With the expansion of clinical research and development, precise labeling of investigational products is not merely a formality but a critical aspect of ensuring participant safety, product traceability and regulatory compliance throughout clinical trials. Pharmaceutical companies must follow an integrated approach to clinical trial labeling, considering clinical study planning, product characteristics, packaging requirements and the needs of participants across different countries.
Under US regulations, an investigational new drug is a drug or biological product used in a clinical investigation. In the European Union (EU), an investigational medicinal product (IMP) is defined under Regulation (EU) No 536/2014 as a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial. The EU definition also covers certain authorised medicinal products used or assembled differently from their authorised form where the Regulation applies.
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Explore Labeling Services →Clinical supplies require appropriate labeling to communicate essential information to stakeholders involved in clinical trials. This includes product identification, instructions for use, storage conditions, the applicable period of use and trial-specific information. Label requirements can differ between countries, depending on the product’s regulatory status, packaging configuration and applicable regulations.
In blinded trials, the labeling of active products, comparators and placebos must support the study’s blinding arrangements without compromising participant safety or product accountability. Auxiliary medicinal products (AMPs) are medicinal products used in a clinical trial as described in the protocol but not as investigational medicinal products. The term “non-investigational medicinal product” (NIMP) is also used in some clinical research settings, but the terms should not automatically be treated as legally interchangeable. The applicable regulatory framework determines the relevant classification and labeling requirements.
Purpose of Regulatory Clinical Labeling Requirements
In clinical trials, regulatory labeling requirements are essential for protecting participants and ensuring that investigational products are correctly identified and used. Researchers, investigators, pharmacists and participants need clear information about the medicinal product, its intended use and relevant handling instructions.
Additionally, regulatory labeling services helps identify the trial and supports reliable documentation of its conduct. In blinded studies, appropriate product coding and controlled access to treatment assignments help preserve the blind while allowing emergency unblinding when necessary.
The principal objectives of clinical trial labeling include:
- Clear product identification: Reducing the risk of product mix-ups.
- Dosage and administration information: Supporting correct use where applicable.
- Batch traceability: Connecting products with their manufacturing and packaging records.
- Clinical trial reference: Linking the product to the relevant study and site.
- Expiry or period-of-use control: Helping ensure products are used within the applicable period.
- Storage conditions: Maintaining product quality during storage and handling.
- Safety information: Communicating required warnings and investigational-use statements.
- Product accountability: Supporting dispensing, reconciliation, returns and final disposition.
Standard Requirements for Clinical Labeling
The information required on a clinical trial label depends on the jurisdiction, product status, packaging configuration and study design. A structured review helps sponsors determine which particulars must appear on immediate packaging, outer packaging or supporting documentation.
Labeling element | Purpose |
Product identification | Identifies the product, strength and pharmaceutical form. |
Trial and participant identification | Links the product to the trial, site and participant or treatment allocation, where required. |
Sponsor and batch details | Supports contact, traceability and product accountability. |
Dosage and administration | Provides relevant directions for use and route of administration. |
Expiry date and storage | Communicates the applicable use period and storage conditions. |
Warnings and safety information | Includes required cautionary statements and other applicable safety details. |
EU Clinical Trial Labeling Requirements: CTR and Annex VI
The EU regulatory framework for clinical trial labeling has changed significantly since the earlier Clinical Trials Directive (Directive 2001/20/EC). Regulation (EU) No 536/2014, commonly known as the Clinical Trials Regulation (CTR), became applicable on 31 January 2022. The transition period for trials previously authorised under the Directive ended on 30 January 2025. From 31 January 2025, ongoing EU clinical trials must operate under the CTR framework.
The CTR sets out labeling requirements in Articles 66 and 67, with detailed particulars in Annex VI. The applicable provisions depend on whether the investigational medicinal product or auxiliary medicinal product is authorised or unauthorised.
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Explore EU Clinical Regulatory Support →Labeling of unauthorised IMPs and AMPs
Under Article 66, specified information must appear on both the immediate and outer packaging of unauthorised IMPs and unauthorised AMPs. This information must identify the relevant contact persons, clinical trial, medicinal product and its use.
Annex VI provides the detailed particulars. Depending on the product and applicable section, these can include the main contact’s details, substance name and strength, pharmaceutical form, route of administration, quantity, batch or code number, clinical trial reference, directions for use, investigational-use wording, storage conditions and period of use. The required information must be clearly legible and appropriate to the clinical trial’s design. Sponsors must assess the specific Annex VI provisions instead of assuming that every label requires an identical set of particulars.
Labeling of authorised IMPs and AMPs
Article 67 provides a different route for authorised IMPs and AMPs. They may be labeled in accordance with the relevant CTR provisions or, where applicable, the ordinary medicinal-product labeling requirements under Title V of Directive 2001/83/EC. Where the protocol’s specific circumstances require additional information to protect participant safety or the reliability of clinical trial data, Article 67(2) and Section C of Annex VI provide for additional particulars on the immediate and outer packaging of authorised IMPs.
Amendments to Annex VI and small-packaging considerations
Commission Delegated Regulation (EU) 2022/2239 amended Annex VI, including provisions concerning participant, treatment and visit identifiers and the period of use on certain immediate packaging.
Under the specified conditions in Section B of Annex VI, the expiry or retest date may be omitted from the immediate packaging of certain unauthorised auxiliary medicinal products. This exception applies where the required conditions concerning immediate and outer packaging are met, including the provision of the required particulars on the outer packaging. Sponsors should verify the applicable provision and packaging configuration before approving label artwork.
Practical considerations for EU IMP labeling
- Confirm whether the product is authorised or unauthorised and whether it is an IMP or AMP.
- Identify the applicable provisions of Articles 66 and 67 and Annex VI.
- Review requirements for immediate and outer packaging separately.
- Verify whether a permitted small-packaging or period-of-use exception applies.
- Confirm the required language with the relevant Member State.
- Ensure the labeling strategy supports blinded trials and participant or treatment identification where applicable.
- Document the regulatory assessment and final artwork approval.
The CTR provides a harmonised EU framework, but the correct labeling approach still depends on the product, trial design and applicable provisions.
Clinical Trial Packaging and Labeling in the United States
In the United States, investigational new drug labeling is governed in part by 21 CFR 312.6. The regulation also prohibits false or misleading statements in the labeling of an investigational new drug. These requirements differ from the EU CTR framework. A label that satisfies the EU requirements should not automatically be assumed to satisfy US requirements, or vice versa. Sponsors conducting multinational trials should assess each jurisdiction separately and maintain appropriate label specifications and approval records.
Clinical trial packaging should also protect the product from contamination and unacceptable deterioration during transport and storage. Packaging decisions need to account for the dosage form, storage conditions, shipping arrangements, handling at study sites and the need to maintain blinding where applicable. The sponsor’s responsibilities extend beyond the printed label. Packaging, labeling and coding should be managed as part of the broader investigational product control process.
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Clinical trial sponsors must consider applicable FDA requirements for investigational drug labeling, including statements required for investigational use and the relevant product-specific provisions. DDReg Pharma provides clinical regulatory support to help sponsors plan documentation and assess applicable submission requirements.
Explore US Clinical Regulatory Services →Managing Multilingual Trials and Country-Specific Requirements
Multinational clinical trials introduce additional challenges for clinical packaging and labeling. Information that is acceptable in one country may need to be translated, reformatted or supplemented to meet the requirements of another jurisdiction.
The EU CTR states that the Member State concerned determines the language of the label information, and products may be labeled in multiple languages. Sponsors must therefore establish the applicable language requirements for the participating countries before finalising clinical supply artwork. A structured process can help reduce artwork revisions, relabeling activities and delays in supplying trial sites.
A practical approach includes:
- Map the markets: Identify all participating countries and the regulatory framework applicable to each.
- Confirm label particulars: Establish the information required on immediate and outer packaging.
- Plan translations: Identify required languages and apply a controlled review process to translated text.
- Protect blinding: Align label design, product coding and randomisation arrangements with the clinical trial protocol.
- Review packaging constraints: Ensure required information remains legible on small containers and complex packaging configurations.
- Control label versions: Maintain approved artwork, version history and documented approvals.
- Verify before release: Compare printed labels against approved specifications and applicable regulatory requirements.
Common Risks in IMP Labeling and Clinical Supply Management
Labeling errors can affect participant safety, product quality, clinical trial conduct and the reliability of study data. They can also result in rework, supply delays and regulatory findings.
Common issues include incorrect expiry information, inconsistent product strength, missing required particulars, translation errors, illegible text and discrepancies between approved artwork and printed labels. Blinded studies introduce additional risks. A label that reveals treatment allocation can compromise the blind, while inadequate product coding or reconciliation can make product accountability difficult. A controlled labeling process should address these risks before clinical supplies are released.
Common risk | Potential consequence | Recommended control |
Incorrect or inconsistent expiry information | Use of supplies outside the applicable period or unnecessary product rejection | Verify expiry calculations, approved dating and packaging-level requirements. |
Missing or inaccurate label particulars | Non-compliant labeling and potential delays in supply | Use a jurisdiction-specific label checklist and documented review. |
Translation errors | Misinterpretation of product information | Apply controlled translation review and approval. |
Artwork version mismatch | Incorrect information on printed labels | Maintain version control and verify final artwork against the approved master. |
Compromised blinding | Potential bias in trial conduct or data integrity | Review coding and label design against the blinding plan. |
Inadequate traceability | Difficulty reconciling product distribution, use and returns | Maintain appropriate batch, code and accountability records. |
Incorrect storage information | Potential impact on product quality | Verify storage statements against approved product and stability information. |
These controls should be proportionate to the product, packaging process and risks associated with the clinical trial.
Label Change Control and Clinical Supply Traceability
Clinical trial labeling is not a one-time activity. Changes to the protocol, product shelf life, packaging configuration, participating countries or applicable regulatory requirements may trigger a label review. Sponsors should assess the impact of each change before implementing revised artwork or releasing new clinical supplies. This includes determining whether existing labels remain suitable, whether additional regulatory steps are needed, and how different label versions will be controlled across study sites.
A robust change-control process should include:
- Documented assessment of the proposed change and its regulatory impact.
- Review of affected label particulars and packaging components.
- Approval of revised artwork by the appropriate functions.
- Verification of printed labels against the approved version.
- Reconciliation of obsolete and current labeling materials.
- Appropriate communication to clinical supply teams, depots and trial sites.
The Role of Current Good Clinical Practice in Investigational Product Labeling
ICH Good Clinical Practice (GCP) E6(R3) provides guidance on the management of investigational products, including packaging, labeling, coding, storage and the protection of blinding where applicable. The core Principles and Annex 1 reached ICH Step 4 in January 2025. Annex 2 was subsequently adopted at Step 4 on 3 June 2026, extending the guideline’s coverage of clinical trial designs such as decentralised and pragmatic trials and trials incorporating real-world data.
E6(R3) supports a quality-by-design and risk-proportionate approach to clinical trials. For labeling, this means considering potential risks during study planning rather than relying solely on checks performed before distribution. Sponsors should integrate labeling into product quality controls, clinical supply planning, documentation and oversight, while ensuring that investigational products comply with applicable regulatory requirements. The relevant implementation status should be confirmed for each jurisdiction.
A Practical Checklist for Clinical Trial Labeling
Before releasing clinical supplies for distribution, sponsors should complete these checks:
- Confirm the applicable regulatory framework and labeling requirements.
- Verify product details, batch/code information, expiry and storage conditions.
- Check required warnings, administration details and investigational-use statements.
- Review translations, local-market requirements and participant identification or blinding.
- Assess immediate and outer packaging separately.
- Document artwork approval, version control, final label checks and product traceability.
This checklist should be adapted to the product, study protocol and jurisdictions involved. It is a practical quality control aid, not a substitute for a formal regulatory assessment.
Conclusion
Regulatory clinical trial labeling requirements serve several purposes, including protecting participants, supporting accurate data collection and maintaining traceability throughout clinical research. Effective labeling requires more than including a standard set of particulars. Sponsors must consider the product, clinical study design, packaging configuration and applicable regulatory requirements in every participating market.
The EU CTR and its Annex VI provisions, US investigational new drug labeling rules and current GCP expectations provide important frameworks for planning and controlling clinical supplies. Sponsors should confirm the applicable requirements before label approval and maintain appropriate controls through packaging, distribution, use and product reconciliation.
DDReg provides pharmaceutical labeling and regulatory affairs support to help companies assess applicable requirements and manage labeling activities across markets. Explore our Pharmaceutical Product Labeling Services to learn more.
Frequently Asked Questions
The required information depends on the product's regulatory status, jurisdiction and packaging configuration. Common particulars include product identification, clinical trial details, contact information, batch or code information, directions for use, storage conditions and the applicable period of use. Sponsors must verify the specific legal requirements for each product and market.
EU IMP labeling is governed by Regulation (EU) No 536/2014, particularly Articles 66 and 67 and Annex VI. The requirements differ according to whether the IMP or AMP is authorised or unauthorised. Commission Delegated Regulation (EU) 2022/2239 amended Annex VI, including specific conditions under which the expiry or retest date may be omitted from certain immediate packaging.
The EU applies the CTR framework, including Annex VI requirements for investigational and auxiliary medicinal products. In the US, 21 CFR 312.6 requires a specified investigational-use cautionary statement on the immediate package and prohibits false or misleading labeling. Sponsors conducting multinational trials must assess each jurisdiction separately.
Clinical trial packaging and labeling help prevent product mix-ups, support correct handling and administration, preserve blinding where required and maintain product traceability. They also help study teams verify product identity, storage conditions and the applicable period of use, reducing risks to participants and the reliability of clinical trial data.