What you need to know in order to prepare for Companion Diagnostics (CDx)?

1. What is Companion Diagnostics (CDx)?

As the importance of precision medicine increases, lots of biotech companies and pharmaceutical companies have been focusing on developing companion diagnostics (CDx). Companion diagnostics is a medical device, often an in vitro device, which provides information that is essential for the safe and effective use of a corresponding drug or biological product. The test helps a health care professional determine whether a particular therapeutic product’s benefits to patients will outweigh any potential serious side effects or risks. [1] The very first FDA-approved CDx was Trastuzumab and HER2 immunohistochemical (IHC) assay. Starting with this one, the total number of approvals by the end of 2021 is 44. 

It is important because CDx can
 

-identify patients who are most likely to benefit from a particular therapeutic product.

-identify patients likely to be at increased risk for serious side effects as a result of treatment with a particular therapeutic product; or

-monitor response to treatment with a particular therapeutic product for the purpose of adjusting treatment to achieve improved safety or effectiveness.

A CDx assay is an important treatment decision tool on which crucial treatment decisions are made, and an increasing number of drugs guided by a CDx are expected to reach the clinic in the near future.

However, getting FDA approval does not mean it can be used worldwide. Regulation of CDx different depends on the countries, and this article will cover the United States and Europe. 

2. Companion Diagnostics (CDx) by countries 

2.1 United States (U.S)

2.1.1 Classification of CDx
In the U.S, medical device classes are classified into three according to their level of risk, and Medical device subclasses are classified according to clinical use. There are about 1,700 medical devices classified by the FDA in CFR Part 862-892, and of the 1,700 devices, 45% are classified as Class I, 47% as Class II, and 8% as Class III. To add, Regulations (permission types) applied to in vitro diagnostic medical devices are divided according to the classification of medical devices. The submission types are 510(k) exception, 510(k), and PMA. Taking GENECAST cancer diagnosis product ADPSTM EGFR Mutation Test Kit v1(링크) as an example, since it is a cancer diagnosis product, the product code is OWD, and the device class is III, and accordingly, the submission type is Premarket approval (PMA) [2]

2.1.1 Applying for CDx

CDx using Real-time PCR in the United States belongs to Class III, which must follow the PMA procedure. 

PMA is the FDA process of scientific and regulatory review to evaluate the safety and effectiveness of Class III medical devices. Class III devices are those that support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential, unreasonable risk of illness or injury. Due to the level of risk associated with Class III devices, FDA has determined that general and special controls alone are insufficient to assure the safety and effectiveness of Class III devices. Therefore, these devices require a premarket approval (PMA) application under section 515 of the FD&C Act in order to obtain marketing approval.[3][4]

The PMA procedure is divided into Traditional PMA, Modular PMA, and Streamlined PMA, and the PMA application form of GENECAST corresponds to Traditional PMA. Traditional PMA is the most common PMA application and requires the submission of all review materials required by FDA. This includes all data such as device description, intended use, non-clinical or clinical data, manufacturing method, or labeling. 

Because CDx needs clinical trials, the Investigational Device Exemption (IDE) application must be applied first(after checking whether IDE Application is applied), and a clinical trial protocol is developed, and a clinical trial is performed. Non-Significant risk studies are possible only with IRB approval. [2]

2.2 Europe (EU)

2.2.1 Classification of CDx

Classification of in vitro diagnostic medical devices (IVD) is conducted in accordance with the seven rules (Rule 1 to Rule 7) of Annex VIII of IVDR 2017/746 and is classified into four classes (Grades A, B, C, and D) considering the purpose of use and inherent risks of medical devices. CDx corresponds 

2.2.2 Applying for CDx

To get approval of In-vitro diagnostic medical devices in Europe, a conformity assessment of the device should be conducted in accordance with the corresponding conformity assessment procedures prescribed for each medical device class in Annex IX to XI of IVDR 2017/746.

According to section 5.2 in Annex IX, IVDR 2017/746, consultation with the Competent Authority or EMA is needed. This is to evaluate whether a drug used for companion diagnosis is appropriate for use with a medical device. [6]

3. Companion Diagnostic in a spotlight 

3.1 Clinical efficiency of CDx

According to “Influence of companion diagnostics on efficacy and safety of targeted anti-cancer drugs: systematic review and meta-analyses”, targeted drugs used in experimental arms of included trials showed improved PFS and OS. This study concluded that CDx increased the magnitude of clinical benefit as well as reduced toxicity compared to the target agent without an accompanying diagnostic test. Targeted drugs with companion diagnostics are associated with improved safety and tolerability. [7]

3.2 Economic benefit of Companion Diagnostics.

Exempt from the above benefits, pharmaceutical companies can save on the development cost of tyrosine kinase inhibitors through companion diagnostics. According to the Ark investment research, the total clinical trials’ expense can be reduced by up to 60%.[8] This impressive outcome is highly related to the selection of the participants of clinical trials. Traditionally, it is very hard to sort out the patient pool that will respond well to the therapies, especially the drug targeting the small populations. However, companion diagnostics can identify which patients will respond well to the candidate drug. In other words, the efficacy of drugs can be evaluated with smaller size clinical trials. 

This powerful advantage can be applied to the various treatment field, but oncology will be the biggest beneficiary of CDx. According to the above chart, CDx can save 23 billion$. If the total R&D cost is decreased, it can be a powerful trigger to lower the cancer drug. Additionally, pharmaceutical companies can conduct more clinical trials of a new drug candidate with saved R&D expenses. Consequently, cancer patients will be treated more precisely and economically. 

3.3 Regulator’s view on CDx

FDA comprehended the advantage of companion diagnostics earlier than any other institutions, and issued Guidance for ‘Industry: in vitro companion diagnostic devices’ in 2014. The purpose of this guidance was to help companies adopt companion diagnostics at an earlier stage of the drug development process. Since the issue of guidance, the demand for co-development of the drug and the diagnostic assay has increased explosively. Moreover, FDA additionally issued the draft guidance of ‘Principle for co-development of an In-vitro companion diagnostic device with a therapeutic product’ in 2016 and ‘Developing and labeling in vitro companion diagnostic devices for a specific group or class of oncology therapeutic product’ in 2018. It promoted the settlement of companion diagnostics on the existing system of FDA approval well. 

4. How can maximize the efficacy of companion diagnostics?

4.1 Why the development of Tyrosine kinase is so important?

To overcome cancer, many researchers and pharmaceutical companies have developed various types of cancer drugs. Among them, tyrosine kinase inhibitors (TKIs) are an attractive choice rather than other treatments in selectivity, efficacy, and safety. [9]. Considering the fact that mutation genes cause cancer, tyrosine kinase inhibitors approached the cancer occurrence issue fundamentally by restraining the occurrence of mutation genes. Accordingly, TKIs can improve important factors like progression-free survival or overall survival [9]. Through the clinical trials for TKIs approval, we can easily check the amazing performance of Tyrosine Kinase Inhibitors. 

4.2 The key factor of detection kit for developing efficient Companion Diagnostics 

However, TKIs are not effective for every cancer patient. Tyrosine kinase inhibitors can come into their own when they are prescribed for the right patients. For example, EGFR TKIs can be effective for patients who have EGFR mutation gene, but it does not work for cancer patient do not. Additionally, classifying cancer patients who have the right mutation genes for the specific TKIs can affect the result of clinical trials. Therefore, detecting which types of mutation gene patients have is very important and necessary for not only treatment but also CDx too.

However, because early-stage cancer patients have fewer amount of mutation genes, it is more difficult to diagnose without error. At least the detection sensitivity of 0.1% is required for testing the cancer patients before 3A, but the conventional products and technology are still far away from it. If pharmaceutical companies plan to recruit cancer patients with specific mutation genes and 3B stage to raise the response rate, they should test a large group of patients. This may occur the large amount of research expenses. Especially the total number of cancer patients with rare mutation genes is very small, so recruiting a enough participants will be a big burden for drug development. At this point, the detection sensitivity becomes a key factor in the success rate of clinical trials.

4.3  Cooperating with GENECAST

In this way, ADPS EGFR Mutation Test Kit v1 has a decisive advantage. The detection sensitivity of our product is around 0.01~0.05%. It is at least ten times better performance compared with other conventional products. It’s because of the proprietary technology called ADPS system. It consists of the ADPS polymerase, primer & probe, and buffer. Through a long development period, we improved the selectivity of the polymerase up to limitation. Furthermore, we upgraded the primer-probe design and the buffer to stabilize the performance of our products. Consequently, our product can discriminate even one mismatch. It means that our kit can detect cancer patients 1B~3A. Therefore, finding suitable cancer patients with fewer tests is possible. With this high performance, our product can raise clinical trial efficacy dynamically.

Reference

[1]Companion Diagnostics, FDA, https://www.fda.gov/medical-devices/in-vitro-diagnostics/companion-diagnostics

[2] FDA PMA procedure and analytical performance evaluation

[3] QP-814 FDA PMA Procedure_Rev.0_220328

[4] Premarket Approval (PMA)_ FDA

[5]03 QP-811_CE MARK Management Procedure

[6]04 IVDR 2017/746

[7] Influence of companion diagnostics on efficacy and safety of targeted anti-cancer drugs: systematic review and meta-analyses, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741844/#R10

[8]Manisha Samy, ALK inveestment resources page, ARK invest web site, Companion Diagnostics (CDx): More Drugs At A Fraction Of The Cost, https://ark-invest.com/articles/analyst-research/companion-diagnostics-cdx/

[9]Mongre, R. K., Mishra, C. B., Shukla, A. K., Prakash, A., Jung, S., Ashraf-Uz-Zaman, M., & Lee, M. S. (2021). Emerging Importance of Tyrosine Kinase Inhibitors against Cancer: Quo Vadis to Cure?. International journal of molecular sciences, 22(21), 11659. https://doi.org/10.3390/ijms222111659

[10] Fiala, C., & Diamandis, E. P. (2018). Utility of circulating tumor DNA in cancer diagnostics with emphasis on early detection. BMC medicine, 16(1), 166. https://doi.org/10.1186/s12916-018-1157-9