By Kevin E. Noonan --
As reported in Fierce Medical Devices by Damian Garde, the FDA has issued a Warning Letter to personal genomics company 23andMe, demanding that the company stop selling its Personal Genomic Services (PGS) product without obtaining FDA approval. The letter characterizes the PGS product of being a "medical device" falling within the scope of Section 201(h) of the Food, Drug and Cosmetic Act (21 U.S.C. § 321(h)) and thus requiring FDA approval prior to marketing (something 23andMe has failed to obtain).
The letter was sent on November 22 by Alberto Gutierrez, Director of the Agency's Office of In vitro Diagnostics and Radiological Health and Center for Devices and Radiological Health to 23andMe's CEO Ann Wojcicki. In it, the Agency provides its rationale for determining that the company's PGS product is a device within the meaning of the statute, saying that it "is intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or is intended to affect the structure or function of the body." The letter cites the company's website for touting the product as providing "health reports on 254 diseases and conditions" (today, the site says 260 diseases and conditions), which include "carrier status" (for the genetic predisposition of particular diseases), "health risks" and drug response[s]"(see "how it works"). Also noted in the letter are 23andMe's claims that its PGS product can be used as "[a] first step in prevention" wherein users can "take steps toward mitigating" disease like diabetes, coronary artery disease, and breast cancer (including Myriad's BRCA genes). And the letter evinces the Agency's frustration at the company's apparent recalcitrance in obtaining approval, stating that "[m]ost of these uses have not been classified and thus require premarket approval or de novo classification, as FDA has explained to you on numerous occasions."
The Agency's letter sets out as particular concerns inclusion of the BRCA genes in the company's tests, as well as testing related to genetically based, individualized reactions to warfarin, clopidogrel, and 5-fluorouracil "because of the potential health consequences that could result from false positive or false negative assessments for high-risk indications such as these." At issue is patients undergoing unnecessary prophylaxis or "self-managing" their drug dosing depending on their personal genetic proclivities, in ways that are best done under a doctor's supervision. The genetic information provided by 23andMe's PGS product could be misinterpreted or provide patients with misunderstood, incorrect, or misleading information, according to the Agency's letter.
The Agency notes that the company submitted an application under Section 510(k) for "several of these indications" but that 23andMe has "failed to address the issues described during previous interactions with the Agency," including specifically requests for additional information sent in September and November, 2012. As a consequence, 23andMe's applications are considered by the Agency to be withdrawn, meaning there are currently pending no applications for the PGS product as required by law.
The Agency attests to its willingness to "work with" 23andMe to assist the company in complying with Agency requirements, and cites its efforts since July 2009 in this regard. These include:
FDA has spent significant time evaluating the intended uses of the PGS to determine whether certain uses might be appropriately classified into class II, thus requiring only 510(k) clearance or de novo classification and not PMA approval, and we have proposed modifications to the device's labeling that could mitigate risks and render certain intended uses appropriate for de novo classification. Further, we provided ample detailed feedback to 23andMe regarding the types of data it needs to submit for the intended uses of the PGS. As part of our interactions with you, including more than 14 face-to-face and teleconference meetings, hundreds of email exchanges, and dozens of written communications, we provided you with specific feedback on study protocols and clinical and analytical validation requirements, discussed potential classifications and regulatory pathways (including reasonable submission timelines), provided statistical advice, and discussed potential risk mitigation strategies.
Nevertheless, the Agency complains that it has not yet received the necessary assurances that the PSG product has been "analytically or clinically validated" for its intended uses, which have "expanded" since the company's original 510(k) submissions (and even in the past week). Despite a letter from the company in January 2013 attesting that it was "completing the additional analytical and clinical validations for the tests that have been submitted" and is "planning extensive labeling studies that will take several months to complete" that evidence has yet to be submitted. And these promises were made "months after [23andMe] submitted your 510(k)s and more than 5 years after [23andMe] began marketing" the PGS product. The litany of failure continues:
You have not worked with us toward de novo classification, did not provide the additional information we requested necessary to complete review of your 510(k)s, and FDA has not received any communication from 23andMe since May.
Instead, the letter alleges, "we have become aware that you have initiated new marketing campaigns, including television commercials that, together with an increasing list of indications, show that you plan to expand the PGS's uses and consumer base without obtaining marketing authorization from FDA."
The FDA then issues the following warning: "23andMe must immediately discontinue marketing the PGS until such time as it receives FDA marketing authorization for the device," which will fall within the scope of the following provisions of FDA law and regulation:
The PGS is in class III under section 513(f) of the FD&C Act, 21 U.S.C. 360c(f). Because there is no approved application for premarket approval in effect pursuant to section 515(a) of the FD&C Act, 21 U.S.C. 360e(a), or an approved application for an investigational device exemption (IDE) under section 520(g) of the FD&C Act, 21 U.S.C. 360j(g), the PGS is adulterated under section 501(f)(1)(B) of the FD&C Act, 21 U.S.C. 351(f)(1)(B). Additionally, the PGS is misbranded under section 502(o) of the Act, 21 U.S.C. § 352(o), because notice or other information respecting the device was not provided to FDA as required by section 510(k) of the Act, 21 U.S.C. § 360(k).
The company is given fifteen days to comply, or provide a reason why it cannot comply within this time, and required to provide "the specific actions you have taken to address all issues noted above, [including] documentation of the corrective actions you have taken." If not, the Agency threatens actions which "include, but are not limited to, seizure, injunction, and civil money penalties."
Despite the copy on 23andMe's website extolling the virtues of its testing for disease prevention and mitigation, it also carries the disclaimer that the results are "intended for research and educational purposes only and [are] not intended for diagnostic use" (which in itself might implicate state consumer protection laws). The company has acknowledged the FDA's action and issued a statement, as reported on the Fierce Medical Device site that "we have not met the FDA's expectations regarding timeline and communication regarding our submission. Our relationship with the FDA is extremely important to us, and we are committed to fully engaging with them to address their concerns."
The Agency's actions raise interesting questions on the future of genetic testing, particularly under circumstances where the Supreme Court has raised significant barriers to obtaining patent protection for these types of testing. In such an environment there may be a much lower impetus for disclosing the "natural law" correlations between disease propensity and genetic variability, because once that disclosure is made it cannot be retracted. If patent exclusivity is not possible, there could easily arise a "tragedy of the commons," where no company is motivated to undertake the type of efforts demanded by the Agency of 23andMe just to have those efforts coopted by its competitors. In this situation, the Agency may be required to permit applicants to keep substantial portions of their submissions confidential and be satisfied by a showing that the correlation between a particular genetic variant and a particular disease is sufficiently robust to justify approval. And even that arrangement is problematical, as most confidentiality provisions in applications for government approval can be overcome on notice to the proprietor that a member of the public has filed a Freedom of Information Act request. It is hard to discern instances where there would not be intense political pressure to rescind confidentiality for genetic testing regarding a medical disease or condition, with that propensity increasing with increased reliability of the test and incidence of the disease or condition. Of course, the Agency cannot disclose what it doesn't know, so perhaps (and against the tendencies of governments and particularly science-based government agencies like the FDA) approval could be obtained without disclosing the identities of the genes involved in the testing. The perpetual nature of this state of nondisclosure is such that even if the Agency were willing to permit nondisclosure for a time it is unlikely that it would agree to less than a reasonable term, for example, 20 years from the date the application was submitted for approval. Thus it could be that in such a roundabout way Agency action could achieve what the patent system has always provided, but perhaps in a form less amenable to meddling from the Court.