Regulation of Personalized Medicine: A Status Report

June 12, 2012
Expect evolution within the industry, as well as at FDA, as personalized medicine becomes the standard, rather than the exception, to biomedical innovation and product development.

Personalized Medicine seeks to individualize health care by identifying the most effective or comfortable treatment for that individual. Finding the right treatment for the right individual at the right time can be applied preventively or therapeutically. In one aspect of personalized medicine, an individual’s genetic code is analyzed and used to identify the individual’s response potential to a variety of available drugs. After testing, the appropriate healthcare strategy can be implemented to provide the best treatment for that patient’s disease rather than through a trial-and–error approach.

Herceptin [1] is one example of a drug that has a test (a “companion diagnostic”) that identifies patients amenable to treatment based on the patient’s genetic code. The drug is reported to slow down or stop the growth of breast cancer in the 25% of patients with metastatic disease who overexpress the HER2 gene or HER2 receptors. Several tests are available to test for overexpression and therefore, the likelihood that Herceptin will treat the patient [2].

Many patients have received the benefits personalized medicine with over 70 products currently on the market [3]. However, widespread implementation of personalized medicine, and in particular companion diagnostics, has been hampered in part by unclear regulatory requirements. The Personalized Medicine Coalition (a nonprofit trade organization that seeks to provide a structure for achieving consensus positions among its members on crucial policy issues [4]) reports that the current state of medical testing regulation for personalized medicine products has created uncertainty for companies in terms of how much investment is necessary to get a product on the market and keep it there [5].

Companion Diagnostics – Kits or Lab Tests

Companion diagnostics are the workhorse of personalized medicine as they link the individual’s genomics to the therapeutic or treatment. The tests typically fall into two main categories, diagnostic kits and laboratory-developed tests (“LDTs”). Diagnostic tests contain all the reagents and information necessary to carry out the test and are regulated by the Food and Drug Administration (“FDA”) as medical devices. The majority of companion diagnostics are LDTs. LDTs require more extensive sample preparation and specialized equipment to perform the tests. The FDA and the Centers for Medicare and Medicaid Services (CMS) have jurisdiction to regulate LDTs. Historically, the FDA has not exercised its regulatory authority over LDTS thereby allowing CMS to regulate LDTs under the Clinical Laboratory Improvement Amendment (CLIA) rules.

In Vitro Companion Diagnostic Devices Guidance

Recently, the U.S. Food and Drug Administration (FDA) took a step toward addressing concerns that the FDA is not keeping up with the pace of innovation in this fast-moving field [6]. In July of 2011, the agency issued a Draft Guidance (“Guidance”) to assist those (1) who are planning to develop a therapeutic product that depends on the use of such a device/test for the product’s safe and effective use, and (2) who develop a companion diagnostic device intended for use with a corresponding therapeutic product. A brief overview of the FDA’s proposed regulations is provided below.

Recommended Regulatory Process

In the Draft Guidance, the FDA recommends contemporaneous development of a drug and its corresponding diagnostic device. If the device and its test results are essential for the drug’s safety and efficacy, the FDA will not approve the product or use of the product with the device if the FDA has not also approved/cleared the device itself. However, the FDA will retain discretion to approve a drug for use with a companion device, even if the FDA has not yet approved/cleared the device. In this situation, the FDA expects it will approve/clear the device subsequently, and that sponsors will revise relevant therapeutic product labeling accordingly, with certain additional precautions to protect public safety.

Investigational Use

A diagnostic device used to make treatment decisions in a clinical trial is considered to be an investigational device (“IVD”) unless the device is used in a manner that is already approved/cleared. If the device/test is used to make critical treatment choices, such as patient selection or treatment, the diagnostic test will be considered a significant risk device because it presents serious risk to health, safety or welfare of the patient. In such situations, the device sponsor must comply with investigational device exemption (IDE) regulations.

A diagnostic device and therapeutic product may be studied in the same investigational study, as long as the study otherwise meets IDE and investigational new drug (IND) regulations. The planned use of an IVD companion diagnostic device and its use in clinical trials should be submitted by the sponsor in an investigational submission. The Draft Guidance also recommends that the device sponsor and the therapeutic product sponsor submit information about the proposed IVD companion diagnostic device in a preIND submission.


The Draft Guidance also addresses labeling of therapeutic products that depend on a diagnostic test. Existing FDA regulations indicate that product labeling must include information relating to relevant laboratory tests. Where appropriate, the Indications and Usage section of a label must define the patient subpopulation that would be treated with the drug. If a diagnostic test is essential for monitoring beneficial or adverse effects of a therapeutic product, the Warnings and Precaution section must identify the type of test necessary for monitoring effects. Labeling must include information about the type of device (i.e., intended use of the device), rather than a specific manufacturer’s device. Moreover, if the FDA approves/clears a companion diagnostic device after it approves a relevant therapeutic product, the product label must be amended to incorporate such information.

For the labeling of an IVD companion diagnostic device, the FDA notes that the labeling should specify the intended use of the device, as well as relevant therapeutic products. When appropriate, the labeling can name a class of therapeutic products, rather than specific products within the class. Device labeling should be expanded (i.e., approved/cleared) to reflect use in a new disease or setting, or with a different/new therapeutic product.

Industry Comments

The FDA invited public comments on the Draft Guidance Document to help the agency formulate its final version. Thirty-three official comments were submitted from a variety of industry experts, researchers and patient advocacy groups [7]. A common theme among the commentators was an appreciation of the FDA’s effort to provide guidance on the co-development of companion diagnostics and therapeutics to the end of ensuring patient safety and high-quality care. However, many noted that the Draft Guidance does not clearly identify what tests are, and are not, intended within the defined IVD companion diagnostic. For example, many in the industry questioned whether LDTs, now regulated by CMS, will now be regulated by the FDA, thereby requiring them to pursue a premarket application (PMA) or 510(k). Some within the industry advocated for the inclusion of LDTs as a companion diagnostic because the current lack of FDA oversight of LDTs, particularly when a cleared or approved IVD companion diagnostic device is available, has created an imbalance in which manufacturers of diagnostic tests develop, verify and validate the tests which are subject to FDA scrutiny, while clinical laboratories may develop and offer these tests without having appropriate regulatory oversight.

On the other hand, others argued that the linkage of a personalized pharmaceutical agent with a single approved (or approvable) companion diagnostic is a major disincentive for drug companies to continue diagnostic research and development. LDTs, it was argued, should remain a viable alternative for the approval of clinical trials and approval of drugs. In addition, the Draft Guidance failed to address how the FDA will treat LTDs that are considered “standard-of-care” yet not currently not FDA approved.

Many in the industry commented that the Draft Guidance lacks a real world appreciation of the typical development pathway for in vitro companion diagnostics [8]. For example, BIO [9] opined that according to the Draft Guidance, the FDA believes that sponsors will typically co-develop the therapeutic and companion diagnostic and seek approval in a synchronous, contemporaneous manner. BIO argues that this is not typical of the industry to date. The FDA’s approach precludes situations where contemporaneous co-development is not possible or has not occurred, which may reflect the more prevalent development pathway in current practice. For example, a diagnostic test may not be developed until well after the safety and efficacy of the therapeutic has been established. BIO requested that the FDA revise the Guidance to either 1) acknowledge that contemporaneous approval may not be possible; or 2) provide guidance for the data requirements in these situations where the need for a companion diagnostic is not recognized until a point late in the development cycle of the therapeutic.

Many of the commentators also requested more clarity, consistency and definition within the various agencies involved with drug and diagnostic oversight. In addition, commentators also requested further clarity regarding the data requirements and evidentiary standards for the reciprocal labeling of therapeutics and diagnostics and guidance on the procedure – if any – for updating a therapeutic product’s label to reflect the subsequent approval of a new companions diagnostic.  

One Step Forward . . .

Without a doubt, personalized medicine is a current priority of the FDA. In it recent report entitled “Driving Biomedical Innovation: Initiatives to Improve Products for Patients” [10], the FDA acknowledged the promise and potential of personalized medicine to optimize therapeutic efficacy of a treatment with the least amount of risk, thereby avoiding the difficulties of the current trial-and-error process that many patients endure to find the correct drug and dose to treat a condition. The agency likewise accepted that much of the applied regulatory science for evaluating the strategies and outcomes for personalized medicine is still underdeveloped. The FDA also acknowledged that because many new products fall within the purview of multiple centers at the FDA, the review and approval of new personalized medicine products present new challenges to the agency.

The Draft Guidance is recognized as a solid step toward addressing and clarifying some regulatory aspects [11]. Published industry comments suggest an appreciation by industry that the FDA is moving to address the new technology.  It is likely that the final FDA guidelines will address the perceived lack of specific details regarding evidentiary data and process as well as procedures for the approval of a companion diagnostic subsequent to its therapeutic product. 

While the FDA acknowledges that coordination within the agency is required to accommodate the new technology, the FDA’s emphasis on co-development signals the need for diagnostic and therapeutic companies to collaborate earlier in the development of the therapeutic, or look to establish joint ventures with diagnostic companies to provide the needed expertise. Thus, evolution of industry, as well as the FDA, is likely as personalized medicine becomes the standard, rather than the exception, to biomedical innovation and product development.


1. Herceptin® is manufactured by Genentech. The drug is approved for the treatment of early-stage breast cancer that is Human Epidermal growth factor Receptor 2-positive (HER2+) and has spread into the lymph nodes, or is HER2+ and has not spread into the lymph nodes. For more information, see, last accessed on January 16, 2012.

2. “Will Herceptin Work For You ?” , available at, last accessed on January 8, 2012.

3. “The Case for Personalized Medicine” 3rd Ed., released by the Personalized Medicine Coalition, available, last accessed on January 16, 2012.

4. Abrahams et al. “The Personalized Medicine Coalition: Goals and Strategies” Am. J. Pharmacogenomics, Vol. 5(6):345-355 (2005).

5. “The Case for Personalized Medicine” 3rd Ed., released by the Personalized Medicine Coalition, available, last accessed on January 16, 2012.

6. Kahan et al. “FDA Regulations Lag Development of Diagnostics” PMC Members Newsletter, Spring 2010, page 8, available at, last accessed on January 16, 2012.

7. All public comments are available at the following FDA web address:, docket ID: FDA-2011-D-0215, last accessed January 20, 2012.

8. “Companion Diagnostics: BIO comments on FDA Draft Guidance” available at, last accessed on January 16, 2012.

9. BIO defines itself as the world's largest biotechnology organization, providing advocacy, business development and communications services for more than 1,100 members worldwide. Its members are involved in the research and development of innovative healthcare, agricultural, industrial and environmental biotechnology products. Corporate members range from entrepreneurial companies developing a first product to Fortune 500 multinationals.  BIO’s mission is to be the champion of biotechnology and the advocate for its member organizations - both large and small.  See, last accessed on January 16, 2012.

10. “Driving Biomedical Innovation: Initiatives for Improving Products for Patients”  available at, last accessed on January 16, 2012.

11. Park, “FDA Releases Guidance on Companion Diagnostics” published in IVD Technology on November 2, 2011, available at, last accessed on January 16, 2012.

About the Author

Antoinette F. Konski | Partner