R. ALTA CHARO
AN IDEAL pharmaceutical development and regulatory system delivers new drugs or new indications for old drugs in a timely manner, with an assurance of both safety and effectiveness. It incentivizes innovation, particularly for those medical products that address conditions for which we need options that are more effective, less risky, and more affordable than existing offerings. And it is capable of self-correction when errors are made. Indeed, from a systems analysis viewpoint, it can sometimes be more important to build in the capacity to detect and correct inevitable errors than to build a system so chock full of protections that error minimization comes with overwhelming rigidity and stifling regulation.
It is this last observation that is perhaps at the center of the newer approaches now being discussed for drug development in the United States. A number of them focus on getting drugs out faster and correcting mistakes later. The Food and Drug Administration (FDA) already has a number of expedited programs. “Fast track” designation offers closer collaboration with the agency to ensure collection of appropriate data needed to support drug approval, including such things as the design of the proposed clinical trials and use of biomarkers. “Accelerated approval” allows marketing based on a surrogate marker that is believed to be indicative of a disease state and treatment effect but not demonstrative of a direct health gain to the patient. “Priority review” will have the agency acting on applications within six (rather than the standard ten) months. And the “breakthrough therapy” designation is a kind of “fast track” on steroids, with intensive agency guidance as early as Phase I in an effort to expeditiously move the drug through premarket testing. To make these as effective as possible, a final “Guidance for Industry Expedited Programs for Serious Conditions—Drugs and Biologics” was issued in May 2014 (FDA 2014).
For this to work, though, there are some parts of the system that are in need of reform but are not getting the attention they deserve. Specifically, marketing restrictions would help to identify mistakes early and correct them before too many people are harmed. And attention must be paid to the business model for drug development and to de-risking the process so that there will be less resistance to regulatory actions that limit or withdraw marketed drugs as needed.
I. SPEED AND SAFETY
Historically, drug regulation began with an emphasis entirely on error correction; there was either no premarket screening or, as came in 1938, there was premarket screening only for risks (FFDCA 1938). Postmarket realization that a drug was overly dangerous could be addressed by removing the drug from the market. But this error correction system was hampered by inadequate postmarket surveillance and many litigation barriers for regulators.
The turning point undoubtedly lies in the experience with thalidomide, which produced thousands of grossly disabled newborns in other countries. It was never approved in the United States, however, because one medical reviewer, Frances O. Kelsey, found the anecdotal evidence and short-term studies inadequate to confirm the safety of the drug, which was being prescribed to pregnant women to control extreme morning sickness (Bren 2001). As a result, FDA was lauded as a “gold standard” for drug regulatory agencies, and its cautious approach was applauded as the best balance between patient safety and patient needs.
The thalidomide experience led U.S. regulators to shift emphasis to the premarket period, with extensive requirements to demonstrate both safety and efficacy (Kefauver-Harris 1962). This resulted in vast improvements in the quality of the pharmaceuticals reaching market, but it made innovation slow and expensive. In response, incentives were created in the form of limitations on commercial speech that allowed the government to give innovators who submitted to regulation the opportunity to cash in on extended periods of exclusive marketing rights, separate from and in addition to patent protections. The restrictions and the recent attacks thereon are covered in depth in other chapters of this book.
Controlled clinical trials are at the core of evidence-based medicine. Without them, it can be impossible to distinguish between coincidence and connection, correlation and causation. There are notable examples of public health failures due to the decision to forego or truncate clinical trials. In one such case, a study of perioperative beta blockers was stopped early because while initial results in a small trial indicated reduced risk of heart attacks, a much larger study later showed a dramatic increase in the risk of strokes and death (Poldermans 1999). Another example would be the Women’s Health Initiative (WHI) study of estrogen and progesterone in treating postmenopausal women. It was expected to confirm the widely held view that these hormone replacement therapies could reduce cardiovascular disease in older women, but in fact, large, long-term trials found quite the opposite (Majumdar 2004).
By the 1970s, pressure began to build for faster access to therapies for serious diseases, for example, from cancer patients who had few options in standard medicine and so were drawn to try ultimately ineffective alternatives such as laetrile, a substance found in apricot pits (Wilson 2013). This trend toward emphasizing speed rather than cautious trials for safety and effectiveness continued in the 1980s with the AIDS crisis and the emergence of an organized effort in the gay community to obtain access to investigational drugs in the face of an incurable disease without any approved therapies (Harden 2012). That this coincided with a political atmosphere emphasizing economic competitiveness and deregulation only made the call for loosening some of the “gold standard” regulatory restrictions that much more compelling.
Even into the 1990s, concerns about drug development seemed to focus more on lack of access to new (presumably better) drugs rather than fear that existing drugs on the market were proving to be less effective or more dangerous than anticipated. These concerns even extended to debates about expanding clinical trials to subject populations previously thought to be particularly vulnerable to injury or coercion (e.g., children, fertile and pregnant women, ethnic and racial minorities) on the theory that participation in research was no longer to be viewed as a form of exploitation but rather as an opportunity for early access to superior care (Charo 1993; Mastroianni 1998; Noah 2003; Coleman 2007).
And yet, as one moves into the current century, the pendulum begins to swing wildly between public outrage over newly discovered problems with common drugs such as Vioxx and Avandia and frustration with slow approvals to the point of constitutional challenges to the very basis of FDA regulation and its careful attention to phases of drug development (Abigail Alliance 2008). And outside of limited alternatives such as priority review vouchers (Robertson 2012), running alongside this debate is the repeated use of the same technique—extending market exclusivity to enhance potential profits and incentivize R&D—to promote development of products that meet special needs, for example, for orphan diseases or pediatric populations (FDA 2006).
Using exclusive market rights to enhance premarket control has led to extensive product development, but it has also created its own problems. Among them are lengthy development times; uncertainty about approvals; resistance to limiting or withdrawing drugs once marketed; and higher prices for consumers, due both to development costs and the lack of early competition from generics (Moors 2014).
The result, it seems, is that no one is happy with FDA. Industry spokespersons complain it is too picky, too temperamental, and generally too slow. The result, they say, is that drugs do not get developed or—if they do—are unnecessarily expensive (Kaitin 2010). Patients with diseases as yet imperfectly managed with existing pharmaceuticals, ranging from Alzheimer’s to hepatitis C, also clamor for new options (Stix 2012; Herschler 2014). At the same time, the predictable, periodic failures of pharmaceuticals on the market—whether less effective than predicted or more dangerous than expected—lead to criticism from the media, watchdog groups, and Congress.
Against this backdrop is a growing appreciation for the inherent limitations of traditional premarket clinical trials, which for reasons of practicality, finance, and diminishing returns will often be neither long enough, nor large enough, nor demographically comprehensive enough to achieve the level of postmarket safety and effectiveness that the public expects (Kramer 2010; Singh 2012). This has only energized the calls for far less time in premarket testing, followed by enhanced postmarket surveillance to confirm effectiveness and detect problems (von Eschenbach 2012).
Shorter, smaller trials could facilitate faster patient access to innovative therapies and lower the financial hurdles that can deter development of new drugs. But, as many have noted, clinical trials are already inadequate with regard to duration and scale. Although powered to confirm efficacy in carefully selected populations—often characterized by an absence of comorbidities or complicating drug–drug interactions and narrow age ranges emphasizing young adulthood and early middle age—clinical trials are not necessarily good predictors of a new drug’s effectiveness in the broader range of ages and medical conditions in clinical practice. As to safety, almost no trial can be powered to pick up the rare adverse event or a subtle increase in frequency of otherwise common events (Duijnhoven 2013). Because these shortcomings cannot be overcome without increasing the duration, scale, and cost of trials, some have said that we get too little at too high a price and have called for much of Phase III testing to be abandoned completely so we can at least answer the demand for getting drugs to market more efficiently (von Eschenbach 2012).
Using this approach, accelerated drug approval through use of breakthrough designations (Sherman 2013; Calabrese 2013), pharmacogenomics for targeted testing, biomarkers, surrogate endpoints, and abbreviated trials can be integrated with better postmarket surveillance and the use of Risk Evaluation and Mitigation Strategies (REMS), topics covered in great depth in other parts of this book. Indeed, FDA has already taken precisely these steps for a number of products. For example, the agency announced that it would look for changes in biomarkers rather than clinical endpoints for Alzheimer’s disease, a slow-developing, degenerative condition (Kozauer 2013). But as noted above, some proposals argue that once proof of concept and the absence of major risks for a new drug have been confirmed, the remaining effort to prove efficacy and safety should move entirely to the postmarket phase (von Eschenbach 2012).
Without stronger mechanisms to take action based on postmarket data, however, it is unlikely that surveillance and FDA’s REMS can satisfactorily offset any increased risks due to the abbreviated premarket testing. Experience with postmarket measures does not provide confidence in their effectiveness (Gibson 2015; Parasidis 2015). For years, postmarket (Phase IV) study commitments went unfulfilled, and even the new REMS have yet to demonstrate consistent use and effectiveness (HHS 2013). And while some studies suggest that the risks associated with the most innovative new drugs are not significantly greater than for all drugs generally (Mol 2013), others note that accelerated processes and deadlines lead to just-in-time decision making associated with higher subsequent rates of adverse events (Carpenter 2011).
While REMS are a beginning, offsetting increased risks due to abbreviated clinical trials probably also requires stronger marketing limitations. Particularly for drugs whose new mechanisms of action or new molecular entities pose the greatest uncertainties, it may be important to control their speed of diffusion, for example, by limiting their use to narrow populations, restricting off-label prescribing, and curbing the direct-to-consumer advertising known to drive patient demand and physician acquiescence (IOM 2006). The challenge here is to increase control over diffusion of a drug without running up against constitutional protection of freedom to engage in commercial speech and without straying beyond regulation of products and beginning to invade physician judgment in the practice of medicine. A system of “conditional approvals” akin to that now being used in Europe might help (EC 2006).
In addition, the postmarket measures that limit drug sales or even cause drugs to more frequently be removed from the market may make return on pharmaceutical investments less predictable and less profitable. The existing approach, which relies exclusively on extended periods of postmarket exclusivity to provide financial incentives for innovation, may need to be supplemented by more premarket incentives, such as the research grants, tax credits, awards, and prizes that have been proposed for antimicrobial development, another area in which postmarket returns are not sufficient to promote investment by companies (So 2011).
II. MARKETING LIMITATIONS
As the White House Office of Science and Technology stated, effective postmarket measures would be helped enormously by limiting marketing and prescribing of drugs in the first years after approval, at least for drugs that are the first in their class; the properties for such drugs are most likely the least tested and predictable (PCAST 2012). Such limitations would slow the diffusion of new drugs into clinical practice and provide time for postmarket studies to reveal more robust information about effectiveness and safety.
But limitations on the marketing and prescribing of recently approved drugs pose legal and strategic challenges. The explosive growth in direct-to-consumer advertising has fueled patient demand for new drugs, and FDA has little regulatory authority over physician prescribing. For companies, restrictions on commercial speech have been slowly eliminated through a series of federal court decisions, the most recent of which comes perilously close to calling the current restrictions on off-label marketing unconstitutional (United States v. Caronia 2012). The implications of this case are discussed in several chapters of this book.
FDA is not primarily a research agency. It offers the incentive of marketing exclusivity to companies that invest in proving the safety and efficacy of new drugs or new indications for existing drugs. It does this by deeming the promotion of an unapproved drug or indication a form of prohibited misbranding, on the theory that the drug cannot be considered safe and effective for its intended use, even if evidence not submitted to FDA would suggest otherwise. This has given FDA what might loosely be considered a monopoly on truth. Because FDA will not approve an identical drug or indication for a period of years, this gives companies that invest in proving safety and efficacy to FDA a period of market exclusivity that provides high-profit margins. These margins decrease sharply as soon as generics can be sold. As a result, any innovation that threatens to shorten the years of exclusivity or limit the scope of sales within those years makes uncertain a company’s calculation of the return on the substantial investment required for clinical trials. Strategically, therefore, one can predict strenuous resistance to any effort to withdraw drugs, or to add new limits to the kinds of patients or indications for which they can be used, such as was the case for midodrine, an antihypotensive agent that FDA unsuccessfully attempted to withdraw for failure to meet postmarket study commitments (Mitka 2012).
The European Medicines Agency is in the early stages of implementing a system of conditional drug approval that might remedy two problems: getting drugs out more quickly but with greater regulatory control in the postmarket stage (Duijnhoven 2013). In 1993, the European Union introduced a system to offer approval and early market access for drugs that met the definition of exceptional circumstances (ECs). This included situations in which comprehensive safety and efficacy data was unattainable, for example, for an orphan disease. The sponsors would gain early approval but then commit to a variety of “specific obligations” for postmarket surveillance and management after obtaining marketing approval. Over time, the EC pathway came to be used not only for rare diseases but also for common diseases that still had unmet needs. In the latter situation, however, it was at least in theory possible to obtain comprehensive data.
As a result, the European Commission created two pathways. The first, like the original EC pathway, works for drugs for which it is not possible to provide the European Medicines Agency with additional data. The second, called “conditional approvals” (CAs), allows drugs to enter the market with less than the usual level of safety and efficacy data, if they have a good risk–benefit ratio demonstrated in the initial trials and it is expected that more data will be obtainable once marketed (Tsang 2005; Arnardottir 2011).
In some ways, this resembles the proposals made in the United States to dispense with Phase III trials for drugs that have good Phase II results. The “breakthrough therapies” designation, mentioned above, has been greeted enthusiastically by developers, and as of late 2013 had already been applied to more than thirty new products (Mullard 2013). FDA’s draft guidance requires that applicants show “preliminary clinical evidence” that a drug offers “substantial improvement” over available therapies on at least one “clinically significant” endpoint in a “serious or life-threatening disease” (FDA 2013).
It also has parallels to the Limited Population Antibacterial Drug (LPAD) Pathway legislation supported by the Infectious Diseases Society of America. LPAD legislation would provide a faster approval mechanism for antibacterial drugs for patients with serious or life-threatening infections and few or no treatment options. LPAD drugs would be approved based upon smaller clinical trials, as these infections typically occur in too few patients to populate a large traditional trial. LPAD drugs would be clearly labeled and monitored to guide their appropriate use in the limited indicated population for whom the benefits have been shown to outweigh the risks.
As with the effort to address the need for new antimicrobials to address the serious and rapidly growing threat of resistance, the CA pathway in Europe is only for drugs intended to fulfill unmet needs, such as for serious diseases—orphan as well as common—for which there are no good treatments available or for which the new drug offers a substantial improvement over existing options. Thus, the CA pathway moves some drugs into the market when early indications suggest a positive benefit-to-risk ratio.
Importantly, however, CA does this without losing control over the medication, by incorporating sunset provisions. In other words, “conditionally” approved drugs lose their approval status and are removed automatically from the market if sponsors fail to meet their postmarket commitments for further trials. While it is too early to document a pattern of approval sunsets, initial research at least has shown that the frequency of adverse events and special communications to providers has not been significantly higher for drugs that went to market with this abbreviated clinical trial period (Boon 2010).
Conditional approval creates, in theory, a real assurance that the necessary information for drug evaluation will be obtained in a timely manner. It is always easier for regulatory agencies to do nothing than to do something. In the United States, withdrawal of a marketed drug takes positive action. Under conditional approval in the European Union, the mere failure to either submit postmarket data to support the initial release or to apply for a limited-time renewal of the conditional approval means that the drug can no longer be marketed.
III. ADVERTISING
Another means of balancing the need for safety with the desire for shorter development times lies in restricting direct-to-consumer advertising (DTCA) for the initial period following approval, at least for truly new drugs built on unfamiliar mechanisms and formulations. Given that there is not yet broad experience with these drugs, it can be argued that the safest course is to slow diffusion and allow physicians an unpressured atmosphere in which to play their appointed role as “learned intermediaries” who consider all aspects of a patient’s condition before choosing the best medication. Under these circumstances, physicians might well choose an older, better-understood medication, at least until there was some reason to think a newer drug offered distinct benefits.
Drug companies tend to invest in DTCA for drugs that treat chronic conditions, have few side effects, have little or no generic competition, or that have recently experienced a change (new indication approved, expecting to switch to over-the-counter status, patent about to expire so competition is expected soon, etc.). One study indicates that by 2001, 25 percent of Americans had asked their doctor about a drug they had heard about or seen advertised. Later studies show this percentage to be between 10 and 35 percent (Atherly and Rubin 2009; Rosenthal 2003; Rosenthal 2002).
Restricting DTCA will not completely stop overly rapid diffusion of new drugs into population-wide use, as a formulary or payer’s preference for a particular drug is more likely determining which drug in a drug class the doctor prescribes rather than the patient’s request for a specific drug (Atherly and Rubin 2009). In the managed care setting, providers’ prescription choices are often limited, and DTCA may do more to increase prescriptions for a type of drug than a specific brand. A study published by the National Bureau of Economic Research in January 2003 found that the effects of DTCA for prescription drugs are more significant and consistent for the drug class than for an individual drug (Rosenthal 2003). And only 5.5 percent of the time do doctors admit to prescribing a DTC-advertised drug when they think another drug is more effective (Atherly and Rubin 2009).
But even if the data are mixed depending upon the study, it does appear that the explosion of radio and television DTCA has affected consumer behavior, with patients now requesting brand-name drugs (i.e., newer drugs). To the extent that physicians comply, rather than prescribing older medications, there is the risk that newer drugs are being used broadly without the benefit of a slower introduction within a smaller population from whom new insights might be gained (Ventola 2011). This was, indeed, one of the ideas addressed in the 2006 IOM report (IOM 2006) and considered for FDAAA.
However, in the end, concerns that legislating such limits might run afoul of constitutional free speech protections led to abandoning the idea in favor of REMS and industry voluntary actions regarding DTCA. Given subsequent developments in the Sorrell and Caronia cases, the constitutional concerns seem justified.
IV. COMMERCIAL SPEECH JURISPRUDENCE AND ITS EFFECT ON POSTMARKET SAFETY MEASURES
The fundamental issue presented in Caronia concerns FDA’s prohibition on off-label marketing, a prohibition based on a presumption that any marketing for an indication, dose, or population for which the drug was not tested is presumably a form of misbranding (21 USC § 321). But in Caronia, the court noted that off-label prescribing is perfectly lawful. In a substantial blow to FDA’s enforcement theory, it held that FDA cannot prosecute off-label promotion of a drug if the off-label use is lawful and the promotion used information that was truthful and not misleading. The court narrowly avoided overturning the entire structure of the drug regulatory system by focusing on some very specific aspects of the case, but the dissent nonetheless cautioned that the decision may effectively prohibit all uses of off-label promotional speech to support a misbranding conviction under the Federal Food, Drug, and Cosmetic Act (FDCA). Indeed, all three judges on the Caronia panel acknowledged that the decision may have left the enforcement of the misbranding provisions of the FDCA on shaky ground.
Limiting FDA’s ability to restrict off-label promotion has a number of effects that can undermine efforts to promote drug safety efforts, both before and after drug approval (Kesselheim and Mello 2015; Robertson 2015), and it might even have the effect of turning pharmacogenomics into a short-cut that allows narrower approval trials to nonetheless result in wide population use beyond the label. It could mean that drugs will be used in large populations and at doses or for indications for which there has been no independent governmental arbiter of safety and effectiveness.
In many cases off-label use is perfectly justifiable. But the combination of pharmacogenomics and accelerated approval pathways coupled with a retreat from the ability to limit off-label marketing means that companies would no longer have much R&D incentive at all—not even an exclusive market for supplemental indications—and investment in exploring these supplemental uses will likely decrease, with no obvious alternative player inclined to spend the time and effort to confirm the value of these drugs for these new uses (Stafford 2012).
V. CONDITIONAL APPROVAL
In the United States, a conditional approval system akin to that used in Europe might avoid some of the tension between marketing restrictions and commercial speech. The Caronia decision is grounded in an analysis of off-label marketing of an approved drug. Conditional approval—which would be given when less than the usual amount of data is available—is fundamentally different. In essence, a conditionally approved drug or indication would still be considered investigational, and the protections for commercial speech provided in Caronia might not apply, thus paving the way for restrictions on DTCA labeled indications as well as on all promotion of off-label indications.
But a conditional approval system may still fail to address the need for a predictable and reasonable return on investment for companies. It is uncertain that a conditionally approved drug could be sold for profit; many insurers may assume that such a drug is experimental and therefore not pay for it. Even if these issues were addressed—and they should be, through coverage with evidence development or other means—some promising new drugs may lack financial backing. Other factors would create substantial uncertainty, including conditional approval itself, the prospect of strong postmarket measures, and the threat of liability. Thus, it makes sense to consider other types of financial incentives for industry.
The European Union’s “Innovative Medicines Initiative” is one example. Its “Joint Technology Initiatives” bring together companies, universities, public laboratories, patient groups, and regulators, with cofunding from industry and the EU budget, to the tune of several billions of euros. They establish their own research agenda and selectively fund projects based on open competition, citing successes in developing new or improved tools and models for diseases as disparate as schizophrenia and diabetes (European Commission 2013).
This approach has been advocated for antibiotics; market exclusivity is a poor incentive if new antibiotics are only used as a last resort against multidrug resistant organisms. The Infectious Diseases Society of America and others have claimed that the antimicrobial market fails to adequately compensate manufacturers for the investment necessary to develop new antimicrobials because they will likely be stockpiled or used judiciously and not be blockbusters that generate large returns (IDSA 2014). In such a situation, a lengthy period of market exclusivity—known as a “pull” mechanism—is not sufficient to offset development costs. Additional pull mechanisms might help, such as offering prizes or awards for reaching specified development markers. In addition, “push” mechanisms could be used, for example, by reducing the obstacles to research or offering grants and tax breaks (Pogge 2005; Outterson 2014).
Similarly, in order to offset the return-on-investment uncertainties created by moving to a conditional approval system that slows the rate at which a new drug penetrates the market and increases the risk of limitations on its uses or even the loss of the approval to market, a new set of push-and-pull mechanisms could de-risk development and maintain the incentives to innovate. In general, a system of grants, rewards, prizes, and tax credits could provide a supplemental source of revenue for research and development.
VI. FINAL COMMENTS
As long as speed and safety are seen as opposing forces in drug development and approval, progress will be halting. But enhanced safety measures can generate the confidence needed to permit earlier release of drugs. Those enhanced safety measures should include measures to slow the uptake of those new drugs and new indications for which uncertainties are the greatest. To do that, one must address the constitutional protections for commercial speech, include an action-forcing mechanism that ensures continued surveillance and data collection, and provide an economic incentive to developers other than the prospect of uninterrupted and unconstrained market exclusivity for decades to come. With all these moving pieces, there might well be a way to achieve a system of pharmaceutical development and regulation that is both faster and safer.
The author gratefully acknowledges the assistance of Jennifer Carter, University of Wisconsin Law, 2014.
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