Part IV - The Impact of Medical Device Regulation on Patients and Markets

What do we know about the products we put in our bodies? It is hard enough to determine the safety and efficacy of drugs, which go through a premarket approval process. In contrast, many medical devices are not subject to premarket approval, and even those that are approved tend to undergo iterative changes during their lifecycle, such that the versions now being used may be quite different designs than the versions originally proposed to, and reviewed by, the FDA. Or the same designs may be used for an altogether new purpose or a new patient population.

Unfortunately, the evidence is not very good. To peek into just one part of the medical device ecosystem, consider panel-track supplements. Of the six different pathways for reviewing modification to approved devices, the “panel track” is the only one that always requires submission of clinical data, because the manufacturer is proposing a “significant change in design or performance of the device, or a new indication for use of the device.” In 2017, JAMA published a report by Sarah Zheng, Sanket Dhruva, and Rita Redberg reviewing the clinical studies used by the US Food and Drug Administration to approve such modifications to high-risk medical devices over nearly a decade.¹ Of the eighty-three clinical studies for all seventy-eight panel-track supplements approved between 2006 and 2015, less than half (45 percent) were randomized clinical trials, less than a third were at least somewhat blinded, and all but a fifth (19 percent) used surrogates rather than mortality and morbidity as primary endpoints. And most disconcertingly, all but 38 percent lacked control groups, which is typically a necessity for causal inference. If we cannot isolate the effects caused by the device, what is the point?

On the basis of this relatively weak data, it is hard to know if these devices are actually safe and effective for their intended purposes. Without that information, it is hard for patients and their doctors to know whether the devices are right for them, and it is hard for payors to determine whether the products are worth their prices.² Frankly, that is exactly the situation that rational purveyors of these devices desire, trading on hope and conjecture, while they selectively release whatever information is favorable to their product. The chapters in this section pick up this theme around proof and value.

In their chapter, Jody Lyneé Madeira and colleagues are worried about the relationship of the drug and device industry with specialized drug courts, in the era of opioid abuse. Here the primary medical device is called “the Bridge” and it provides neurostimulation as a preliminary step to reduce cravings in the treatment of substance use disorder. A 2020 review of the literature on such devices yielded only five studies meeting inclusion criteria, with a combined total subjects of N=150 across all five studies.³ The review authors conclude that, “the studies that have been performed have suffered from small sample sizes and poor characterization of the study population and their substance use patterns, as well as inadequate attempts at participant masking and controlling sources of bias. As such, there is a paucity of high‐quality, rigorously‐conducted research.”⁴ Only one of these studies focused on the Bridge device itself, and it was coauthored by the patent holder for the device, who also serves as consultant for the company marketing it. The Bridge is a great example of how the FDA is a weak gatekeeper for medical devices, and how weak regulation begets weak evidence.

Kate Kraschel is also concerned with unproven medical products, specifically those used for fertility services. Preimplantation genetic screening is one such service, which can be used to select embryos that are more likely to yield healthy babies, but it has a false-negative problem, often screening out healthy embryos. In this domain, the FDA has been largely silent, due to complicated political questions and the fact that the devices themselves are secondary to clinicians’ decisions about whether and how to use them. Accordingly, since no regulator requires proof of safety and efficacy, no such reliable evidence is produced. In this regulatory gap, money flows in to exploit the hopes of patients who are eager to become parents of healthy babies.

Preeti Mehrotra and colleagues take on the problem of dirty devices. Specifically, how should duodenoscopes be disinfected, and what role should the FDA have in setting those standards? This chapter exposes the problems with a binary approach to regulatory approval, where the device itself may be safe and effective, but only if downstream users properly sterilize it. This chapter also reflects a fragmentation of entities providing guidance in this space, including hospital policymakers, professional associations, and governmental regulators.

Wendy Netter Epstein focuses on the safety/innovation tradeoff for the FDA’s policy setting. Not unlike driving a car, the faster one goes, the greater the risk. For medical products, the faster we move to bring new medical products to market, the less information regulators will have and the greater the risk that some of those products will turn out to be bad. This risk can arise on the efficacy front, where approved products can come on the market, displacing the standard of care and sucking billions of dollars out of the health care system, only to turn out to be useless. Epstein focuses on the more worrisome problem that a product comes onto the market, but ultimately does more harm than good.

Together these chapters contribute to our understanding of how the regulation of medical devices, or the lack thereof, shapes what we do or do not know about them. In the race to help patients, it is necessary to make sure that our new medical products actually help them. As I have written before, it cannot simply be presumed.⁵

12 Clouded Judgment Preventing Conflicts of Interest in Drug Courts

Jody Lyneé Madeira , Barbara Andraka-Christou , Lori Ann Eldridge , and Ross D. Silverman ^*

12.1 The Growing Relationship Between Pharmaceutical and Medical Device Manufacturers and Drug Courts

United States’ pharmaceutical companies and medical device manufacturers are marketing their products directly to drug courts – with controversial results.¹ These activities can be associated with court policies and staff beliefs that are anti-agonist – opposed to forms of medications for opioid use disorder (MOUD²) containing opioids. Anti-agonist beliefs and policies can harm client outcomes when judges narrow MOUD options to one medication, or partner with providers who prefer one medication.

In the Greenwood City, Indiana, drug court overseen by Judge Lewis Gregory, patients received a neurostimulation medical device called the Bridge to assist them with detoxification before transitioning to Vivitrol. Judge Gregory began using the device in February 2017 after meeting with the manufacturer, Innovative Health Solutions (IHS). His court also only used Vivitrol because he “was certainly not going to do a medication-assisted treatment program with drugs which people used to get high.”³ But IHS did not receive FDA marketing authorization until November 2017, and existing research used controversial methodology and lacked IRB oversight.⁴ Were such concerns raised with the decision makers? Perhaps not, given that these decisions were occurring in a court rather than in a clinical setting. In the Hocking County Municipal Vivitrol Drug Court near Athens, Ohio, Judge Fred Moses decided to only allow clients to access the non-agonist medication Vivitrol – a choice he made after meeting Vivitrol’s manufacturer, Alkermes, at a professional conference and asking sales representatives to send the court’s affiliated clinician free starter doses.⁵ This decision ran counter to medical standards and professional guidance supporting client access to all types of MOUD.⁶

Manufacturer relationships with criminal justice institutions and drug courts represent a new frontier. Alkermes sales representatives have marketed Vivitrol to court officials in numerous states, including Missouri, Massachusetts, Ohio, West Virginia, Alaska, and Indiana, and administered injections to parolees in Michigan, Illinois, Wisconsin, Vermont, New Hampshire, and Pennsylvania; it has also lobbied state and national policy makers for laws favoring Vivitrol.⁷ As of 2017, Vivitrol was used in 450 publicly funded initiatives, such as court and parole programs, in 39 states.⁸ While manufacturer-court relationships are relatively novel, their conventional counterpart, the pharmaceutical sales representative-physician marketing efforts, has generated a robust body of scholarship that is helpful in understanding their potential consequences.

One might assume that effective gatekeepers keep watch over these relationships and their consequences, including the FDA, federal and state legislatures, state court systems, and/or legal and medical professional associations that at least ensure that public officials receive accurate and complete information about MOUD. But these gatekeepers are nonexistent, lack important knowledge, or are susceptible to manufacturer influence. Meanwhile, these industries are attempting – and succeeding – at persuading local communities and states to use limited or less-effective MOUD options.

This chapter examines the growing relationships between medical device and pharmaceutical manufacturers and drug courts, arguing attention must be paid to reveal and interrogate potentially detrimental influences that can harm client outcomes. Section 12.2 describes the manufacturer-drug court relationship, explores treatment team beliefs about MOUD, and explores two examples. Section 12.3 applies a conflict-of-interest framework to assess these relationships and discusses how treatment teams can be “moral entrepreneurs” that make non-evidence-based choices against clients’ best interests. Section 12.4 poses potential solutions to this dilemma.

12.2 The Relationship Between Drug Courts and Medical Manufacturers

States have created drug courts as a therapeutic alternative to incarceration in cases involving nonviolent, low-level criminal charges.⁹ Instead of incarceration, drug court clients can live and work in the community if they follow drug court requirements, including treatment policies. Studies suggest that, on balance, drug court program participation is more effective than incarceration at preventing drug use relapse and reincarceration.¹⁰ The Trump Opioid Crisis Commission commended drug courts as a “central component of the pretrial diversion process,”¹¹ encouraging their implementation in all ninety-three Federal district courts and every US county.¹²

12.2.1 Drug Court Staff Beliefs Regarding Treatment for Substance Use Disorder

Drug courts typically do not provide treatment directly, but rather set treatment policies, establish relationships with community substance use disorder (SUD) treatment providers to whom they refer clients, and monitor treatment adherence. Participant noncompliance with drug court policies can result in program expulsion and incarceration. Drug courts are operated by teams headed by a judge.¹³ Court teams may also include a program coordinator, court case manager, prosecutor, probation/parole officer, law enforcement official, counselor, and clinical case manager.¹⁴ Most team members lack medical training, most teams lack physicians, and counselors and clinical case managers engaged on treatment teams typically are employed by a partnering health care organization, and not the court. To date, little is known about how drug court teams set treatment policies, especially with respect to opioid use disorder (OUD) treatment.

The gold standard of care for OUD is MOUD with methadone, buprenorphine, or naltrexone.¹⁵ Methadone and buprenorphine (including but not limited to Suboxone) are opioid agonists that activate the brain’s mu opioid receptors, decreasing opioid cravings and preventing painful withdrawal symptoms. Agonist treatment is associated with as much as a 50 percent decrease in mortality from overdose.¹⁶ In contrast, naltrexone is a non-opioid antagonist that blocks opioids from activating the brain’s mu opioid receptors. Vivitrol, approved for OUD treatment in 2010, is an intramuscular injectable extended-release version of naltrexone that is more effective than a placebo at preventing return to drug use, including for criminal justice system participants.¹⁷

While few studies to date have directly compared the efficacy of buprenorphine or methadone to Vivitrol, buprenorphine and methadone appear more effective at preventing overdose deaths, do not necessitate complete detoxification, and are more cost-effective.¹⁸ Additionally, Vivitrol is harder to start because it requires complete detoxification from opioids.¹⁹ According to one randomized controlled comparative study, it was harder to initiate patients onto Vivitrol than oral buprenorphine, creating a relatively higher rate of return to drug use for patients randomized to Vivitrol as compared to oral buprenorphine; however, patients who successfully initiated onto Vivitrol had comparable rates of return to drug use as those on oral buprenorphine.²⁰ Therefore, patients may need detoxification support and/or high motivation levels to successfully start Vivitrol.²¹ Two more recent studies found that agonists were more protective against opioid overdose than Vivitrol.²² Lastly, at approximately $1,300 per thirty-day dose, Vivitrol is significantly more expensive, and far less cost-effective, than other OUD medications.²³

Unfortunately, drug court OUD treatment policies may run contrary to best practices. A 2013 study found that up to 50 percent of adult drug courts prohibit methadone and buprenorphine; and a 2021 study found that judges are more likely to have favourable policies toward Vivitrol as compared to buprenorphine or methadone.²⁴ The substance and accuracy of court teams’ treatment policies relate to program member beliefs about treatment safety, efficacy, and diversion potential.²⁵ Compared to agonist treatments, court staff appear to have relatively more positive beliefs about Vivitrol,²⁶ despite emerging data suggesting that agonist treatments are comparatively more effective at preventing overdose death.²⁷

Device and pharmaceutical manufacturers (Industry) may directly inform court staff beliefs about MOUD. From 2010 to 2017, as the opioid epidemic exploded, few OUD treatment education options were available to courts beyond industry representatives.²⁸ Media articles,²⁹ a qualitative study of Indiana courts,³⁰ and a quantitative study of Florida courts³¹ suggest that many court staff receive information about OUD treatments directly from pharmaceutical companies, especially Alkermes. For example, in a convenience sample of 121 Florida court staff, 36 percent reported receiving training from Alkermes, 24 percent from a buprenorphine manufacturer, and 11 percent from a methadone manufacturer. Among those who received training from a medication manufacturer, 55 percent received training from at least two companies. Another recent study found that, after controlling for opioid overdose deaths in an area, drug courts’ location was significantly and positively associated with pharmaceutical payments to physicians for MOUD (tracked under sunshine laws),³² suggesting that pharmaceutical companies may target physicians in areas where they know drug courts make referrals.

Some court staff’s understanding of substance use may reflect cultural and personal perspectives about addiction, “viewing it as moral weakness that call[s] for tough paternalism.”³³ According to Andraka-Christou, judges have differing conceptions of sobriety, from living life without any substances (including medications) to living life without misusing substances.³⁴ Some court staff view agonists merely as “trading one drug for another” or “not really quitting.”³⁵ Court staff beliefs about MOUD may also reflect beliefs and practices of the treatment providers with whom they collaborate, with one study of a convenience sample of court staff finding that half felt their collaborating provider did not encourage agonist MOUD.³⁶

Despite the effectiveness of agonist MOUD at decreasing overdose death and return to drug use, several studies have documented hostile court staff attitudes towards agonist treatment,³⁷ particularly methadone,³⁸ due to its perceived diversion and misuse potential, distrust of methadone providers (often located in high-crime areas), and misunderstandings about medication safety and efficacy.³⁹ Court staff view buprenorphine slightly more favorably, but may require or strongly encourage clients to transition off upon entering the program⁴⁰ despite medical studies indicating that longer-term buprenorphine use is more effective than shorter-term use.⁴¹ As with methadone, court staff appear to distrust providers and worry about potential client misuse or diversion of buprenorphine.⁴² One Ohio drug court judge stated, “the Suboxone zombies aren’t getting better … The people who want the Vivitrol are the ones who want to get healthy and get better.”⁴³

Court staff have more favorable beliefs about Vivitrol because it cannot be misused or diverted and lacks an opioid ingredient.⁴⁴ Judges are critical of its cost, however, even though clients can get free samples or discounts through state-funded programs or Alkermes. One judge stated, “we work really closely with the drug rep from Alkermes … and they ‘ve been very supportive in finding us, giving us discounts for some of our people, even providing a month or two of free doses.”⁴⁵

12.2.2 Examples of Direct-to-Court Marketing: the Bridge and Vivitrol

Medical device manufacturers market their products directly to drug courts. The National Association of Drug Court Professionals (NADCP) is the primary standard-setting organization for adult drug courts, and heavily influences court staff education. Innovative Health Solutions, the manufacturers of the Bridge, have been a regular presence promoting their product as an adjunct to Vivitrol-based treatment at the NADCP national conference. Even though the device received FDA approval, that status rested solely upon a heavily criticized study that lacked a control group, reported no dropout rate, and lacked IRB oversight. IHS also marketed the Bridge as early as 2016, over a year before receiving FDA approval, engaging in off-label promotion and violating FDA regulations.⁴⁶

As compared to other MOUD manufacturers, Alkermes is most widely known for engaging and “educating” drug court judges. Alkermes initially found that conventional marketing practices were ineffective for Vivitrol⁴⁷ and began to cultivate new markets by reaching out to criminal justice officials, drug court judges, and professional associations.⁴⁸ In 2014, Alkermes paid $50,000 to become a “champion” sponsor of the NADCP.⁴⁹ Alkermes also detailed its strategic targeting of drug court judges and criminal justice institutions at a 2016 analyst and investor event,⁵⁰ where CEO Richard Pops described “priming” state “ecosystems” to shape and penetrate markets by aligning messaging to court staff opinions.⁵¹ Alkermes’ “road map for future growth” included both a “traditional commercial approach (MD, patient, payer)” and “generat[ing] organic conversations among [a] broad range of stakeholders (criminal justice, policy, caregivers, etc.)”⁵² These strategies directly positioned Vivitrol as a novel and superior drug; Alkermes’ Vice President of Marketing described “stimulat[ing] organic conversations about ‘deserving to know all options’ and the potential to end dependence on opioids.”⁵³

12.3 Moral Entrepreneurship and Conflict of Interest

To understand the potential for bias and conflicts of interest in selecting treatment providers and the associated forms of treatment made available to drug court program enrollees, it is helpful to examine these issues in a related context: the industry sales representative-physician relationship. Some experts believe conflicts arise because business and medical ethics differ: businesses, including medical device and pharmaceutical companies, commonly reward vendors to stimulate sales, while such conduct could be problematic or unethical in medicine.⁵⁴ The most controversial practices are industry sponsorship of continuing medical education programs (CME) and “detailing,” where industry sales representatives (ISRs) “visit physician offices to discuss the availability and suitability of products.”⁵⁵

Advocates of close industry-physician relationships describe them as “a full, honest, fair, and balanced discussion of materials” that gives providers “invaluable assistance” in selecting appropriate medications, and providers reciprocate by giving drugs “preferred status on a hospital’s formulary.”⁵⁶ Because physicians cannot keep up with extensive literature and innovations, the ISR visit is an “extremely effective” encounter, providing essential information in five or ten minutes.⁵⁷ Thus, pro-industry advocates assert, marketing communications sell products and facilitate “technology transfer.”⁵⁸ The potential for bias here is clear; but industry advocates argue that “[a]lthough information coming from a commercial source does present the product in the best possible light, physicians are well aware of this bias and correct for it.”⁵⁹ Moreover, they contend, visits from competing ISRs “expose[] physicians to multiple biases,” allowing them to “make a more informed choice.”⁶⁰ They concede, however, that physicians make prescription decisions by “relating the decision to a personal value system” to which ISRs can appeal.⁶¹

A 2019 study found that pharmaceutical manufacturers alone spent more than $20 billion marketing to health care professionals in 2016, including $5.6 billion for prescriber detailing.⁶² This study also acknowledged their statistics significantly underestimated the amount industry spent on professional marketing, as the authors were unable to acquire data on marketing related to devices, meetings, and events. While independent firms produce CME programs, they have been found to “skew training material in favor of commercial interests” to retain business.⁶³

Critics of close industry-physician relationships describe a conflict between product promotion and education and assert that patients’ interests are not best served by industry-influenced prescribing practices.⁶⁴ Although physicians often believe they are not influenced by marketing, research clearly shows otherwise.⁶⁵ These sophisticated promotional activities exploit the professional’s vulnerabilities, often at subconscious levels, to create biases⁶⁶ and influence prescribing habits in ways that may not best serve the care recipient.

12.3.1 Applying a Conflict-of-Interest Framework

A conflict-of-interest (COI) framework can structure our understanding of relationships between industry and drug court treatment teams, especially since, as shown above, we know: 1) industry representatives already serve either as significant sponsors or appear as vendors at drug court conferences, and 2) industry has been engaged in court team members education and detailing.

As described by Stark,⁶⁷ whose work examined COI as it applied to public officials, and has since been applied to health professionals,⁶⁸ motivated bias is a process (FN69), and COIs are broken down into three behavioral stages.⁶⁹ First, antecedent acts prepare the target of influence’s state of mind for partiality or bias, making the target more likely to exercise responsibility for private or personal interests instead of the interests of the public (or patient/program enrolee).⁷⁰ Second, antecedent acts influence the target towards certain perspectives, biases, or affinities.⁷¹ Third, the target behaves in ways influenced by antecedent factors.⁷² Industry interactions with court team members are, at minimum, antecedent acts toward more favorable arrangements for the industry (in this case prioritizing one MOUD in court treatment referrals or in court policies).

Stark also distinguishes external influences from internal convictions, differentiating between an internal “genuinely subjective belief or commitment” that might become “an encumbrance when its proximate cause lies without, in the importunings of a litigant, the ministrations of a lobbyist or the pressure of a campaign contributor.”⁷³ For example, lobbying is an external attempt to “mobilize the bias,” or “strengthen the commitment members have to an already established position on a given question.”⁷⁴ Internal convictions are difficult or impossible to disclose and divest; there is no disclosure form, and disclosure itself only suggests “an irremediable capacity to make an unencumbered decision.”⁷⁵ Someone who discloses beliefs might “develop an encumbering interest” in maintaining them.⁷⁶

12.3.2 Judges as Moral Entrepreneurs

Sociologist Howard Becker coined the term “moral entrepreneurs” to describe individuals in power who work to construct systems that reinforce their beliefs about deviancy (often through criminalization).⁷⁷ For example, a moral entrepreneur who believes that all people who use medications with misuse potential are morally deviant would punish and/or exclude people who utilize these products and develop systems that prioritize the use of medications/devices without misuse potential.

For years, judges and drug court treatment teams have been forging ahead in the opioid epidemic, handling massive increases in the proportion of clients with opioid use disorder, including treatment referrals, without much organized guidance. More research must be conducted on the mechanics underlying the selection of treatment providers for drug court teams. That said, our research has found that program managers, as well as judges, are receiving education from industry representatives.⁷⁸

According to Stark, “in law, business, and medicine, the professional (lawyer, manager, doctor) is thought to have fiduciary or ‘role-moral’ obligations … to pursue and protect certain interests possessed by a defined, identifiable set of principles: clients, shareholders, patients.”⁷⁹ Because drug courts are structured to facilitate opportunities for program enrolees (clients) to access treatment services that effectively address their SUD and help them avoid incarceration and recidivism, judges and treatment team members, as the creators and managers of these systems of care, are charged with the role-moral obligation to act in clients’ best interests. This section focuses explicitly on drug court judges because, in the unique setting of the drug court, they lead teams that select and engage treatment providers, are fiduciaries, and must adhere to ethics codes. Even if a manufacturer communicates directly with other team members, such as court program coordinators, judges will have the final say about court policies.

Industry education from antagonist manufacturers and device companies position their products as morally superior to agonist treatments. In this way, antagonist manufacturers motivate bias against the moral entrepreneur – in this case, the judge – and their existing negative beliefs regarding opioids.

Some external standards exist to determine clients’ best interests as to MOUD, including medical standards of care or best practices and professional guidance.⁸⁰

A judge who supports recovery should follow medical standards for recovery support, rather than engage as moral entrepreneurs. Narrowing treatment options to Vivitrol and/or the Bridge ignores patients for whom these interventions are contraindicated, including pregnant women. Because Vivitrol is costlier, requires detoxification, and is less protective against overdose, judges preferencing Vivitrol in their systems also create a more difficult recovery road for court clients with limited financial means. As the former head of SAMHSA’s Center for Substance Abuse Treatment commented, “what we continue to have is a political philosophy colliding with therapeutic strategies, and that political philosophy has less to do with the individual and more to do with moral views about drug abuse.”⁸¹

Because of the unique nature of the relationship between courts and MOUD manufacturers, it would be difficult to regulate these decisions based upon extant judicial conduct rules. American Bar Association Model Code of Judicial Conduct Rule 2.2 requires judges to “uphold the law” when deciding cases; an accompanying comment states, “[a]lthough each judge comes to the bench with a unique background and personal philosophy, a judge must interpret and interpret the law without regard to whether the judge approves or disapproves or the law in question.” Yet, there is no law compelling judges to use the highest and best scientific and medical evidence in judicial decision making. In fact, one might argue that this is not the type of “decision making” the model code envisaged.

12.4 Identifying a Range of Potential Solutions

Much can be done to avoid improper influences that may occur in relationships between pharmaceutical manufacturers and drug courts and defuse any potential resulting conflicts. These solutions range from “light” to “heavy.” In practice, widespread changes in approaches to court-industry relationships may occur gradually.

An effective “light” solution would be to systematically affirm that a judge’s role is overseeing court proceedings as “captain of the ship” and monitoring clients. This role does not, however, include making treatment decisions. Decisions like whether MOUD is appropriate for individual clients, and in which form, must be left to a treatment provider.⁸² Judges’ comments that they will not allow forms of MOUD that can be diverted or with opioid ingredients reflect inappropriate encroachment on the treatment provider’s role. Physicians should receive complementary educational messaging through professional medical associations such as the AMA. Drug courts should also be encouraged to include local physicians on treatment teams or as consultants. Logically, the ideal medical professional would be a practitioner offering holistic treatment options to whom the drug court judge refers clients seeking MOUD. This may be difficult in several areas of the country, however, based on qualified providers’ availability and willingness to serve, although new telehealth and expanded methadone rules may extend access to more distant providers. Additionally, since court staff select the health care providers with whom programs partner, they may opt into relationships with providers who have anti-MOUD attitudes.

Another solution would be to provide judges and staff with alternative educational resources free from industry sponsorship. It is not suggested that judges and staff intentionally invited industry representatives to influence court proceedings in earlier years. Rather, courts’ eagerness for informational resources were an educational vacuum that pharmaceutical and medical device manufacturers were prepared to fill. Alternative educational content can be provided online and at professional conferences and are currently coordinated through professional associations such as NADCP and NCSC. Some governmental and non-profit organizations have begun offering MOUD-focused education tailored to judges, including information about the appropriate MOUD decision-making role of court team members.⁸³

A more involved solution would be to attach restrictions and requirements to court funding, such as conditioning grant monies on court compliance with best practices of allowing all three kinds of MOUD. Recipients of federal Bureau of Justice Assistance (BJA) grants, for example, have to demonstrate that they will not deny clients access to their programs because of MOUD use.⁸⁴ This would provide some federal regulatory oversight enforcing best practices; however, this solution has limited reach as only approximately 200 out of 3,000 drug courts nationwide receive BJA funds. State grants could incorporate similar conditions.

A still more comprehensive solution would be to impose state-level certifications mandating that drug courts adhere to certain standards, such as permitting all three forms of MOUD, agreeing to refer clients to certain licensed facilities that must accept Medicaid, etc. For example, Michigan’s certification program⁸⁵ requires courts to comply with several standards and best practices, including the BJA’s Key Components⁸⁶ and the National Center for DWI Courts’ Ten Guiding Principles of DWI Courts.⁸⁷ These guidelines require drug courts to allow MOUD use “when appropriate, based on a case-specific determination and handle MOUD very similarly to other kinds of treatment” and assert that “the court does not determine the type, dosage, and duration of” MOUD.⁸⁸ Similarly, states can pass statutes or regulations prohibiting MOUD bans within courts, as has already occurred in some states.⁸⁹

Finally, a model sunshine law for drug courts could be an integral component of an effective solution scheme. Federal court and employee rules require financial disclosures for gifts and reimbursements above a certain threshold.⁹⁰ Federal laws such as the Physician Payments Sunshine Act, passed in 2010, make financial relationships between medical industrial corporations and physicians more transparent and reveal COIs, requiring pharmaceutical, medical device, biological and medical supply manufacturers who are covered by Medicare, Medicaid and the State Children’s Health Insurance Program to track financial relationships with teaching hospitals and physicians and report that data to the Centers for Medicare and Medicaid Services. A mandatory disclosure approach acknowledges the role of those seeking to influence system development (the manufacturers) as well as the system participants. A model state sunshine law could encourage states to re-evaluate decisions made years ago, particularly court policies or referral practices prioritizing Vivitrol over agonist treatments.

A sunshine law by itself, however, will have little impact. Disclosure plays a paramount role in avoiding liability for COI but it alone is not a viable solution. If disclosures are made after antecedent acts produce relationships that enable improper influences, the harm has already occurred. An efficacious intervention should take place before acts can lead to partiality.⁹¹ Disclosure alone does not eliminate problematic relationships, thwart influence, or prevent partial behavior.⁹² Disclosure of judicial beliefs regarding MOUD would do little but expose easy marks for manufacturers to exploit. Thus, sequestration – prohibition of most industry engagement with drug court team members – may be more effective than disclosure, because eliminating problematic relationships eliminates COIs.⁹³ Full sequestration need not be imposed due to First Amendment concerns. Instead, state courts administrators could prohibit court team members from meeting with industry representatives, or accepting free lunches or other items from manufacturers.⁹⁴ Additionally, state professional licensing boards (e.g., bar associations) could forbid licensees from applying manufacturer-provided training toward required continuing legal education credits.

Of course, the most effective strategy would be to deploy a web involving many of these proposals. Here, policy makers can follow Alkermes’ example, implementing a comprehensive array of educational opportunities and regulatory and oversight measures at local, state, and national levels, in partnership with diverse professional organizations representing law, medicine, and the court system.

13 Disrupting the Market for Ineffective Medical Devices

Wendy Netter Epstein

The current debate over medical device regulation pits safety against innovation. Those in favor of greater regulation point to the need to protect patients from the harms of insufficiently tested devices. Those in favor of less regulation cite the need to promote innovation and move potentially lifesaving devices to market faster.¹ At present, the less regulation, more innovation camp is winning the debate – in part on the argument that postmarket surveillance systems can adequately address safety concerns. But framing the debate this way leaves out key inputs: efficacy and relative effectiveness.

Not all innovation is created equal nor is it equally desirable. The best innovation creates medical devices that are superior to current alternatives, either because they lead to better patient outcomes or because outcomes are just as good, but the care is cheaper. The ideal innovation creates devices that are both clinically better and cheaper. While the potential for devices to significantly improve health outcomes is great – and many devices have had such a positive impact – the prevalence of ineffective devices is nonetheless troubling.²

In 2016, the 21st Century Cures Act was signed into law.³ The Act was designed in large part to accelerate device development and approval. But even under the somewhat stricter regulatory regime that had been in place prior to the Act, there was evidence that ineffective and expensive medical devices were used pervasively. One study identified nearly forty such ineffective medical devices.⁴ As shown in Chapter 1, the use of these devices can harm the health of patients and adds significant costs to an already immensely costly system.

Perhaps none of this is surprising given that market mechanisms can be ineffective at promoting ideal device innovation, the regulatory regime is underpowered (even when the Food and Drug Administration (FDA) requires evidence of effectiveness, the bar is low),⁵ and the products liability and tort systems do little to force providers to assess relative efficacy.⁶ This chapter describes the serious negative consequences that flow from the use of ineffective medical devices and explores some solutions, focusing on the underexplored role that providers and payors might play in beginning to address this problem.

13.1 The Kind of Innovation We Want Versus the Medical Devices We Get

Sometimes medical devices are brand new innovations in that they do not replace anything that came before them. For instance, the stethoscope was first invented in 1816 to improve upon the only method that existed at the time to listen to a patient’s heart – placing one’s ear on the patient’s chest.⁷ More often, however, medical devices purport to be improvements to treatments that already exist – an improvement over an existing device (say a next-generation pacemaker) or an alternative to another practice (for example, substituting device technology to control hypertension for pharmaceutical therapy).⁸ But how do we evaluate what type of medical device innovation is most desirable?

There are two primary dimensions to consider: the extent to which the device improves patient outcomes⁹ and the effect on cost. The best new medical devices simultaneously improve patient outcomes and reduce cost. But we may also be happy when new devices either improve outcomes or are cheaper. One thing is clear: we do not want devices that score poorly on both patient outcome and cost metrics. To the extent our current system is prompting new devices that simultaneously add cost and do not improve patient outcomes,¹⁰ that is problematic. Yet there is a growing body of evidence showing that such devices are getting approved (or cleared) by the FDA and are being used in practice, without patient knowledge.

When medical devices are determined to be unsafe, it is front page news. Consider the plight of surgical mesh used to repair hernias that had severe side effects,¹¹ the cement application device used in spinal fusions that grew bone where it was not supposed to,¹² or metal-on-metal replacement hips that caused flesh-rotting metallosis.¹³ These devices were recalled, class action lawsuits were filed, and policymakers rightly focused on how these harms could have been avoided.¹⁴ But the same is not true of ineffective medical devices – those that might not be killing people or causing horrendous side effects, but that can nonetheless cause considerable harm when they do not do what they are supposed to do.

Consider the example of the bispectral index monitor (BIS) intended to address anesthesia awareness, which occurs when surgical patients under general anesthesia are aware of events that happened during the surgery after they awaken, sometimes feeling pain.¹⁵ These experiences are associated with posttraumatic stress disorder and anxiety. The BIS monitor was designed to fix the problem by measuring consciousness, allowing the anesthesiologist to titrate anesthesia to avoid awareness.¹⁶ The device was approved by the FDA in 1996. Its use spread so much that BIS monitors were in more than half of all operating rooms.¹⁷ Then, ten years after FDA approval, a large, randomized trial that compared use of the BIS monitor with standardized monitoring procedures found no benefit of the BIS monitor to anesthesia awareness.¹⁸ The monitors were not necessarily unsafe, but they were ineffective and costly.

The story of hip protectors is similar. Hip protectors are devices designed to protect older patients, typically who suffer from osteoporosis, from fracturing their hips in a fall.¹⁹ The FDA has approved a number of different hip protector devices.²⁰ But now, several postmarket studies have been conducted. None have found evidence that hip protectors are effective in preventing hip fractures.²¹ In some studies, patients were more likely to fracture hips when using hip protectors than when not.

Mechanical cardiopulmonary resuscitation (CPR) devices provide a final example. When a patient goes into cardiac arrest, delivering high-quality CPR improves patient outcomes.²² CPR, however, can be difficult to perform correctly – both to perform chest compressions at the right rate and to compress the chest to the right depth. Mechanical CPR devices ostensibly reduce human error by performing automated CPR at a specified rate and to a specified depth.²³ These devices were originally introduced in the 1960s and have been approved or cleared by the FDA.²⁴ They are expensive, at an average price of $15,000 each, and are increasingly being used, particularly by EMS agencies.²⁵

Counterintuitively, many studies have now shown that mechanical CPR leads to worse patient outcomes than manual CPR, particularly when used outside the hospital.²⁶ Mechanical CPR is both more costly than manual CPR and also leads to poorer health outcomes. Yet its use persists.

These examples are likely the tip of the iceberg. While these devices were studied after adoption, most do not get the postmarket randomized trial treatment.²⁷ Nonetheless, the systematic study of medical device effectiveness that has been done provides further reason for concern.

In 2019, authors conducted a comprehensive review of the randomized clinical trials published in three leading medical journals – The Journal of the American Medical Association and the Lancet between 2003 and 2017, and the New England Journal of Medicine between 2011 and 2017.²⁸ The study aimed to identify medical reversals, which the authors define as “practices that have been found, through randomized controlled trials, to be no better than a prior or lesser standard of care.”²⁹ BIS monitors, hip protectors, and mechanical CPR devices, are all medical reversals.

The authors’ review found close to forty medical reversals involving medical devices.³⁰ The authors only studied randomized controlled studies that had been published in leading medical journals, but of those studies, a surprisingly high 13 percent of all randomized trials were medical reversals.³¹ These findings are consistent with other analyses that have been conducted.³²

The next section explores why it is likely that many ineffective devices have prevailed in the market despite the fact that they do not work (or work less well) than other less-expensive options.

13.2 Why Ineffective Medical Devices Are in Use

How exactly do we end up with ineffective medical devices? In theory, three protections should prevent or at least minimize the occurrence: markets, the regulatory regime, and tort law.³³ In practice, however, all are flawed.

13.2.1 Market Insufficiencies

Well-functioning markets should check false claims of effectiveness. If a vacuum is advertised to pick up pet hair and it turns out that it does a lousy job, word will get out and people will not buy the vacuum. If the vacuum is merely adequate at picking up pet hair, but the model is more costly than similarly effective alternatives, consumers will not buy the vacuum. In the medical device context, if a glucose monitoring system does not accurately read glucose levels, and this fact is discoverable, patients should not buy it. And if the glucose monitoring system is adequate but more expensive than alternatives, people should not buy it.

But several characteristics make the medical device market unique. First, while a consumer can see whether the vacuum does a good job removing pet hair, a patient often cannot tell if the medical device does what it is supposed to do. Most patients are unable to tell if they need the medical device in the first place and are ill-equipped to select the best one even if they have access to necessary information, which they often do not. Second, patients are not making decisions alone. They must rely on doctors and other providers to act as their agents to choose the most effective device. But providers can be swayed by reimbursement rates, conflicts of interest such as side deals with device manufacturers, a desire to experiment with the latest technology, and pressure from patients and advocacy groups. When a device is not effective, it is not necessarily in the best interests of the provider to disclose that information. And even after evidence is shared that a device does not work, providers who have used a device for a long time may be hesitant to change their practices. Finally, another complication is that a third-party payor typically reimburses for device cost, lessening the impact of cost considerations on decision making. So low-value and high-value devices can be profitable just the same.

13.2.2 Regulatory Failures

When markets alone are not sufficient, we turn to regulation. One might assume that the FDA only approves devices that are both safe and effective. But that may not be the case.

To start, the FDA classifies devices based on risk to the patient, with Class I devices being low risk (e.g., bandages), Class II being intermediate risk (e.g., wheelchairs), and Class III being highest risk (e.g., implantable pacemakers). As others in this volume have noted, more than 80 percent of devices are exempted from the FDA’s premarket approval process based on their classification and either do not require review or are instead permitted to be marketed following clearance through the 510(k)-approval pathway.³⁴

Let us start with the 510(k) pathway. Devices subject to its requirements need not provide independent evidence of effectiveness. Manufacturers only need establish that the device is “substantially equivalent” to a predicate device already on the market. Devices have been cleared even if the predicate had been removed from the market or if the predicate had been initially approved without judging effectiveness.³⁵ While the 510(k) pathway must exist for minor adjustments to approved devices, concerns about the process are well documented.³⁶

But even for Class III devices that must submit to the more rigorous premarket review process, where evidence of effectiveness is theoretically required, there is still little guarantee that the device will be effective and even less so that it will be better for patient outcomes and less costly.³⁷ The Federal Food, Drug & Cosmetic Act is vague about what a showing of effectiveness requires³⁸ and the federal regulations do not provide much additional guidance, stating:

There is reasonable assurance that a device is effective when it can be determined, based upon valid scientific evidence, that in a significant portion of the target population, the use of the device for its intended uses and conditions of use, when accompanied by adequate directions for use and warnings against unsafe use, will provide clinically significant results.³⁹

But the term “clinically significant results” is not defined in the medical device statute or in the regulations. It is nonetheless generally understood that even a study without statistical significance can be enough to gain approval for a device.⁴⁰ Often applications are approved based on a single clinical study that might not even be a randomized trial.⁴¹ There has been almost no focus in case law on what it means for a medical device to be “effective,” which is consistent with the secondary importance that effectiveness plays relative to safety of medical devices.⁴²

To put a sharper point on it, consider the difference in effectiveness approval standards for devices and drugs. For a drug to be approved by the FDA, a manufacturer must submit at least two adequate and well-controlled studies, each convincing on its own, to establish effectiveness.⁴³

There might be good reason for not requiring the same level of evidence for medical devices – in that it is more difficult and costly to run trials of sufficient size given heterogeneity of test subjects for at least some medical devices as compared to drugs.⁴⁴ And yet, studies that are not blinded and nonrandomized often provide poor evidence.⁴⁵ Thus, the regulatory framework does little to prevent ineffective devices from hitting the market.

13.2.3 Limited Role for Products Liability and Tort Law

Another check that should deter companies from selling – and doctors from using – ineffective medical devices is products liability and tort law. A patient who was harmed by an ineffective device should be able to sue the manufacturer who sold it or the doctor who used it.

But the US Supreme Court in Riegel v. Medtronic, Inc.,⁴⁶ held that federal law preempts state law products liability claims for devices that were approved through the FDA’s premarket approval process. For such devices, the FDA has in theory adjudged effectiveness. Despite the very limited nature of the review in practice, individuals harmed by such ineffective devices cannot sue manufacturers under products liability doctrine.

Claims are preserved for devices cleared through the 510(k) pathway for which there is no effectiveness screen.⁴⁷ However, this can be of little help if the patient does not learn of device ineffectiveness and its contribution to poor health outcomes, as is often the case. For this reason, cases that do get brought tend to be based on safety issues rather than effectiveness concerns.

Another potential check on ineffective devices is the right to sue the medical provider who used an ineffective medical device to the detriment of the patient. These types of cases could, in theory, motivate doctors not to use ineffective devices – or to rely on evidence of effectiveness more consistently in making treatment choices. In practice though, there are a number of hurdles. The first is that just mentioned – that patients often will not discover that the device was ineffective. Second, a doctor using a device approved (or cleared) by the FDA for the purpose approved by the FDA will generally not be liable under the custom and practice-based malpractice standards.⁴⁸ If a doctor can prove that he or she followed the same course as a reasonable provider would under the same circumstances, the doctor will generally prevail. A doctor could be liable for failure to warn a patient about potential dangers of a device, but if this information is not easily discoverable by the doctor (for instance if randomized controlled trials have not been done that have shown the device to be ineffective), there will be no liability.

As a practical matter then, products liability and tort law are underpowered to deter the use of ineffective medical devices.

13.3 The Harm Caused by Ineffective Medical Devices

The harm that flows from unsafe devices is clear. But ineffective medical devices also cause harm – in worse health outcomes and the waste of valuable financial resources. Also, more subtly but still importantly, ineffective devices provide a false sense that problems have been solved, quelling innovation in necessary areas, and engendering mistrust in the health care system.

13.3.1 Worse Health Outcomes: The Hazy Line Between Safety and Effectiveness

Perhaps the most famous example of an ineffective medical device concerns stents. For over a decade, in stroke patients, many physicians looked for the narrowing of the smaller vessels in the brain. If they were found, physicians placed stents – small metal mesh tubes – to prop open the vessel for the purpose of reducing future risk of stroke.⁴⁹ In 2011, a robust randomized controlled trial was conducted – the first of its kind to test the effectiveness of the stenting procedure, although it had already been approved by the FDA and had been in use for a decade. The study found that stents were not effective in preventing a stroke, and in fact, actually led to worse health outcomes.⁵⁰

This example shows how the line between safety and effectiveness can be a blurry one. Often times, when a choice is made to use a device that is ultimately ineffective, it is to the exclusion of a different device (or medication) that works better. Not all medical reversals will result in worsened health outcomes. But there is a heightened risk.

Relatedly, ineffective medical devices can lead to patient harm by giving a false sense of security. The use of hip protectors may (subconsciously) have led nursing home personnel to do less to prevent falls. And because it does not work to lessen fractures, the result might be an increase in hip fractures. An anesthesiologist who relied on the BIP monitor to prevent anesthesia awareness may have been lulled into not as diligently checking other signals of awareness, resulting in increased patient trauma.

While often times the harm from ineffective medical devices is not as obvious as from devices that are deemed unsafe, ineffective medical devices still make patients worse off.

13.3.2 Economic Harms

The other obvious harm that flows from the use of ineffective devices is economic. The US health care system is more expensive than that of all other industrialized nations.⁵¹ By some estimates, a third of all US health care spending is unnecessary.⁵² That includes spending on ineffective medical devices.

While medical devices currently only account for about 6 percent of health care spending in the United States, the market is growing rapidly.⁵³ In 2018, the US market was valued at $169 billion,⁵⁴ and it is on a strong growth trajectory with revenues expected to double in the next decade.⁵⁵

Additionally, the cost of an ineffective medical device often goes beyond just the cost of the actual device. We pay doctors to place the devices. Sometimes additional scans and diagnostics are ordered because of the medical device.⁵⁶ Surgeries may be required to remove ineffective implanted devices.

13.3.3 Other Harms

There are other less obvious harms that flow from the use of ineffective medical devices. For one, the appearance that a device exists to solve a problem – when in reality it does not – stifles innovation in that domain. The use of ineffective medical devices also harms public trust in the medical system and specifically in medical providers.

13.4 Incentivizing Effectiveness

In the current system, ineffective medical devices (and comparatively ineffective ones) are too frequently approved by the FDA and used on patients. Practices concerning these devices are often difficult to stop once they become a part of the standard of care and they can cause both significant patient harm and unnecessary expense. But in order to fix the problem, ineffective medical devices have to be identified, and if they are adopted before identification, there must be a mechanism for discontinuing them. These are not easy problems to solve.

Many scholars promote stricter regulatory standards for ex ante proof of effectiveness.⁵⁷ While this would be a logical solution – requiring manufacturers to prove effectiveness before any patients are harmed and any funds are unnecessarily spent – making this change in practice is difficult. There is a strong movement to reform the 510(k) process, which might address those devices that are cleared without any effectiveness review at all. But as to the Class III premarket authorization process, the FDA is under pressure to get devices to market quicker and at a lower cost, which is at odds with tightening effectiveness standards.

One way to address the cost concerns would be for the government to fund this research. But that does not do anything to lessen the overall cost of the endeavor, nor does it address the time-to-market concerns.

The other commonly proposed solution is to improve the postmarket surveillance process – which is already underway with the 21st Century Cures Act.⁵⁸ There are initiatives like the National Evaluation System for health Technology (NEST) – a public-private partnership intended to conduct active surveillance on postmarket medical devices.⁵⁹ And the Patient-Centered Outcomes Research Institute (PCORI) already conducts postmarket comparative effectiveness research on drugs and devices.⁶⁰

The concept is laudable. But as currently conceived, the postmarket surveillance process largely depends on voluntary reporting. The FDA does not have the resources to police and ensure compliance.⁶¹ The postmarket surveillance process is also more likely to identify safety concerns than effectiveness concerns. While the FDA can also order postmarket clinical studies, that is generally only in response to adverse events reports. The process could be improved with a registry that requires reporting of all device-related patient outcomes. The registry would have to be actively monitored and analysed to produce useful information.⁶²

PCORI’s medical device research intended to aid doctor and patient decision making is also a step in the right direction. But it lacks a mechanism to incentivize using the results of the work. For instance, the law currently forbids government payors from adjusting reimbursement on the basis of PCORI data.⁶³

It may be possible to build on these ideas, but the role that both providers and payors play in constraining the use of ineffective devices also deserves more focus. While providers may not often be held liable when devices are ineffective, they would still benefit from better technology that makes their jobs easier and results in better outcomes for patients. In recognition of this, there are initiatives to involve professional societies in the identification of ineffective devices.⁶⁴ For instance, the Choosing Wisely campaign tasked medical societies with preparing lists of ineffective interventions, including medical devices.⁶⁵ But Choosing Wisely has to have data on which to base its recommendations. It can be helpful in uprooting ineffective devices when new studies suggest lack of efficacy (or when PCORI data does). But providers are unlikely to run or fund studies of devices themselves. Nonetheless, working to change professional norms can be impactful. More broadly, medical education has started to focus decision making more squarely on evidence and data.⁶⁶ If providers can learn to rely less on the imprimatur of FDA approval or clearance and more on reliable studies of devices, it can make a big impact.

Perhaps the most promise, however, lies in an expanded role for private payors – and possibly even for government payors. Payors have the motivation to quell the use of ineffective devices.⁶⁷ Profit-motivated insurers, but even government payors, benefit from higher-quality, less-expensive care. Payors could make a huge impact by tying reimbursement decisions to data of effectiveness, as is the practice in most European countries.⁶⁸

Admittedly, there are many reasons we might be leery of US payors playing this role. Insurers may take an overly aggressive stance in denying coverage, motivated more by profit maximization than by the betterment of patient health and the banishment of truly ineffective devices. Also, medical device efficacy may be heterogeneous. Even if a device is not effective for certain patients, it may nonetheless be for others. This can be hard to discern from studies, particularly if the test population is not diverse. Payors might also not have as much leverage as they do in other reimbursement decisions in a world of limited alternatives.

But the biggest impediment to tying reimbursement to effectiveness data is the lack of the data on which these decisions might rely. Payors are already engaging private technology assessment organizations to do effectiveness analyses, but those assessments are limited by the lack of published data on which to conduct the analyses. So perhaps the better question is what can payors do to incentivize the creation of the necessary data?

Payors may be able to better mine and use their own data to assess effectiveness. Or they could use their bargaining power to incentivize the study of device effectiveness. Payors negotiate with manufacturers over the price the payor is willing to pay for a device. While refusing reimbursement entirely may be impossible, payors can condition reimbursement on manufacturer agreement to fund or participate in a study of device effectiveness. The Government already does this to a limited degree. The Centers for Medicare and Medicare Services (CMS) may conditionally approve reimbursement for a device while requiring that additional evidence be collected about device effectiveness through a clinical trial or device registry.⁶⁹

Payors can also play a more active role in steering providers away from devices that may be ineffective based on the results of those studies.⁷⁰ In general, payors have bargaining power that could be better employed to promote the study, not just of device safety, but also of device effectiveness.

14 Preventing Medical Device-Borne Outbreaks The Case of High-Level Disinfection Policy for Duodenoscopes

Preeti Mehrotra , David J. Weber , and Ameet Sarpatwari

14.1 Introduction

Multiple outbreaks of antibiotic-resistant bacteria in recent years have been traced to contaminated duodenoscopes in health care facilities in the United States and Europe.¹ These events prompted intensive postmarket surveillance of three large duodenoscope manufacturers, the creation of voluntary hospital-based culturing programs,² and US Food and Drug Administration (FDA) safety warnings emphasizing the importance of following manufacturers’ instructions for use (IFUs) for performing high-level disinfection (HLD) or sterilization of equipment, also known as reprocessing.³ However, as outbreaks continued, the US Joint Commission made high-level disinfection or sterilization of all reusable scopes and probes a central component of its 2018 hospital accreditation programming.⁴ This chapter highlights the regulations governing medical devices, the etiology of the duodenoscope outbreaks, and the policy measures implemented and regulatory challenges persisting in the wake of the outbreaks. Given the proliferation of scopes and probes in medical care – including outbreak settings of highly infectious diseases such as the Ebola virus disease⁵ and carbapenem-resistant Enterobacteriaceae (CRE)⁶ – reprocessing cannot and should not remain an abstract part of device regulation. Amplifying the perspective of infection prevention and control in the medical device regulatory landscape is critical to achieve optimal and sustainable reforms.

14.2 Regulatory History and Duodenoscope Outbreaks

Under FDA regulations, devices fall into three classes. Duodenoscopes are categorized as Class II devices, which confer moderate risk and require regulatory controls such as the establishment of performance standards, postmarket surveillance, patient registries, and/or labeling requirements.⁷ Class II devices require only premarket notification through the FDA’s 510(k) pathway.⁸ By contrast, Class III devices such as implantable pacemakers, which “support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential, unreasonable risk of illness or injury,”⁹ require premarket approval (PMA), the most stringent type of device market application required by the FDA.

Yet despite its classification as a Class II device, duodenoscopes were linked to at least twenty-five outbreaks of CRE between 2012 and 2015.¹⁰ The actual toll was likely far higher, but unknown given gaps in reporting and surveillance.¹¹ By early 2013, the manufacturer Olympus knew of two independent lab reports, which found that one of their duodenoscope models featuring a difficult-to-access elevator channel could harbor bacteria even after cleaning according to the manufacturer’s instructions.¹² Even though the FDA began investigating elevator channels in 2013 in collaboration with the Centers for Disease Control and Prevention (CDC), Olympus did not forward the laboratory reports to the FDA or alert US hospitals, physicians, or patients to the risk of infection until February 2015.¹³ Further investigation revealed that two major duodenoscope manufacturers failed to pursue a new 510(k) premarket notification prior to bringing their devices with elevator channels to market. Custom Ultrasonics, the manufacturer of an automated reprocessor that was implicated in some outbreaks, also failed to report critical updates to their device to FDA as required by law.¹⁴ Finally, the FDA was also unaware of manufacturer warnings to European regulators that had occurred as early as 2013.¹⁵

These events highlighted various inadequacies in manufacturer reporting, hospital investigation, and regulator action, which prompted the CDC and FDA to reexamine reprocessing IFUs. In March 2015, the CDC released an interim duodenoscope surveillance protocol for health care facilities in cooperation with the FDA and the American Society for Microbiology (ASM).¹⁶ In October of the same year, the FDA ordered three major duodenoscope manufacturers to conduct postmarket surveillance studies to better understand duodenoscope-transmitted infections.¹⁷

However, it was not until June 2017 that the FDA promulgated regulations to require manufacturers of certain high-risk reusable Class II medical devices to include validated IFUs regarding cleaning, disinfection, and sterilization in their premarket notification 510(k).¹⁸ These regulations acknowledged that the design of some devices, such as those with lumens or crevices, were higher risk than others.¹⁹ Additionally, the regulations emphasized the importance of the validated instructions not only for automated reprocessors and washing devices, but also for such high-risk devices.²⁰

Over the next four years, the FDA released six general updates of reprocessing instructions, twelve general communications on duodenoscopes, and sixteen public correspondences to duodenoscope manufacturers.²¹ In November 2015, there was a mandatory recall of Custom Ultrasonics reprocessors and in February 2018, the FDA, CDC, and ASM released voluntary standardized protocols for duodenoscope surveillance culturing.²² Yet in an August 2019 safety communication, the FDA’s postmarket surveillance report noted a continued “elevated rates of contamination, including the presence of high concern organisms” such as E. Coli and Pseudomonas aeruginosa, highlighting persisting concerns of HLD and complex endoscope design.²³

These concerns have helped fuel a growing market for single-use equipment, with manufacturers of varying scopes and probes developing completely disposable designs. In November 2019, the FDA recommended transitioning to duodenoscopes with disposable components and one month later, gave market clearance for the first fully disposable duodenoscope.²⁴

14.3 Challenges

Amid this backdrop, several practical difficulties and regulatory challenges remain. First, although IFUs for reprocessing higher-risk medical devices must now be validated in accordance with FDA regulation, processes for validation are not standardized and are often unclear. Current FDA guidance refers manufacturers to technical information reports (TIRs) developed by the Association for the Advancement of Medical Instrumentation (AAMI), specifically AAMI TIR 2 (“labeling instructions for reusable medical device”) and TIR 30 (“compendium of processes, materials, test methods, and acceptance criteria for cleaning reusable medical devices”).²⁵ However, most AAMI TIRs were last published in 2010 and are in critical need of updating.

In 2015, AAMI published the more rigorous “Standard 91: Flexible and semi-rigid endoscope processing in healthcare facilities,” which outlines facility-level quality control practices, addresses human factors issues related to reprocessing, and comments on the design and flow of reprocessing departments.²⁶ Yet full implementation of this standard, including cleaning verification processes, schedules, and tracking and tracing of all related endoscope equipment, remains challenging.²⁷ Additionally, given rapid advances in disinfection and sterilization science and changes in regulation, this guidance also requires updating.²⁸ Work on this has been ongoing since early 2019, but a new draft document had not yet been released as of December 2020.²⁹

Thus, over the past decade, manufacturers have largely been left to author IFUs without clear guidance as to what is an acceptable or standard cleaning protocol,³⁰ resulting in widespread variation in how IFUs are structured and written, the methods used to demonstrate that effective disinfection has occurred, and storage and handling practices.³¹ For example, there are no agreed-upon standards to assess if proper cleaning (e.g., detection of protein versus blood versus microbial DNA) has occurred,³² when older equipment should be sent for maintenance, repair, or replacement, or whether borescopes – an optical device – should be used to detect microscopic rips or tears, particularly in otherwise inaccessible cavities.³³

Particularly critical to the disinfection process are manual precleaning steps. Although the FDA requires that reprocessing instructions “should be understandable,”³⁴ many IFUs are dense and difficult to follow (some IFUs exceed 100 pages). In mandated human factors postmarketing surveillance studies conducted by Fujifilm and Olympus, “most participants expressed some difficulty adhering to the reprocessing manual,” with one study concluding that the materials “are not sufficient to consistently ensure user adherence in these core reprocessing areas: precleaning, manual cleaning, manual high-level disinfection, rinsing, and storage and disposal.”³⁵

IFUs can also contradict guidance from professional societies, which can be in conflict with each other. For example, the Society of Gastroenterology Nurses, the Association for Professionals in Infection Control and Epidemiology, and the Association of Perioperative Registered Nurses all have different recommendations on storage and “hang time” – the maximum duration of storage time before the endoscope is processed for next use.³⁶ Recognizing such variability, the Joint Commission recently released its own clarification for hospitals, outlining that the IFU remains paramount to professional society guidance and consensus documents. Yet, gaps remain when IFUs are nonspecific or do not address key concerns, leaving hospitals in the position of having to reach out to manufacturers directly.³⁷

The interplay between IFUs can also be a challenge. While device manufacturers create their own IFUs, they typically do so separately from the manufacturers of automated reprocessors and high-level disinfectants.³⁸ This creates another layer of complexity for end users in health care facilities, particularly those that use manual methods of disinfection. In reconciling IFUs, a hospital’s ability to swiftly recognize concerns and call attention to appropriate leadership can be hampered.³⁹ Some device manufacturers of scopes create their own reprocessing equipment exclusively for their own devices,⁴⁰ which can mitigate the burden of IFU coordination but can also result in undue contractual leverage, limiting the ability of hospitals to diversify their inventories.

More broadly, concern exists that HLD may be insufficient for scopes.⁴¹ The decades-old Spaulding criteria outlines the use of HLD for semi-critical devices such as scopes and sterilization for critical devices such as surgical instruments.⁴² Performing HLD typically results in a 6-log₁₀ reduction of micro-organisms, whereas sterilization results in at least a 12-log₁₀ reduction.⁴³ However, flexible endoscopes acquire high levels of microbial contamination or bioburden during each use, and may contain ten⁴⁴ enteric micro-organisms after use, with buildup around closed channels.⁴⁵ Accordingly, some infection prevention experts refer to HLD as creating a “nonexistent margin of safety” that is unable to achieve disinfection consistently.⁴⁶

Challenges also exist with sterilization. Typical scope materials cannot handle the high temperatures required for the most commonly available and robust methods of sterilization (i.e., steam).⁴⁷ Additionally, existing sterilants have notable drawbacks. For example, ethylene oxide, a sterilant for rigid scopes, requires lengthy processing and aeration time.⁴⁸ In high quantities, it also poses health hazards, including carcinogen risk.⁴⁹ Because of this risk, ethylene oxide is unavailable in many US hospitals. In 2019, two large device facilities were closed by state environmental protection agencies in response to higher than acceptable levels of ethylene oxide in the air, creating abrupt shortages of sterilized devices.⁵⁰

Finally, while the market for single-use equipment may be viewed as a clear path forward, inadequate attention has been given to associated waste streams. Use of disposable duodenoscopes⁵¹ would contribute to the market growth of disposable designs for other scopes and probes, but the environmental footprint of single-use equipment has yet to be modeled nationally and internationally.⁵² In one study, single-use laryngoscope handles generated an estimated sixteen to eighteen times more lifecycle carbon dioxide equivalents (CO₂-eq) than traditional low-level disinfection of the reusable steel handle, and single-use plastic tongue blades generated an estimated five to six times more CO₂-eq than the reusable steel blade treated with high-level disinfection.⁵³ However, some studies suggest higher emissions of C0₂-eq may be offset by the cost of personal protective equipment (PPE), and that the energy consumption of reprocessing equipment also needs to be considered.⁵⁴ These comments underscore the need for further data points to build comprehensive models.

14.4 Solutions and Future Discussion

Addressing the above challenges requires engagement between manufacturers, clinicians, regulators, central processing departments, infection prevention and control leadership, and health care administrators. Inconsistencies between IFUs and the lack of transparency and standardization around validation in all domains – precleaning, disinfection, storage, maintenance, and repair – should be key priorities for the FDA and AAMI. Encouragingly, updates to key TIRs are in progress.⁵⁵ While working groups developing these documents include diverse stakeholders, including key manufacturers, regulators, and infection prevention experts, TIRs are not made available for public comment.⁵⁶ The AAMI standards are made available for public comment, but are solicited by notice in “appropriate AAMI publications or on the AAMI website.”⁵⁷ Making drafts of TIRs under review publicly available for comment, and making AAMI standards more widely available for review may present opportunities for improvement and promote swifter uptake by manufacturers and health care facilities.⁵⁸ Additionally, ensuring timely and concordant adoption of TIRs by the CMS could help ensure that health care facilities and manufacturers keep up to date.

Even with updated AAMI standards, however, implementation will remain a challenge. To facilitate optimal execution, health care administrators should seek to invest in competency and training programs for reprocessing staff and consider including them in contracted services with manufacturers and vendors.⁵⁹ Coordination of IFUs across vendors requires close coordination of health care facility infection prevention and control, biomedical/clinical engineering, supply chain, and contracting departments. While committees comprised of representatives from these groups may be found at many large acute care inpatient centers, they may not exist in ambulatory settings or surgical centers, where procedures are common.⁶⁰ The absence of such committees should be considered in a facility’s gap analysis and should be examined as part of regulatory and reaccreditation requirements.⁶¹

Since the outbreaks began in 2012, the FDA has expanded its ability to examine the regulatory controls for medical device regulation. The Medical Device Innovation Consortium (MDIC) is a 501(c)(3) public-private partnership with the objective of advancing approaches that “promote patient access to innovative medical technologies and the use of real world evidence in guiding the needs for all stakeholders.”³⁶ As part of the MDIC, the National Evaluation System for Health Technology coordinating center (NESTcc) aims to conduct “efficient and real-world evidence studies throughout the total product life cycle,” to “develop, verify, and operationalize methods of evidence generation” and data use in both the pre and postmarket space, and to bring together stakeholders, including the voice and preferences of the patient.⁶² The MDIC patient-centered benefit-risk framework creates decision analysis models that evaluate tradeoffs such as risk of infection or associated length of stay associated with a device that a patient may consider.⁶³ However, the MDIC and NESTcc should ensure the completeness of data to inform such metrics. For example, the risks of device-associated infection cannot be properly quantified without understanding real-world gaps in IFUs related to disinfection and sterilization.

The NESTcc could also elevate its voice in the postmarket space. In partnership with the FDA, the MDIC should continue to support and use evidence from medical device safety reporting by hospitals and device manufacturers through portals like the MedWatch and MedSun.⁶⁴ The MDIC and the NESTcc could also offer support in the design and development of postmarket surveillance studies. Though small, the human factors studies mandated by the FDA for Fujifilm and Olympus manufacturers in postmarket surveillance were revealing.⁶⁵ In particular, they plainly demonstrated the difficulty in adhering to complex IFUs.⁶⁶ If these studies were part of active surveillance in the postmarket period, they could offer critical and earlier insight for manufacturers, health care personnel, and the FDA.

In appreciating the pitfalls of complex IFUs, many infection prevention and control experts have called for the reclassification of scopes as critical devices that require sterilization.⁶⁷ There is regulatory precedent for such action. In 1992, the FDA mandated a shift from disinfection to sterilization for dental handpieces, even though there were no documented cases of disease transmission associated with dental hand pieces.⁶⁸ Professional societies should support this transition, and accreditation agencies should start developing standards to facilitate institutional accountability.⁶⁹

Incentives will likely be needed to encourage further development of sterilization options, including low temperature sterilization technologies (LTSTs). The FDA recently started this process, announcing in November 2019 four participants in an “innovation challenge” to identify disinfection and sterilization alternatives that can be implemented at a large scale and maintain high throughput.⁷⁰ Two of these participants will focus on the use of vaporized hydrogen peroxide technology that is currently being used on a large scale to disinfect respirators during the COVID-19 pandemic.⁷¹ While participation does not constitute “regulatory acceptance,” manufacturers should expect that the FDA remains committed to expeditiously clearing LTSTs as they are developed if safety and effectiveness standards are met.³⁸ In turn, manufacturers should commit to the FDA’s endorsement of creating scopes with innovative designs, including manufacturing scopes with materials that are compatible with LTSTs.⁷²

More recently, the FDA announced a second innovation challenge to decrease ethylene oxide emissions.⁷³ In parallel and in light of closures of sterilization facilities due to high ethylene oxide emissions, the US Environmental Protection Agency (EPA) issued a notice of proposed rulemaking to solicit information from industry and the public on strategies for further reducing ethylene oxide emissions from commercial sterilization and fumigation operations. This includes reviewing and updating regulations for sources that emit ethylene oxide and to better understand and address ethylene oxide emissions at facilities.⁷⁴ Such interagency coordination will be needed to more identify the optimal role of ethylene oxide in medical device sterilization, the effects of endoscope sterilization, and the impact on the supply chain and transportation operations.⁷⁵

Finally, hospitals and clinics will need to consider the far-reaching impacts of incorporating disposable equipment, especially as pathogens of high consequence such as CRE, take hold.⁷⁶ Hospitals and clinics will need to partner and engage early with major biomedical waste companies and recycling vendors both in the United States and globally to create a regulated, functional waste stream.⁷⁷ These groups will need to understand large throughput hospital- and clinic-based workflows, calculate new labor costs, and consider implications for their supply chains. Corporate social responsibility platforms should expand to account for the impact of such activities and integrate this work into ongoing sustainability efforts, including tracking fleet and incinerator emissions.⁷⁸ To more fully weigh complete environmental impact, cradle-to-grave lifecycle assessment and lifecycle costing methods should be used.⁷⁹ For example, the EPA’s Tool for the Reduction and Assessment of Chemical and other Environmental Impacts can be used to model environmental impacts of greenhouse gases and other pollutant emissions.⁸⁰ As is required to examine ethylene oxide impacts, a sustained FDA and EPA partnership can help, facilitating detailed data gathering to inform national and international economic and environmental analyses. This effort should discuss how to weigh energy consumption of reprocessing departments and facilities, human labor costs, and PPE usage.

While the NESTcc represent the FDA’s efforts to modernize the 510(k) process, the FDA will need to embed both the perspectives of infection control and environmental sustainability to transform its approach.⁸¹ In particular, understanding the tradeoffs associated with sustainable production and consumptions practices can shift the FDA approach from reactive to proactive.⁸²

14.5 Conclusions

High-level disinfection and sterilization of medical equipment has slowly evolved over the past three decades. The outbreaks of drug-resistant bacteria traced to contaminated duodenoscopes offer a case study in understanding the gaps in medical device regulation. Although the FDA has made strides in closing these gaps, important and critical problems persist; the concerns exposed in the duodenoscope outbreaks expand beyond scopes and spans larger concerns around device design, cleaning, disinfection, management, uptake and care. Together, these experiences call for a greater voice for infection prevention and control in the medical device ecosystem. The NESTcc and the FDA’s ongoing private-public partnership consolidate national efforts for medical device safety: minimizing disease transmission and considering environmental harms should be part of that mission.

15 Regulating Devices that Create Life

Katherine L. Kraschel

In vitro fertilization (IVF) led to approximately 74,590 births in 2018.¹ IVF success rates have increased roughly three-fold since the first live birth in 1978. Yet today the chance of giving birth using IVF is barely better than a coin toss, even for the youngest, healthiest patients.² Scientists and industry are pursuing methods to improve IVF success rates. However, many clinics seem unconcerned with the effectiveness of new methods. Marketing of these methods, so-called IVF “add-ons,” to vulnerable patients seeking to start a family has led to calls for greater regulatory scrutiny.³

Add-ons include methods such as selecting the “best” sperm in a semen sample, or artificially “activating” eggs to prepare embryos for transfer to a uterus.⁴ They run from a couple hundred dollars to more than ten thousand dollars. Data on their utilization is limited, but one estimate suggests that 74 percent of fertility patients used at least one add-on.⁵

Most notoriously, the practice of preimplantation genetic screening or preimplantation genetic testing for aneuploidies (PGS or PGT-A) is used to identify (and usually discard) embryos that show an abnormal number of chromosomes.⁶ Mounting evidence illustrates that the $6,000–$12,000 test is not a good predictor of whether an embryo will develop into a healthy baby; one estimate suggests that approximately 40 percent of healthy embryos may have been unnecessarily discarded based on PGS results.⁷ While the test may accurately identify cells exhibiting aneuploidies, many questions remain regarding whether and how those results predict the health of a child resulting from the embryos tested. This means that many patients’ hopes at biological parenthood may have been squandered due to their reliance on an expensive, erroneous test. To date, there has been no regulatory activity in the United States to stop clinics from making claims about, providing, or charging for PGS testing.

This chapter describes the genesis of the direct-to-consumer nature of the US fertility services market that makes consumers uniquely susceptible to offers of unproven technologies in hopes of increasing their likelihood of pregnancy success. It explores the many modes of regulation in the United States and their shortcomings as well as the limits of the Food and Drug Administration’s (FDA’s) lack of jurisdiction over embryos and the tests used to select and modify them. In light of these limitations, the chapter concludes by posing a two-pronged path forward to address the most pressing concerns about add-ons: 1) amendments to existing federal law to require fertility clinics and labs to report a list of all services they offer patients and tie their utilization to rates of success and 2) Federal Trade Commission enforcement action against clinics who make deceptive and/or unsupported claims about add-ons and other technologies.

15.1 Fertility Services Direct-To-Consumer Market

Modern assisted reproduction in the United States is a health care anomaly. First, fertility treatments are not consistently covered by private or public insurance, although coverage has increased in recent years. Consumer patients are cost-sensitive and will select providers based upon particular services offered.⁸ Patients do not benefit from signals of necessity or quality from insurance companies’ coverage decisions. People seeking fertility treatments rely heavily on the Internet and fertility center websites to inform their choices.⁹ The resulting direct-to-consumer fertility markets makes the veracity of claims made by clinics critical to ensure consumers make informed choices. Yet, most fertility clinic websites do not comply with the guidelines outlined by the American Medical Association or the industry’s own self-regulatory body.¹⁰

The medical component of the fertility industry does not act alone. Physician-run clinics interact with other for-profit players including multi-million-dollar sperm banks and agencies that broker provision of sperm, eggs, embryos, and surrogacy services. These transactions take place outside the context of any physician-patient relationship and contribute to the transactional atmosphere of fertility services. The market creates competition for patients and an incentive for providers to distinguish themselves by offering services that could improve patient consumers’ likelihood of success.

Second, fertility innovation has been left to rely on private funds due to a ban on government funding.¹¹ Public funding triggers ethical obligations in developing new technologies, including informed consent requirements. Without public funding, fertility innovation occurs free from restrictions placed on most biomedical research. Coupled with its transactional nature, it is no surprise that fertility clinics offer and sell unproven add-ons in order to attract patients. At best, this means that empowered consumers are knowingly subsidizing the development of unproven technologies in hopes they might be lucky. At worst, vulnerable consumers are being exploited to spend significant funds for futile or harmful services they believe increase their odds of success.

The dangers of add-ons seem to be precisely the type of threat to public health that state medical boards and the FDA are designed to address – to eliminate unsafe or unproven medical interventions from the market or to “assur[e] the safety, effectiveness, quality, and security”¹² of medical interventions. Could the FDA not regulate these new technologies as medical devices applied to the earliest forms of human life? These questions are addressed in the following sections.

15.2 The US Fragmented Patchwork of ART Regulation

Federal oversight over the Assisted Reproductive Technology (ART) industry is well discussed within the academic literature and the popular press. Many have called the United States the “wild west”;¹³ however, as one of the editors of this volume points out, a number of mechanisms moderate behavior in US ART markets, resulting in a fragmented patchwork of regulation.¹⁴ In fact, the American Society for Reproductive Medicine (ASRM) claims that “Assisted Reproductive Technologies are among the most regulated medical procedures in the United States.”¹⁵

If the United States is the “wild west” of ART, it is not because there are no sheriffs in town. There are multiple sheriffs, mayors, and informally deputized leaders each trying to address their own overlapping concerns. Some of these regulations and private law controls are discussed in this section.

15.2.1 Federal Regulation of Fertility Industry & Reproductive Medicine

Within the federal government, four agencies regulate ART: the FDA, the Centers for Medicare and Medicaid Services (CMS), the Department of Health and Human Services, through the Centers for Disease Control (CDC), and the Federal Trade Commission (FTC). The FDA regulates the approval of fertility drugs and requires gamete screening to prevent transmission of communicable diseases. The future of the role of the FDA and FTC will be further discussed in Sections 15.3 and 15.4 respectively.

CMS regulates laboratories through the Clinical Laboratory Improvement Amendment of 1988 (CLIA).¹⁶ However, CLIA applies to tests connected with human diagnoses, such as testing blood or semen for fertility-related issues; it does not extend to testing on embryos.

The Department of Health and Human Services (through the CDC) is explicitly charged with oversight of ART. The Fertility Clinic Success Rate and Certification Act of 1992 (FCSRCA) requires fertility clinics to report their success rates and ART data.¹⁷ The FCSRCA was passed in light of public concern with fertility clinics overstating the likelihood of success to prospective patients. FCSRCA also attempts to step in where CLIA leaves off by issuing model guidance for embryology laboratory certification. However, there is no enforcement mechanism to compel clinics to comply, and the model recommendations create no legal obligation for labs to adopt them.¹⁸

Finally, the FTC has broad authority to prohibit “unfair or deceptive acts or practices affecting commerce.”¹⁹ The billion-dollar fertility industry clearly affects commerce and falls under FTC control. In contrast to FCSRCA, the FTC Act includes enforcement power. The FTC previously exercised its authority in fertility services when it filed charges for deceptive practices against five clinics for misrepresenting their success rates in October 1992.²⁰ Additionally in July 1995, the FTC authored an editorial in the leading journal of reproductive medicine in which it described its “concerns with advertising pregnancy success rates.”²¹

15.2.2 State Regulation of Fertility Industry and Reproductive Medicine

State practice of medicine laws, including licensing of medical professionals, facilities, laboratories, and pharmacies, apply to ART. State medical boards could act to suspend or revoke licenses if clinics or providers make false claims about their success or perform procedures that harm their patients. However, reliance on practice of medicine and licensing may be ineffective; state medical boards are reticent to turn against one of their own even in the face of repeated patterns of bad behavior.²²

Much of the innovation in the space of reproductive medicine is happening in the laboratory, not the clinic, and procedures are performed by embryologists (scientists usually with masters or doctorate level training who create and manipulate embryos), not physicians. States do not license embryologists; like laboratories, embryologist certification is available but optional.²³ IVF clinics rarely require a license of the physical space separate from the professional license held by the providers who practice within it. Without enacting licensing and regulatory authority over labs, clinics, and embryologists, states currently have little ability to intervene. However, there has been some recent legislative action to require licensing of labs that handle embryos.²⁴

State law also governs tort claims for medical malpractice or other harms caused by mistakes in the fertility industry. However, the tort system leaves plaintiffs, in cases against fertility clinics and laboratories, empty handed due to its unwillingness or inability to recognize and monetize the types of harms caused by mistakes in reproduction.²⁵ Finally, similar to the FTC at the federal level, state attorneys general have enforcement power over fraud and unfair trade practices within their state, but none have taken actions similar to the FTC’s.

15.2.3 Professional Self-Regulation

Professional self-regulation plays an important role in the US fertility market. ASRM is the most influential governing body; its Practice and Ethics Committees issue guidelines and reports on clinical practice and guiding principles, respectively.²⁶ Compliance with ASRM recommendations is not legally required, nor does ASRM have enforcement power. In addition, ASRM has been criticized for its inherent conflict of interest, since its members are those that have a financial stake in the industry’s success.²⁷

The ASRM Ethics Committee issued an opinion on innovative new techniques in 2015. It stated:

Consider the consequences of bringing interventions to practice before they have been adequately studied and sufficiently validated … a new practice becomes commonplace before there is evidence to support its effectiveness … enthusiasm to address a vexing clinical problem led to the premature adoption of a new treatment. Such enthusiasm can lead to dissemination of an innovative treatment through media reports, lectures, and conferences before adequate data are available and before peer review has been accomplished. Early adoption can be confusing for patients, who may not understand that a treatment they have read about lacks a basis in evidence and may, in fact, do them more harm than good.²⁸

The tension between the benevolent desire to help patients and the ethical necessity for patience to first produce robust and reliable data, coupled with the lack of federal funding leaves clinics with three options: 1) subsidize research – bear the cost of innovation and do not charge patients for unproven procedures/new technologies; 2) focus on static clinical care and refuse to offer any innovative treatments to patients; or 3) adopt a problematic hybrid approach by charging patients for unproven innovative treatments. This third scenario – of conflating research (generating generalizable knowledge through a process in which patients understand they may not benefit from participation) and clinical care – is the problematic approach the ASRM guidance seeks to discourage; it is also the behavior that has given rise to the growing number of stories of patients who needlessly lost embryos due to the widespread use of PGS and calls for concern over add-ons.

15.3 FDA Regulation of Reproductive Technology Devices (or Embryos?)

The FDA’s regulation of ART is limited to its authority under the Food Drug and Cosmetic Act (FDCA)²⁹ and the Public Health Services Act (PHSA).³⁰ The jurisdictions of the FDA depends upon how a technology is used and how embryos are characterized. Coherently regulating many facets of ART under the FDCA and/or PHSA would require the FDA to decide: if an embryo is legally equivalent to a human warranting protection and the objects of regulation the devices used to manipulate it, or if the gestating human is to be protected and the embryo the object of regulation as a “biological product” or “drug” used to create a pregnancy. The legal, ethical, and political implications of such a determination may be one of many reasons the FDA has not actively exercised enforcement powers over add-ons and why categorization of embryos and ART innovations remains unclear. Since 2015, Congress has signaled annually that it does not want to empower the FDA to make determinations with such vast societal implications.³¹

The FDA has classified one device used to manipulate embryos for implantation. This move implicates its jurisdiction over such devices; it also illustrates that it may be an ineffective regulator even if doing so is a proper exercise of its jurisdiction.

15.3.1 Are Add-Ons Devices?

Section 201(h) of the FDCA defines a medical device as “an instrument, apparatus … or other similar or related article …

1. 2) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or

2. 3) intended to affect the structure or any function of the body of man or other animals.”³²

To illustrate, consider lasers used for “assisted hatching.” The laser is intended to weaken the outer layer of cells (the structure and function) of the embryo prior to implantation to increase the chances of implantation in the uterine wall. If lasers are medical devices, it would follow that the FDA concluded that the embryo is “body of man or other animals.” As discussed below, if the “device” is intended to treat infertility, then the embryo would be the device itself, not the laser that manipulated it.

In 2004, the FDA received a premarket notification and a request for device classification for “Assisted Reproduction Laser Systems.”³³ It granted the request and issued guidance to ensure its use is safe and effective.³⁴ Conversely, the Human Fertilisation and Embryology Authority (HFEA) in the United Kingdom deemed assisted hatching “experimental” and found no evidence of safety and effectiveness, and other researchers agree.³⁵ Guidance from the FDA identified many of the risks that have come into focus since 2004, including “damages to the embryo” and “ineffective treatment.”³⁶ There have long been concerns about the FDA’s ability to effectively compel postmarket surveillance that would be needed in light of the mounting evidence.³⁷ Taken collectively, FDA regulation of assisted hatching lasers may be a case study to illustrate that even if the FDA appropriately exercised its jurisdiction over medical devices (which is a big if), it is ill-suited to regulate effectively.

Now consider PGS. PGS is used to identify a condition – having an abnormal number of chromosomes. However, PGS tests an embryo, not “man or other animals.” The FDA has asserted its enforcement power over genetic tests for human medical conditions;³⁸ however, FDA guidance regarding in vitro diagnostic testing expressly excludes “pre-implantation embryos,” suggesting that a diagnostic device used on an embryo does not trigger the same regulatory attention as the homologous test on a human.³⁹

15.3.2 Are Add-On-Manipulated Embryos Biological Products or Drugs?

The FDA regulates biological products through the PHSA,⁴⁰ and its applicability to the provision of sperm and eggs is often cited as the FDA’s “only” role in regulating fertility services.⁴¹ The purpose of the PHSA is to prevent the introduction, transmission, or spread of communicable disease (not ensure safety and efficacy of any clinical interventions).⁴² Under the law, a biological product is:

a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component … or analogous product … applicable to the prevention, treatment, or cure of a disease or condition of human beings.⁴³

It is not clear that an embryo is an “analogous product.” The listed products are components of a biological organism while an embryo is an organism in itself.⁴⁴ However, the FDA lists embryos as biological products in guidance regarding which types of biological specimens are considered biological products and which are devices.⁴⁵ Regulating embryos as biological products does not address the concerns raised by IVF add-ons. The purpose of regulating biological products is to prevent communicable disease transmission, so they do not undergo premarket review.

However, different regulations apply if the product is more than “minimally manipulated.”⁴⁶ The FDA has concluded that technologies such as human cloning and mitochondrial transfer constitute more than minimal manipulation and make them biologic drugs requiring premarket approval before use.⁴⁷ Some, but not all, add-ons would move embryos out of the “biological product” definition. Embryos screened for aneuploidy with PGS might remain biological products if the screening is considered minimal manipulated while others (such as embryos punctured to encourage hatching) would be considered drugs, adding further confusion to the regulatory patchwork.

Assuming an embryo is an analogous biological product or a drug depending upon how manipulated it is, the definition of a drug poses an additional question – is an embryo an article intended to affect the structure of function of the body? Its effect on the gestating person’s body is the most compelling jurisdictional hook for FDA regulation of manipulated embryos as drugs. Courts have upheld the FDA’s jurisdiction over regenerative medicine for similar biological specimens being (re)implanted into humans for treatment.⁴⁸ However, if add-on-manipulated embryos are drugs, every unique, manipulated embryo created could require preapproval. Such a regulatory scheme would likely bring using add-ons and the innovation creating them to a screeching halt.

Perhaps more importantly, such a conclusion, that a human embryo is the object of federal regulation, signals other normative values, which administrative agencies are not empowered to impose.

15.3.3 Should Congress Expand FDA Jurisdiction to Include Embryos and the Devices Used to Manipulate Them?

Currently, FDA regulation of manipulated embryos intended for transfer into a uterus to create a pregnancy is unclear at best. At worst, it is incoherent and intentionally obfuscated in order to side-step thorny ethical and political issues or to further particular ethical views. It is impossible for the FDA to regulate add-on-manipulated embryos without signaling their moral status as either worthy of protection like people or as articles to be regulated like devices, and administrative agencies are not the appropriate bodies to make such determinations.

Congress could address the issue by enacting legislation to expand the FDA’s power to include regulation of human embryos; however, this is a politically untenable solution. Suppose conservative legislators proposed treating embryos like people, making nearly all add-ons drugs or devices. Such a move would raise questions about the permissibility of all IVF because the majority of cycles result in discarding one or more embryos, and even conservative constituencies want access to IVF. Second, more liberal lawmakers are unlikely to favor federal oversight of ART. Many might fear that any federal regulation of reproduction, particularly one that implicates the legal status of embryos, could jeopardize reproductive justice by inviting restrictive regulations such as restricting access to abortion.

In sum, trying to twist the FDA’s mandate into a mechanism to regulate add-ons or attempting to pass new legislation to expand its mandate are not feasible options. Even if either was successful, expanding the FDA’s jurisdiction would only create an incomplete method to address the mounting concerns raised by information provided to patients about the value of add-ons in improving the likelihood of achieving a healthy, successful pregnancy.

15.4 Moving Consumer Protection (and Innovation) Forward

In many ways, the HFEA in the United Kingdom provides the ideal example for the United States to adopt.⁴⁹ It would consolidate oversight into a central, federal agency and provide consumer-centric information to inform decision making. However, federal action to create a new agency charged with overseeing embryos and the fertility industry is not a pragmatic resolution for many of the same reasons a change to the FDA’s charge is unlikely.⁵⁰

Similarly, state action to regulate in this space may be difficult. Even if state action is plausible, forum-shopping lessons learned from areas related to ART governed by state law (such as surrogacy) teach us that national-level control is desirable. In light of these limitations, I propose a two-pronged solution: 1) amendments to FCSRCA to require fertility clinics and labs to report a list of all services it offers patients, and 2) enforcement by the FTC. In sum, the approach taken almost thirty years ago to rein in fertility clinics overstating their success rates should be similarly utilized to protect consumers from unproven add-ons that claim to improve success.

First, Congress should amend the FCSRCA to require clinics and labs to report a list of services it offers to its patients, particularly those it lists on its website and in promotional materials. In addition, it should expand reporting to link utilization of those technologies with the success rate reporting already required such as confirmed pregnancy and live births. While such a system would not offer the gold standard of randomized controlled trials for new technologies, it would generate retrospective studies to provide indicators of effectiveness. The additional reporting could provide an imperfect postmarket surveillance mechanism. As noted above, the FDA has underperformed in postmarket activity even in areas in which its regulatory power is clear. If a clinic is consistently selling its patients laser-assisted hatching but there is no evidence that it improved rates of success, clinics could be held accountable for representations made to patients about the value of assisted hatching.

Revisions to the FCSRCA could also include a mechanism by which the CDC, much like the United Kingdom’s HFEA, could grade innovations based upon the data collected, and disseminate the evaluation publicly. This proxy for necessity/value addresses one of the unique problems posed by the direct-to-consumer nature of fertility services and could fill the void left by the lack of insurance providers’ coverage decisions. Fertility market consumers’ propensity to turn to the internet for guidance regarding fertility treatments suggests this could be an effective way to protect them from paying for unproven services. In addition, the data could be used by the FTC to trigger disclamatory language requirements or limit the types of representations that players in the ART market can make to consumers.

Amendments to the FCSRCA are politically feasible. Expanded reporting requirements do not involve governmental judgments regarding when life morally and legally begins. Moreover, the current political moment resembles the conditions that gave rise to the FCSRCA in 1992 – there is growing concern with new technologies thanks to popular press coverage.

To address pushback from the industry due to the cost of additional reporting requirements, Congress could make the legislation more attractive by limiting the FDA’s role as it did regarding in the original FCSRCA, and explicitly place embryos and the devices used to manipulate them outside of the FDA’s wheelhouse. Reporting requirements may seem like an inexpensive price to pay for protection from a more cumbersome regulatory scheme like premarket FDA approval.

Second, the FTC should exercise its enforcement power against clinics and labs that make unsubstantiated claims about the efficacy of add-ons. Given previous FTC activity on the heels of FCSRCA’s passage, amendments to the FCSRCA and the public attention that could follow may be a good catalyst to motivate FTC enforcement. Expending federal funds is justified in light of the size of the fertility market. This work undertaken in conjunction with an updated FCSRCA would allow the FTC to gauge the veracity of claims clinics make about the ways the services they provide improve the likelihood of success. This is strikingly similar to the claims the FTC brought in the 1990s when clinics inflated or used deceptive methods of calculation to inflate about their IVF success rates.

As for those claims that may not go so far as to be deceptive but raise concerns given the consumer reliance on the clinic’s expertise, FTC regulation of over-the-counter drugs and cosmetics advertising may be a helpful analogy to consider; it requires advertising to be truthful and substantiated by evidence.

In addition, FTC enforcement could apply across other parts of the fertility industry, including sperm, egg, and surrogacy brokers, and could be a centralized “sheriff.” For example, sperm and egg banks make problematic representations regarding the traits and anonymity of sperm and egg providers. The FTC could provide an effective mechanism to address these concerns.

15.5 Conclusion

Consumers are willing to pay an unusually high emotional, physical, and financial price to have a chance at becoming a genetic parent. The evolution of the consumer-centric US fertility market and inefficient patchwork of overlapping regulatory bodies and legal systems has left them without sufficient safeguards against purchasing unproven interventions to increase their likelihood of success. The FDA is the familiar actor to protect patient consumers from unproven treatments; however, it is not clear if it is legally empowered to exercise jurisdiction, and it is undesirable and infeasible for Congress to expand its purview.

Greater FTC enforcement and legislation to expand reporting requirements represent politically feasible, appropriately consumer-protective, and innovation-preserving options to address the challenges posed by innovation in this unique industry. Hopefully, these changes will avoid a repeat of the devastating reality faced by many patients whose embryos were perhaps prematurely discarded and protect intended parents from harmful or opportunistic behavior in an already physically, emotionally, and financially draining process.