Attorney East Hampton

By Mark I. Schwartz –
This was FDA’s recent admonition to ChemRite CoPac, Inc. (ChemRite), in a Warning Letter issued on June 29, 2017. Apparently the manufacturer of several over-the-counter oral rinses and oral moisturizing drug products uses the same equipment to manufacture numerous non-pharmaceutical materials, including an industrial car care product.
The letter stated in part that: “[t]his car care product is paraffin-based and labeled as ‘Harmful or fatal if swallowed’ and ‘Keep out of reach of children.’ You also manufacture other toxic non-pharmaceutical industrial and automotive care products, such as leather treatments…Leather Care,…Leather Lotion and sealants…, using the same mixing tank and filling line you use for OTC oral drug products.”
“The ingredients in your non-pharmaceutical products are extremely difficult to remove from manufacturing equipment, and could contaminate the drug products that you manufacture on shared equipment, such as the various oral solutions discussed above. It is unacceptable as a matter of CGMP to continue manufacturing drugs using the same equipment that you use to manufacture toxic industrial-grade car care products.”
So, to summarize, FDA is alleging that ChemRite has violated the Federal Food, Drug, and Cosmetic Act (FDCA) because: (a) the facility manufacturers non-pharmaceuticals on the same manufacturing equipment as it is manufacturing OTC drug products; (b) the non-pharmaceuticals (industrial and automotive care products) are toxic; and (c) the ingredients in these toxic products are extremely difficult to remove from the dual use manufacturing equipment.
This leads to some inevitable questions, such as: whether FDA would allege a violation of the FDCA if only the first two conditions had occurred but not the third, or if only the first condition had occurred. In other words, does the FDA believe that the FDCA forbids the manufacture of non-pharmaceuticals on pharmaceutical equipment regardless of whether or not the non-pharmaceuticals manufactured are toxic to humans? If so, what is the regulatory basis for this claim?
One also has to wonder how FDA would respond if ChemRite provided the agency with data that showed in a validated way not only that their dual use manufacturing equipment could be thoroughly cleaned without leaving a residue, but that in fact the equipment had been thoroughly cleaned prior to each of the lots of drug product manufactured on this equipment, without leaving any residue from the non-pharmaceutical manufacturing.
We probably won’t have answers to these questions anytime soon, but rest assured that when we do we will report them to our readers.

By McKenzie E. Cato* & James E. Valentine –
FDA’s Center for Devices and Radiological Health (CDRH) recently announced in the Federal Register and the FDA Voice blog that it has scheduled the first-ever meeting of the Patient Engagement Advisory Committee (PEAC), which will provide recommendations to FDA regarding the regulation of medical devices and the use of devices by patients.
This initiative is the result of 2012 legislation, section 1137 of the Food and Drug Administration Safety and Innovation Act (FDASIA), and public input that FDA solicited in response to it (see prior blog post here and FDA report here). This provision added section 569C (“Patient Participation in Medical Product Discussion”) to the Federal Food, Drug, and Cosmetic Act (FDC Act). It states: “The Secretary shall develop and implement strategies to solicit the views of patients during the medical product development process and consider the perspectives of patients during regulatory discussions. . . .” FDC Act § 569C(a)(1).
The topic of the first PEAC meeting, which will occur on October 11-12, will be patient input regarding medical device clinical trials. In particular, CDRH is seeking to (1) better understand challenges for patients in medical device clinical trials, (2) better understand how patient input is being used to overcome these challenges, and (3) receive recommendations from the PEAC on top areas for FDA to consider for action. The nine members of the PEAC include patient advocacy experts, patient representatives, consumer representatives, and directors of patient advocacy organizations.
According to the FDA Voice blog post announcing this meeting, FDA chose the topic of medical device clinical trials for the inaugural PEAC meeting because “patients often have concerns about participating in clinical trials or drop out once they have enrolled in a trial.” This, says CDRH, has the effect of making it more difficult to reach reliable conclusions in device trials and it can delay public access to technological advances.
The PEAC is the latest effort in the Agency’s larger shift towards inserting the patient voice into regulatory decision-making arising out of its implementation of section 1137 of FDASIA. Just last month, FDA’s Office of Health and Constituent Affairs (OHCA) announced it would be working with the Clinical Trials Transformation Initiative (CTTI) to create a work group with patient advocacy organizations, modeled after the European Medicines Agency’s Patients’ and Consumers’ Working Party, to talk about patient engagement at FDA.
We have been following closely CDER/CBER’s Patient-Focused Drug Development (PFDD) Initiative, a commitment under the fifth authorization of the Prescription Drug User Fee Act (PDUFA V) (see prior blog posts here and here), including a very successful parallel externally-led PFDD meeting program (see prior post here). By comparison, CDRH has been slower to provide formal, more direct opportunities for patient engagement as part of medical device regulatory decision-making.
Last September, CDRH and CBER finalized a guidance document on the inclusion of patient preference information in premarket approval applications, humanitarian device exemption applications, and de novo requests (see blog post here). However, since that guidance was finalized, the option to include patient preference information in certain device submissions does not seem to have been widely embraced by industry. In contrast, the PEAC will allow for engagement with patients in a more structured environment, which will hopefully lead to broader influence on CDRH decision-making.
* Summer Associate

By Jeffrey K. Shapiro –
When you think about it, FDA’s general regulatory paradigm for regulating medical devices has enjoyed a tremendous run. The overarching statutory and regulatory foundation was started in 1976 and largely in place in its current form by 1997. (Think 510(k)/de novo/IDE/PMA requirements for the premarket phase and registration and listing/MDR/Part 806 and QSR procedures for the postmarket phase.) Yet, this structure has been sufficiently flexible to evolve administratively and to efficiently regulate a broad range of ever‑advancing device technology up through the present day. That is a run of more than 40 years, and counting – no small achievement.
The recent developments in digital health technologies has brought the first existential challenge to this regulatory paradigm. Of course, software has long been incorporated in medical devices and subject to traditional regulation (Software In A Medical Device, or SIMD). And early iterations of software as a medical device (SAMD) fared reasonably well under FDA’s 1989 draft policy for computer products and software. The 1989 draft policy was withdrawn in 2005. Nonetheless, for a period of years after that, FDA still managed to address SAMD reasonably well within existing regulatory structures.
There were stumbles. For instance, the Medical Device Data System (MDDS) regulation, issued in 2011, addressed software and hardware that transfers, stores, and displays medical device data. It was an example of fitting new software into the existing regulatory structure. It was supposed to be an innovative, “light touch” regulation, because it placed MDDS products in Class I, exempting them from all premarket review and subjecting them primarily to the QSR for quality control. By 2015, however, FDA had learned that QSR compliance was not particularly necessary for MDDS products; the agency therefore withdrew all active regulation as an exercise of enforcement discretion.
Still, the torrential development of digital health software has continued and indeed accelerated since 2011. We have seen the widespread advent of big data, machine learning, health care apps for both physicians and consumers/patients, health‑related wearables, and more. As a result, FDA has now publicly recognized that a new regulatory structure is needed. On July 27, 2017, FDA’s new Commissioner stated: 

FDA’s traditional approach to medical devices is not well suited to these [digital health] products. We need to make sure our approach to innovative products with continual updates and upgrades is efficient and that it fosters, not impedes, innovation. Recognizing this, and understanding that the potential of digital health is nothing short of revolutionary, we must work toward establishing an appropriate approach that’s closely tailored to this new category of products. We need a regulatory framework that accommodates the distinctive nature of digital health technology, its clinical promise, the unique user interface, and industry’s compressed commercial cycle of new product introductions.

In line with this thinking, FDA has issued a “Digital Health Innovation Action Plan.” Many elements of this plan appear to be a round up of actions already taken. The interesting thing is that many FDA actions have involved getting out of the way, i.e., identifying categories of software that do not require regulatory oversight even though they could fit within the broad statutory definition of a medical device. For instance, the plan reminds everyone:

We focused our oversight on mobile medical apps to only those that present higher risk to patients, while choosing not to enforce compliance for lower risk mobile apps;
We confirmed our intention to not focus our oversight on technologies that receive, transmit, store or display data from medical devices;
We chose not to focus our oversight on products that only promote general wellness. [Id. at 2.]

Notwithstanding FDA’s efforts, Congress has taken a step as well. The recent 21st Century Cures Act has a software provision (section 3060) that brought greater clarity by statutorily defining the categories of digital health software that FDA shall not regulate, including clinical decision support software (CDSS) for physicians. We summarized section 3060 here.
There remains the question about how to regulate SAMD that should be subject to FDA premarket oversight. A developer of SAMD needs to rapidly bring a product to market, obtain user/market feedback and iterate with modifications in order to discover functionality that truly adds value (and is worth paying for). As the Commissioner acknowledges, the traditional premarket review processes are too slow to support this process. At the same time, while it may be acceptable to rush slightly buggy but cool “beta” software to the consumer market, it is not acceptable in the medical arena if the beta software puts patients at risk.
FDA now proposes to balance the competing considerations with a Software Pre‑Cert pilot (a beta regulatory program, if you will). The pilot (including how to apply) is described in a Federal Register notice here. The crux is that the Software Pre‑Cert pilot will be used to develop “criteria [that] can be used to assess whether a company consistently and reliably engages in high-quality software design and testing (validation) and ongoing maintenance of its software product” (p. 5). Companies meeting these criteria could eventually “bring certain types of digital health products to market without FDA premarket review or after a streamlined, less-burdensome FDA premarket review.” A detailed FDA slide presentation is here.
This idea is interesting, because it will enable FDA to develop trust in the engineering robustness of the software up front, and perhaps focus more on clinical considerations in product review. That may be a viable way to shorten the review cycle, especially for software modifications.
Or it may not. In the world of digital health, it is difficult to predict what will and will not work. It is a time once again for “bold persistent experimentation.” So, while the remainder of the device industry is still evolving reasonably well within the old regulatory structure, FDA is developing a new regulatory paradigm for digital health. The Software Pre‑Cert pilot is a promising first step. It remains to be seen whether it succeeds well enough to move out of beta and into more general use.

On July 27, 2017, the Drug Information Association (DIA) journal, Therapeutic Innovation & Regulatory Science, published recommendations from the Clinical Trials Transformation Initiative (CTTI) Patient Groups & Clinical Trials (PGCT) Project team, of which HP&M Attorney James E. Valentine is a member, on the best practices for effective patient group engagement.  This publication supplements the PGCT Project’s official recommendations, originally released by the team in October 2015 (see prior blog post here), and describes the team’s research methods and key takeaways from the endeavor.
CTTI is a public-private partnership to develop and drive adoption of practices that will increase the quality and efficiency of clinical trials. CTTI comprises more than 80 organizations, including representatives from government agencies (e.g., FDA, CMS, NIH), industry representatives, patient advocacy groups, professional societies, investigator groups, academic institutions, and others.  More information on CTTI is available on their website, here. 
CTTI’s PGCT Project was initiated to find evidence-driven, actionable solutions to questions on how patient groups and sponsors can best work together to increase the chances of successful clinical trials and therapy development.  The Project team consists of engagement experts from patient advocacy organizations, industry, academia, and FDA.
The team conducted 45- to 60-minute telephone interviews of 32 senior-level leaders from patient groups, academia, and industry who could provide insights into the development of meaningful partnerships between industry and patients. The discussion questions for the interview were developed by the team in consultation with an independent qualitative research and professional moderator, and were partially informed by findings from a previously reported joint CTTI/DIA survey.
A report of the team’s findings from these interviews was presented during a January 2015 expert meeting of industry, academia, patient group, and government stakeholders.  The meeting attendees provided feedback on the team’s qualitative research results, and worked in subgroups to help establish detailed recommendations for best practices for patient groups and sponsors.
Key Themes Identified
Ultimately, the team identified three key themes which characterize successful patient group engagement: (1) establishing meaningful partnerships, (2) demonstrating mutual benefits, and (3) collaborating early and often.
On the first theme, the interviewees noted that meaningful partnerships require choosing partners based on complimentary interests, capabilities, expertise, and resources. Sponsors look to the following factors when choosing patient group collaborators: the size of their constituency and reach; the effectiveness of their website; their social media savvy; the group’s track record; the extent of their assets; and their level of expertise in trial recruitment.
The second theme, demonstrating mutual benefits, was important to interviewees because these benefits can serve as bargaining chips for the patient group in exchange for meaningful involvement in the clinical trial process. Some commonly cited assets of patient groups were patient registries, tissue or blood banks, and a nuanced understanding of the target patient population.
Third, despite the historical practice of seeking patient group input late in the clinical trial process, interviewees noted that patient groups can add value to clinical trial accrual and retention if they provide input early in the planning process. This input gives research sponsors the ability to make trials more relevant, acceptable, and tolerable for patients.
Best Practices for Engagement
Using the data and input collected from interviews and the expert meeting, the PGCT team formulated recommendations for best practices for effective patient group engagement. The recommendations were grouped into three categories: recommendations for all stakeholders, recommendations for research sponsors (academic and industry), and recommendations for patient groups.  Several of the recommendations are excerpted below:

Engage the “patient voice” by establishing partnerships from the beginning of the research and development program to improve trial design and execution
From the start, clearly define the expectations, roles, and responsibilities of all partners, including the resources being committed, data being shared, and objectives of the program
Build the trust required for successful partnerships by being transparent and trustworthy, following through on commitments, and honoring confidentiality
Ensure that [patient groups] are essential partners through the [research and development] process and not token voices
Select sponsors who have a product or program with significant promise for your constituents and who are committed to engaging in a meaningful way

As suggested by the stakeholders who were interviewed and who attended the 2015 expert meeting, a significant barrier to patient engagement can be the lack of well-defined best practices and guidelines. These recommendations will hopefully address this barrier and serve as a helpful resource to research sponsors and patient groups seeking to collaborate to insert the patient voice into clinical trial design and medical product development.

By Douglas B. Farquhar & Jennifer M. Thomas –
Developing jurisprudence on FCA qui tam (whistleblower) cases, in addition to the important False Claims Act settlement discussed in a recent FDA Law Blog post (here), the First Circuit Court of Appeals issued a decision on July 26 in a case brought against DePuy Orthopaedics, Inc., alleging false claims had been submitted to government insurance programs for hip replacement prostheses. The holdings of the decision are clear. But the rationale for some of the holdings requires more discussion.
The decision (United States ex rel. Nargol v. DePuy Orthopaedics, Inc.) upheld the district court’s dismissal of claims relating to allegations of false statements made to FDA in connection with DePuy’s seeking clearance of the devices to be distributed in the United States. The First Circuit found that, even if DePuy had made false representations, any argument that those representations were materially false must fail, because FDA didn’t retract the devices’ clearance after the Agency had been informed of problems. “[I]t is not plausible that the conduct of the manufacturer in securing FDA approval constituted a material falsehood capable of proximately causing the payment of a claim by the government” when “there is no allegation that the FDA withdrew or even suspended product approval upon learning of the alleged misrepresentations,” the Nargol court said.  The court further affirmed the district court’s dismissal of plaintiff’s allegations about false statements to doctors caused the doctors to falsely certify the devices as “reasonable and necessary” for reimbursement, holding that plaintiff failed to adequately allege that differences in the devices’ stated failure rates could be material to a doctor’s decision whether to certify an FDA-cleared hip replacement as “reasonable and necessary.”
The second holding in the decision reversed the district court’s dismissal of the plaintiff’s claims alleging that large numbers of defective devices were paid for by the federal government. Specifically, the complaint alleged that devices were sold that did not comport with the specifications set forth in the devices’ FDA clearance. The District Court dismissed these allegations pursuant to Fed. R. Civ. P. 9(b), which requires claims that sound in fraud (including FCA claims) to be pleaded with particularity. The First Circuit disagreed with the District Court that plaintiff had failed to meet the 9(b) standard, and held that the plaintiff’s allegations were sufficient to survive a Motion to Dismiss on this claim: “the plain, specific misrepresentation (assuming the allegations to be true)” resulting in payment of government claims “was that the device was . . . an FDA-approved product, rather than a defectively manufactured, nonconforming variant.” But it’s more complicated than that.
Nargol’s lawyers alleged that DePuy’s sale of the out-of-specification, and thus defective, devices violated the federal FCA, and many state analogues. The First Circuit reversed the lower court’s dismissal of those claims under federal law and the laws of the State of New York, but affirmed the lower court’s dismissal of other state FCA claims. Here’s why:
Over the years, there have been many cases discussing whether allegations in FCA qui tam cases sufficiently described claims that were filed with the federal government (for Medicare, Medicaid, Veterans Administration sales, and for claims under the TriCare system that provides health insurance to military veterans and their families) for pharmaceuticals or medical devices. In early cases, motions to dismiss brought under Fed. R. Civ. P. 9(b) often succeeded because many of the whistleblowers alleging false claims for pharmaceuticals or medical devices were company employees who did not have access to information about specific claims that were filed for the products. Most courts held that it was not enough for these whistleblowers to allege, relying on statistics rather than specifics, that false claims must have been filed. The majority ruled that an FCA complaint must allege specific false claims that were actually submitted to the government. But some courts have continued to espouse a more “flexible” approach to Fed. R. Civ. P. 9(b) in FCA cases – including the First Circuit. In DePuy, the First Circuit determined that just two allegations were sufficient to keep the case against DePuy alive:

A “single exemplar false claim” originating when “surgeon at Stony Brook Medical Center in New York implanted” the device in a patient, and the device “failed ‘as a result of manufacturing defects in the device,’” resulting in submittal of a Medicaid claim.
Between 2005 and 2010, “New York State Medicaid paid for an average of approximately 1280 claims each year for total hip replacement devices,” Medicaid paid for 50 percent of the procedures, and given both DePuy’s market share and the percentage of sales of the relevant device in DePuy’s sales, “nearly 425” of the defective devices “would have been paid for by New York State Medicaid.”

The Nargol court noted that “a consensus has yet to develop” among the federal circuit courts “on whether, when, and to what extent a relator must state the particulars of specific examples of the type of false claims alleged.” In this case, the court reasoned, there was “no reason to suspect that physicians did not seek reimbursement” for the allegedly defective product, and “it is also highly likely that the expense is not one that is primarily borne by uninsured patients.” The court concluded that it is “virtually certain that the insurance provider in many cases was Medicare, Medicaid, or another government program.” Because “it is statistically certain,” assuming the complaint’s allegations to be true, that the defendant “caused third parties to submit many false claims to the government, we see little reason . . . to require Relators to plead false claims with more particularity than they have done here.” The First Circuit said the “complaint alleges the details of a fraudulent scheme with ‘reliable indicia that lead to a strong inference that claims were actually submitted . . . from the United States and from the State of New York.’”
Yet the court refused to extend the statistical analysis to claims brought under other states’ FCAs. With regard to other state Medicaid programs, the Court found that “Relators for the most part have made conclusory allegations that state and municipal analogues to the FCA were violated,” and the “complaint does nothing to allege” that the devices were “advertised to and implanted by physicians in . . . any other state or municipality except for the state of New York.” On those grounds, counts relating to claims under other state FCA analogues were correctly dismissed.
So, how much detail is enough about claims paid by the federal government? Under Nargol, description of one specific Medicaid claim, when combined with statistical projections of market share and payer mix suggesting that “many” claims were likely filed, can be enough.

By Riëtte van Laack –
Natural claims remain fodder for litigation. Although FDA’s December 2015 request for comments certainly impacted the filing of lawsuits (as discussed in our previous post), new cases continue to be filed, and plaintiffs bring up new arguments against natural claims.
One relatively recent trend sees plaintiffs challenging the presence of trace amounts of an agricultural pesticide in food. In these lawsuits, plaintiffs allege that natural (or 100% natural) claims are false or misleading because the products contain small amounts of glyphosate, a synthetic pesticide. Plaintiffs usually allege that the presence of glyphosate, no matter how small the amount, disqualifies the food from a natural claim.
In 2016, a number of plaintiffs filed lawsuits against General Mills, Inc. for its marketing of Nature Valley Products with the claim “Made with 100% Natural Whole Grain Oats.” Plaintiffs alleged that this claim was misleading, false, and deceptive because Nature Valley Products contain trace amounts of the chemical glyphosate. One such case, consolidating four other cases, was recently before the District Court of Minnesota on a motion to dismiss. The Court dismissed the case because Plaintiffs failed to plausibly allege that the statement “Made with 100% Natural Whole Grain Oats” means, or could be interpreted by a reasonable consumer to mean, that there is no trace glyphosate in Nature Valley Products. The Court concluded that “it is implausible that a reasonable consumer would believe that a product labelled as having one ingredient – oats – that is ‘100% Natural’ could not contain a trace amount of glyphosate that is far below the amount permitted for organic products.” Plaintiffs could not reasonably apply a higher standard to natural than applies to “organic” claims (organic foods may contain pesticide residues at levels of no more than 5% of the tolerance level.) Moreover, the Court concluded, Defendant “did not represent or warrant that Nature Valley Products would be free from trace glyphosate.”
We will be monitoring further developments in the “natural” litigation landscape to see if the good sense illustrated in this decision proves contagious.

By Anne K. Walsh & Andrew J. Hull –
The Department of Justice announced on July 24, 2017, that Celgene agreed, without admitting liability, to pay a total of $280 million to settle a qui tam case relating to two of its drug products, Thalomid® and Revlimid®. The qui tam complaint filed in the U.S. District Court for the Central District of California, alleged that Celgene promoted the use of these two drugs to treat cancer patients outside the scope of the FDA-approved uses for those drugs. In addition to allegations that the company promoted the drug for numerous uses that were off-label, the relator alleged that:

Celgene encouraged the tampering of the coding used in seeking reimbursement from government healthcare programs in order to conceal that the drugs were being prescribed for off-label uses;
Celgene made “false and misleading statements” by “improperly influencing the content” of authoritative literature and compendia, concealing or downplaying adverse events, and encouraging doctors to change diagnosis codes relating to Revlimid®; and
Celgene violated the Anti-Kickback Statute by paying physicians who prescribed Thalomid® or Revlimid® to conduct speaker programs, to conduct clinical trials, and to serve as authors on publications, to work as consultants, and to induce purchases of the drugs by “defraying patients’ co-payment obligations” for those drugs through its contributions to foundations that provided financial support to patients that met certain income requirements.

All issues were resolved in the parties’ Settlement Agreement. The $280 million payout will be paid in a federal settlement amount of more than $259 million and a payment of nearly $21 million to states for Medicaid expenditures. The agreement states that relator Beverly Brown, a former Celgene employee, will receive a share of the settlement pursuant to a separate agreement.The government’s decision not to intervene in this case is noteworthy, even though the reason for the government’s decision is unknown. The following factors may have played a role: 

This case involves oncology drugs, and cancer-related therapies are in a different category when it comes to reimbursement of off-label uses and government enforcement. Longstanding CMS Policy allows reimbursement of certain off-label uses of drugs to treat cancer if those uses are supported in accepted drug compendia or supported by clinical research. See CMS Policy Manual, chap. 15, § 50.4.5. FDA officials have also recognized the value of off-label use of drugs in oncology treatment (see here and here).
The venue of this case (U.S. District Court for the Central District of California) may have dissuaded the government from intervening as the same court in 2014 dismissed a similar qui tam complaint based on an off-label promotion theory. See United States ex rel. Modglin v. DJO Global Inc., 48 F. Supp. 3d 1362, 1392 (C.D. Cal. 2014).

We have discussed the application of the Supreme Court’s recent Escobar decision on materiality in FCA implied false certification cases involving FDA-related activities, particularly in the First Circuit’s D’Agostino decision (see our post here) and the Ninth Circuit’s Gilead decision (see our post here). It does not appear that the favorable findings in Escobar would have helped Celgene here given that the allegations –taken at face value – describe the company having caused physicians to submit false claims by changing the appropriate diagnosis code for the Revlimid® prescriptions.
At the end of the day, the government receives a big payment, even though it did not intervene and litigate the matter. Winner, winner.

By James E. Valentine & Gugan Kaur –
On July 25, 2017, FDA announced the availability of a guidance on “IRB Waiver or Alteration of Informed Consent for Clinical Investigations Involving No More Than Minimal Risk to Human Subjects.” FDA issued this guidance for immediate implementation, without initially seeking prior comment, based on a determination that prior public participation was not feasible or appropriate because the guidance presents a less burdensome policy consistent with the public health.
This guidance addresses an amendment to the Federal Food, Drug, and Cosmetic Act (“FDC Act”) that provides FDA with the authority to permit an exception from informed consent for minimal risk clinical investigations when specific criteria are met. Title III, Section 3024 of the 21st Century Cures Act (“Cures Act”), enacted in December 2016, amends sections 520(g)(3) and 505(i)(4) of the FDC Act to alter the informed consent requirements for both drugs and medical devices such that a waiver of informed consent may now be granted for “proposed clinical testing [that] poses no more than minimal risk to . . . human beings and includes appropriate safeguards . . . .” (see our previous post here). Minimal risk is defined in FDA regulations as “the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests” (21 C.F.R. §§ 50.3(k), 56.102(i)).
This provision of the Cures Act is more aligned with how minimal risk is handled under the Federal Policy for the Protection of Human Subjects (“Common Rule”), which sets forth requirements for the protection of human subjects involved in research that is conducted or supported by the Department of Health and Human Services (“HHS”) and 15 other federal departments and agencies (see our previous post on the Final Common Rule).
Although FDA-regulated research is not subject to the Common Rule, efforts to harmonize human subject protections have led to this expression by FDA of its intent to promulgate revisions to its informed consent regulations by adding the Common Rule provisions for waivers of informed consent. Specifically, the guidance asserts that FDA intends to revise its regulations to add a waiver or alteration of informed consent for certain FDA-regulated minimal risk clinical investigations to the two existing exceptions from informed consent (i.e., in life-threatening situations and for emergency research).
However, until those regulations are promulgated, the guidance makes clear that FDA does not intend to object to an Institutional Review Board (“IRB”) approving a consent procedure that does not include, or that alters, some or all of the elements of informed consent set forth in 21 C.F.R. § 50.25, or waiving the requirements to obtain informed consent when the IRB finds and documents that:The clinical investigation involves no more than minimal risk to the subjects;

The waiver or alteration will not adversely affect the rights and welfare of the subjects;
The clinical investigation could not practicably be carried out without the waiver or alteration; and
Whenever appropriate, the subjects will be provided with additional pertinent information after participation.

Additionally, FDA does not intend to object to a sponsor initiating, or an investigator conducting, a minimal risk clinical investigation for which an IRB waives or alters the informed consent requirements as described above.
In the past, FDA has been criticized for utilizing guidance documents instead of promulgating regulations to regulate industry (see, e.g., our previous posts here and here). However, in this instance, FDA’s guidance may be appropriate as a stopgap to provide IRBs and sponsors comfort in operating under the new statutory framework. Indeed, the guidance explicitly states that FDA intends to withdraw the guidance after it promulgates regulations to permit a waiver or alteration of informed consent under appropriate human subject protection safeguards consistent with section 3024 of the Cures Act.

By David B. Clissold –
In a stunning development, newly appointed FDA Commissioner Scott Gottlieb, M.D. held a briefing last Friday to announce a multi-year plan for tobacco and nicotine regulation.  The Commissioner’s remarks are available here, and a press release announcing the policy is available here. The Agency’s new approach places nicotine, and the issue of addiction, at the center of tobacco regulation efforts. The policy more formally embraces the notion that nicotine is delivered through products that represent a “continuum of risk,” and is most harmful when delivered through smoke particles in combustible cigarettes. Under this new plan, FDA will:

Explore lowering nicotine levels in combustible cigarettes to non-addictive levels through product standards. The Agency will issue an Advance Notice of Proposed Rulemaking (ANPRM) to seek input on the potential public health benefits and possible adverse effects of lowering the level of nicotine in cigarettes.
Extend timelines to submit tobacco product review applications for newly regulated tobacco products that were on the market as of Aug. 8, 2016. These timelines were already extended once (see our previous post  ), but FDA will issue a guidance extending application submission timelines for newly-regulated combustible products (such as cigars, pipe tobacco, and hookah tobacco) to August 8, 2021, and for non-combustible products (such as e-cigarettes) to August 8, 2022.
Develop product standards to address public health risks, such as electronic nicotine delivery systems (ENDS) battery issues, and concerns about children’s exposure to liquid nicotine.
Issue an ANPRM to seek public comment on the role that flavored tobacco products (including menthol) may play in attracting youth to consume such products, and in helping some smokers to switch to potentially less harmful forms of nicotine delivery.
Issue an ANPRM to solicit additional comments and scientific data related to the patterns of use and resulting public health impacts from premium cigars, which were included in FDA’s 2016 deeming rule (see our previous post here).
Examine actions to increase access and use of FDA-approved medicinal nicotine products intended to help smokers quit.
Issue rules to make the product review process more efficient, predictable, and transparent, including regulations outlining the information the Agency expects in submissions of Premarket Tobacco Applications (PMTAs), Modified Risk Tobacco Product (MRTP) applications, and reports to demonstrate Substantial Equivalence (SE).

Mitch Zeller, J.D., Director of FDA’s Center for Tobacco Products, and Anna Abram, FDA’s Deputy Commissioner for Policy, Planning, Legislation and Analysis, took questions on the new policy in a conference call. Mr. Zeller emphasized that although nicotine itself is not associated with negative health consequences, the Agency was basing its policy on a recognition that the various nicotine delivery systems fall along a “continuum of risk.” Under this continuum, combustible cigarettes are the riskiest products, and nicotine replacement products sold for smoking cessation (i.e., nicotine gums, lozenges, and patches) are at the opposite end of the spectrum. He also emphasized that the new nicotine policy was “agency wide,” and specifically mentioned the Center for Drug Evaluation and Research, which will play a role with respect to the regulation of smoking cessation products and tobacco research.
FDA’s new approach to the regulation of nicotine will have profound effects on the tobacco product industry. We will continue to monitor this bold new plan as it unfolds.

By Ricardo Carvajal & JP Ellison –
FTC and FDA issued a blog posting co-authored by senior officials that encourages the public to report potentially violative dietary supplements to one or both agencies.  The posting lists the following as circumstances that should prompt a report: 

“You bought a dietary supplement that didn’t work as advertised – or you had an adverse reaction or illness.”
“You’re suspicious that a company is making false or overstated claims in its labeling or marketing.”
“You’re concerned about the content, purity, or safety of the product.”

The posting goes on to explain which agency has jurisdiction over which issues, but makes clear that mastering that jurisdictional divide is not a prerequisite for reporting:  “If you’re still not sure who to report to, just report it to one of us and we’ll sort it out – the important thing is that you report!”
For those who presumed that the current administration’s deregulatory agenda would reduce the likelihood of all regulatory activity, the posting is a timely reminder that some types of regulatory activity – especially in the enforcement arena – will remain relatively unaffected.