Why is comparator documentation such an important consideration when planning supplies?

For any clinical trial to be successful it has to be built on a foundation of safety, efficacy and the ability to demonstrate compliance with regulations throughout, and this extends to the commercial drugs (commonly ‘comparators’) that are used.
There are many stakeholders involved in planning and decision making when it comes to sourcing comparators, and each will likely have their own view on what documentation is essential, and which may just be a ‘nice to have’.

What is essential to understand is how documentation can impact the ability to use a drug within a trial, and how the cost and availability of a drug can vary based upon the documentation that is required. This White Paper will look at those points and provide an overview of the key types of documents that you need to be aware of, and the purpose they serve.

How does documentation impact the sourcing strategy?

There are two principal methods by which a commercial medicine can be sourced for a trial: directly from the product manufacturer or indirectly from licensed wholesalers and distributors.
If you are sourcing directly from a product manufacturer then it’s a reasonable expectation that they should also provide you with a core set of supporting documents to accompany the drug.

Sourcing indirectly has many more variables and the picture around documentation is more complex. There are countries that make the provision of a Certificate of Analysis (CoA) with all wholesale medicines a legal requirement (Eastern European countries are a good example) but there are many countries that do not. Understanding what documentation is required can begin to narrow the search for a suitable supply route.

However, not all countries have the same drug prices or the same levels of availability, so by making the CoA an absolute requirement your vendor may be excluding regions that would otherwise have been more cost effective or with better lead times.

I’ve been told I need a lot of documents, is that right?

When planning to use a comparator, there is often a ‘wish list’ of documentation which is communicated to sourcing vendors. This wish list tends to be exhaustive, with every conceivable document requested. As we’ve found out above, requesting potentially unnecessary documentation can have a very significant impact on the sourcing strategy employed, so it’s important to understand which documents may just be a ‘nice to have’. Your vendor should be able to provide their insight into which documents are easily available, which may not be necessary, and which are simply not possible.

It is not often the case that an exhaustive set of documents is needed. For example, if you are using an EU centrally licensed drug as a comparator within an EU trial site, then the documentation needed should only be to provide proof of the drugs authenticity and that it has been stored and handled in the right way.If, however, you are looking to use an EU drug outside of the EU, then it’s likely that more documentation could be needed. A CoA may be required for importing into a different country (LATAM territories, for example).

Overview of key documents:

Statement of Authenticity / Pedigree Statement

A Statement of Authenticity (SoA) and a Pedigree Statement are the same thing, the only difference being the terminology your Vendor/CDMO chooses to employ. It’s also very much the ‘entry level’ in terms of documentation and you should always expect to get one.

The SoA/Pedigree Statement is issued by the Responsible Person (RP) or Quality Manager of the sourcing vendor and confirms all of the drugs key information (description, batch number, license number, expiry date, manufacturer/license holder). It should also attest to the drug having been procured in line with applicable regulations and stored and handled in line with its licensed conditions.
For EU drug it would also confirm that Falsified Medicines Directive checks have been carried out and confirm the drugs status (active or inactive).
This document should always be provided, and if your vendor can’t provide one then they shouldn’t be providing the drug!

Certificate of Analysis (CoA) and Certificate of Conformance (CoC)

When a new batch of commercial drug is manufactured, it undergoes a series of quality control tests to ensure that it conforms to all of the necessary standards. When these standards have been met, the QP will sign the CoA and release the product so that it can be sold, distributed and given to patients.

A CoA is the most commonly requested document in comparator sourcing. It is the document a QP would take the most comfort from when releasing a drug into a clinical trial and can also be a requirement when importing drug into certain countries (Brazil, Argentina, South Korea to name a few).
As mentioned above though, it is perhaps the most over-requested document, as it is very likely not required unless you are moving a drug out of its licensed territory.

A Certificate of Conformance (CoC) is very often combined with a CoA. Different manufacturers have different approaches, some creating two separate documents and some combing them into one. Both methods are acceptable.
The CoC is little more than a paragraph that confirms that the batch of drug listed has been manufactured, tested, packaged and labelled in accordance with Good Manufacturing Practice (GMP).

GMP Certificates (for manufacturing sites)

GMP/CGMP, or Good Manufacturing Practice, is the framework which ensures that medicinal products are consistently produced to the quality standards appropriate to their intended use as required by the product specification.

A product’s manufacturing facility can be based in any country, and are inspected regularly by competent authorities, the frequency of which varies depending on past performance. A clinical trial sponsor may choose to reject a particular comparator from a manufacturing site that has a history of poor regulatory inspections, as this may be viewed as an unnecessary risk within their clinical trial supply.
Each manufacturing site will have a GMP certificate which is held on a centralised database which is straightforward to access. GMP certificates are not generally regarded as sensitive documents and can be provided in most circumstances.

It is not uncommon for a product to be produced at several different manufacturing locations. The manufacturing address information can usually be found on the CoA/CoC, which should correspond to the GMP license. In the absence of a CoA/CoC the manufacturing site is listed on the Patient information leaflet.

BSE/TSE Statement

BSE (Bovine Spongiform Encephalopathy) and TSE (Transmissible Spongiform Encephalopathy) are diseases that can be transmitted from animals to humans through certain products. It is the responsibility of pharmaceutical manufacturers to demonstrably eliminate the risk of their products being contaminated with BSE/TSE.A BSE/TSE Statement is not a standard document, and it’s not a requirement for a manufacturer to create or distribute a specific statement, which can often make them difficult to get. Thankfully, they are not often required and there are alternative methods of demonstrating BSE/TSE compliance.

By virtue of a drug having a CoA/CoC it is clear that it has been manufactured to GMP, which in itself demands that BSE/TSE regulations have been adhered to.
For further proof, your vendor can direct you to the EPAR Assessment on the EMA website which will likely contain a statement confirming that BSE/TSE standards were met during the licensing process.
Proof of BSE/TSE compliance is only really necessary when a product contains animal derived materials (such as capsules made from gelatin) or if the commercially finished product needs to enter a territory with strict BSE/TSE policies in place.

Summary

Documentation does impact a sourcing strategy and taking time to understand what you ‘need’ vs. what is ‘nice to have’ is essential during the planning phase of a trial.
Striving for unnecessary documentation will likely mean that your supply route is not optimal and could be expensive or unduly slow. Not enough documentation may mean that the drug you’ve sourced could go to waste.

It’s important that you arm yourself with the right information to be able to have informed discussions with stakeholders about which documents are needed. Your QP will be able to offer their insights, but so will your vendor, and it can be necessary to challenge a long list of required documentation to make sure your supply chain is optimal.
This list of documentation isn’t exclusive, other examples of documents that are often ‘required’ are equivalency statements and stability data. If you’d like to know more on these documents or have any questions on this White Paper, then please reach out to Midwinter Solutions at:
ben.everington@midwinter-solutions.com

To download a copy of this Whitepaper, please click here.