Access to Unapproved Medical Interventions
unmet medical need for treatment may have access to investigational drugs. Although challenges remain with specific diseases, we believe that FDA implementation of the expanded access program appropriately balances the competing obligations to the compassionate provision of investigational drugs to patients with serious life-threatening and/or debilitating diseases who lack suitable alternative treatments, and the need to protect the public health through data establishing the safety and effectiveness of those treatments. All access to investigational drugs in the United States, including to single patients under expanded access, is subject to the IND regulations. As such, the specific concerns raised by Walker and colleagues, such as ethical oversight, informed consent, and data collection, are addressed by those regulations. &
REFERENCES U.S. Food and Drug Administration. 1987. Part 312—Investigational new drug application, Sec 312.3 Definitions and interpretations, (b) Clinical investigation. Code of Federal Regulations Title 21. Available at: http://www.accessdata.fda.gov/scripts/cdrh/ cfdocs/cfcfr/CFRSearch.cfm?fr=312.3 U.S. Food and Drug Administration. 2009. Final rule 21, CFR Parts 312 and 316. Expanded access to investigational drugs for treatment use. Federal Register 74(155): 40900. Available at: http:// www.gpo.gov/fdsys/pkg/FR-2009-08-13/pdf/E9-19005.pdf Walker, M. J., W. A. Rogers, and V. Entwistle. 2014. Ethical justifications for access to unapproved medical interventions: An argument for (limited) patient obligations. American Journal of Bioethics 14(11): 3–15.
SAPs: A Different Perspective Jess Rabourn, ALS Emergency Treatment Fund Richard S. Bedlack, Duke University We enjoyed the well-written target article entitled “Ethical Justifications for Access to Unapproved Medical Interventions: An Argument for (Limited) Patient Obligations” (Walker, Rogers, and Entwistle 2014). We come at special access programs (SAPs) from a different perspective than the ethicists who wrote this. One of us (JR) is an economist who lost two family members to amyotrophic lateral sclerosis (ALS) and has initiated multiple nonprofit initiatives aimed at improving the treatment landscape for presentday patients, and the other (RB) is a neurologist who directs of one of the largest ALS clinics in the world and has gotten to know 2,000 patients affected by this disease. We applaud the authors’ poignant arguments for SAPs, and agree with their suggestion that people enrolled in SAPs contribute to research. However, their arguments against SAPs are not particularly convincing, they fail to adequately highlight the potential advantages of certain SAP design features, and, perhaps as a result of their nonclinical perspective, they miss two important concepts upon which this entire discussion might have been differently framed. The authors present two common but flawed arguments against SAPs. First they claim that these “may weaken regulatory processes insofar as they bypass standard procedures for evaluation before approval.” This is theoretical. We know of no example in which any regulatory process or regulatory agency was demonstrably weakened or damaged by an SAP. Indeed, SAPs can just as easily be portrayed as strengthening these processes and
agencies by adding precision and accommodating, at a class level, the needs of people who face near-term death with no alternative medical options available to them. The authors go on to review the concept of “corporate good” and show how regulatory processes are a benefit to society at large. They contrast this with “aggregative good” in which individuals benefit in bypassing the “rules” to the detriment of society. They place SAPs in the latter category and thus SAPs appear to suffer by association. This is overly simplistic. SAPs extend the medical optionality enjoyed by clinical trial participants to a wider proportion of the population. By increasing a society’s options, SAPs can be a corporate good like any other element of accessible health care. Their second argument is that SAPs “can delay or impede the development of robust evidence about safety, efficacy, and effectiveness, for example, by undermining recruitment into research trials.” Here the authors provide some data, but their selections are biased. They show rare examples in which SAPs appeared to slow recruitment/ enrollment, but this is clearly not universal. Enrollment rates in 36 published ALS trials were not affected by having the study drug available outside the trial (Bedlack et al. 2008). The authors acknowledge that it is possible to dislocate the enrollment criteria of SAPs from the enrollment criteria of trials, but cast doubt on the effectiveness of such strategies. In fact, using these exact strategies, Gleevec, Tykerb, and Iressa were able to support large SAPs while rapidly enrolling their Phase 2 and Phase 3
Address correspondence to Richard Bedlack, MD, PhD, Associate Professor and Director, Duke ALS Clinic, 932 Morreene Rd, Box 3333, Durham, NC 27702, USA. E-mail: [email protected]
November, Volume 14, Number 11, 2014
ajob 19
The American Journal of Bioethics
clinical trials (Capdeville et al. 2008; Capri et al. 2010; Stahel et al. 2003). The authors do an impressive job of organizing key features of SAP regulations in different regions (in their Table 1). However, in the United States as of 2009 there are actually three categories of SAPs, not two. These are Single Patient INDs (21CFR312.310) in which Emergency Use INDs are included, Intermediate INDs (21CFR.312.315), and the larger sized Treatment IND/Treatment Protocol (21CFR312.320). The authors also list various design aspects that differ between SAPs but they fail to delineate the obvious potential advantages of some of these features over others (as listed below). One important point this article fails to emphasize is that the majority of patients with incurable, disabling and invariably fatal diseases are going to seek treatment with unapproved therapies (Wasner, Klier, and Borasio 2001). It is not a question of if, but a question of how. Currently most patients are seeking these autonomously, guided by the Internet, where the information ranges from absent to flawed to inaccurate. These patients do not usually share information on what happens to them in such pursuits. Small or individualized SAPs promote shared decision making between a patient and that patient’s clinician, but these lack transparency and reproducibility, place significant demands on the engaged clinician that may not be feasible in today’s medical systems, and again do not systematically gather or share data. We support large centralized SAPs in which a committee of experts transparently creates a suggested protocol and cost structure, and organizes data collection and sharing. The other point these authors miss is that most people want to contribute to research. In our experience this
opportunity would be an added benefit of the type SAPs we describe in the preceding paragraph, rather than an added cost that must be paid to society to justify their existence. &
REFERENCES Bedlack, R. S., D. Pastula, E. Welsh, D. Pulley, and M. Cudkowicz. 2008. Scrutinizing enrollment in ALS clinical trials: room for improvement. Amyotrophic Lateral Sclerosis 9: 257–265. Capdeville, R., T. Krahnke, A. Hatfield, J. M. Ford, I. Van Hoomissen, and I. Gathmann. 2008. Report of an international expanded access program of imatinib in adults with Philadelphia chromosome positive leukemias. Annals of Oncology 19(7): 1320–1326. doi:10.1093/annonc/mdn050 Capri, G., J. Chang, S. C. Chen, et al. 2010. An open-label expanded access study of lapatinib and capecitabine in patients with HER2overexpressing locally advanced or metastatic breast cancer. Annals of Oncology 21(3): 474–480. doi:10.1093/annonc/mdp373 Stahel, R., A. Rossi, L. Petruzelka, et al. 2003. Lessons from the “Iressa” Expanded Access Programme: Gefitinib in special nonsmall-cell lung cancer patient populations. British Journal of Cancer 89(Suppl. 2): S19–S23. Walker, M. J., W. A. Rogers, and V. Entwistle. 2014. Ethical justifications for access to unapproved medical interventions: An argument for (limited) patient obligations. American Journal of Bioethics 14(11): 3–15. Wasner, M., H. Klier, and G. Borasio. 2001. The use of alternative medicine by patients with amyotrophic lateral sclerosis. Journal of the Neurological Sciences 191: 151–154.
Access to Unapproved Medical Interventions in Cases of Catastrophic Illness Udo Schuklenk, Queen’s University A BIT OF HISTORICAL CONTEXT I proposed in the mid to late 1990s that patients suffering from catastrophic illnesses ought to be able to access investigational new drugs outside the clinical trials system, and that we should utilize the information about their experiences with these agents in our evaluation of these investigational agents (Schuklenk 1990). Much of the debate
during the 1980s and 1990s was informed by the horrific experiences of people with HIV and AIDS in our clinical trials systems during the early years of the AIDS pandemic (Nussbaum 1990). Patients died unnecessary deaths in poorly designed clinical trials. Anthony Fauci, head of the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases, conceded reportedly that the clinical trials system routinely asks physicians to
Address correspondence to Udo Schuklenk, Ontario Research Chair in Bioethics and Public Policy, Bader Lane, Watson Hall, Queen’s University, ON, K7L 3N6, Canada. E-mail: [email protected]
20 ajob
November, Volume 14, Number 11, 2014
unmet medical need for treatment may have access to investigational drugs. Although challenges remain with specific diseases, we believe that FDA implementation of the expanded access program appropriately balances the competing obligations to the compassionate provision of investigational drugs to patients with serious life-threatening and/or debilitating diseases who lack suitable alternative treatments, and the need to protect the public health through data establishing the safety and effectiveness of those treatments. All access to investigational drugs in the United States, including to single patients under expanded access, is subject to the IND regulations. As such, the specific concerns raised by Walker and colleagues, such as ethical oversight, informed consent, and data collection, are addressed by those regulations. &
REFERENCES U.S. Food and Drug Administration. 1987. Part 312—Investigational new drug application, Sec 312.3 Definitions and interpretations, (b) Clinical investigation. Code of Federal Regulations Title 21. Available at: http://www.accessdata.fda.gov/scripts/cdrh/ cfdocs/cfcfr/CFRSearch.cfm?fr=312.3 U.S. Food and Drug Administration. 2009. Final rule 21, CFR Parts 312 and 316. Expanded access to investigational drugs for treatment use. Federal Register 74(155): 40900. Available at: http:// www.gpo.gov/fdsys/pkg/FR-2009-08-13/pdf/E9-19005.pdf Walker, M. J., W. A. Rogers, and V. Entwistle. 2014. Ethical justifications for access to unapproved medical interventions: An argument for (limited) patient obligations. American Journal of Bioethics 14(11): 3–15.
SAPs: A Different Perspective Jess Rabourn, ALS Emergency Treatment Fund Richard S. Bedlack, Duke University We enjoyed the well-written target article entitled “Ethical Justifications for Access to Unapproved Medical Interventions: An Argument for (Limited) Patient Obligations” (Walker, Rogers, and Entwistle 2014). We come at special access programs (SAPs) from a different perspective than the ethicists who wrote this. One of us (JR) is an economist who lost two family members to amyotrophic lateral sclerosis (ALS) and has initiated multiple nonprofit initiatives aimed at improving the treatment landscape for presentday patients, and the other (RB) is a neurologist who directs of one of the largest ALS clinics in the world and has gotten to know 2,000 patients affected by this disease. We applaud the authors’ poignant arguments for SAPs, and agree with their suggestion that people enrolled in SAPs contribute to research. However, their arguments against SAPs are not particularly convincing, they fail to adequately highlight the potential advantages of certain SAP design features, and, perhaps as a result of their nonclinical perspective, they miss two important concepts upon which this entire discussion might have been differently framed. The authors present two common but flawed arguments against SAPs. First they claim that these “may weaken regulatory processes insofar as they bypass standard procedures for evaluation before approval.” This is theoretical. We know of no example in which any regulatory process or regulatory agency was demonstrably weakened or damaged by an SAP. Indeed, SAPs can just as easily be portrayed as strengthening these processes and
agencies by adding precision and accommodating, at a class level, the needs of people who face near-term death with no alternative medical options available to them. The authors go on to review the concept of “corporate good” and show how regulatory processes are a benefit to society at large. They contrast this with “aggregative good” in which individuals benefit in bypassing the “rules” to the detriment of society. They place SAPs in the latter category and thus SAPs appear to suffer by association. This is overly simplistic. SAPs extend the medical optionality enjoyed by clinical trial participants to a wider proportion of the population. By increasing a society’s options, SAPs can be a corporate good like any other element of accessible health care. Their second argument is that SAPs “can delay or impede the development of robust evidence about safety, efficacy, and effectiveness, for example, by undermining recruitment into research trials.” Here the authors provide some data, but their selections are biased. They show rare examples in which SAPs appeared to slow recruitment/ enrollment, but this is clearly not universal. Enrollment rates in 36 published ALS trials were not affected by having the study drug available outside the trial (Bedlack et al. 2008). The authors acknowledge that it is possible to dislocate the enrollment criteria of SAPs from the enrollment criteria of trials, but cast doubt on the effectiveness of such strategies. In fact, using these exact strategies, Gleevec, Tykerb, and Iressa were able to support large SAPs while rapidly enrolling their Phase 2 and Phase 3
Address correspondence to Richard Bedlack, MD, PhD, Associate Professor and Director, Duke ALS Clinic, 932 Morreene Rd, Box 3333, Durham, NC 27702, USA. E-mail: [email protected]
November, Volume 14, Number 11, 2014
ajob 19
The American Journal of Bioethics
clinical trials (Capdeville et al. 2008; Capri et al. 2010; Stahel et al. 2003). The authors do an impressive job of organizing key features of SAP regulations in different regions (in their Table 1). However, in the United States as of 2009 there are actually three categories of SAPs, not two. These are Single Patient INDs (21CFR312.310) in which Emergency Use INDs are included, Intermediate INDs (21CFR.312.315), and the larger sized Treatment IND/Treatment Protocol (21CFR312.320). The authors also list various design aspects that differ between SAPs but they fail to delineate the obvious potential advantages of some of these features over others (as listed below). One important point this article fails to emphasize is that the majority of patients with incurable, disabling and invariably fatal diseases are going to seek treatment with unapproved therapies (Wasner, Klier, and Borasio 2001). It is not a question of if, but a question of how. Currently most patients are seeking these autonomously, guided by the Internet, where the information ranges from absent to flawed to inaccurate. These patients do not usually share information on what happens to them in such pursuits. Small or individualized SAPs promote shared decision making between a patient and that patient’s clinician, but these lack transparency and reproducibility, place significant demands on the engaged clinician that may not be feasible in today’s medical systems, and again do not systematically gather or share data. We support large centralized SAPs in which a committee of experts transparently creates a suggested protocol and cost structure, and organizes data collection and sharing. The other point these authors miss is that most people want to contribute to research. In our experience this
opportunity would be an added benefit of the type SAPs we describe in the preceding paragraph, rather than an added cost that must be paid to society to justify their existence. &
REFERENCES Bedlack, R. S., D. Pastula, E. Welsh, D. Pulley, and M. Cudkowicz. 2008. Scrutinizing enrollment in ALS clinical trials: room for improvement. Amyotrophic Lateral Sclerosis 9: 257–265. Capdeville, R., T. Krahnke, A. Hatfield, J. M. Ford, I. Van Hoomissen, and I. Gathmann. 2008. Report of an international expanded access program of imatinib in adults with Philadelphia chromosome positive leukemias. Annals of Oncology 19(7): 1320–1326. doi:10.1093/annonc/mdn050 Capri, G., J. Chang, S. C. Chen, et al. 2010. An open-label expanded access study of lapatinib and capecitabine in patients with HER2overexpressing locally advanced or metastatic breast cancer. Annals of Oncology 21(3): 474–480. doi:10.1093/annonc/mdp373 Stahel, R., A. Rossi, L. Petruzelka, et al. 2003. Lessons from the “Iressa” Expanded Access Programme: Gefitinib in special nonsmall-cell lung cancer patient populations. British Journal of Cancer 89(Suppl. 2): S19–S23. Walker, M. J., W. A. Rogers, and V. Entwistle. 2014. Ethical justifications for access to unapproved medical interventions: An argument for (limited) patient obligations. American Journal of Bioethics 14(11): 3–15. Wasner, M., H. Klier, and G. Borasio. 2001. The use of alternative medicine by patients with amyotrophic lateral sclerosis. Journal of the Neurological Sciences 191: 151–154.
Access to Unapproved Medical Interventions in Cases of Catastrophic Illness Udo Schuklenk, Queen’s University A BIT OF HISTORICAL CONTEXT I proposed in the mid to late 1990s that patients suffering from catastrophic illnesses ought to be able to access investigational new drugs outside the clinical trials system, and that we should utilize the information about their experiences with these agents in our evaluation of these investigational agents (Schuklenk 1990). Much of the debate
during the 1980s and 1990s was informed by the horrific experiences of people with HIV and AIDS in our clinical trials systems during the early years of the AIDS pandemic (Nussbaum 1990). Patients died unnecessary deaths in poorly designed clinical trials. Anthony Fauci, head of the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases, conceded reportedly that the clinical trials system routinely asks physicians to
Address correspondence to Udo Schuklenk, Ontario Research Chair in Bioethics and Public Policy, Bader Lane, Watson Hall, Queen’s University, ON, K7L 3N6, Canada. E-mail: [email protected]
20 ajob
November, Volume 14, Number 11, 2014
