How A Comparator Is Really Bought
By Hedley Rees
Every other line on a study’s bill of materials is under the sponsor’s control. The investigational product and the placebo are made to a specification the sponsor owns, by a CDMO the sponsor has qualified, on a schedule the sponsor sets. The comparator is different. It is somebody else’s commercial medicine, made for pharmacies and patients in a particular market, and bought at the far end of a supply chain that was never designed with clinical trials in mind.
That one fact explains most of what follows. The sponsor does not own the specification, the shelf life, the presentation, the manufacturing site or the release schedule. The manufacturer of the comparator is often a direct competitor and has no commercial reason to make the sponsor’s job easier. What the sponsor can control is where it buys, from whom, how much, and when. Those are procurement decisions. Some of them are also clinical decisions, which is the argument of this article.
What Really Drives The Choice Of Source Market
When a sourcing vendor presents options for a comparator, the decision is usually framed around five things.
Price. The same medicine can cost very different amounts in different markets, and for a high-value biologic used in a long phase III study, the difference between source countries can run to millions. This is a legitimate consideration. Comparator spend is often one of the largest single items in a clinical supply budget, and procurement teams are rightly expected to manage it.
Availability in the right quantity and lot structure. Supply teams would ideally buy enough from a single manufacturing lot to cover the study, or at least each blinding campaign, because one lot means one set of release data, one stability profile and one expiry date to manage. Commercial markets rarely support this. Wholesalers hold stock in quantities sized for pharmacy demand, not for a 600-patient trial, and buying large volumes in one country can draw the attention of the manufacturer or the regulator.
Willingness of the manufacturer to supply. Direct purchase from the marketing authorization holder gives the best documentation and the cleanest chain of custody, but originators can and do decline, delay or ration supply to competitors. The scale of this problem is illustrated by the US CREATES Act of 2019, which created a legal route for generic and biosimilar developers to sue brand companies that refuse to sell them samples on commercially reasonable terms.1 The problem was serious enough that Congress legislated to address it. When direct supply is refused, the sponsor is pushed towards wholesalers and third-country markets, with everything that implies for documentation.
Pedigree and documentation. A comparator bought through a wholesale chain needs a documented line of custody back to the manufacturer. The MHRA is explicit that authorized comparators should be sourced from a supplier suitably authorized to do so, with checks on the wholesale distribution authorization and GDP certificate (or equivalent) documented, and that sourcing from a non-EU country requires similar controls and a QP declaration.2 A certificate of analysis tells you about the lot. It does not, on its own, tell you where the packs have been.
Grey-market and falsification risk. The further a comparator travels from its manufacturer, the greater the risk of diversion, poor storage or outright falsification. In the EU, packs carry a unique identifier under the Falsified Medicines Directive safety-features regulation, and the Commission’s guidance is that this identifier should be verified and decommissioned before a commercial pack is used in a clinical trial, and, for packs that are relabeled or repackaged, before that operation takes place.3That gives EU-sourced product a verifiable link to the legitimate supply chain. Product bought in markets without an equivalent system carries more risk, and that risk has to be managed through audits, documentation and testing.
There is a sixth driver that tends to be treated as a constraint rather than a choice: regulatory acceptability. It is easiest to source from a market whose product the regulators already recognize. In the EU, a comparator authorized in the EU/EEA, an ICH region or an MRA-partner country and sourced from there can be supported with the MA holder’s name, the MA number and the SmPC or prescribing information; product sourced from outside those regions and countries needs full quality documentation.4 In the US, a drug sourced from a manufacturing site other than the one in the approved US labelling is treated as unapproved, so it needs to be covered by the IND.5
In practice these six factors pull in different directions. The cheapest market may not have the volume. The market with the volume may not have the documentation. The market with the best documentation may be the one where the manufacturer is rationing supply. The procurement decision is the weighting given to each factor, and that weighting is usually set against cost and timeline targets.
Planning Around Commercial Reality
Once the comparator is bought, supply teams have to plan around three features of commercial product that do not apply in the same way to the sponsor’s own IMP.
Short dating. Shelf life starts at manufacture, so by the time a lot has been tested and released by the manufacturer, distributed to a wholesaler, bought, shipped, received and released again for the trial, a meaningful part of it has already elapsed.
Relabeling and repackaging. Commercial packs have to be relabeled for the trial and often repackaged or modified for blinding. Each operation takes time from the remaining shelf life, and repackaging can impose a new and shorter use-by date if the product is no longer in its original container.
Expiry extension. For the sponsor’s own IMP, expiry can be extended as new stability data come in. For a comparator, the sponsor usually does not own the stability data and cannot generate a full program for somebody else’s product. The manufacturer’s expiry is, in practice, the ceiling. EMA makes the same point for modified comparators: any extrapolation of shelf life may not exceed the shelf life the MA holder assigned to that batch.6 That makes comparator expiry the hard constraint in many supply plans.
The result is a planning trade-off that every supply manager knows. Buy a large quantity early and you get lot consistency and security of supply, at the cost of expiring stock and waste if the study runs slowly. Buy in smaller tranches and you reduce waste, at the cost of more purchases, more lots, more release activity and more exposure to changes in the market.
Where The Planning Breaks Down
The plan is built on the forecast, and the forecast is built on the protocol’s recruitment assumptions. When enrollment runs slower than expected, or the study is extended, the comparator stock bought at the start begins to expire before it is used. At the same time, the window to buy more of the same lot has usually closed. The vendor goes back to the market and finds whatever is available at that point, which may be a different lot, a different country, a different pack or, sometimes, a different presentation.
Other triggers come from the market itself: a shortage, a manufacturer withdrawing a pack size, a device change, a reformulation, or a decision to stop supplying a particular country. None of these is unusual. Comparators are marketed medicines and are exposed to the same disruptions as anything else on a pharmacy shelf.
A Composite Example
Consider a composite phase III study, built from situations I have seen, in which the comparator is an injectable biologic supplied in a prefilled pen, with 12 months’ treatment per participant.
At study start, the sourcing vendor buys from Market A, an EU country, because the originator will supply through a wholesaler there, the packs carry EU safety features and the product is supported in the IMPD by its MA number and SmPC. The plan assumes 18 months’ recruitment, so the vendor buys two lots with 20 months’ remaining shelf life after relabeling, with a further purchase from Market A planned for around month 12.
At month 12, recruitment is running at about 70% of forecast and the sponsor extends enrollment by nine months. The first lot will expire before it can be used up. Market A’s wholesaler can no longer supply the required volume because the originator has introduced allocation controls in that country.
The vendor finds stock in Market B, outside the EU/EEA, the ICH regions and the MRA-partner countries. The price is good and the volume is there. The pen is the same molecule from the same company but a different presentation, with a different needle-shield design and patient leaflet. In supply terms, the problem is solved: the stock is bought, a QP declaration and comparability documentation are prepared, the product is relabeled and loaded into the IRT, and no site runs out.
What has also happened is that the product in the control arm has changed. Participants randomized in the first year will finish treatment on a different presentation. The IMPD now has to cover a product sourced outside the EU/EEA, the ICH regions and the MRA-partner countries, which means full quality documentation rather than an SmPC.7 And nobody has yet asked whether participants need to be retrained on the new pen, told about the change, or reconsented.
Part 2 of this series examines how these sourcing decisions are documented and why they can be separated from clinical oversight. Part 3 of this series returns to this example to examine what the change means for participants and who should be responsible for the clinical decisions it raises.
References:
- U.S. Food and Drug Administration. Access to Product Samples: The CREATES Act. https://www.fda.gov/drugs/guidance-compliance-regulatory-information/access-product-samples-creates-act
- MHRA Inspectorate. Annex 16 QP Certification and Batch Release: Frequently Asked Questions, Part 2. 2017. https://mhrainspectorate.blog.gov.uk/2017/08/14/annex-16-qp-certification-and-batch-release-frequently-asked-questions-part-2/
- European Commission. Safety Features for Medicinal Products for Human Use: Questions and Answers, Version 21. See Question 3.7. https://health.ec.europa.eu/document/download/2e49010a-0071-4f39-8b00-c90a266aba76_en
- European Medicines Agency. Guideline on the Requirements for the Chemical and Pharmaceutical Quality Documentation Concerning Investigational Medicinal Products in Clinical Trials (EMA/CHMP/QWP/545525/2017). https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-requirements-chemical-and-pharmaceutical-quality-documentation-concerning-investigational-medicinal-products-clinical-trials-revision-1_en.pdf
- NIH Clinical Center. What Is an IND? https://www.cc.nih.gov/orcs/ind/what-is-an-ind
About The Author:
Hedley partners with pharma and biotech leaders, investors, and policymakers who recognize that today’s fragmented supply chains, outsourcing dependencies, and opaque practices are no longer fit for purpose. Working across nonclinical, clinical, and commercial stages, Hedley helps organizations redesign end‑to‑end supply networks, rethink CDMO strategies, and build operational models that are resilient, data‑driven, and accountable to patients and society.
His work shines a light on hidden risks, perverse incentives, and gaps between regulatory intent and industry behavior. As an outspoken commentator and advocate for change, Hedley contributes to public and boardroom debates on drug shortages, reshoring, vertical integration, and regulatory reform.
He is the author of Transforming the Pharmaceutical Supply Chain (Wiley, 2025) and Supply Chain Management in the Drug Industry: Delivering Patient Value for Pharmaceuticals and Biologics (Wiley, 2011).