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October 02, 2018 Feature

Regulatory Frameworks for Precision Medicine at the Food & Drug Administration

By Jordan Paradise

The concept of precision medicine is not new; its promise and allure have a rich history in genetics and genomics, building squarely on international research efforts begun decades ago and culminating in the publication of the complete human genome sequence in 2004.1 Now, nearly 15 years following the conclusion of the Human Genome Project (HGP), the terminology describing the idea of channeling genomic information into more targeted medical products has evolved, to include pharmacogenomics, personalized medicine, targeted medicine, and, most recently, precision medicine. All envisage the ability to make medical care and medical products “precise” for the patient; that is, tailored to an individual’s genetic makeup in order to maximize safety, efficacy, mortality, and quality of life. In his unveiling of the Precision Medicine Initiative in 2015, President Obama noted this program is about “delivering the right treatments, at the right time, every time to the right person.”2

Similar to prior federal funding initiatives (such as the Human Genome Project, the National Nanotechnology Initiative, the BRAIN Initiative, and the Cancer Moonshot 2020), the Precision Medicine Initiative (PMI) has at its core a goal of fostering multidisciplinary approaches to research and development that support both scientific discovery and clinical medicine innovation. The PMI sets forth five core objectives: (1) discovery of cancer treatments; (2) development of a voluntary, national research cohort; (3) robust privacy protections and interoperability; (4) assessment of regulatory regimes; and (5) strong partnerships in research.3 While each objective deserves concerted examination and discussion, this article addresses the existing regulatory regimes that provide a framework for the Food and Drug Administration (FDA) as precision medicine products emerge.

While many large-scale efforts to develop applications for precision medicine can be traced largely to the outcomes of the HGP and subsequent genomic advances, the structure of the PMI serves to set forth a principled plan for implementation and continuing robust funding. The original plan for a PMI Cohort Program was announced in September 2015, led by National Institutes of Health (NIH) Director Francis Collins.4 Subsequently renamed the All of Us Research Program, the goal is to recruit a million participants to gather blood samples for DNA analysis, collect clinical information, and access electronic health records as well as other health-related data.5 In December 2016, the 21st Century Cures Act further enhanced federal funding for precision medicine, appropriating an initial $4.8 billion in funding to the NIH for the PMI over the next decade.6 Along with targeted funding, the 21st Century Cures Act establishes an organizational framework for the PMI, including authority to the Secretary of the Department of Health and Human Services (HHS) to implement the initiative and foster rapid innovation.7 The Secretary is also expressly required to coordinate with the FDA to achieve the goals of the initiative,8 which will be crucial to the regulatory aspects.

This article will explore precision medicine as related to the scope of products regulated by the FDA. First, it will analyze existing FDA regulatory frameworks for relevant products, including drugs, biologics, medical devices, and combination products. Second, it will explore FDA-approved products characterized as precision medicine and discuss FDA policy on use and labeling. Third, it will explore important recent legislative authority directed to precision medicine research and regulatory review and approval by the FDA. Last, it will identify several aspects of precision medicine that will pose both opportunities and challenges going forward for the FDA as the agency is faced with innovative diagnostics and therapeutics in this realm.

Existing FDA Frameworks for Medical Products

The FDA relies on two federal statutes to oversee medical product review. The first, the Food, Drug, and Cosmetic Act (FDCA), addresses the review and approval of human and animal drugs, medical devices, cosmetics, food (including dietary supplements), tobacco products, and products emitting radiation.9 A second statute, the Public Health Service Act (PHSA), contains provisions for the FDA’s regulation of biological products, which are biologically derived therapeutic products rather than chemically synthesized products.10 Congress frequently amends both the FDCA and PHSA, with the most recent significant amendments contained in the 21st Century Cures Act, enacted in December 2016.11

The new drug and biological product approval processes share similar features, largely due to efforts from both Congress and the agency to streamline requirements. Historically, the oversight for each had been split into two public health–related statutes owing to the manner in which Congress initially established agency authority. Each is subject to three phases of clinical trials that include laboratory and manufacturing controls, human subject protections, adverse event disclosure, reporting and tracking, labeling requirements, post-market measures, and rigorous review and approval procedures.12 The FDA has much discretion to require information as part of the premarket approval process for drugs and biological products and to interpret the FDCA and PHSA. The FDA has promulgated a vast landscape of regulations regarding all aspects of the drug and biological product life cycle. However, there are also abbreviated routes to market for both drugs13 and biologics,14 although these abbreviated routes differ significantly, largely attributable to the existing statutory frameworks and the complexity of biological products.15

Medical devices are reviewed on one of two tracks to market: a premarket approval process or a premarket notification (known as the “clearance”) process. The premarket approval process, similar to the drug and biologic approval process, involves clinical trials and related provisions to demonstrate safety and efficacy; however, the structure of medical device clinical trials is specific to the perceived risk level of the device and may involve specific safeguards linked to the nature of the intervention.16 On the other hand, the clearance process involves demonstrating that a device is substantially equivalent to a predicate medical device already on the market; the sponsor need not perform clinical trials but rather submit a descriptive comparison addressing technological characteristics and intended use. The FDA then “clears” the product to enter the market, rather than approving it on the basis of safety and efficacy shown by clinical trials. The FDA’s current position is that all first-in-kind medical devices providing a diagnostic or imaging role to inform the use of a drug or biologic is subject to the premarket approval process.

The FDA also houses an Office of Combination Products (OCP) to assess emerging technologies at the interface of these three product realms.17 The OCP classifies a product as a drug, biologic, or medical device according to its “primary mode of action” (PMOA) and directs it to the appropriate FDA Center (i.e., the Center for Drug Evaluation and Research, the Center for Biologic Evaluation and Research, or the Center for Devices and Radiological Health) and route to market based on this determination. The PMOA is the mode of action having the primary therapeutic effect (i.e., is it acting primarily chemically, biologically, or mechanically on the body). Once assigned an FDA Center, the FDA will assess that product according to the accompanying statutory and regulatory requirements, but also may adjust requirements to reflect novel elements as related to safety and efficacy. The combination product process faces ongoing criticisms, flowing from perceived definitional shortcomings in the three product classifications, and the resulting “silo” effect of the FDA’s determination for products that integrate chemical, biological, and mechanical mechanisms of action in often novel and innovative ways.18 This “silo” effect refers to the singular product characterization of a product with multiple modes of action.

Exploring FDA-Approved Products

Precision medicine is already being realized, and regulated, in the United States. The FDA has reviewed and approved medical products that are directed to a particular genetic variant or customized for a particular patient. The scope of these products is no longer “one-size-fits-all” in any sense and products span the spectrum of drugs, biologics, and medical devices and may be utilized in tandem to diagnose and treat a particular individual as a combination product. A primary example is Genentech’s metastatic breast cancer biologic Herceptin (trastuzumab), approved in 1998 for women with a genetic variant causing the overproduction of the human epidermal growth hormone receptor 2 protein known as HER2.19 Herceptin is clinically effective in women for whom a diagnostic test shows elevated HER2 protein levels at the cancer site; however, it is completely ineffective for those patients without elevated HER2 protein levels.20 The corresponding diagnostic test developed collaboratively by DAKO was approved as a medical device as a means to inform the appropriate prescription of Herceptin.21 This device was the first approved companion diagnostic in the United States, meaning that its use was directly tied to whether and to whom would receive the biologic Herceptin. There are now 10 companion diagnostic tests on the market in the United States for Herceptin.22

Despite many notable products on the market, the task of deciphering genetic information related to its role in drug and biologic efficacy and response has proven more difficult in practice given the complexity of the human genome. At this point in time there are currently only 24 FDA-approved drugs or biologics on the market that can truly be characterized as pharmacogenomic, in that they are tailored specifically to a given genetic profile or genetic variant that can be identified by a diagnostic test.23 The FDA has cleared or approved several dozen in vitro diagnostic and imaging tools to detect whether these drugs or biologics have a relevant safety or efficacy implication for a particular genetic makeup.24 These companion diagnostics provide important information for the safe and effective use of a corresponding therapeutic drug or biologic and are distinct from nucleic-acid-based tests that are not linked to a particular drug or biologic product. General nucleic-acid-based tests assess variations in deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) to infection or disease or determine carrier status alone. Companion diagnostics partner the test outcome to a particular drug or biologic. The FDA requires that the instructions for use and the labeling of both the diagnostic device and the corresponding therapeutic product stipulate that the two products must be used together; this applies to generic and biosimilar equivalents as well.

Figure 1 identifies the 24 FDA-approved drugs and biologics that are linked to, and require, the concurrent use of a companion diagnostic. There are other types of FDA-regulated products that are considered “precise” in the sense that they are tailored for a particular individual, yet are not necessarily based on applied genetic information. For example, physicians and surgeons often modify marketed devices for patients in the medical setting in order to assure an appropriate fit, and there are regulatory exemptions for custom devices in specialty settings. The FDA also has approved or cleared medical devices based on individual specifications or for cell – or tissue-based products that utilize stem cells or other tissue derived from a particular patient. In fact, the nascent industry of three-dimensional bioprinting also has been described as precision medicine as it creates individualized prosthetics or implants for a given patient using biomaterials to mimic human connective tissue, bone, or cartilage. However, this article focuses on the realm of companion diagnostics tied to a particular therapeutic, where a diagnostic genetic test is partnered with a drug or biologic product as the measure of precise tailoring to a genetic variant or mutation.

The 21st Century Cures Act of 2016

Previous legislation such as the Biologics Price Competition and Innovation Act of 2009 (part of the enacted Affordable Care Act), the Food & Drug Administration Safety and Innovation Act of 2012, and others have provided incremental changes to the statutory structure of the FDCA and PHSA. These changes include the creation of a breakthrough therapy status for drugs and the biosimilar and interchangeable biologic route to market for biologic products. As Congress provides these statutory changes, the FDA responds with implementation of the regulatory framework to support them. Typically, this may be done through either notice-and-comment rulemaking or guidance for industry.

The 21st Century Cures Act25 provides several significant changes to the law relevant to the continued support of innovations in precision medicine. As noted earlier, the Act generally advances precision medicine, tasking HHS with developing new approaches, ensuring the protection of human participants in research, and coordinating with other federal agencies.26 More specifically, it directs the FDA to make changes to the FDA processes involved in product review and gives much discretion to the FDA to determine how to implement those changes. Several examples include a requirement for the inclusion of patient experience data with drug approval information,27 development of new review mechanisms for biomarkers in clinical trial design for new drugs,28 the inclusion of real-world evidence for support of new drug indications,29 allowance of centralized IRB reviews for medical devices,30 and the creation of a breakthrough medical device category.31

Alone, none of these provisions is a particularly groundbreaking alteration to existing FDA regulatory structures, as the FDA has been innovating in many of these areas prior to the legislation, but together they signal opportunities for increased collaboration, information sharing, and new approaches to apply to precision medicine going forward. The next section discusses what this may mean for the FDA.

The Future of Precision Medicine

As researchers, industry, and the FDA move forward with precision medicine, there several aspects worth highlighting that may pose novel challenges, and opportunities. The first is the current capability of next generation sequencing (NGS) set against the rate at which that genetic information can be linked to disease states. Current NGS technologies use high-throughput platforms to sequence millions of small DNA fragments in parallel rather than relying on conventional biochemistry sequencing.32 Once sequenced, NGS analyses enable the fragments to be mapped onto a reference human genome, flagging unexpected variations in DNA, often called genetic variants.33 Today, an entire individual genome can be sequenced using NGS for about $1,000, compared to over $10 million just 10 years ago.34

Despite tremendous promise, a major impediment for use of genetic information derived from NGS is tying it to particular biomarkers that are meaningful for drug and biologic safety and efficacy. The 21st Century Cures Act defines a biomarker as “a characteristic (such as a physiologic, pathologic, or anatomic characteristic or measurement) that is objectively measured and evaluated as an indicator of normal biologic processes, pathologic processes, or biological responses to a therapeutic intervention.”35 The hope is that discoveries fueled by NGS capabilities will identify genetic biomarkers critical for cancer screening and appropriate treatment based on an individual genetic profile. For example, the FDA approved Merck’s Keytruda (pembrolizumab) in May 2017 for “the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having a biomarker referred to as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).”36 While the FDA has permitted the use of biomarkers in the approval of non-cancer drugs, this is the first cancer drug approval supported by the use of a biomarker.37 Likewise, NGS technology has enabled the development of medical devices to screen genetic samples for dozens of cancer mutations simultaneously, some of which have a corresponding approved drug.38

Despite success stories, the sheer amount of information derived from NGS will prove challenging to identify relevant genomic signals, and research identifying relevant biomarkers is a significant priority. In that regard, the FDA has launched the online portal precisionFDA in December 2015, providing “a community platform for NGS assay evaluation and regulatory science exploration.”39 Deciphering information generated and published on this crowdsourced, cloud-based site may be integral to biomarker identification, industry standard setting, clinical trial development, and, ultimately, regulatory assessment and adaptability.40 The FDA also has published draft guidance documents41 and discussion papers42 on analytical and clinical strategies to support development of NGS diagnostic tests in the wake of the PMI. The FDA has expressed that they are “committed to implementing a flexible and adaptive regulatory oversight approach” for NGS in vitro diagnostics.43

A second aspect is the shift from large-scale clinical trials to smaller populations–based trials. The long-standing blockbuster drug development model is in direct conflict with precision medicine, which aims to identify and treat patients with identifiable genetic variations. This shift to smaller populations challenges traditional clinical trial protocols and design, as well as the assessment of risk and benefit. Many of the measures of efficacy may be moved into post-market trials or addressed with targeted risk evaluation and mitigation strategies. The FDA may begin operating on a more case-by-case basis for review and approvals, accepting different clinical measures, and redefining particular regulatory procedures. Certainly, the 21st Century Cures Act contemplates a broader spectrum of patient input in the process, as well as types of information and evidence considered during approval. For example, the Act defines real-world evidence as “data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than randomized clinical trials.”44

Relatedly, a third aspect of precision medicine is the increasing role of patient advocacy groups. The patient advocacy movement has generated a push for more stakeholder input in the FDA process, as reflected in the 21st Century Cures Act and in publicized involvement in drug review.45 Specifically, patient experience data in the Act is defined as data that “are collected by any persons (including patients, family members and caregivers of patients, patient advocacy organizations, disease research foundations, researchers, and drug manufacturers)” and “are intended to provide information about patients’ experience with a disease or conditions, including—(A) the impact of such disease or condition, or a related therapy, on patients’ lives; and (B) patient preferences with respect to treatment of such disease or condition.”46 It remains to be seen how the FDA will integrate this into product review and make this patient experience data part of the public record along with the approval information. There are also concerns related to the reliability of some of these types of data; for example, recent reports have raised concerns about industry funding of patient advocacy groups, which often exceeds amounts industry spends on lobbying efforts.

A fourth aspect is that research and development in the realm of precision medicine is uniting drug, biologic, and medical device sponsors, once operating as distinct industries, toward a common goal. FDA requires a companion diagnostic to accompany a drug or biologic when there is a well-defined genetic basis of the disease or condition. However, questions arise as to how those relationships are to be structured and how to develop incentives for co-development. Many of the innovative NGS research and data-sharing models also depart in significant ways from traditional research and development relationships in the life sciences and the pharmaceutical industry.

Finally, there is an increasing need to educate physicians and medical specialists about the reality of precision medicine. In addition, there is a danger that the hype of precision medicine may overshadow the limitations in its ability to treat particular patients. Although we are closer to understanding the mysteries of the human genome, we are nowhere near attaining mastery of them.


1. Int’l Human Genome Sequence Consortium, Finishing the Euchromatic Sequence of the Human Genome, 431 Nat. 931 (2004).

2. White House, Office of the Press Secretary, Remarks by the President on Precision Medicine, Jan. 30, 2015, available at

3. Press Release, White House, Office of the Press Secretary, Fact Sheet: President Obama’s Precision Medicine Initiative (Jan. 30, 2015),

4. Precision Med. Initiative Working Grp., Report to the Advisory Committee to the Director, National Institutes of Health: The Precision Medicine Initiative Cohort Program—Building a Research Foundation for 21st Century Medicine (Sept. 17, 2015), available at

5. Jocelyn Kaiser, NIH Opens Precision Medicine Study to Nation, 349 Sci. 1433 (2015).

6. 21st Century Cures Act, Pub. L. No. 114-255, 130 Stat. 1033 (2016); Press Release, U.S. House of Representatives Comm. on Energy & Commerce, The 21st Century Cures Act Fact Sheet,

7. Pub. L. No. 114-255, §§ 2011–2014, 130 Stat. at 1047–51.

8. Id. § 2011, 130 Stat. at 1047–49.

9. Food, Drug & Cosmetic Act (FDCA) § 101 et seq.; also codified in title 21 of the U.S. Code.

10. Public Health Service Act (PHSA) § 351; 42 U.S.C. § 262.

11. Pub. L. No. 114-255.

12. See FDCA § 505, 21 U.S.C. § 355 & PHSA § 351, 42 U.S.C. § 262.

13. FDCA § 505(j), 21 U.S.C. § 355(j).

14. Patient Protection and Affordable Care Act, Pub. L. No. 111-148, 124 Stat. 119 (2010), including the Biologics Price Competition and Innovation Act of 2009, tit. VII, §§ 7001–7003
(codified in 42 U.S.C. § 262).

15. See Jordan Paradise, The Legal and Regulatory Status of Biosimilars: How Product Naming and State Substitution Laws May Impact the United States Healthcare System, 41 Am. J. L. & Med. 49 (2015).

16. FDCA §§ 513, 515, 21 U.S.C. § 360.

17. See Medical Device User Fee and Modernization Act of 2002, Pub. L. No. 107-250, sec. 204, 116 Stat. 1588, 1611 (codified at 21 U.S.C. § 353(g)(4)(A) (2006)).

18. See Jordan Paradise, Reassessing Safety for Nanotechnology Combination Products: What Do Biosimilars Add to Regulatory Challenges for FDA?, 56 St. Louis U. L.J. 465 (2012).

19. Personalized Medicine and Companion Diagnostics Go Hand-in-Hand, U.S. Food & Drug Admin., (last updated Sept. 27, 2017).

20. Id.

21. Angelo DePalma, FDA Approves DAKO HercepTest for HER2 Overexpression (Sept. 29, 1998), Bioprocess Online,

22. See List of Cleared or Approved Companion Diagnostic Devices, U.S. Food & Drug Admin., (last updated June 13, 2018).

23. See Personalized Medicine and Companion Diagnostics Go Hand-in-Hand, supra note 19; see also Jordan Paradise, Cultivating Innovation in Precision Medicine Through Regulatory Flexibility at the FDA, 11 NYU J. L. & Lib. 672, 679 (2017).

24. List of Cleared or Approved Companion Diagnostic Devices, supra note 22.

25. 21st Century Cures Act, Pub. L. No. 114-255, 130 Stat. 1033 (2016).

26. Id. § 2011, 130 Stat. at 1047–49.

27. Id. § 2014, 130 Stat. at 1051.

28. Id. § 3011(a), 130 Stat. at 1086–89.

29. Id. § 3022, 130 Stat. at 1196–98.

30. Id. § 3056, 130 Stat. at 1128.

31. Id. § 3051, 130 Stat. at 1121–24.

32. Sam Behjati & Patrick S. Tarpey, What Is Next Generation Sequencing?, 98 Archives Disease Childhood 236, 236 (2013); Jay Shendure & Henlee Ji, Next-Generation DNA Sequencing, 26 Nat. Biotech. 1135, 1135 (2008).

33. Behjati & Tarpey, supra note 32.

34. The Cost of Sequencing a Human Genome, Nat’l Human Genome Research Inst., (last updated July 6, 2016).

35. Pub. L. No. 114-255, § 3011(a), 130 Stat. at 1089 (codified at 21 U.S.C. § 507(e)(1)(A)).

36. News Release, U.S. Food & Drug Admin., FDA Approves First Cancer Treatment for Any Solid Tumor with a Specific Genetic Feature (May 23, 2017),

37. See Biomarkers at CDER, U.S. Food & Drug Admin., (last updated Oct. 11, 2017).

38. List of Cleared or Approved Companion Diagnostic Devices, supra note 22; see Justin Petrone, FDA Wades into Sequencing-Based Diagnostics Regulation, 34 Nat. Biotech. 681, 681 (2016).

39. U.S. Food & Drug Admin., Introduction, precisionFDA,

40. Jordan Paradise, Exploring PrecisionFDA, an Online Platform for Crowdsourcing Genomics, 58 Jurimetrics J. 267–282 (2018).

41. See U.S. Food & Drug Admin., Draft Guidance: Use of Standards in FDA Regulatory Oversight of Next Generation Sequencing (NGS)-Based In Vitro Diagnostics Used for Diagnosing Germline Diseases 2 (July 8, 2016),

42. U.S. Food & Drug Admin., Preliminary Discussion Paper, Use of Databases for Establishing the Clinical Relevance of Human Genetic Variants (Nov. 13, 2015),; U.S. Food & Drug Admin., Preliminary Discussion Paper, Developing Analytical Standards for NGS Testing (Nov. 12, 2015),; U.S. Food & Drug Admin., Preliminary Discussion Paper, Optimizing FDA’s Regulatory Oversight of Next Generation Sequencing Diagnostic Tests (undated),

43. U.S. Food & Drug Admin., Use of Standards, supra note 41.

44. 21st Century Cures Act, Pub. L. No. 114-255, § 3022, 130 Stat. 1033, 1096–98 (2016).

45. Jordan Paradise, 21st Century Citizen Pharma: The FDA and Patient-Focused Product Development, 44 Am. J. L. & Med. 309 (2018).

46. Pub. L. No. 114-255, § 3001, 130 Stat. at 1084 (codified at 21 U.S.C. § 360bbb-8c(c)).

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Jordan Paradise

Jordan Paradise ([email protected]) is Georgia Reithal Professor of Law at the Beazley Institute for Health Law & Policy, Loyola University Chicago School of Law. She researches and publishes on the intersection of law, science, and technology, focusing on life science and legal and policy issues in the development and regulation of pharmaceuticals, medical devices, and innovations in medicine.