I was concerned that thousand of requests would pu
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(Total Views: 788)
Posted On: 12/25/2020 12:36:14 AM
I was concerned that thousand of requests would put a financial strain on the company. And naturally as you pointed out, the press will be priceless. However - https://www.nejm.org/doi/full/10.1056/NEJMhle1409465
One factor is the administrative burden for the drug maker. The FDA has estimated that 120 hours of human effort are required for a company to prepare a protocol for an intermediate-size patient population, with the task divided among a director of clinical research (60 hours), a regulatory affairs director (24 hours), and a clinical research associate (36 hours).10 These burdens may weigh particularly heavily on smaller manufacturers.20 Even if manufacturers are willing and able to devote the necessary time, production capacity may not be sufficient to meet demand for both expanded use and ongoing clinical trials.10
Because of these factors and the substantial manufacturing costs of some prescription drugs (particularly biologic agents), expanded-access programs may also be seen as financially problematic. The FDA allows companies to charge patients or their insurers the direct costs of the expanded-access program, including manufacturing and shipping costs. For intermediate-size and widespread-use programs, companies can also charge the costs of monitoring and reporting.21 Charging direct costs, however, could lead to adverse publicity because these costs will be far less than the price of a drug when it is ultimately approved by the FDA, a price that sometimes exceeds $1,000 per pill or $200,000 per patient per year.22,23 Some manufacturers, therefore, guard cost information carefully, even if it means forgoing the modest revenue that might be obtained through this pathway.24 If a manufacturer does seek to impose charges, it may be under pressure from patients to waive costs because they may not be covered by insurance.25 The FDA accordingly reports that most manufacturers do not charge for their products.26
Manufacturers must additionally consider the effect of expanded-access programs on ongoing development and regulatory approval efforts. Generally, limited data are collected during expanded-access protocols (particularly as compared with clinical trials), and the FDA has recognized that such data may not be collected in a systematized fashion and therefore may not be useful.10 However, all adverse events that occur in any patient receiving a drug during its preapproval period must be reported to the FDA,11 and patients receiving treatment under expanded-access protocols are often sicker than trial participants.10 Companies may worry that this obligation could reduce the chance of approval, lead to additional label warnings, or create negative publicity.24,27
Expanded-access programs can also deter enrollment in clinical trials, thereby increasing the amount of time and effort necessary to accrue requisite statistical power, especially in studies involving patients with rare conditions. At the extreme, such programs may encourage gaming of clinical trials in ways that ensure access to a potentially effective medication.28 Although many phase 3 trials of investigational agents are blinded, it can be possible for patients to determine whether they have been randomly assigned to receive placebo, particularly if expected side effects do not occur,29 and then withdraw from the trial.30 In one case, a woman withdrew from a cancer trial after being assigned to the control group and sought expanded access to the active treatment.31 The company denied her request.
Finally, expanded-access programs could bring liability exposure.32 Litigation in this arena, however, has been limited to obtaining access rather than seeking redress of treatment-related harm. The lack of adverse-event lawsuits may reflect the willingness of such patients to assume risks33 as well as the adequacy of existing regulatory and manufacturer safeguards.
PHYSICIAN KNOWLEDGE AND COOPERATION
Effective expanded-access programs require the active participation of treating physicians. Some may be unaware of particular investigational drugs or unfamiliar with the process of obtaining them.34 Physician-directed expanded-access requests are infrequent.10 One explanation may be the difficult situation facing a physician who is considering an expanded-access request: regulations require that the physician determine that the risks of the disease outweigh the risks of the drug, but there is usually little published literature relating to the drugs at issue. The clinical information that manufacturers submit to the FDA is proprietary and, thus, available only to the extent that manufacturers permit.10
Physicians may also be reluctant to shoulder the administrative burden, since it takes approximately 8 hours for a physician to prepare an individual patient request.10 Federal regulations require obtaining appropriate informed consent and approval from institutional review boards, maintaining accurate case histories and drug-disposition records, and reporting adverse events.11 The FDA considers the use of expedited procedures with respect to institutional review boards inappropriate for expanded access,10 and full reviews can be costly. Many academic centers charge $2,000 to $3,500 for a protocol review, although fee-waiver requests in these settings may be available.35,36 For clinicians outside academic medical centers, locating and obtaining review by an institutional review board can be even more challenging.27
Legal Challenges
The difficulties in accessing investigational drugs have led to three primary kinds of legal challenges. First, some patients have argued that the FDA regulatory apparatus itself violates their constitutional rights if it limits their ability to access drugs at any stage of testing. However, courts have generally ruled that no constitutional right of access exists in these circumstances. In the landmark 1979 case United States v. Rutherford, the Supreme Court found no right of terminally ill cancer patients to access amygdalin (Laetrile), a now discredited treatment, for which an application for clinical testing was pending before the FDA.37 More recently, in Abigail Alliance v. von Eschenbach, a federal court of appeals explicitly held that “there is no fundamental right . . . to experimental drugs for the terminally ill.”38 In 2008, the Supreme Court declined to review the case.
Second, some patients have asserted contractual rights to expanded access. These claims have sometimes prevailed when a patient received a drug during the course of a clinical trial and then requested continued access after the trial ended but before the drug was approved.39 However, this contractual right may be unavailable if post-trial access was not promised,40,41 and some courts have ruled that investigators' promises do not bind manufacturers.42
Table 3.
Features of Existing “Right-to-Try” Laws in Three States.
Third, some state legislatures have sought to override the restrictions imposed by the FDA regulatory system. In 2013 and 2014, for example, Colorado, Missouri, and Louisiana passed so-called “right-to-try” laws that permit manufactures to provide experimental medicines to terminally ill patients without FDA authorization, purportedly eliminating certain obstacles to expanded access.43 These three laws require that the treating physician recommend the experimental therapy, and the Colorado and Louisiana statutes further mandate that the treating physician attest to the inadequacy of FDA-approved treatment alternatives (Table 3).44-46 The laws shelter physicians from professional discipline and negligence actions for making good-faith recommendations; Colorado and Missouri also extend limited civil immunity to manufacturers related to harms that experimental drugs may cause.44-46
Right-to-try laws, which have also been adopted in Michigan and Arizona, will have limited effect. They do not compel manufacturers and insurers to supply and pay for experimental therapies. They also cannot prevent the federal government from rescinding Drug Enforcement Administration registration of physicians who prescribe experimental drugs independent of the FDA,47,48 though such action is very unlikely if no controlled substances are involved. Only Colorado requires eligible patients to have been unable to participate in a clinical trial “within one hundred miles of the patient's home address” or not to have been “accepted to the clinical trial within one week of completion of the clinical trial application process.”44 Without addressing the structural limitations to making experimental treatments available outside pivotal clinical trials, such strategies will not improve access and could instead exacerbate existing tension over the fair distribution of available supplies.
In addition, right-to-try laws are unlikely to withstand a constitutionality challenge that is based on conflict with the FDA's enabling legislation and existing expanded-access regulations. Under the Supreme Court's long-standing preemption doctrine, state laws that conflict with federal statutes or regulations are “without effect.”49 Limiting the reach of these state laws to patients with terminal illnesses cannot avoid the conflict. As Justice Thurgood Marshall noted in Rutherford, “Nothing in the history of the [Food, Drug, and Cosmetic Act] suggests that Congress intended protections only for persons suffering from curable diseases.”37 The frustration that these laws reflect may nonetheless mount pressure on Congress and the FDA to reassess the expanded-access system.
Ethical Issues
The primary ethical argument for expanded access is that patients should have a right to mitigate extreme suffering and to enhance self-preservation. This logic holds that as rational actors, patients are presumed to be capable of making well-informed treatment decisions in consultation with their physicians. According to this argument, not only can patients with serious or life-threatening conditions accurately identify promising experimental drugs, but they should also be entitled to utilize their own risk–benefit thresholds in deciding whether to consume such products. Advocates of expanded access argue that deference to the assumed capacity of patients to thereby make appropriate treatment decisions should be greatest when the stakes are highest (i.e., when death is likely or certain).
By contrast, those who seek to limit access to unapproved medications argue that the odds of an experimental therapy working in many expanded-access settings are extremely small — the probability of clinically meaningful benefit from early-stage experimental trials may be less than 10%50,51 — and informational asymmetries can lead to patient vulnerability. By definition, data on experimental drugs are very limited, and patients generally do not have access to all the information that does exist, because some of it is proprietary. Moreover, most patients do not have the training or experience to evaluate the combined pharmacologic, clinical, and statistical information on experimental therapies that is available to them. Risk comprehension among the general public is low,52 is not strongly correlated with self-perceived ability to understand risk,53 and may be more impaired in sicker patients.54 Skeptics of expanded access caution that the risk of treatment-selection decisions that could exacerbate suffering or hasten death justifies greater — not reduced — paternalism for patients with serious or life-threatening conditions.
The clash between autonomy and informed consent in decision making by vulnerable patients mirrors the discussion of the appropriateness of physician-assisted suicide in the context of a serious illness. In both scenarios, patients are seeking to avoid a “hard death.”55 The two issues differ, however, in that expanded-access programs have broader public health implications by prolonging the process of drug development and delaying drug availability to the general population by potentially diverting resources and patients from preapproval clinical trials.
Expanded-access programs can also raise concerns about equity. Most but not all manufacturers shoulder the cost of expanded access,26 and when they fail to do so, insurers may refuse to step in. Medicare, for example, covers only treatments that are “reasonable and necessary,”56 and many private insurers have similar policies.57 Some observers have accordingly argued that expanded access generally favors the rich or well-connected over the poor.5,58
Policy Recommendations
As frequently recognized by the courts, the best pathway to widespread access to experimental drugs is found by showing their efficacy and safety sufficiently to earn prompt FDA approval. Even an augmented system of expanded access can never match the access that occurs once the FDA grants approval. Thus, one of the most straightforward means of addressing the issue of expanded access is to shorten the time between the determination that a new substance may be clinically useful and the point at which it becomes widely available.
Review times for U.S. drugs have decreased considerably and are now similar to or better than those in most industrialized countries.59 The FDA has created several kinds of fast-track approval mechanisms, and a priority-review designation ensures review within 6 months or less.60 It may be possible to shorten this interval further for truly important new treatments by innovative means of drug evaluation, such as adaptive trial design.61 Plans for bridging the gap between early promise and market availability could also be addressed when a drug first enters clinical trials so that more manufacturers are prepared for expanded-access demands on products that prove to be successful. For devices, the Medicare program has introduced the concept of “coverage with evidence development,” in which it will pay for a new medical device despite poorly documented effectiveness and safety, as long as such use comes with collection of additional data about how the product performs. A modification of this approach for medications could harvest useful clinical information about drugs that are provided through expanded-access programs.
Although right-to-try laws are misguided, a more pragmatic — and lawful — approach is for states to work collaboratively with the FDA to make expanded access more practical when it is appropriate. For example, since the FDA has acknowledged that gaining approval from an institutional review board can pose a barrier,62 states could partner with the FDA to fund multicenter institutional review boards that focus specifically on expanded-access requests. Such multicenter panels would conduct full reviews, but their subject-matter expertise and limited dockets would translate into faster review times. Through subsidies, states and the FDA could eliminate the need for patients or clinicians to incur fees for proposal review, which would facilitate expanded-access requests outside of academic medical centers.
Practical obstacles to enhancing expanded-access programs, including administrative burdens and industry costs, would also be best tackled by the states in partnership with, instead of in opposition to, the FDA. For example, a manufacturer's reluctance to provide product because of financial concerns could be addressed by permitting companies to charge amounts closer to the likely postapproval cost of drugs. Falit and Gross propose that manufacturers place any profits in interest-bearing escrow accounts until experimental-drug approval.34 This requirement would enable manufacturers to recoup development and distribution expenses without revealing proprietary financial information. Such a policy would provide incentives to expanded-access programs while precluding financial gain from products that ultimately prove to be unsafe or ineffective, with escrowed profits then reallocated to other health-related government use. But this approach could also increase patients' financial burdens and disparities in access.
The ethical and policy debate on the appropriate balance between access to and protection from potentially useful but also possibly harmful or ineffective medicines began with the passage of the Pure Food and Drug Act in 1906. The escalation of the battle over expanded access has rekindled this debate a century later. In the ensuing years, Congress has unambiguously delegated authority over striking this balance to the FDA, but growing antiregulatory sentiment has begun to threaten this assumption, with the most persuasive arguments being made concerning patients with terminal illnesses who appear to have much to gain and little to lose by accessing unapproved drugs. However, this debate will need to take into account the simple concept that led to the regulatory authority of the FDA in the first place: that it may well not be in the interest of patients, however sick they may be, to have easier access to products that are ineffective and may actually worsen their clinical status.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Author Affiliations
From the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School — both in Boston.
One factor is the administrative burden for the drug maker. The FDA has estimated that 120 hours of human effort are required for a company to prepare a protocol for an intermediate-size patient population, with the task divided among a director of clinical research (60 hours), a regulatory affairs director (24 hours), and a clinical research associate (36 hours).10 These burdens may weigh particularly heavily on smaller manufacturers.20 Even if manufacturers are willing and able to devote the necessary time, production capacity may not be sufficient to meet demand for both expanded use and ongoing clinical trials.10
Because of these factors and the substantial manufacturing costs of some prescription drugs (particularly biologic agents), expanded-access programs may also be seen as financially problematic. The FDA allows companies to charge patients or their insurers the direct costs of the expanded-access program, including manufacturing and shipping costs. For intermediate-size and widespread-use programs, companies can also charge the costs of monitoring and reporting.21 Charging direct costs, however, could lead to adverse publicity because these costs will be far less than the price of a drug when it is ultimately approved by the FDA, a price that sometimes exceeds $1,000 per pill or $200,000 per patient per year.22,23 Some manufacturers, therefore, guard cost information carefully, even if it means forgoing the modest revenue that might be obtained through this pathway.24 If a manufacturer does seek to impose charges, it may be under pressure from patients to waive costs because they may not be covered by insurance.25 The FDA accordingly reports that most manufacturers do not charge for their products.26
Manufacturers must additionally consider the effect of expanded-access programs on ongoing development and regulatory approval efforts. Generally, limited data are collected during expanded-access protocols (particularly as compared with clinical trials), and the FDA has recognized that such data may not be collected in a systematized fashion and therefore may not be useful.10 However, all adverse events that occur in any patient receiving a drug during its preapproval period must be reported to the FDA,11 and patients receiving treatment under expanded-access protocols are often sicker than trial participants.10 Companies may worry that this obligation could reduce the chance of approval, lead to additional label warnings, or create negative publicity.24,27
Expanded-access programs can also deter enrollment in clinical trials, thereby increasing the amount of time and effort necessary to accrue requisite statistical power, especially in studies involving patients with rare conditions. At the extreme, such programs may encourage gaming of clinical trials in ways that ensure access to a potentially effective medication.28 Although many phase 3 trials of investigational agents are blinded, it can be possible for patients to determine whether they have been randomly assigned to receive placebo, particularly if expected side effects do not occur,29 and then withdraw from the trial.30 In one case, a woman withdrew from a cancer trial after being assigned to the control group and sought expanded access to the active treatment.31 The company denied her request.
Finally, expanded-access programs could bring liability exposure.32 Litigation in this arena, however, has been limited to obtaining access rather than seeking redress of treatment-related harm. The lack of adverse-event lawsuits may reflect the willingness of such patients to assume risks33 as well as the adequacy of existing regulatory and manufacturer safeguards.
PHYSICIAN KNOWLEDGE AND COOPERATION
Effective expanded-access programs require the active participation of treating physicians. Some may be unaware of particular investigational drugs or unfamiliar with the process of obtaining them.34 Physician-directed expanded-access requests are infrequent.10 One explanation may be the difficult situation facing a physician who is considering an expanded-access request: regulations require that the physician determine that the risks of the disease outweigh the risks of the drug, but there is usually little published literature relating to the drugs at issue. The clinical information that manufacturers submit to the FDA is proprietary and, thus, available only to the extent that manufacturers permit.10
Physicians may also be reluctant to shoulder the administrative burden, since it takes approximately 8 hours for a physician to prepare an individual patient request.10 Federal regulations require obtaining appropriate informed consent and approval from institutional review boards, maintaining accurate case histories and drug-disposition records, and reporting adverse events.11 The FDA considers the use of expedited procedures with respect to institutional review boards inappropriate for expanded access,10 and full reviews can be costly. Many academic centers charge $2,000 to $3,500 for a protocol review, although fee-waiver requests in these settings may be available.35,36 For clinicians outside academic medical centers, locating and obtaining review by an institutional review board can be even more challenging.27
Legal Challenges
The difficulties in accessing investigational drugs have led to three primary kinds of legal challenges. First, some patients have argued that the FDA regulatory apparatus itself violates their constitutional rights if it limits their ability to access drugs at any stage of testing. However, courts have generally ruled that no constitutional right of access exists in these circumstances. In the landmark 1979 case United States v. Rutherford, the Supreme Court found no right of terminally ill cancer patients to access amygdalin (Laetrile), a now discredited treatment, for which an application for clinical testing was pending before the FDA.37 More recently, in Abigail Alliance v. von Eschenbach, a federal court of appeals explicitly held that “there is no fundamental right . . . to experimental drugs for the terminally ill.”38 In 2008, the Supreme Court declined to review the case.
Second, some patients have asserted contractual rights to expanded access. These claims have sometimes prevailed when a patient received a drug during the course of a clinical trial and then requested continued access after the trial ended but before the drug was approved.39 However, this contractual right may be unavailable if post-trial access was not promised,40,41 and some courts have ruled that investigators' promises do not bind manufacturers.42
Table 3.
Features of Existing “Right-to-Try” Laws in Three States.
Third, some state legislatures have sought to override the restrictions imposed by the FDA regulatory system. In 2013 and 2014, for example, Colorado, Missouri, and Louisiana passed so-called “right-to-try” laws that permit manufactures to provide experimental medicines to terminally ill patients without FDA authorization, purportedly eliminating certain obstacles to expanded access.43 These three laws require that the treating physician recommend the experimental therapy, and the Colorado and Louisiana statutes further mandate that the treating physician attest to the inadequacy of FDA-approved treatment alternatives (Table 3).44-46 The laws shelter physicians from professional discipline and negligence actions for making good-faith recommendations; Colorado and Missouri also extend limited civil immunity to manufacturers related to harms that experimental drugs may cause.44-46
Right-to-try laws, which have also been adopted in Michigan and Arizona, will have limited effect. They do not compel manufacturers and insurers to supply and pay for experimental therapies. They also cannot prevent the federal government from rescinding Drug Enforcement Administration registration of physicians who prescribe experimental drugs independent of the FDA,47,48 though such action is very unlikely if no controlled substances are involved. Only Colorado requires eligible patients to have been unable to participate in a clinical trial “within one hundred miles of the patient's home address” or not to have been “accepted to the clinical trial within one week of completion of the clinical trial application process.”44 Without addressing the structural limitations to making experimental treatments available outside pivotal clinical trials, such strategies will not improve access and could instead exacerbate existing tension over the fair distribution of available supplies.
In addition, right-to-try laws are unlikely to withstand a constitutionality challenge that is based on conflict with the FDA's enabling legislation and existing expanded-access regulations. Under the Supreme Court's long-standing preemption doctrine, state laws that conflict with federal statutes or regulations are “without effect.”49 Limiting the reach of these state laws to patients with terminal illnesses cannot avoid the conflict. As Justice Thurgood Marshall noted in Rutherford, “Nothing in the history of the [Food, Drug, and Cosmetic Act] suggests that Congress intended protections only for persons suffering from curable diseases.”37 The frustration that these laws reflect may nonetheless mount pressure on Congress and the FDA to reassess the expanded-access system.
Ethical Issues
The primary ethical argument for expanded access is that patients should have a right to mitigate extreme suffering and to enhance self-preservation. This logic holds that as rational actors, patients are presumed to be capable of making well-informed treatment decisions in consultation with their physicians. According to this argument, not only can patients with serious or life-threatening conditions accurately identify promising experimental drugs, but they should also be entitled to utilize their own risk–benefit thresholds in deciding whether to consume such products. Advocates of expanded access argue that deference to the assumed capacity of patients to thereby make appropriate treatment decisions should be greatest when the stakes are highest (i.e., when death is likely or certain).
By contrast, those who seek to limit access to unapproved medications argue that the odds of an experimental therapy working in many expanded-access settings are extremely small — the probability of clinically meaningful benefit from early-stage experimental trials may be less than 10%50,51 — and informational asymmetries can lead to patient vulnerability. By definition, data on experimental drugs are very limited, and patients generally do not have access to all the information that does exist, because some of it is proprietary. Moreover, most patients do not have the training or experience to evaluate the combined pharmacologic, clinical, and statistical information on experimental therapies that is available to them. Risk comprehension among the general public is low,52 is not strongly correlated with self-perceived ability to understand risk,53 and may be more impaired in sicker patients.54 Skeptics of expanded access caution that the risk of treatment-selection decisions that could exacerbate suffering or hasten death justifies greater — not reduced — paternalism for patients with serious or life-threatening conditions.
The clash between autonomy and informed consent in decision making by vulnerable patients mirrors the discussion of the appropriateness of physician-assisted suicide in the context of a serious illness. In both scenarios, patients are seeking to avoid a “hard death.”55 The two issues differ, however, in that expanded-access programs have broader public health implications by prolonging the process of drug development and delaying drug availability to the general population by potentially diverting resources and patients from preapproval clinical trials.
Expanded-access programs can also raise concerns about equity. Most but not all manufacturers shoulder the cost of expanded access,26 and when they fail to do so, insurers may refuse to step in. Medicare, for example, covers only treatments that are “reasonable and necessary,”56 and many private insurers have similar policies.57 Some observers have accordingly argued that expanded access generally favors the rich or well-connected over the poor.5,58
Policy Recommendations
As frequently recognized by the courts, the best pathway to widespread access to experimental drugs is found by showing their efficacy and safety sufficiently to earn prompt FDA approval. Even an augmented system of expanded access can never match the access that occurs once the FDA grants approval. Thus, one of the most straightforward means of addressing the issue of expanded access is to shorten the time between the determination that a new substance may be clinically useful and the point at which it becomes widely available.
Review times for U.S. drugs have decreased considerably and are now similar to or better than those in most industrialized countries.59 The FDA has created several kinds of fast-track approval mechanisms, and a priority-review designation ensures review within 6 months or less.60 It may be possible to shorten this interval further for truly important new treatments by innovative means of drug evaluation, such as adaptive trial design.61 Plans for bridging the gap between early promise and market availability could also be addressed when a drug first enters clinical trials so that more manufacturers are prepared for expanded-access demands on products that prove to be successful. For devices, the Medicare program has introduced the concept of “coverage with evidence development,” in which it will pay for a new medical device despite poorly documented effectiveness and safety, as long as such use comes with collection of additional data about how the product performs. A modification of this approach for medications could harvest useful clinical information about drugs that are provided through expanded-access programs.
Although right-to-try laws are misguided, a more pragmatic — and lawful — approach is for states to work collaboratively with the FDA to make expanded access more practical when it is appropriate. For example, since the FDA has acknowledged that gaining approval from an institutional review board can pose a barrier,62 states could partner with the FDA to fund multicenter institutional review boards that focus specifically on expanded-access requests. Such multicenter panels would conduct full reviews, but their subject-matter expertise and limited dockets would translate into faster review times. Through subsidies, states and the FDA could eliminate the need for patients or clinicians to incur fees for proposal review, which would facilitate expanded-access requests outside of academic medical centers.
Practical obstacles to enhancing expanded-access programs, including administrative burdens and industry costs, would also be best tackled by the states in partnership with, instead of in opposition to, the FDA. For example, a manufacturer's reluctance to provide product because of financial concerns could be addressed by permitting companies to charge amounts closer to the likely postapproval cost of drugs. Falit and Gross propose that manufacturers place any profits in interest-bearing escrow accounts until experimental-drug approval.34 This requirement would enable manufacturers to recoup development and distribution expenses without revealing proprietary financial information. Such a policy would provide incentives to expanded-access programs while precluding financial gain from products that ultimately prove to be unsafe or ineffective, with escrowed profits then reallocated to other health-related government use. But this approach could also increase patients' financial burdens and disparities in access.
The ethical and policy debate on the appropriate balance between access to and protection from potentially useful but also possibly harmful or ineffective medicines began with the passage of the Pure Food and Drug Act in 1906. The escalation of the battle over expanded access has rekindled this debate a century later. In the ensuing years, Congress has unambiguously delegated authority over striking this balance to the FDA, but growing antiregulatory sentiment has begun to threaten this assumption, with the most persuasive arguments being made concerning patients with terminal illnesses who appear to have much to gain and little to lose by accessing unapproved drugs. However, this debate will need to take into account the simple concept that led to the regulatory authority of the FDA in the first place: that it may well not be in the interest of patients, however sick they may be, to have easier access to products that are ineffective and may actually worsen their clinical status.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Author Affiliations
From the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School — both in Boston.
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