Clinical Therapeutics/Volume 37, Number 4, 2015
Editor-in-Chief’s Note The Patient Protection and Affordable Care Act: Politics and Pills The year 2015 marks the 50th anniversary of the Social Security Amendments of 1965 (Medicare and Medicaid) and the 5th anniversary of the Patient Protection and Affordable Care Act (ACA). Medicare was intended to promote and ensure the health and well-being of disabled and elderly Americans, whereas Medicaid provided health insurance coverage to the poor. To achieve political acceptance, Medicare coverage was separated into inpatient and outpatient portions, and cost-deflecting copayments and deductibles were included. Drug coverage and long-term care were conspicuously absent from Medicare in its initial form. Coverage for prescription medications was added when the Medicare Prescription Drug, Improvement, and Modernization Act was passed in 2003; long-term care has yet to be addressed. The ACA was intended to provide the uninsured and underinsured with insurance coverage by way of an expansion of Medicaid; in turn, access to health care services would lead to improved outcomes for the Richard I. Shader, MD newly insured. The ACA also aimed at improving the quality of health care, lowering the growth rate in health care spending, and expanding access to health care services to particularly vulnerable groups, such as children and pregnant women. As with most social programs in recent times, both Medicare and the ACA have been political footballs, kicked about by both parties. The Republican Party vocally and deliberately continues to make concerted efforts to deflate the ACA. Republicans regard the ACA as incompatible with the party’s commitment to a health care delivery system based on competition and free markets. Government-run health care is seen as non-patient– centered, inefficient, and more costly. Among other problems, party members foresee lengthy waiting periods and compromised patient–clinician relationships.1 The Democratic Party views the ACA as a major step toward keeping a longstanding promise to the public to make health care available to all Americans. In addition to increasing coverage for women and children, Democratic goals include eliminating discrimination for preexisting conditions, reducing costs and promoting innovation, and expanding coverage to many currently uninsured Americans.2–5 Stepping aside from its awkward and embarrassing rollout and its politically biased claims and counterclaims, the ACA appears to be achieving many of its goals. More people are now covered than in the past, and costs are either coming down or are increasing by smaller increments; the Congressional Budget Office indicates both lower premiums and a meaningful contribution to deficit reduction; and there is evidence of innovation, through the creation of 4350 accountable care organizations nationwide.4,5 Contrary to the Republicans’ warning about lengthy waiting periods, a recent article in the New England Journal of Medicine showed that as a consequence of the ACA there has been “…improved appointment availability for Medicaid enrollees among participating providers without generating longer waiting times.”6 In this issue, our Topic Editors Joshua P. Cohen and Cheryl D. Coon and their invited contributors present various perspectives on the implementation of the ACA.7–11 One of these articles in particular has a backstory that deserves explication and elaboration. Orsulak et al9 discuss the role played by the ACA in increasing the number of women in Louisiana with access to 17-α-hydroxyprogesterone caproate (17-AHPC), which succeeded in reducing the likelihood of preterm births. The steroid 17-α-hydroxyprogesterone is a naturally occurring hormone produced by fetal adrenal glands in the final trimester of pregnancy and, to a lesser extent, by adult adrenal glands and the corpus luteum. When conjugated with caproate dextran, it is known as 17-AHPC. Squibb first marketed
April 2015
687
Clinical Therapeutics the drug in 1956 as an injectable for conditions responding to progestogens, including threatened and habitual abortions. The approval by the US Food and Drug Administration (FDA) of Squibb’s New Drug Application was based on safety. This approval was before the passage of the 1962 Kefauver-Harris Amendments, which required data supporting not only safety but also effectiveness. Squibb’s trade name for 17-AHPC was Delalutins.12 What happened to 17-AHPC over the next 4 decades is a curious saga. In 1973, the FDA decided that 17AHPC lacked substantial evidence for its claims about threatened and habitual abortions and required that this indication be deleted from the label. The FDA also required the addition of language indicating a potential risk for birth defects. In retrospect, there were no data linking 17-AHPC to teratogenicity, as the warning was a result of class labeling for progestogens. In 1999, Squibb (now Bristol-Myers Squibb) voluntarily took Delalutin off the market and stated that it had not been sold for “several years.” The FDA withdrew the Delalutin New Drug Application in 2000.12–14 During these years, 17-AHPC was also available from compounding pharmacies and was called 17P. Compounding pharmacies produce drugs that are not available or are not in a form that is suitable for a specific patient. For example, a tablet too big for some to swallow may be put into a liquid suspension. As recent publicity has made clear, compounding pharmacies are not regulated to the same degree as major pharmaceutical companies, and their products may present safety, efficacy, and manufacturing risks.15 In 2006, CUSTOpharm brought a citizens’ petition to the FDA that requested removal of any language stating that 17-AHPC had been withdrawn for lack of safety or effectiveness. CUSTOpharm is a company that provides “chemistry and manufacturing controls (CMC) and regulatory support to companies with limited resources and those seeking to expand into new areas.”16 In 2010, the FDA published their acquiescence to the petition in the Federal Register.14 This action was based on data from several studies from the National Institutes of Health supporting the drug’s clinically successful use in reducing premature births.17,18 The saga did not end there. In 2011, the FDA approved marketing of 17-AHPC by K-V Pharmaceutical Company through the premarket process. Calling the drug Makena™, its indication was narrowed to single-birth pregnancies in women who had had spontaneous singleton premature births. In 2012, K-V filed for bankruptcy (in 2008 it had been convicted on felony charges unrelated to Makena). K-V blamed the FDA for undercutting their profitability by allowing compounding pharmacies to sell 17-AHPC for $10 to $20 per injection and for not dealing with reimbursement limits imposed by a number of state-based Medicaid plans. K-V cut its Makena pricing from $1500 to $690 per injection. K-V emerged from bankruptcy in 2013 and changed its name to Lumara Health; in 2014, AMAG Pharmaceuticals purchased Lumara. AMAG currently markets Makena through its Lumara Health Division.19 The good news is that after this unprecedented game of musical chairs, both17-AHPC and 17P are available to women who may now be able to carry their pregnancies to term, and some Medicaid programs are facilitating availability of these agents. The April issue of Clinical Therapeutics also features a collection of articles20–22 on immune checkpoint inhibition as a strategy for treating melanoma, including the reviews “CTLA-4 Blockade in Melanoma” by Buchbinder and McDermott and “The Next Immune Checkpoint Inhibitors: PD-1/PD-L1 blockade in Melanoma” by Mahoney et al. This topic is summarized in an editorial by the journal’s Oncology Topic Editor, James W. Mier, MD, entitled “Immune Checkpoint Inhibitors in the Treatment of Metastatic Melanoma.” Richard I. Shader, MD Editor-in-Chief
REFERENCES 1. Republican views on healthcare. http://www.repubilicanviews.org/republican-views-on-health-care. Accessed February 20, 2015. 2. Healthcare. http://www.democrats.org/issues/health_care. Accessed February 20, 2015. 3. Obamacare pre-existing conditions. http://obamacarefacts/pre-existing-conditions. Accessed February 20, 2015. 4. Schiliro P. The Affordable Care Act is working. http://www.politico.com/magazine/story/2014/03/affordable-care-act-is-working104942.html#ixzz3R6OZ8uQk. Accessed February 20, 2015.
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Editor-in-Chief’s Note 5. New York Times. Is the Affordable Care Act working? http://www.nytimes.com/interactive/2014/10/27/us/is-the-affordablecare-act-working.html. Accessed February 20, 2015. 6. Polsky D, Richards M, Basseyn S. Appointment availability after increases in Medicaid payments for primary care. N Engl J Med. 2015;372:537–545. 7. Cohen JP. Implementing the Affordable Care Act: remaining hurdles. Clin Ther. 2015;37:717–719. 8. Beland D, Rocco P, Waddan A. Polarized stakeholders and institutional vulnerabilities: the enduring politics of the Affordable Care Act. Clin Ther. 2015;37:720–726. 9. Orsulak MK, Block-Abraham D, Gee RE. 17 Alpha-hydroxyprogesterone caproate access in the Louisiana Medicaid population. Clin Ther. 2015;37:727–732. 10. Schoonveld E, Coyle B, Markham J. Impact of ACA on the dinner-for-three dynamic. Clin Ther. 2015;37:733–746. 11. Dubois RW. The Affordable Care Act: how can we know whether the intended consequences are occurring and the unintended ones being avoided? Clin Ther. 2015;37:747–750. 12. 17-Hydroxyprogesterone Caproate. http://en.wikipedia.org/wiki/17-Hydroxyprogesterone_caproate. Accessed February 15, 2015. 13. Chaudhuri S. K-V Pharmaceutical files for Chapter 11. http://www.wsj.com/articles/SB10000872396390444246904577 572990406558860. Accessed February 20, 2015. 14. Determination that DELALUTIN (hydroxyprogesterone caproate) injection, 125 milligrams/milliliter and 250 milligrams/ milliliter, was not withdrawn from sale for reasons of safety or effectiveness. Fed Register. https://www.federalregister.gov/ articles/2010/06/25/2010-15416/determination-that-delalutin-hydroxyprogesterone-caproate-injection-125-milligramsmilliliterand-250. Accessed February 20, 2015. 15. New England Compounding Pharmacy meningitis outbreak. http://en.wikipedia.org/wiki/New_England_Compounding_Center_ meningitis_outbreak. Accessed February 20, 2015. 16. CUSTOpharm, Inc. www.custopharm.com. Accessed February 20, 2015. 17. Meis PJ, Klebonoff M, Thorn E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003;348:2379–2385. 18. Northern AT, Norman GS, Anderson K, et al. Follow-up of children exposed in utero to 17 α-hydroxyprogesterone caproate compared with placebo. Obstet Gynecol. 2007;110:865–872. 19. KV Pharmaceutical. http://en.wikipedia.org/wiki/KV_Pharmaceutical. Accessed February 20, 2015. 20. Buchbinder E, McDermott DF. CTLA-4 blockade in melanoma. Clin Ther. 2015;37:755–763. 21. Mahoney K, Freeman GJ, McDermott DF. The next immune checkpoint inhibitors: pd-1/pd-l1 blockade in melanoma. Clin Ther. 2015;37:764–782. 22. Mier JW. Immune checkpoint inhibitors in the treatment of metastatic melanoma. Clin Ther. 2015;37:753–754.
http://dx.doi.org/10.1016/j.clinthera.2015.03.007
Allergy, Asthma and Immunology (AAI) Specialty Updates AAI Specialty Updates are published annually and are available as FREE ACCESS content on the journal’s website. The previous AAI Update, entitled “Extracellular Exosomes and Microvesicles in Allergic and Immunological Diseases,” was published in Volume 36, Number 6 of Clinical Therapeutics. To view the previous AAI Update, see the articles below: 1. G, N and Gundogan, B et al. Exosomes as Immunotheranostic Nanoparticles. 2. Revenfeld, ALS et al. Diagnostic and Prognostic Potential of Extracellular Vesicles in Peripheral Blood. 3. Oksvold, MP et al. Expression of B-Cell Surface Antigens in Subpopulations of Exosomes Released From B-Cell Lymphoma Cells. 4. Sun, Y and Liu, J. Potential of Cancer Cell–Derived Exosomes in Clinical Application: A Review of Recent Research Advances. 5. Fujita, Y et al. Intercellular Communication by Extracellular Vesicles and Their MicroRNAs in Asthma. 6. Tsilioni, I et al. Exosomes in Neurologic and Psychiatric Disorders.
April 2015
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Editor-in-Chief’s Note The Patient Protection and Affordable Care Act: Politics and Pills The year 2015 marks the 50th anniversary of the Social Security Amendments of 1965 (Medicare and Medicaid) and the 5th anniversary of the Patient Protection and Affordable Care Act (ACA). Medicare was intended to promote and ensure the health and well-being of disabled and elderly Americans, whereas Medicaid provided health insurance coverage to the poor. To achieve political acceptance, Medicare coverage was separated into inpatient and outpatient portions, and cost-deflecting copayments and deductibles were included. Drug coverage and long-term care were conspicuously absent from Medicare in its initial form. Coverage for prescription medications was added when the Medicare Prescription Drug, Improvement, and Modernization Act was passed in 2003; long-term care has yet to be addressed. The ACA was intended to provide the uninsured and underinsured with insurance coverage by way of an expansion of Medicaid; in turn, access to health care services would lead to improved outcomes for the Richard I. Shader, MD newly insured. The ACA also aimed at improving the quality of health care, lowering the growth rate in health care spending, and expanding access to health care services to particularly vulnerable groups, such as children and pregnant women. As with most social programs in recent times, both Medicare and the ACA have been political footballs, kicked about by both parties. The Republican Party vocally and deliberately continues to make concerted efforts to deflate the ACA. Republicans regard the ACA as incompatible with the party’s commitment to a health care delivery system based on competition and free markets. Government-run health care is seen as non-patient– centered, inefficient, and more costly. Among other problems, party members foresee lengthy waiting periods and compromised patient–clinician relationships.1 The Democratic Party views the ACA as a major step toward keeping a longstanding promise to the public to make health care available to all Americans. In addition to increasing coverage for women and children, Democratic goals include eliminating discrimination for preexisting conditions, reducing costs and promoting innovation, and expanding coverage to many currently uninsured Americans.2–5 Stepping aside from its awkward and embarrassing rollout and its politically biased claims and counterclaims, the ACA appears to be achieving many of its goals. More people are now covered than in the past, and costs are either coming down or are increasing by smaller increments; the Congressional Budget Office indicates both lower premiums and a meaningful contribution to deficit reduction; and there is evidence of innovation, through the creation of 4350 accountable care organizations nationwide.4,5 Contrary to the Republicans’ warning about lengthy waiting periods, a recent article in the New England Journal of Medicine showed that as a consequence of the ACA there has been “…improved appointment availability for Medicaid enrollees among participating providers without generating longer waiting times.”6 In this issue, our Topic Editors Joshua P. Cohen and Cheryl D. Coon and their invited contributors present various perspectives on the implementation of the ACA.7–11 One of these articles in particular has a backstory that deserves explication and elaboration. Orsulak et al9 discuss the role played by the ACA in increasing the number of women in Louisiana with access to 17-α-hydroxyprogesterone caproate (17-AHPC), which succeeded in reducing the likelihood of preterm births. The steroid 17-α-hydroxyprogesterone is a naturally occurring hormone produced by fetal adrenal glands in the final trimester of pregnancy and, to a lesser extent, by adult adrenal glands and the corpus luteum. When conjugated with caproate dextran, it is known as 17-AHPC. Squibb first marketed
April 2015
687
Clinical Therapeutics the drug in 1956 as an injectable for conditions responding to progestogens, including threatened and habitual abortions. The approval by the US Food and Drug Administration (FDA) of Squibb’s New Drug Application was based on safety. This approval was before the passage of the 1962 Kefauver-Harris Amendments, which required data supporting not only safety but also effectiveness. Squibb’s trade name for 17-AHPC was Delalutins.12 What happened to 17-AHPC over the next 4 decades is a curious saga. In 1973, the FDA decided that 17AHPC lacked substantial evidence for its claims about threatened and habitual abortions and required that this indication be deleted from the label. The FDA also required the addition of language indicating a potential risk for birth defects. In retrospect, there were no data linking 17-AHPC to teratogenicity, as the warning was a result of class labeling for progestogens. In 1999, Squibb (now Bristol-Myers Squibb) voluntarily took Delalutin off the market and stated that it had not been sold for “several years.” The FDA withdrew the Delalutin New Drug Application in 2000.12–14 During these years, 17-AHPC was also available from compounding pharmacies and was called 17P. Compounding pharmacies produce drugs that are not available or are not in a form that is suitable for a specific patient. For example, a tablet too big for some to swallow may be put into a liquid suspension. As recent publicity has made clear, compounding pharmacies are not regulated to the same degree as major pharmaceutical companies, and their products may present safety, efficacy, and manufacturing risks.15 In 2006, CUSTOpharm brought a citizens’ petition to the FDA that requested removal of any language stating that 17-AHPC had been withdrawn for lack of safety or effectiveness. CUSTOpharm is a company that provides “chemistry and manufacturing controls (CMC) and regulatory support to companies with limited resources and those seeking to expand into new areas.”16 In 2010, the FDA published their acquiescence to the petition in the Federal Register.14 This action was based on data from several studies from the National Institutes of Health supporting the drug’s clinically successful use in reducing premature births.17,18 The saga did not end there. In 2011, the FDA approved marketing of 17-AHPC by K-V Pharmaceutical Company through the premarket process. Calling the drug Makena™, its indication was narrowed to single-birth pregnancies in women who had had spontaneous singleton premature births. In 2012, K-V filed for bankruptcy (in 2008 it had been convicted on felony charges unrelated to Makena). K-V blamed the FDA for undercutting their profitability by allowing compounding pharmacies to sell 17-AHPC for $10 to $20 per injection and for not dealing with reimbursement limits imposed by a number of state-based Medicaid plans. K-V cut its Makena pricing from $1500 to $690 per injection. K-V emerged from bankruptcy in 2013 and changed its name to Lumara Health; in 2014, AMAG Pharmaceuticals purchased Lumara. AMAG currently markets Makena through its Lumara Health Division.19 The good news is that after this unprecedented game of musical chairs, both17-AHPC and 17P are available to women who may now be able to carry their pregnancies to term, and some Medicaid programs are facilitating availability of these agents. The April issue of Clinical Therapeutics also features a collection of articles20–22 on immune checkpoint inhibition as a strategy for treating melanoma, including the reviews “CTLA-4 Blockade in Melanoma” by Buchbinder and McDermott and “The Next Immune Checkpoint Inhibitors: PD-1/PD-L1 blockade in Melanoma” by Mahoney et al. This topic is summarized in an editorial by the journal’s Oncology Topic Editor, James W. Mier, MD, entitled “Immune Checkpoint Inhibitors in the Treatment of Metastatic Melanoma.” Richard I. Shader, MD Editor-in-Chief
REFERENCES 1. Republican views on healthcare. http://www.repubilicanviews.org/republican-views-on-health-care. Accessed February 20, 2015. 2. Healthcare. http://www.democrats.org/issues/health_care. Accessed February 20, 2015. 3. Obamacare pre-existing conditions. http://obamacarefacts/pre-existing-conditions. Accessed February 20, 2015. 4. Schiliro P. The Affordable Care Act is working. http://www.politico.com/magazine/story/2014/03/affordable-care-act-is-working104942.html#ixzz3R6OZ8uQk. Accessed February 20, 2015.
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Editor-in-Chief’s Note 5. New York Times. Is the Affordable Care Act working? http://www.nytimes.com/interactive/2014/10/27/us/is-the-affordablecare-act-working.html. Accessed February 20, 2015. 6. Polsky D, Richards M, Basseyn S. Appointment availability after increases in Medicaid payments for primary care. N Engl J Med. 2015;372:537–545. 7. Cohen JP. Implementing the Affordable Care Act: remaining hurdles. Clin Ther. 2015;37:717–719. 8. Beland D, Rocco P, Waddan A. Polarized stakeholders and institutional vulnerabilities: the enduring politics of the Affordable Care Act. Clin Ther. 2015;37:720–726. 9. Orsulak MK, Block-Abraham D, Gee RE. 17 Alpha-hydroxyprogesterone caproate access in the Louisiana Medicaid population. Clin Ther. 2015;37:727–732. 10. Schoonveld E, Coyle B, Markham J. Impact of ACA on the dinner-for-three dynamic. Clin Ther. 2015;37:733–746. 11. Dubois RW. The Affordable Care Act: how can we know whether the intended consequences are occurring and the unintended ones being avoided? Clin Ther. 2015;37:747–750. 12. 17-Hydroxyprogesterone Caproate. http://en.wikipedia.org/wiki/17-Hydroxyprogesterone_caproate. Accessed February 15, 2015. 13. Chaudhuri S. K-V Pharmaceutical files for Chapter 11. http://www.wsj.com/articles/SB10000872396390444246904577 572990406558860. Accessed February 20, 2015. 14. Determination that DELALUTIN (hydroxyprogesterone caproate) injection, 125 milligrams/milliliter and 250 milligrams/ milliliter, was not withdrawn from sale for reasons of safety or effectiveness. Fed Register. https://www.federalregister.gov/ articles/2010/06/25/2010-15416/determination-that-delalutin-hydroxyprogesterone-caproate-injection-125-milligramsmilliliterand-250. Accessed February 20, 2015. 15. New England Compounding Pharmacy meningitis outbreak. http://en.wikipedia.org/wiki/New_England_Compounding_Center_ meningitis_outbreak. Accessed February 20, 2015. 16. CUSTOpharm, Inc. www.custopharm.com. Accessed February 20, 2015. 17. Meis PJ, Klebonoff M, Thorn E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003;348:2379–2385. 18. Northern AT, Norman GS, Anderson K, et al. Follow-up of children exposed in utero to 17 α-hydroxyprogesterone caproate compared with placebo. Obstet Gynecol. 2007;110:865–872. 19. KV Pharmaceutical. http://en.wikipedia.org/wiki/KV_Pharmaceutical. Accessed February 20, 2015. 20. Buchbinder E, McDermott DF. CTLA-4 blockade in melanoma. Clin Ther. 2015;37:755–763. 21. Mahoney K, Freeman GJ, McDermott DF. The next immune checkpoint inhibitors: pd-1/pd-l1 blockade in melanoma. Clin Ther. 2015;37:764–782. 22. Mier JW. Immune checkpoint inhibitors in the treatment of metastatic melanoma. Clin Ther. 2015;37:753–754.
http://dx.doi.org/10.1016/j.clinthera.2015.03.007
Allergy, Asthma and Immunology (AAI) Specialty Updates AAI Specialty Updates are published annually and are available as FREE ACCESS content on the journal’s website. The previous AAI Update, entitled “Extracellular Exosomes and Microvesicles in Allergic and Immunological Diseases,” was published in Volume 36, Number 6 of Clinical Therapeutics. To view the previous AAI Update, see the articles below: 1. G, N and Gundogan, B et al. Exosomes as Immunotheranostic Nanoparticles. 2. Revenfeld, ALS et al. Diagnostic and Prognostic Potential of Extracellular Vesicles in Peripheral Blood. 3. Oksvold, MP et al. Expression of B-Cell Surface Antigens in Subpopulations of Exosomes Released From B-Cell Lymphoma Cells. 4. Sun, Y and Liu, J. Potential of Cancer Cell–Derived Exosomes in Clinical Application: A Review of Recent Research Advances. 5. Fujita, Y et al. Intercellular Communication by Extracellular Vesicles and Their MicroRNAs in Asthma. 6. Tsilioni, I et al. Exosomes in Neurologic and Psychiatric Disorders.
April 2015
689
