Companion Diagnostics and the Drug–Diagnostic Codevelopment Model

Abstract

Preclinical Research The concept of using a predictive or selective diagnostic assay in relation to drug development goes back to the 1970s when the selective estrogen receptor modulator, tamoxifen (AstraZeneca) was developed for metastatic breast cancer. Clinical data showed that the estrogen receptor status correlated well with the clinical outcome when the patients were treated with tamoxifen. Although this datum was published more than 35 years ago, the adaption of the drug–diagnostic codevelopment model has been relatively slow, and it is only within the last decade that it has gained widespread acceptance. In this model, the drug and the diagnostic are interdependent, and if the development project proves successful, the companion diagnostic assay (CoDx) will end up determining the conditions for the use of the drug. This gatekeeper role obviously requires that the CoDx assays adhere to the same strict rules and regulations that are known from the development of drugs. For any CoDx assay, it must be documented that it is robust and reliable and that it possesses clinical utility. The article focus on some of the most important aspects of the CoDx development process with emphasis on the clinical validation and clinical utility but also other critical issues such as the biomarker selection process, determination of the cut‐off value, and the analytical validation are discussed.

A new look at the corporate capability of personalized medicine development in the pharmaceutical industry

“…One of the best-known examples is Trastuzumab (Herceptin ® , Roche/Genentech), the humanized monoclonal antibody directed toward human epidermal growth factor receptor 2 (HER2) and its corresponding CoDx, the immunohistochemical assay HercepTest ® (Dako). During clinical development, Trastuzumab clearly showed an increase in the clinical benefit of first-line chemotherapy in metastatic breast cancer that overexpresses HER2, while the use of the immunohistochemical assay for selecting HER2-positive breast cancer has served as a major inspiration for the parallel drug-diagnostic co-development model (Slamon et al, 2011;Jørgensen, 2012). The recent draft guideline issued by the US Food and Drug Administration (FDA) (FDA, 2011) specifies that CoDx assays could be essential in three main ways: (i) identifying patients who are most likely to benefit from a particular therapeutic product; (ii) identifying patients likely to be at an increased risk of serious adverse reactions as a result of treatment with a particular therapeutic product; and (iii) monitoring response to treatment to improve its safety or effectiveness.…”

“…One of the best‐known examples is Trastuzumab (Herceptin ® , Roche/Genentech), the humanized monoclonal antibody directed toward human epidermal growth factor receptor 2 (HER2) and its corresponding CoDx, the immunohistochemical assay HercepTest ® (Dako). During clinical development, Trastuzumab clearly showed an increase in the clinical benefit of first‐line chemotherapy in metastatic breast cancer that overexpresses HER2, while the use of the immunohistochemical assay for selecting HER2‐positive breast cancer has served as a major inspiration for the parallel drug–diagnostic co‐development model (Slamon et al., ; Jørgensen, ).…”

“…Moreover, they pointed out that the number of partners in the CoDxD process should be as few as possible to avoid product delays and inefficiency. Similarly, Jørgensen () suggested that collaborations between pharmaceutical and diagnostics companies for CoDxD begin from an early stage of drug development. Ideally, as the clinical efficacy data generated during phase II must be used to provide an indication of the predictive or selective value of the assay, a CoDx assay should be developed during the preclinical development of the drug, or at least at the beginning of phase I.…”

Companion Diagnostics in Oncology - Current Status and Future Aspects

“…A definition that focuses on the predictive or selective characteristics of the CDx assay is: ‘A pre-treatment test performed in order to determine whether or not a patient is likely to respond to a given therapy. This type of test is classified as a predictive or selective test and is a prerequisite for implementation of personalized and stratified medicine' [3]. …”

“…These mechanisms are often very complex and we are far from a complete understanding of the molecular biology. However, what we do understand is that drugs work at the molecular level, and it is here we must seek the solution to a more rational drug development process and the subsequent treatment of the individual patients in the clinic [1,3]. …”