At the Illumina Genomics Forum conference this fall, former President Obama explained that precision medicine has a “significant role to play in making the healthcare system more efficient and producing better outcomes,” but it has yet to realize its full potential.
Indeed, precision medicine is extremely promising, but still has a long way to go, especially when it comes to effectively connecting the dots between diagnosis and therapeutics. during clinical development.
Clinical Validity and Utility
Precision medicine relies on clinical validity diagnostic tests or the precise identification of patients with certain biomarker alterations. Clinical validity is however a necessary and not sufficient condition for a successful implementation of personalized medicine. To succeed, clinical utility is necessary, which means that the results of biomarker tests are actionable in terms of guiding decision-making – the prescription of specific drugs, for example – and this in turn leads to positive health outcomes.
But even in oncology, where precision medicine is most advanced, levels of biomarker testing differ dramatically across clinical practice settings and tumor types, according to an article recently published in Precision oncology. In the case of non-small cell lung cancer, for example, it is estimated that more than 70% of patients have tumors with alterations in biomarkers that are in some way related to the efficacy and safety of different treatment options. However, many patients still do not receive biomarker tests. And when lung cancer patients get tested and get actionable results, nearly 30% aren’t prescribed targeted therapies indicated by the tests as appropriate.
We don’t know why that is. Challenges exist around the tests themselves, clinician buy-in, and also paying the payer for the tests. However, perhaps the most important hurdle to overcome is the frequent disconnect between clinical validity and utility.
Co-development of diagnostics and therapeutics
Companion diagnostic tests have become increasingly important to optimize drug use, especially in oncology. This means tailoring the use of certain treatments to those with a better chance of benefit or less risk of harmful side effects. For many cancers and a growing number of other diseases, personalized treatment relies on diagnostics that identify specific biomarkers.
Obstacles remain, however, as to the most effective way to personalize medicine; co-development diagnosis and therapy. There are clinical and practical challenges related to co-development, but also economic issues, such as the lack of comprehensive insurance coverage for many companion and complementary diagnostics. Indeed, this continues to be a major impediment to achieving personalized medicine more generally.
As knowledge about biomarkers increases, more drugs are coming to market with Food and Drug Administration (FDA)-approved labels indicating their use with a particular diagnostic test. Nevertheless, most of these diagnoses are post-hoc, that is, the approved treatment comes first, and then a corresponding new diagnosis is developed. Either, an already existing diagnosis turns out to correspond to a therapy after its approval.
In contrast, co-development of drugs and diagnostics involves the parallel identification, development, and testing of a treatment and its corresponding diagnosis. The holy grail of precision medicine is the co-development of companion therapies and diagnostics, as it facilitates the drug development process and tailors drugs – before market approval – to the patients who benefit most. more or have fewer side effects. This, in turn, simplifies reimbursement decision-making after approval, generally favoring positive coverage decisions for treatments and diagnostics.
Regulatory incentives for co-development have been in place for some time. In an FDA guidance issued in August 2014, the agency stated, “Ideally, a therapeutic product and its corresponding companion in vitro diagnostic device should be developed concurrently, with the clinical performance and clinical significance of the companion in vitro diagnostic established using data. of the clinical development program for the corresponding therapeutic product.
Here are three examples of co-developed companion diagnostics:
- the IDH1 test, developed by Abbott, in association with ivosidenib (Tibsovo); a drug sponsored by Servier indicated in acute myeloid leukemia
- the CDx BRCA test, developed by Foundation Medicine, in collaboration with rucaparib (Rubraca); a drug sponsored by Clovis indicated for recurrent epithelial ovarian cancer
- the ALK CDx test, developed by Abbott, in combination with crizotinib (Xalkori); a drug sponsored by Pfizer indicated for non-small cell lung cancer
But, of the current list of FDA-approved companion diagnostics, most are not co-developed with therapeutics.
The challenges of co-development
Twenty years ago, the mapping of the human genome opened up new opportunities for genomic or genetic testing to identify diseases and guide treatment modalities, tailored to specific patient subpopulations. The completion of the genome project has raised the possibility that co-development will become de rigueur. However, in reality, co-development has encountered many clinical, economic and practical challenges.
Currently, there are thousands of genetic and genomic tests on the market for over 10,000 conditions. Additionally, hundreds of drugs have genetic markers on their FDA-approved labels, and at least a third of drugs in development include genetic markers. These can be purely informative in the sense that they inform about a (possible) link between a particular genetic marker and an indication or a disease. Alternatively, the presence of genetic markers on the label may inform prescribers and patients of potential adverse events in certain susceptible subpopulations or, ideally – as is the case with co-developed drugs and diagnostics – be directly related to the use of a drug with a biomarker test.
Note the difference, however, between identifying disease-associated genes and developing an effective new drug that depends on the use of companion diagnostics. Genetic findings have certainly provided clinicians with important insights into disease pathology. But the complexity of gene expression involving multiple causal pathways – with many possible confounders – means that there is often not a strong link between a specific set of genotypes and how the disease progresses. In turn, this may make it more difficult to co-develop genomics-based therapies and diagnostics.
For example, checkpoint inhibitors – immunotherapies that target cytotoxic T cell antigen 4 or the programmed cell death 1 (PD1) pathway – have shown success in treating different types of cancer. Yet only a relatively small subset of patients derive clinical benefit. Immune checkpoint inhibitor efficacy is affected by a multitude of factors involving tumor genomics, host germline genetics, levels of PD1 ligand 1, but also environmental characteristics, including the gut microbiome. Ultimately, a better understanding of precisely how all of these variables interact would be needed to optimize the prescription of checkpoint inhibitors.
In addition to clinical issues, practical issues hinder co-development. There is the temporal aspect, for example. Ideally, a pharmaceutical company would like to launch a therapeutic and a diagnostic simultaneously. But this implies that the diagnostic must be developed and ready to be deployed in clinical trials; preferably before Phase 2, and certainly before Phase 3.
Another significant challenge is the lack of early engagement among stakeholders in drug diagnostic co-development models. Currently, most manufacturers choose not to develop their own companion diagnostics. Instead, they partner with outside companies.
Even then, when there is an external partnership, financial incentives for the development of companion diagnostics are sometimes hampered by limited intellectual property protections. Diagnostics do not benefit from the same type of patent protection as therapeutics. Additionally, diagnostics typically face lower margins and higher reimbursement hurdles than pharmaceuticals.
In short, developing a new biomarker test in parallel with a treatment – in hopes that the biomarker test will be included in the FDA-approved label – has come with a persistent set of clinical and economic challenges.
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