Comparator sourcing for clinical trials

A comparator is the product a clinical trial measures the investigational product against. It can be an authorised medicine used as an active control, a placebo or standard of care. For sponsors and contract research organisations, sourcing a commercially available comparator sounds simple, but it is one of the steps most likely to delay a study. The protocol may require a specific market version, the quantity may exceed what normal distribution can release from one batch, and every pack has to arrive with records that let the sponsor show where it came from.

India is a common source of comparators. Multinational brands are sold there in packs made for the Indian market, Indian manufacturers make many multisource medicines, and exporters can consolidate stock for a trial depot. This guide explains how the rules treat comparators, which market version a study needs, what documents to ask for and how to plan the supply.

What counts as a comparator

ICH E6(R3), adopted on 6 January 2025, defines a comparator as an investigational or authorised product, a placebo or standard of care used as a reference in a trial. The same guideline treats a product with a marketing authorisation as an investigational product when it is used or packaged in a way different from its approved form, or used to gather further information. In practice, once a marketed medicine is used as a reference in a trial, the sponsor's duties for investigational products apply to it. EMA applies the E6(R3) principles and Annex 1 from 23 July 2025, with Annex 2 following on 15 January 2027.

The EU Clinical Trials Regulation 536/2014 uses three related terms:

• An investigational medicinal product is a medicinal product being tested or used as a reference, including as a placebo, in a clinical trial.
• An authorised investigational medicinal product is one authorised under EU law or in the Member State concerned, whatever changes are made to its labelling.
• An auxiliary medicinal product is used for the needs of the trial as described in the protocol, but not as an investigational product, for example a rescue or background medicine. Article 59 says only authorised auxiliary products may be used unless none is available in the Union, with a justification in the protocol.

Reference products and market versions

Before any quote, the sponsor needs to know which version of the comparator the study accepts. The answer depends on why the comparator is there.

For a bioequivalence study supporting a United States generic application, FDA's guidance on referencing approved drug products explains that the reference listed drug is the approved product the applicant must match. The reference standard is the specific product FDA selects for the in vivo bioequivalence study, and it is ordinarily the reference listed drug. Both are identified in the Orange Book. A pack of the same brand made for another market is not the FDA reference standard.

For generics assessed outside the United States, WHO publishes guidance on selecting comparator products for equivalence studies of multisource medicines (Technical Report Series 992, Annex 8, 2015), and WHO prequalification maintains a list of international comparators.

For a therapeutic trial where the comparator is the standard of care, the protocol and the trial authorisation set the rule. Some protocols name one brand from one market. Others allow any product authorised in the participating countries.

How an India-sourced comparator fits EU rules

A product sold in India is generally not covered by an EU marketing authorisation, even when it carries the same brand as an EU product. In an EU trial it is therefore normally treated as an unauthorised investigational medicinal product. Regulation 536/2014 then applies in full:

• Article 61 requires an authorisation for the manufacture and import of investigational products into the Union, held by an organisation with a qualified person.
• Article 62 says the qualified person certifies that each imported batch meets the good manufacturing practice requirements.
• Article 63 requires imported products to be made to standards at least equivalent to EU good manufacturing practice, and Delegated Regulation 2017/1569 adds that only products from a third country manufacturer authorised under its own national law should be imported.
• Article 66 and Annex VI set the trial labelling for unauthorised products.

The qualified person can only certify what the documents support. That is why the paper trail from the Indian manufacturer matters as much as the product. On the Indian side, products approved in India are exported against standard export documents, while unapproved or new drugs can need a regulator's export permission, as covered in Indian export rules buyers should know.

Pedigree and chain-of-custody documents

ICH E6(R3) asks the sponsor to keep records of the identity, shipment, receipt, return and destruction of investigational products, and to make sure they stay stable and are used only within their current shelf life. For a comparator bought on the commercial market, that record starts with the manufacturer.

Ask for copies of the certificate of analysis and the manufacturing licence before the order is confirmed, so the sponsor's quality team can review them while stock is allocated. Gaps in the chain, for example a distributor whose licence cannot be shown, are much harder to fix after the goods ship. The guide on how to verify a medicine supplier covers the checks in more detail.

Blinding, relabelling and packaging

ICH E6(R3) requires investigational products, including active controls and placebo, to be coded and labelled in a way that protects the blinding, with a process for emergency unblinding. In practice, comparators are often over-encapsulated, repacked into kits or labelled with trial information. These are manufacturing operations. Delegated Regulation 2017/1569 asks manufacturers to pay particular attention to products during and after any blinding operation and to keep a procedure for rapid unblinding when a recall requires it.

These steps belong to the sponsor's clinical packager, working under good manufacturing practice for investigational products. The supplier of the commercial comparator should ship original, sealed packs and add nothing to them. Regulation 536/2014 exempts some relabelling and repacking by hospital pharmacies for use in the same trial in the same Member State, but that exemption does not cover a commercial supplier.

How to plan comparator supply

1. Write a specification: international non-proprietary name, brand, strength, dosage form, pack size, market of origin, quantity, number of batches allowed, minimum remaining shelf life and the date needed at the packager.
2. Confirm with regulatory and quality colleagues which market versions the protocol and the authorities accept.
3. Ask the supplier for availability, likely batches, lead time and sample documents. Large single-batch quantities may need allocation by the manufacturer or its distributors.
4. Review the certificate of analysis, licences and supply chain before confirming the order.
5. Agree the Incoterm, temperature range and delivery address of the packager or depot. The Incoterms guide and cold-chain transit checker help here.
6. Ship with data loggers and keep the logger files with the batch records.
7. Release at the packager or depot after the sponsor's quality review, and in the EU after qualified person certification.

The lead-time estimator gives a first view of sourcing, export and transit time, and the quote request form collects the specification above in one place.

Common problems

• Shelf life. Dosing at sites can last many months, so a batch with too little remaining shelf life may be unusable even when it is in specification.
• Market differences. Strength, excipients, pack sizes and devices can differ between the Indian and EU or US versions of the same brand.
• Volume. Commercial distribution is sized for patients, not for a trial that needs thousands of packs from one batch at short notice.
• Shortages. A comparator that becomes scarce may be allocated to patients first. The guide on sourcing medicines during a shortage explains how to check official shortage lists.
• Documents arriving late. If the qualified person or the sponsor's quality team cannot see the records, the stock waits in quarantine.