The need for a CDx may arise already at the (early) clinical development stage of a medicinal product. A clinical trial with an investigational medicinal product with such a specific indication can only be successful if potential trial participants are tested for the relevant biomarker or other relevant parameter.
In some cases, a suitable IVD for the required testing may already be commercially available. In such a scenario, pharmaceutical companies should check whether the available product is already certified under the IVDR or still under the former In Vitro Diagnostic Medical Devices Directive (Directive 98/79/EC or the IVDD) and that the use of the product will be on-label (i.e., in accordance with its CE marked intended purpose).
However, the challenge that medicinal product innovators more often face is that there is no certified CDx on the market at all that complies with EU IVD legislation.
Transitional periods of the IVDR for legacy products
If a suitable IVD is available but still certified only under the former IVDD, pharmaceutical companies have to make sure that the IVD still falls under the transitional provisions of the IVDR for so-called legacy IVD. To safeguard the supply of IVDs to the EU market and give manufacturers more time to transition to the new legal framework, Article 110 of the IVDR sets out certain transitional provisions.
CE Certificates of Conformity issued by notified bodies under the IVDD before 25 May 2017 shall remain valid until the end of the period indicated on the certificate (Article 110 no.2 of the IVDR). Certificates issued by notified bodies afterwards shall become void by 27 May 2025 (Article 110 no.2 of the IVDR). These IVDs may be placed on the market or put into service until 26 May 2025 (Article 110 no. 3 of the IVDR).
Devices for which the IVDD conformity assessment procedure did not require the involvement of a notified body, for which an IVDD declaration of conformity was drawn up before 26 May 2022, and for which the conformity assessment procedure under the IVDR requires the involvement of a notified body, may be placed on the market or put into service until the following dates (Article 110 no. 3 of the IVDR):
- 26 May 2025, for class D devices;
- 26 May 2026, for class C devices;
- 26 May 2027, for class B devices;
- 26 May 2027, for class A devices placed on the market in sterile condition.
To benefit from these transitional provisions these IVDs need to continue to comply with the IVDD and no significant changes in the design and intended purpose can take place. It should also be noted that the requirements of the IVDR relating to post-market surveillance, market surveillance, vigilance, and registration of economic operators and devices apply to these legacy IVDs.
General requirements of the IVDR for placing an IVD on the EU market
Where the use of a legacy IVD is not an option, the IVD to be used in a pharmaceutical clinical trial has to meet the requirements of the IVDR for the placing on the market of such IVD.
This is because the use of an IVD to test patient samples to take medical management decisions in the context of a clinical trial conducted in the EU, is considered to be a ‘placing on the market’ of that IVD. Such IVD is therefore subject to the legal requirements of the IVDR. According to the IVDR, an IVD used for such a purpose can only be placed on the market if it is:
- CE-marked for the intended use (pathway 1),
- used in an IVD performance study testing that very IVD (pathway 2); or
- used as a so-called in-house IVD (pathway 3).
It is not legally possible to circumvent these requirements by testing samples from EU trial participants outside the EU (e.g., by sending EU patient samples to a laboratory in the U.S. for testing with an IVD that does not comply with the IVD Regulation). Even such testing of EU patient samples outside the EU would be covered by the IVDR rules. Ultimately, this means that the pharmaceutical company must ensure that any IVD used in its clinical trials falls into one of the three categories above.
Pathways for using IVDs in clinical trials
Pathway 1 (IVD CE-marked for the intended use)
When an innovative medicinal product is being developed for a biomarker-determined indication, there is often no off-the-shelf IVD for that biomarker on the market that has already undergone a conformity assessment procedure for such biomarker testing. The only option to use this pathway would then be to complete the development and conformity assessment process for the CDx before starting clinical trials for the medicinal product candidate. However, this is usually too time-consuming and not commercially viable (given that the medicinal product’s potential has not yet been proven). As a result, this pathway is typically reserved for later phase III clinical trials – or even only for the commercial launch of a pharmaceutical product.
Pathway 2 (IVD for performance study)
Using an IVD for a performance study within the clinical trial is generally a feasible pathway, but involves some risk and uncertainty. Using an IVD for a performance study for patient selection (or other testing) in a pharmaceutical clinical trial basically means that an IVD performance study testing is conducted within the clinical trial for the medicinal product. The regulatory environment under the EU Clinical Trials Regulation (EU) 536/2014 generally recognizes the possibility of such a combined study, testing both the medicinal product and the IVD. However, the regulatory framework does not provide any clear procedures or rules for such combined trials, i.e., both the requirements of the (pharma) clinical trial regulation as well as the requirements of the IVDR for IVD performance testing have to be met in parallel. Further, the use of an IVD (which is itself only being tested) within a pharma clinical trial adds another layer of uncertainty to the pharma trial (e.g.: are trial subjects reliably enrolled or stratified based on the existence of the biomarker?). In practice, this route is rarely taken and it is not easy to get approval from competent authorities for such a combined trial.
If a suitable CDx is not already available and if the pharmaceutical company wants to avoid the uncertain pathway of a combined study, and also the cost and delay that would be involved in completing an IVD performance study before starting a clinical trial for the pharmaceutical product, the pathway of a so-called in-house IVD (pathway 3) comes into play.
Regulatory framework for in-house IVDs
What makes in-house IVDs a potential option for pharmaceutical companies looking for a CDx within their pharma clinical trial is that in-house IVDs are exempted from most of the IVDR requirements for the marketing of IVDs, in particular from the requirement to undergo a conformity assessment procedure (Article 5 no. 5 of the IVDR).
In-house IVDs are defined as IVDs that are manufactured and used only within health institutions in the EU and are not transferred to other legal entities. They must comply with the general safety and performance requirements of the IVDR and be manufactured and used under adequate quality management systems. However, the exemption from the need to carry out a full conformity assessment procedure is still a significant simplification. The purpose of the in-house IVD concept is to reduce the burden on hospitals and other health care providers that develop and manufacture IVDs for use within their own organization. A similar concept is known under U.S. law as Laboratory Developed Tests or LDTs. An important prerequisite for the use of this exemption, in addition to the others listed in Article 5 no. 5 of the IVDR, is that the IVD is developed and used within a single legal entity, i.e., the test cannot be made available to third parties.
Health institutions in the sense of Article 5 no. 5 of the IVDR are organizations whose primary purpose is the care or treatment of patients or the promotion of public health. Typical examples of health institutions are hospitals as well as institutions that do not directly treat patients but support health care systems, e.g., laboratories that provide testing of patient samples.
Potential of in-house IVDs for pharmaceutical companies
Pharmaceutical companies will therefore typically not be considered health institutions and cannot directly benefit from the exemption under Article 5 no. 5 of the IVDR. However, pharmaceutical companies can collaborate with a health institution in the EU that has developed and uses a suitable assay/CDx. Such a health institution can then be established as the central laboratory for testing all patient samples from the company's clinical trials throughout the EU. This is permitted under the IVDR, which requires the IVD to be manufactured and used within a single legal entity. It does not require the samples tested with the in-house IVD to come from the same legal entity (i.e., only from patients of that very health institution). However, this possibility needs to be assessed on a case-by-case basis and under the national law of each EU Member State (as the rules for the qualification of ‘health institutions’ vary and some countries have adopted specific guidance in this regard).
Partnering with a health care institution for early-phase clinical trials may enable a pharmaceutical company to focus on its clinical medicinal product development by utilizing an in-house assay/IVD – and to develop or have developed the CDx for phase III trials and later commercialization in parallel to their clinical development program for their medicinal product candidate.
Of course, the CDx IVD development would have to be fiercely pursued, often with the help of a diagnostics company under a CDx development and collaboration agreement. For the commercial phase, the option of performing biomarker testing solely by the in-house IVD route is usually not practicable or viable. Regarding the key aspects to consider when negotiating a CDx development and collaboration agreement, we will be issuing another article.
This is an article in our “Life Sciences Transactional Insights” series, which aims to provide key practical takeaways for our transactional colleagues by anticipating the needs of their regulatory, intellectual property, and business stakeholders. Our dedicated team of life sciences and health care licensing and commercial transactions lawyers understand the challenges and opportunities that strategic alliances and other partnering relationships present. We draw on the depth of our life sciences practice and work seamlessly with our regulatory experts to provide unparalleled transactional support. Ensure you are subscribed to Hogan Lovells Engage to receive our insights.
