Regulatory Considerations for Co-Development Activities for a Therapeutic and an In Vitro or Companion Diagnostic within a Pharmaceutical or Biotech Company

In Vitro Diagnostics and Companion Diagnostics

The landscape for therapeutics is continually evolving in the US as well as globally. Changes to the landscape are influenced by factors such as requirements by the regulatory agencies and health authorities, or strategic Perspective positioning of the product in the marketplace. Various articles have been published addressing the topic of In Vitro diagnostics and companion diagnostics; from the viewpoint of the manufacturer developing the diagnostic assays to the pharmaceutical companies strategically collaborating with the Contract Research Organizations. In 2010, an article was published describing the development of novel IVDs from a manufacturer’s perspective [1]. Cotter et al., proposed a new paradigm for personalized medicine and companion diagnostics, which introduced the concept of a Contract Diagnostic Organization, a new concept designed to aid pharmaceutical companies in addressing challenges in companion diagnostics development [2]. The

pharmaceutical company Merck published a CDx guide that poses critical questions at each stage of the pipeline, and provides access to the resources needed to address these questions [3]. This article provides considerations for regulatory professionals working within pharmaceutical or biotech companies that are actively pursuing In Vitro or companion diagnostics to accompany the products in their therapeutic portfolio.

With the increasing focus on personalized medicine, many biopharmaceutical companies find themselves needing to target for or exclude specific patient populations for their therapies and are turning to medical device In Vitro diagnostics (IVDs) for assistance. In Vitro diagnostics offer the potential of predictability needed to ensure patients get the correct treatment and avoid harmful treatment. This endeavor is not as simple as it sounds; the biopharmaceutical (pharma) and In Vitro diagnostic companies approach the personalized medicine problem from complimentary, yet very different perspectives. Understanding and leveraging these differences can help avoid derailing progress in a therapeutic area and maximize development of innovative therapies.

In Vitro Diagnostics

Looking at the general category of IVDs, we find a wide array of products from reagents to bioassays. IVDs usually have broad uses and are not typically tied to a specific therapeutic; however, the information provided by the IVD coupled with clinical presentation of the patient symptoms can assist physicians in making informed decisions about whether or not any course of treatment is necessary. These IVDs are the fundamental revenue- driving technologies upon which the IVD companies base their businesses. This also affords independent regulatory review of the IVD separate from the treatment. Conversely, pharma companies are looking to pursue an IVD or IVD-based medical device that is directly tied to a therapeutic product, in order to provide their therapeutic product a strategic market advantage over competitors operating in the same therapeutic space or to meet the requirements set forth by the regulatory agencies or health authorities.

Companion Diagnostics

Companion diagnostics pose a different challenge to pharma companies as they are typically developed contemporaneously with an associated therapeutic. Although growing relevance of companion diagnostics is recognized within the industry, many emerging markets (e.g. India, Russia, and Africa) have not specifically called out these devices as independent entities. Most of these emerging markets have not produced specific guidance on the regulatory expectations for these products. In 2014 and 2016, the FDA had previously published two different draft guidance documents directed at helping industry understand the agency’s current thinking regarding how they will regulate these products and their expectations for co-development with a therapeutic [5, 7]. In 2017, the European Parliament approved the new In Vitro Diagnostics Regulation (IVDR), which tightened the regulation of IVDs in the EU, and by association, companion diagnostics have been delineated as part of the IVD organizational structure. As stated previously, although companion diagnostics are a subset of IVDS, what sets them apart from many IVDs is the use of the diagnostic test in conjunction with the therapeutic product. The distinguishing factor is the close connection between the clinical development of the diagnostic and the therapeutic product. Although the two are reviewed and approved separately, they are typically clinically evaluated during the same clinical trial.

Pharma and IVD companies engaged in a strategic partnership for the development of a CDx, face the challenge of coordinating the clinical trials to ensure the appropriate data is available at the right time for both products to be approved contemporaneously. The pharma company is faced with a dilemma: at what point in the development of the therapeutic product should they invest in the development of the diagnostic, when the viability of their therapeutic has yet to be confirmed. Although there is no single correct answer, it is generally accepted that some risk will have to be assumed, and investment in developing a prototype of the diagnostic test for the therapeutic product will be needed. These prototype assays are subsequently used during the Clinical Phases 1 and 2 in order to determine the predictive potential of the biomarker(s) assessed in the diagnostic test [8]. Delaying the development of the diagnostic until Phase 3 increases the risk of delaying the therapeutic product approval and can bring into question the validity of data collected at previous phases. Of course, using bridging and cross-over strategies can reduce the risks to delayed approval. Therefore, it is better to plan for the upfront cost to invest in the development of a prototype of the diagnostic, if Phase 1 data for the therapeutic shows promise, and the company anticipates the need to select or exclude patients in their clinical trials. It is also worth pointing out that there is a significant amount of work (due diligence and establishing infrastructure) to prepare an analytically validated diagnostic test for Phase 3, so strategic planning and a financial commitment to the early development stages of the identified CDx program, is the key to later success.

Laboratory Developed Tests (LDTs)

As discussed earlier, LDTs are designed and manufactured for use within a single laboratory (US or International) and are subject to the CLIA regulations. Some companies will rationalize the use of a CLIA- certified laboratory for development of the Clinical Trial Assay (CTA) as support for the validity of the assay to move forward with the clinical trial. Although CLIA- certified laboratories have advantages over non-CLIA- certified laboratories, that point might not suffice for producing a ready-for-use CTA, depending upon how the laboratory validates the CTA and documents its development.

The CLIA certification does not cover certain quality system requirements for medical devices that IVDs must meet. In the US, the specific requirements that apply are the provision of 21 CFR Part 820.30, the design control provisions. The international standard for medical device quality systems, ISO 13485 also contains similar requirements. These requirements ensure that the development follows traceable good development and engineering processes. One of the major stages of design controls is design validation, which establishes that the product meets the needs of its users. In the case of FDA regulated diagnostics, this means that the diagnostic actually measures what it is supposed to measure at the right level, repeatedly and reliably. In short, you have to ensure your measuring tool is calibrated before you begin measuring.

A significant amount of work is required to achieve a completely-validated diagnostic test, as there is no middle ground as far as validation is concerned. The good news is that the hard work is not effort wasted if the therapeutic proceeds. The validation data developed for the CTA can be used as the basis for the final validation of the near- commercial (GMP manufactured) assay to be used in the Phase 3 clinical trial. The Phase 3 assay should be the planned, commercially viable assay, validated on commercially available platforms.

When considering IVDs, Companion Diagnostics, or LDTs; several factors, such as the business case or intended use of the device, will influence the strategy and final outcome for determining which regulatory pathway (FDA or CLIA) is most suitable for the diagnostic. An example of this would be after completion of the Phase 1 and Phase 2 trials, it is determined that there is no correlation between the biomarker and the clinical outcome. Lack of biomarker correlation would determine that the diagnostic would not be required for use in the Phase 3 trial. However, the early phase trial data may demonstrate the diagnostic test does in fact have some utility, such as an increased likelihood of improved outcomes from use of the test, and the pharma and IVD companies will need to determine if it is commercially advantageous to pursue the diagnostic as an LDT or to pursue it further as a cleared/approved IVD medical device.