinal products, or ATMPs, are a category of therapies that includes gene therapies, cell therapies, and tissue-engineered products. These products present unique regulatory challenges because of their complexity and the difficulty of characterizing them with standard analytical methods.

The classification of ATMPs within the European regulatory framework poses significant challenges, particularly when biomaterials are combined with viable cells. A review of ATMP classification for spinal cord injury therapies examined the regulatory criteria and procedures for ATMP classification in the European Union, with a focus on tissue-engineered products. The review addressed common difficulties in determining the principal mode of action, degree of manipulation, and intended function, which are key factors that guide classification.

The review presented the case of a hydrogel derived from human amniotic membrane extracellular matrix and integrated with induced neural stem cells, developed for spinal cord injury repair. The case highlighted how early classification decisions can influence quality control strategies, nonclinical study design, and clinical development pathways. Early regulatory classification is critical to reduce development uncertainty, especially for academic groups working on complex biomaterial-cell combinations.

Sponsors of ATMPs must engage with regulators early in the development process to clarify the classification of their product and the regulatory pathway that applies. The EMA provides a classification procedure that allows sponsors to request a scientific recommendation on whether a product qualifies as an ATMP. This procedure is voluntary but highly recommended, as it can prevent costly delays later in development.

Orphan Drug Designation and Expedited Programs

Orphan drug designation is available for products intended to treat rare diseases, defined as conditions affecting fewer than 200,000 people in the United States or fewer than 5 in 10,000 people in the European Union. The designation provides benefits including market exclusivity, fee waivers, and tax credits for clinical development costs.

The development of lurbinectedin, a treatment for small cell lung cancer, illustrates the role of orphan drug designation in the regulatory pathway. The drug was granted orphan drug status for the treatment of small cell lung cancer by regulatory authorities in multiple countries and was approved in the United States in June 2020 for the treatment of adult patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy. The FDA and international regulators, including the Australian Therapeutic Goods Administration, collaborated on the review of lurbinectedin under the Project Orbis initiative.

Project Orbis is an initiative of the FDA Oncology Center of Excellence that provides a framework for concurrent submission and review of oncology drugs among international partners. The initiative aims to provide patients with earlier access to promising cancer treatments by reducing the time between submissions in different countries.

Sponsors of products for rare diseases should consider whether their product qualifies for orphan drug designation and other expedited programs. These programs can significantly reduce the time and cost of development, but they also come with obligations, including the requirement to demonstrate that the product meets the criteria for the designation.

Tissue-Agnostic Drug Development

Tissue-agnostic drug development refers to the development of drugs that treat patients based on a biomarker instead of the anatomic site of the tumor. The FDA has approved drugs for patients with tumor types based on a single anatomic site, such as renal cell carcinoma or melanoma, instead of on a biomarker alone. However, regulations do not require that disease be defined solely as a specific tumor type.

The development of tissue-agnostic drugs raises scientific, clinical, and regulatory issues. Differences in biology, natural histories of different cancers, mutation frequencies among cancers, and concomitant therapies may necessitate diverse development considerations. Clinical trial designs for tissue-agnostic drugs must account for the heterogeneity of the patient population and the possibility that the drug may have different effects in different tumor types.

The regulatory pathway for tissue-agnostic drugs requires close collaboration with regulators to define the appropriate patient population, end points, and statistical analysis plan. Sponsors must also consider how the labeling will describe the approved indication, which must state that the drug is indicated for the treatment, prevention, mitigation, cure, or diagnosis of a recognized disease or condition.

Regulatory Requirements for Herbal Medicines and Other Product Categories

Herbal medicines present a different regulatory landscape than conventional drugs. A global comparison of herbal medicine regulations in India, China, Europe, the United States, and Japan found that regulatory approaches vary significantly. Europe and Japan emphasize pre-market validation and scientific evidence, while the United States relies more on post-market monitoring. India and China integrate traditional practices with modern regulatory frameworks.

These differences pose challenges for ensuring consistent safety and quality standards globally. The review recommended adopting Good Manufacturing Practices, harmonizing pharmacopoeial standards, and leveraging emerging technologies such as artificial intelligence for quality assurance and supply chain transparency.

Sponsors of herbal medicines must understand the regulatory requirements in each jurisdiction where they plan to market their product. A product that is regulated as a dietary supplement in the United States may be regulated as a medicinal product in Europe. The regulatory classification determines the evidence required for marketing authorization and the post-market obligations that apply.

Pharmacovigilance and Adverse Event Reporting

Pharmacovigilance requirements apply throughout the product lifecycle, from clinical trials through post-marketing surveillance. A comparative analysis of adverse event reporting obligations across five major regulatory authorities found that, although the International Council for Harmonisation guidelines provide shared foundations, meaningful differences persist in reporting timelines, case thresholds, and special-situation obligations across jurisdictions.

All five authorities share the ICH seriousness criteria and require expedited seven-calendar-day reporting for fatal or life-threatening suspected unexpected serious adverse reactions in clinical trials. Key jurisdictional differences include China's unique 24-hour obligation for post-marketing deaths, the EMA's device vigilance timelines of 10 calendar days for deaths and two calendar days for serious public health threats, and the FDA's 30-calendar-day reporting requirement for certain adverse events.

Sponsors conducting multinational trials must be aware of these differences and ensure that their adverse event reporting systems can meet the most stringent applicable requirements. The failure to report adverse events in a timely manner can result in regulatory action, including clinical holds, warning letters, and fines.

Practical Steps for Regulatory Compliance

The following steps provide a practical framework for sponsors preparing to conduct a clinical trial. These steps are general and must be adapted to the specific product, jurisdiction, and trial design.

First, determine the regulatory classification of the product. Is it a drug, biologic, device, or advanced therapy? Is it a novel product or a biosimilar? The classification determines the primary regulatory pathway and the applicable requirements.

Second, determine whether the trial requires an IND, IDE, or Clinical Trial Application. This determination depends on the product type, the risk level, and the jurisdiction. When in doubt, consult with the relevant regulatory authority through a pre-submission meeting or scientific advice procedure.

Third, prepare the regulatory application. The application must include preclinical data, manufacturing information, the clinical protocol, and investigator information. The level of detail required depends on the phase of the trial and the risk level of the product.

Fourth, obtain institutional review board or ethics committee approval. This approval is required before the trial can begin and must be maintained throughout the trial. The review board must approve the protocol, the informed consent form, and any amendments.

Fifth, register the trial in the appropriate registry. In the United States, most trials must be registered on ClinicalTrials.gov. In the European Union, trials are registered through the Clinical Trials Information System. Registration must occur before the first participant is enrolled.

Sixth, establish systems for adverse event reporting, data management, and monitoring. These systems must be in place before the trial begins and must operate throughout the trial.

Seventh, plan for results reporting. The results of the trial must be submitted to the appropriate registry within the required timelines, and the results should be published in the medical literature.

Records and Measurements

The following records are essential for regulatory compliance and should be maintained throughout the trial and for the required retention period after the trial ends.

The protocol and all amendments document the scientific rationale, design, and conduct of the trial. The informed consent form and the consent process records document that participants were informed of the risks and benefits of the trial. Case report forms and source documents record the data collected for each participant. Adverse event reports document the safety events that occurred during the trial. Monitoring reports document the sponsor's oversight of the trial sites. Regulatory correspondence documents the communications between the sponsor and the regulatory authorities.

The following measurements should be tracked throughout the trial. The enrollment rate measures the number of participants enrolled relative to the target. The retention rate measures the proportion of participants who complete the trial. The protocol deviation rate measures the number of deviations from the approved protocol. The adverse event rate measures the frequency of adverse events by severity and relationship to the study product. The data query rate measures the number of data queries issued relative to the number of data points collected.

Common Failure Patterns

The following failure patterns are common in clinical trial regulatory compliance and should be anticipated and addressed.

Inadequate preclinical data is a common reason for regulatory rejection or clinical hold. Sponsors may submit an IND with toxicology studies that do not adequately characterize the product's safety profile or that use animal models that are not relevant to the human condition. The solution is to engage with regulators early and to conduct preclinical studies that meet the standards described in the relevant guidance documents.

Incomplete manufacturing information is another common deficiency. Sponsors may submit applications without adequate information about the product's manufacturing process, quality control, or stability. The solution is to develop a comprehensive chemistry, manufacturing, and controls package that demonstrates the product can be produced consistently and at adequate purity.

Poor protocol design can lead to regulatory rejection or to trial results that are not interpretable. Common problems include unclear inclusion and exclusion criteria, inappropriate end points, inadequate sample size, and insufficient attention to safety monitoring. The solution is to invest in protocol development and to seek input from statisticians, clinicians, and regulators.

Inadequate adverse event reporting is a serious compliance failure that can result in regulatory action. Sponsors may fail to report serious adverse events within the required timelines, or they may fail to classify events correctly. The solution is to establish robust pharmacovigilance systems and to train all trial staff on their reporting obligations.

Failure to register the trial or report results is a legal violation that can result in penalties and loss of public trust. The solution is to build registration and reporting timelines into the trial plan and to assign responsibility for these tasks to specific team members.

Limitations and Professional Escalation Criteria

The regulatory requirements described in this article are complex and subject to change. Sponsors should not rely solely on this article or on any single source of information. The following limitations apply.

Regulatory requirements vary by jurisdiction. A trial that is compliant with FDA requirements may not be compliant with EMA requirements, and vice versa. Sponsors conducting multinational trials must ensure compliance with the requirements of each jurisdiction where the trial is conducted.

Regulatory requirements change over time. The FDA and EMA regularly issue new guidance documents and update existing ones. Sponsors should monitor regulatory developments and adjust their practices accordingly.

The interpretation of regulatory requirements requires professional judgment. The same set of facts may lead different regulators to different conclusions. Sponsors should seek advice from experienced regulatory professionals and, when appropriate, from the regulatory authorities themselves.

The following escalation criteria indicate when a sponsor should seek professional assistance. If the regulatory classification of a product is unclear, consult with the relevant regulatory authority or a regulatory professional. If a regulatory application is rejected or placed on clinical hold, seek advice on the deficiencies and the appropriate response. If a serious adverse event occurs that was not anticipated in the protocol or the informed consent form, consult with the institutional review board and the regulatory authority. If a trial site is found to have significant GCP violations, consult with the sponsor's legal counsel and the regulatory authority.

Frequently Asked Questions

What is the difference between an IND and an IDE?

An IND, or Investigational New Drug application, is the mechanism by which a sponsor obtains FDA authorization to study an investigational drug or biologic in humans. An IDE, or Investigational Device Exemption, is the mechanism by which a sponsor obtains FDA authorization to study an investigational medical device in humans. The two applications are similar in purpose but differ in the information required and the review process. IND applications are reviewed by the FDA's Center for Drug Evaluation and Research or Center for Biologics Evaluation and Research, while IDE applications are reviewed by the Center for Devices and Radiological Health.

When is an IND not required for a clinical trial?

An IND is not required for certain studies of approved drugs. The FDA provides guidance on when an IND is not required, such as for studies that do not involve a route of administration, dose, or patient population that significantly increases risk. However, the determination of whether an IND is required depends on the specific facts of the study, and sponsors should consult with the FDA when in doubt.

What is the 30-day review period for an IND?

The FDA has 30 days to review an IND after submission. If the agency does not place the trial on clinical hold, the sponsor may begin enrolling participants. A clinical hold is an order to delay or suspend a trial, and it is issued when the FDA identifies significant safety concerns, deficiencies in the protocol, or inadequate manufacturing information. The 30-day period begins when the FDA receives the complete IND application.

What is the EU Clinical Trials Regulation?

The EU Clinical Trials Regulation, Regulation 536/2014, is the legal framework for clinical trials conducted in the European Union. It became fully applicable in January 2022 and replaced the previous Clinical Trials Directive. The regulation introduced a centralized portal and database for clinical trial applications, a coordinated assessment procedure for multinational trials, and enhanced transparency requirements for trial results.

What is Good Clinical Practice?

Good Clinical Practice, or GCP, is the international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve human participants. The ICH E6 guideline is the primary GCP reference used by regulatory authorities in the United States, the European Union, Japan, and many other countries. Compliance with GCP provides assurance that the rights, safety, and well-being of trial participants are protected and that the data from the trial are credible.

What are the requirements for clinical trial registration?

Clinical trial registration requirements vary by jurisdiction. In the United States, the FDA Amendments Act of 2007 mandated that certain clinical trials be registered on ClinicalTrials.gov and that results be submitted to the registry within specified timelines. In the European Union, trials are registered through the Clinical Trials Information System. Registration must occur before the first participant is enrolled, and results must be submitted within the required timelines after the trial ends.

What is the accelerated approval pathway?

The accelerated approval pathway is an FDA program that allows approval of investigational drugs that treat serious conditions and fill an unmet medical need, based on changes to surrogate measures that are reasonably likely to predict clinical benefit. Postapproval clinical trials are then required to confirm whether these drugs offer clinical benefit. The pathway has been used extensively for cancer drugs, but it carries risks, including the possibility that confirmatory trials will not demonstrate clinical benefit.

What are the regulatory requirements for biosimilars?

Biosimilars are biological products that are highly similar to an already approved biological product, with no clinically meaningful differences in safety, purity, and potency. The development of biosimilars follows a distinct regulatory pathway that emphasizes comparability with the reference product. Sponsors must demonstrate similarity through a stepwise approach that includes analytical studies, animal studies, and clinical studies. The extent of clinical testing depends on the residual uncertainty after the analytical and animal studies are complete.

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References and Further Reading

• Laboratory Quality Management System Handbook. World Health Organization.
• Laboratory Biosafety Manual. World Health Organization.
• Assay Guidance Manual. National Center for Advancing Translational Sciences.
• Bioanalytical Method Validation Guidance. U.S. Food and Drug Administration.
• NCBI Literature Resources. National Center for Biotechnology Information.
• PubMed. National Library of Medicine.
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• Clinical trial development for biosimilars.. Seminars in arthritis and rheumatism, 2015.
• Lurbinectedin: First Approval.. Drugs, 2020.
• Clinical trial registration, reporting, publication and FDAAA compliance: a cross-sectional analysis and ranking of new drugs approved by the FDA in 2012.. BMJ open, 2015.
• Association of the FDA Amendment Act with trial registration, publication, and outcome reporting.. Trials, 2017.
• Noncollagen Dermal Fillers: A Summary of the Clinical Trials Used for Their FDA Approval.. Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.], 2019.
• Health roundup.. Science (New York, N.Y.), 2006.
• Tissue-Agnostic Drug Development.. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting, 2017.
• Advanced therapy medicinal product (ATMP) classification - a case study on spinal cord injury.. 2026.
• Semaglutide and Follow-On Peptide Therapeutics: Balancing Innovation, Regulation, and Clinical Outcomes.. 2026.
• Navigating the regulatory landscape of herbal medicines: A global comparison of India, China, Europe, the United States and Japan.. 2026.
• Global pharmacovigilance reporting: comparative analysis of adverse event obligations across five major regulatory authorities.. 2026.
• Innovation in animal health under Regulation (EU) 2019/6: Review and recommendations.. 2026.
• Antibody-drug conjugates in cancer treatment: from molecular design to clinical implementation.. 2026.
• Phage Therapy at the Crossroads Between Clinical Promise and Regulatory Challenge.. 2026.
• How Regulation 536/2014 Is Changing Academic Research with Therapeutic Radiopharmaceuticals: A Local Experience.. 2025.
• Chapter 8 - Preparation of a Preclinical Dossier to Support an Investigational New Drug (IND) Application and First-In-Human Clinical Trial. 2017.
• Figure 8, [- Submit IND Application].. 2016.
• Use of automated quality assessment algorithms in fingermark detection research - Application to IND/Zn vs DFO.. Forensic Science International, 2024.
• Preparation of a Preclinical Dossier to Support an Investigational New Drug (IND) Application and First-In-Human Clinical Trial. 2013.
• TransMolecular receives FDA approval for 131-I-TM-601 IND application.. Expert Review of Anticancer Therapy, 2002.
• Why wasn't an investigational new drug (IND) application required before appropriate study?. Human research report, 2004.
• New IDE manual clarifies FDA policy on clinical studies. Medical Device and Diagnostic Industry, 1997.
• Patient experience before and after treatment with idecabtagene vicleucel (ide-cel, bb2121): qualitative analysis of patient interviews in the KarMMa trial. Leukemia Research, 2022.
• Valve Underexpansion and Clinical Outcomes With ACURATE neo2: Findings From the ACURATE IDE Trial. Journal of the American College of Cardiology, 2025.
• Characterization and Clinical Outcomes of High-Risk Device-Related Thrombus in the Amulet IDE Trial. Jacc Clinical Electrophysiology, 2025.
• IDE status offers direct route to reimbursement. Medical Device and Diagnostic Industry, 2003.

This article is educational and does not replace institutional policy, professional advice, or applicable safety and regulatory requirements.