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When rare becomes the norm - Part 2

27 Feb 2023

In our previous blog, we introduced the topic of testing for rare mutations. In this article, we would like to focus more on the challenges that many stakeholders face when dealing with rare indications or mutations, and what initiatives are being undertaken to address them.

Let’s start with re-emphasizing the impact of ignoring these uncommon mutations, with a common example of the diagnosis of rare hereditary diseases. Many physicians, especially outside of specialized centers, lack extensive education and training in rare diseases as well as in genetics, testing, and interpretation. Yet, they usually rely on their own limited experience and on clinical examination and other lab/imaging tests to try to establish the most common or probable diagnosis, deprioritizing genetic testing. As such, the diagnostic odyssey (multiple referrals, inconclusive tests and incorrect diagnoses before a final diagnosis is obtained by an appropriate genetic test) still prevails in many countries. Not surprisingly, the average diagnostic delay is 1.5 years, and for some patients even more than 5 years, with a third to half of patients with rare diseases still not having an accurate diagnosis1 after this time period. Unfortunately, for many of these rare disease patients, early diagnosis and quick intervention are key for survival and a high quality of life.

But the challenge with rare indications or mutations does not stop at the level of ensuring patients are tested for all appropriate biomarkers; instead, it impacts all stakeholders at multiple levels, as summarized below with key challenges and questions to ask:

After detecting the driver mutation(s) and establishing a diagnosis, what’s next? Is there an existing approved therapy, clinical trial or off-label option? What would be the cost for these orphan therapies?

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Procuring positive samples for analytical validation is challenging;there is much competition for getting these rare samples or a large number of cases are needed to be screened in order to find a reasonable number of useful samples.Also, in a trial, not all the tests (especially Laboratory Developed Tests (LDTs)) have been validatedfor the biomarker of interest, so concordance studies between the Companion Diagnostic (CDx) and the tests used in enrollment might be affected.


Is there enough clinical demand? What is the cost/reimbursement and how easy is it to develop and incorporate testing for these rare biomarkers? This will impact test adoption and availability decisions. For example, labs might decide to batch samples or send testing to another lab if continuous demand and clinical utility are not established. This eventually increases turnaround time by a few days up to a few months (depending on the urgency of the case).


Is there sufficient evidence for clinical utility, safety and cost-effectiveness? Providing this, especially when the proposed affected population is small, can be challenging.


Since most research centers see only a few cases, specimens, models and data may be siloed and difficult to gather. This makes research into a rare biomarker, its therapeutic response, and resistant mechanisms, harder to conduct. Major grants might also be difficult to acquire when the perceived impact is small.


Will developing a therapy for a rare alteration have good ROI? How do you find enough patients to enroll into trials to assess survival benefit or side effects, and eventually establish clinical utility for regulatory submissions? Unfortunately, even when these patients are found, many have gone through multiple lines of treatments, making them ineligible for clinical trial enrollment. This can lead to trial failure/closure. In addition, because timelines are usually compressed for these orphan therapies (breakthrough or accelerated approval), pharma will need to rely on local tests to find patients, which might be unreliable, leading to delays or inconvenience due to repeat testing and/or biopsy.

So needless to say, a change is needed to ensure that all patients are tested for the most appropriate alterations, including empowering all stakeholders in this field to make accurate testing decisions. Trial design and regulatory requirements will also need to be adapted and flexible to accommodate this small, challenging population. Recently, Friends of Cancer Research, along with an expert working group from across the health sectors issued a white paper with recommended strategies and policy considerations to optimize the safe acceleration of companion diagnostic development and review for rare biomarkers/indications2,3. Their recommendations revolve around 2 main areas: 1) improving patient access to clinical trials via establishing minimum performance standards to support use of local tests; 2) de-risking and streamlining CDx development and review to align with those of the drug. For example, regulatory flexibilities by allowing data from contrived samples, similar sample types or prior platform data can supplement clinical samples to provide the required analytical and clinical validation. Ultimately, this white paper aims to start the discussion with FDA in order to exercise greater flexibility and issue guidance for the validation of rare biomarker diagnostics.

Regulatory bodies have also been aware of these roadblocks and challenges, and are open to such flexibilities; one of the main examples is the recent CDx approval by FDA for NTRK fusions. During the FMI PMA review to expand indications to NTRK fusions in solid tumors, FDA leveraged the existing platform validity data for gene fusions in general (in addition to the key studies for accuracy, precision, sensitivity and specificity data for NTRK). By taking the totality of the existing and new clinical/analytical validation data, they decided that the panel is safe and effective, and can be approved. Any remaining questions were left for post-market setting, as long as they are addressed within 2 years4. In addition, in 2020, FDA released guidance outlining considerations for broadening CDx labeling to an oncology therapeutic group (instead of being limited to a specific treatment)5. This can benefit all CDx, but in particular will speed up and facilitate clinical and analytical validation of CDx in rare biomarkers.

To conclude, there is still much work to be done to improve the testing situation for rare mutations/indications. However, although the road seems challenging, it is not impossible. At Diaceutics, we can support in better understanding the patient diagnostic journey from diagnosis to treatment decision, as well as address any potential testing hurdles which could impact rare disease patient care and commercial success.

Contact us to discover more about our Solutions, including DXRX Signal that can help in quickly identifying rare disease patients eligible for a clinical trial or the most effective therapy.
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1. Diaceutics Data Repository

2. https://friendsofcancerresearch.org/wp-content/uploads/Dx_For_Rare_Biomarkers_White_Paper.pdf

3. https://www.youtube.com/watch?v=_Bk1FKhXhK4&ab_channel=FriendsofCancerResea

4. https://www.accessdata.fda.gov/cdrh_docs/pdf17/P170019S017A.pdf

5. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/developing-and-labeling-vitro-companion-diagnostic-devices-specific-group-oncology-therapeutic