Expanding expanded access: How the food and drug administration can achieve better access to experimental drugs for seriously ill patients

Georgetown Law Journal

Volumn 96, Issue 6, 2008, Pages 2143-2175

  Vale, Judy ^a  

^a GEORGETOWN UNIVERSITY LAW CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 51149117577     PISSN: 00168092     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (240)

1. See Jerome Groopman, The Right to a Trial; Should Dying Patients Have Access to Experimental Drugs?, NEW YORKER, Dec. 18, 2006, at 40, 42 (explaining that "with the advent of the AIDS epidemic," patients began demanding expanded access); Philip J. Hilts, How AIDS Made the Drug Regulators Speed Up, N. Y. TIMES, Sept. 24, 1989, § 4, at 5.
2. See Groopman, supra note 1, at 43 ("[P]rotease inhibitors helped reduce the death rate from AIDS in the United States by at least seventy percent.").
3. Abigail Alliance for Better Access to Developmental Drugs v. von Eschenbach, 445 F.3d 470 (D.C. Cir. 2006), rev'd, 495 F.3d 695 (D.C. Cir 2007) (en banc).
4. Abigail Alliance for Better Access to Developmental Drugs v. von Eschenbach, 495 F.3d 695, 697 (D.C. Cir. 2007) (en bane), cert. denied, 128 S. Ct. 1069 (2008).
5. For a discussion of the constitutionality of a right to experimental drugs, see Jon Scott Batterman, Note, Brother Can You Spare a Drug: Should the Experimental Drug Distribution Standards Be Modified in Response to the Needs of Persons with AIDS?, 19 HOFSTRA L. REV. 191, 195 (1990) (arguing that "the courts should recognize a fundamental right of terminal patients to elect and obtain unapproved drugs").
6. See MARK MATHIEU, NEW DRUG DEVELOPMENT: A REGULATORY OVERVIEW 7 (3d ed. 1994).
7. See id. at 10-14 (describing the drug review process).
8. See infra notes 38-43,52-55 and accompanying text.
9. Investigational New Drug Application, 21 C.F.R. § 312.34(a) (2007); see also Hilts, supra note 1, at 5 (noting that the FDA, ceding to "intense pressure" from advocates for fatally ill patients, started to make significant changes in its approach to drug approval for such patients).
10. 21 C.F.R. § 312.24(b).
11. See Grdopman, supra note 1, at 42 (stating that the FDA had already begun drafting new expanded-access regulations when Abigail Alliance was decided).
12. Charging for Investigational Drugs, 71 Fed. Reg. 75,168, 75,172 (Dec. 14, 2006) (to be codified at 21 C.F.R. pt. 312); Expanded Access to Investigational Drugs, 71 Fed. Reg. 75,147, 75,150 (Dec. 14, 2006) (to be codified at 21 C.F.R. pt. 312).
13. In accordance with the proposed FDA regulations, this Note refers to all types of treatment uses of experimental drugs as "expanded access." The term "treatment IND" refers to the large-scale program explicitly authorized in the 1987 regulations and continued in the new regulations. See Expanded Access to Investigational Drugs, 71 Fed. Reg. at 75, 150.
14. Id. at 75, 153-55.
15. Pure Food and Drag Act of 1906, ch. 3915, 34 Stat. 768 (1906) (repealed by the Federal Food, Drag, and Cosmetic Act of 1938).
16. John P. Swann, History of the FDA, in THE FOOD AND DRUG ADMINISTRATION 9, 10-11 (Meredith A. Hickmann ed., 2003).
17. Federal Food, Drag, and Cosmetic Act of 1938, ch. 675, § 301, 52 Stat. 1040, 1042 (1938) (current version codified at 21 U.S.C. §§ 301-92 (2000)).
18. See Swann, supra note 16, at 12.
19. Federal Food, Drag, and Cosmetic Act § 355(a)-(b).
20. Id. § 355(i); see also Louis K. Perrin, Note, The Catch-22 for Persons with AIDS: To Have or Not to Have Easy Access to Experimental Therapies and Early Approval for New Drugs, 69 S. CAL. L. REV. 105,110-11 (1995).
21. See THE INSIGHT TEAM OF THE SUNDAY TIMES OF LONDON, SUFFER THE CHILDREN: THE STORY OF THALIDOMIDE, 1-2 (1979) [hereinafter THE INSIGHT TEAM]; Wallace F. Janssen, The Story of the Laws Behind the Labels, in FOOD AND DRUG ADMINISTRATION 23, 30 (Meredith A. Hickman ed. 2003).
22. THE INSIGHT TEAM, supra note 21, at 78-79 (crediting Frances Kelsey, an FDA administrator, with stopping FDA approval of thalidomide, despite intense pressure from the manufacturer, by remaining suspicious of the lack of safety information regarding thalidomide's effects on fetuses). For an in-depth investigation of thalidomide's history and legal aftermath in Europe and America, see generally id.
23. See id. at 1-2 (explaining that the thalidomide disaster caused several countries "to screen drugs more thoroughly before they reached their populations"); FDA Proposals To Ease Restrictions on the Use and Sale of Experimental Drugs, 1987: Hearing Before the Subcomm. on Human Resources and Intergovernmental Relations of the H. Comm. on Gov. Operations, 100th Cong. 15 (testimony of Richard Cooper) (stating that the thalidomide disaster was "actual triggering point" for 1962 Kefauver-Harris Amendments); Janssen, supra note 21, at 30 (stating that the thalidomide tragedy "focused public attention on pending U.S. legislation to further strengthen the Federal Food, Drug, and, Cosmetic Act").
24. 21 U.S.C. § 355(b)(1) (2007) (requiring manufacturers to submit "full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use").
25. Id. § 355(d) (defining substantial evidence to mean "evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports"). The FDA retained its power to exempt INDs from the shipment ban in order to allow investigation into safety and effectiveness. Id. § 355(i).
26. See generally MATHIEU, supra note 6.
27. See id. at 7.
28. Id. at 10, 107 (explaining that FDA regulations state that Phase I studies are "designed [to] determine the metabolism and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness").
29. Id. at 112.
30. Id. at 113.
31. See FDA CTR. FOR DRUG EVALUATION & RESEARCH, FOOD & DRUG ADMIN., Inside Clinical Trials: Testing Medical Products in People, in FROM TEST TUBE TO PATIENT (4th ed. 2006), available at http://www.da.gov/fdac/special/testtubetopatient/trials.html [hereinafter FDA CTR. FOR DRUG EVALUATION & RESEARCH].
32. MATHIEU, supra note 6, at 117.
33. FDA CTR. FOR DRUG EVALUATION & RESEARCH, supra note 31.
34. Id.
35. Charles Steenburg, The Food and Drug Administration's Use of Postmarketing (Phase IV) Study Requirements: Exception to the Rule?, 61 FOOD & DRUG L.J. 295, 296-97 (2006).
36. MATHIEU, supra note 6, at 13.
37. Id. at 12.
38. Id. at 13-14, 189.
39. Id. at 11.
40. 21 C.F.R. § 314.510 (2008).
41. MATHIEU, supra note 6, at 126.
42. See John Patrick Dillman, Note, Prescription Drug Approval and Terminal Diseases: Desperate Times Require Desperate Measures, 44 VAND. L. REV. 925, 927-29 (1991) (describing the FDA phases and commenting that many "have described the American prescription drug approval system as the most highly regulated system ever created to ensure a safe drug marker).
43. Id. at 936 ("Commentators have studied this gap in new drag introduction between the United States and other developed, drug-producing nations, also known as the 'drug lag.'").
44. See RITA RICARDO CAMPBELL, DRUG LAG: FEDERAL GOVERNMENT DECISION MAKING 16-17 (1976) (summarizing a study by Dr. William Wardell finding that between 1962 and 1971 "nearly four times as many new drugs became available in Great Britain as in the United States" and "about twice as many [drugs] were introduced first in Great Britain as were introduced first in the United States"). See generally Leonard G. Schifrin, Lessons from the Drug Lag: A Retrospective Analysis of the 1962 Drug Regulations, 5 HARV. J.L. & PUB. POL'Y 91 (1982) (summarizing articles and studies on the existence and extent of the drug lag in the United States).
45. CAMPBELL, supra note 44, at 45; see also Schifrin, supra note 44, at 106 (discussing data amassed by Lewis Sarett showing that development times in the United States increased from two years in the late 1950s to up to eight years in the late 1960s and that approval times grew from six months in 1962 to forty months in 1969).
46. Schifrin, supra note 44, at 105 ("Jadlow takes this as support for his results, in which the post-1962 costs per NCE run about six times higher than the pre-1962 costs.").
47. See id. at 109-10 (stating that other factors besides the 1962 Amendments caused the drug lag, such as advances in drug testing methodology, but acknowledging that several scholars present "a strong case for [the Amendments'] significance" in producing the drug lag).
48. See, e.g., Carnohan v. United States, 616 F.2d 1120, 1122 (9th Cir. 1980) (holding "[e]onstitutional rights of privacy and personal liberty do not give individuals the right to obtain laetrile free of the lawful exercise of government police power"); Duncan v. United States, 590 F. Supp. 39, 44 (W.D. OkIa. 1984) (holding new FDA drug approval process not too burdensome to violate Due Process Clause for child suffering from Down Syndrome); Rutherford v. United States, 438 F. Supp. 1287,1301 (W.D. Okla. 1977), aff'd, 582 F.2d 1234 (10th Cir. 1978), rev'd, 442 U.S. 544 (1979) (finding constitutional right of privacy allowed terminally ill patients to access nontoxic laetrile treatments for personal health reasons).
49. United States v. Rutherford, 442 U.S. 544 (1979).
50. Rutherford v. United States, 582 F.2d 1234,1236 (10th Cir. 1978).
51. Rutherford, 442 U.S. at 555.
52. See id. at 558 (stating that terminally ill patients were susceptible to "resourceful entrepreneurs [who] have advertised a wide variety of purportedly simple and painless cures for cancer, including liniments of turpentine, mustard, oil, eggs, and ammonia..."). For a full summary of Rutherford and a discussion of constitutional issues implicated in the Abigail Alliance case, see Batterman, supra note 5.
53. See Perrin, supra note 20, at 119. Compassionate-use INDs were granted by the FDA on a case-by-case basis, usually when the "manufacturer [was] willing to supply the drug, a physician [was] willing to prescribe it, a patient [was] willing to give informed consent, and [there was] some basis for believing that the treatment [was] not an outright fraud or poison." Id.
54. MATHIEU, supra note 6, at 287.
55. Perrin, supra note 20, at 121, 127 (stating that compassionate use and other early programs did not expand access to a significant segment of the population).
56. See Editorial, Ill Treatment, WALL ST. J., Aug. 7, 1985, at 16. ("What justification can there be for the federal government to have the power to tell a human being with a fatal illness that he may or may not use radical or experimental therapies and drugs in the U.S. unless the FDA says he can? Safety? But what do you protect a dying man from?").
57. See id. (discussing Rock Hudson's travel to France for treatment, and how people without wealth and fame were given little access to experimental therapies in comparison); see also Harry Schwartz, Op-Ed., Finding a Cure for AIDS, N. Y. TIMES, Aug. 22, 1985, at A23 (suggesting FDA rules may be too focused on attaining "perfect safety" rather than on the needs of patients). But see Harold H. Osborn, Letter to the Editor, The F.D.A. Keeps the Drug Companies Honest, N.Y. TIMES, Sept. 9, 1985, at A18 (stating that the FDA keeps drug companies honest and that the government should be spearheading the campaign to find a cure for AIDS).
58. Philip M. Boffey, Thousands in U.S. Receive Treatment in Experiments, N.Y. TIMES, Jan. 7, 1986, at Cl (estimating that "only 300 to 450 individuals have been enrolled in clinical trials of drugs designed to attack the virus that causes AIDS, a tiny percentage of the more than 7,000 Americans" infected); Michael D. Greenberg, AIDS, Experimental Drug Approval, and the FDA New Drug Screening Process, 3 N.Y.U. J. LEGIS. & PUB. POL'Y 295, 311 (1999) (describing how "[wjith no experimental drugs available though the government research pipeline, [people with AIDS] began to turn instead to untested compounds," such as egg yolk lipid derivative, and to "[bjlack market buying clubs [facilitating] the purchase of drugs that were unapproved....").
59. See FDA Proposals To Ease Restrictions on the Use and Sale of Experimental Drugs: Hearing Before the Subcomm. on Human Resources and Intergovernmental Relations of the H. Comm. on Gov. Operations, 100th Cong. 67 (1987) (statement of Dr. Frank E. Young, Commissioner, FDA) [hereinafter Young Testimony] ("We are faced with a national emergency due to the natural emergency of a new infectious agent.... With this in mind, I developed a new initiative to work with AIDS...."); see also Judith Havemann, Experimental Drugs, Power and the Limits of Deregulation, WASH. POST, July 15, 1987, at A21 ("Young loyally defended the [1987 regulations] in public meetings and forums, stressing its value to AIDS patients."); Hilts, supra note 1, at A5 (describing how the protests and efforts of AIDS activists led the FDA to depart from traditional procedures and begin using treatment INDs).
60. 21 C.F.R. § 312.34(a) (2007); see also Young Testimony, supra note 59, at 68 (describing how the FDA granted a treatment IND for AZT and Retrovir, new AIDS drugs, in 1986).
61. 21 C.F.R. § 312.34(b)(1)(i)-(iv).
62. See id. § 312.35(a).
63. See id. §§ 312.34(b)(2)-(3), 312.34(d).
64. Id. § 312.34(b)(2).
65. Id. § 312.34(b)(3)(i).
66. Id. § 312.34(b)(3)(ii).
67. Investigational New Drug, Antibiotic, and Biological Drug Product Regulations, 52 Fed. Reg. 19,466, 19,467 (May 22, 1987) (codified at 21 C.F.R. pt. 312) ("FDA will apply a common sense interpretation of the term so that death within more than a year would not normally be considered immediately life-threatening, but also that death within several days or even several weeks would be overly restrictive.").
68. Id. ("For example, an anti-retroviral drug might be found on the basis of Phase 2 studies, when used early after infection, to delay progression .... Although this progression would ordinarily take more than twelve months to occur in most patients, this circumstance would be interpreted as fitting the definition of immediately life-threatening.").
69. 21 C.F.R. § 312.7(d).
70. Id.
71. Id.
72. Perrin, supra note 20, at 129.
73. Id.
74. Id. at 127.
75. Sheila R. Shulman & Jeffrey S. Brown, The Food and Drug Administration's Early Access and Fast-Track Approval Initiatives: How Have They Worked?, 50 FOOD & DRUG L.J. 503, 508 (1995).
76. Id. at 507. Subpart E created a more collaborative process between drug manufacturers and the FDA during development and approval of drugs for life-threatening and serious diseases. See 21 C.F.R. §§ 312.80-88. Accelerated approval allowed drugs providing a "meaningful therapeutic benefit" over existing treatments to be approved based on "surrogate endpoints" reasonably likely to predict a clinical benefit. See 21 C.F.R. §§ 314.500-510, 601.40-41; see also Schulman & Brown, supra note 75, at 514-17. While treatment INDs involved with these two programs had improved FDA approval times, treatment INDs not involved with the programs had approval times almost three years longer than non-treatment INDs. Schulman & Brown, supra note 75, at 507.
77. See Investigational New Drug, Antibiotic, and Biological Drug Product Regulations, 52 Fed. Reg. 19,466, 19,471 ("[C]omments asserted that such use is inconsistent with the grant of authority in section 505(i) of the act allowing FDA to exempt from otherwise applicable provisions of the law new drugs intended 'solely for investigationa) use....'"); see also Richard J. Nelson, Note & Comment, Regulation of Investigational New Drugs: "Giant Step for the Sick and Dying "?, 77 GEO. L.J. 463, 481 (1988) ("Because treatment INDs have never been statutorily approved, they run afoul of Congress' prohibition against introducing or delivering unapproved drugs into interstate commerce.").
78. Nelson, supra note 77, at 484; see also Young Testimony, supra note 59, at 71 (describing the possibility of treatment INDs undercutting controlled clinical trials as one major concern of those criticizing the 1987 regulations).
79. Nelson, supra note 77, at 485.
80. Id. at 478.
81. Perrin, supra note 20, at 137.
82. See Investigational New Drug, Antibiotic, and Biological Drug Product Regulations, 52 Fed. Reg. 19,467-68 (listing examples of when no satisfactory or comparable alternative therapy is available and stating that "comments were concerned that PDA should not interpret th[e] criterion in an overly restrictive way so as, for example, to preclude granting of a treatment IND where there is any approved drug or therapy available"); see also Patient Access to Alternative Treatments: Beyond the FDA: Hearings Before the H. Comm. on Gov't Reform and Oversight, 105th Cong. 28 (1998) [hereinafter Beyond the FDA] (statement of Berkley Bedell, former Member of Congress) (citing the no alternative therapy rule as a "clear obstacle" to patient access). See generally Michael E. Horwin, "War on Cancer": Why Does the FDA Deny Access to Alternative Cancer Treatments?, 13 ALB. L.J. SCI. & TECH. 681, 713 (2003) (heavily criticizing the FDA's no alternative therapy rule as a substantial block to patient access).
83. See Horwin, supra note 82, at 713; see also Beyond the FDA, supra note 82, at 46-47 (statement of Mary Jo Seigel) (discussing her choice between chemotherapy, involving severe side effects and a fifty-percent chance of developing an additional cancer, and a less toxic experimental therapy).
84. Beyond the FDA, supra note 82, at 66 (statement of Jack Kunnari) (discussing how Jack Kunnari refused to submit his son to chemotherapy's side effects after the "doctors could not name a single child who had done well following" this treatment for the same type of cancer); Horwin, supra note 82, at 684 (listing side effects of chemotherapy to include infection, pain, nausea, vomiting, hair loss, ear and lung damage, small stature, ineffectiveness, and even death).
85. Horwin, supra note 82, at 684-85.
86. See Shulman & Brown, supra note 75, at 508 ("[S]ponsors may have become even more wary of the potential problems and uncertainties of IND implementation, including the cost of making the drugs available, third party payers' contractual exclusion of reimbursement for experimental therapies, and, in some cases, for the care associated with their administration.").
87. Id.
88. Id.; see also 21 C.F.R. § 312.34(c) (requiring treatment IND sponsors to comply "with the safeguards of the IND process, including... submission of IND safety reports").
89. Groopman, supra note 1, at 46.
90. Id. at 40-41 (discussing patient who made little headway with the FDA in getting expanded access until a Congressman and Wall Street Journal writer became involved).
91. See id. (discussing how patient died shortly after FDA told her husband that a treatment IND would be granted if the manufacturer submitted an application).
92. Food and Drug Administration Modernization Act of 1997, Pub. L. No. 105-115, 111 Stat. 2296 (1997) (codified in scattered sections of 21 U.S.C.).
93. Id. § 402.
94. Id.
95. Id.
96. Id.
97. Id.
98. Id.; see also Expanded Access to Investigational Drugs for Treatment Use, 71 Fed. Reg. 75,147, 75,149 (Dec. 14, 2006) (to be codified at 21 C.F.R. pt. 312) ("Section 561(c) of the act [authorizing large-scale treatment INDs] closely tracks existing [§] 312.34 of the END regulations.").
99. Food and Drug Administration Modernization Act of 1997, Pub. L. No. 105-115, § 402, 111 Stat. 2296, 2365-67 (codified at 21 U.S.C. § 360bbb).
100. Id.
101. See Groopman, supra note 1, at 42 (stating that the FDA had begun drafting new expanded access regulations when the Abigail Alliance decision came down).
102. See Expanded Access to Investigational Drugs, 71 Fed. Reg. at 75,147, 75,150, 75,157.
103. Id. at 75,150.
104. Id. at 75,151,
105. Id.
106. Id.
107. Id.
108. Id. at 75,150.
109. Id.
110. Id. at 75,153.
111. Id. ("[E]xpanded access for an individual patient would not be available, for example, if the patient can participate in a clinical trial of the investigational drug.").
112. Id. at 75,154.
113. Id. (explaining the second criterion for intermediate-size populations "requires that there be at least preliminary clinical evidence of effectiveness of the drug or of a plausible pharmacologic effect... in the anticipated patient population").
114. Id. at 75,155.
115. Id.
116. Id.
117. Id.
118. Charging for Investigational Drugs, 71 Fed. Reg. 75,168, 75,169 (Dec. 14, 2006) (to be codified at 21 C.F.R. pt. 312).
119. Id. at 75,170, 75,172.
120. Id. at 75,172.
121. Id. at 75,172-73.
122. Id. at 75,173.
123. See Expanded Access to Investigational Drugs, 71 Fed. Reg. 75,147, 75,158 (Dec. 14, 2006) (to be codified at 21 C.F.R. pt. 312) (predicting that proposed regulations will increase the number of individual and intermediate-size expanded access programs).
124. Id. at 75,148.
125. Expanded Access to Investigational Drugs, 71 Fed. Reg. at 75,148 (stating that the 1987 regulations "explicitly provide[d] for one specific kind of treatment use: ... broad access to investigational drugs under... a treatment IND").
126. 21 C.F.R. § 312.34(b)(3)(i).
127. Perrin, supra note 20, at 141 ("In practice the Treatment END merely serves to bridge the time between the end of Phase III and general market approval.").
128. Expanded Access to Investigational Drugs, 71 Fed. Reg. at 75,147, 75,150, 75,157.
129. Id. at 75,153.
130. See id. at 75,158 (predicting that the proposed rule will "increase the number of individual patients seeking access").
131. See id.
132. Id. at 75,154.
133. See id. at 75,158 ("[B]y explicitly clarifying the eligibility criteria and submission requirements... the proposed rule should make the process of obtaining access to investigational drugs more efficient for all affected parties.").
134. See Nelson, supra note 77, at 484; see also Young Testimony, supra note 59, at 71 (describing the possibility of treatment INDs undercutting controlled clinical trials).
135. See generally MATHIEU, supra note 6.
136. See Expanded Access to Investigational Drugs, 71 Fed. Reg. at 75,150.
137. See Steven R. Salbu, Regulation of Drug Treatments for HIV and AIDS: A Contractarian Model of Access, 11 YALE J. ON REG. 401, 426 (objecting to the government forcing seriously ill patients to participate in clinical trials and to undertake the risks of experimental drugs, which they may not have otherwise agreed to). Salbu suggests possible alternative ways of data collection to lessen the need for double blind studies with placebos such as varying levels of dosage, using meta-analysis, or using other types of field research methods. Id. at 434-39.
138. See Nelson, supra note 77, at 484.
139. Expanded Access to Investigational Drugs, 71 Fed. Reg. at 75,150 (stating that "the agency has tried to strike the appropriate balance between authorizing access to promising drugs for treatment... and ensuring the integrity of the drug approval process").
140. 21 C.F.R. § 312.34(b)(1)(iii)-(iv).
141. Expanded Access to Investigational Drugs, 71 Fed. Reg. at 75,152.
142. Id. at 75,151.
143. Id. at 75,152.
144. Charging for Investigational Drugs, 71 Fed. Reg. 75,168, 75,170 (Dec. 14, 2006) (to be codified at 21 C.F.R. pt. 312) ("Generally, the costs of conducting a clinical trial are costs that the sponsor should bear."). Clinical participants expose themselves to unknown risks and should "not be expected to pay for the drug." Id.
145. See Charging for Investigational Drugs, 71 Fed. Reg. at 75,170-71 (allowing direct costs, but not providing any other financial incentives to companies); Expanded Access to Investigational Drugs, 71 Fed. Reg. at 75,150.
146. See Shulman & Brown, supra note 75, at 508; supra notes 104-09 and accompanying text.
147. Expanded Access to Investigational Drugs, 71 Fed. Reg. at 75,151.
148. See id. at 75,151; U.S. Dep't of Health and Human Servs., Food and Drug Admin., Guidance for Industry: Available Therapy, July 2004, available at http://www.fda.gov/cber/gdhis/availther.htm.
149. See Expanded Access to Investigational Drugs, 71 Fed. Reg. at 75,151.
150. Horwin, supra note 82, at 683-84.
151. See id. See generally notes 94-103 and accompanying text.
152. Beyond the FDA, supra note 82, at 66 (statement of Jack Kunnari).
153. See Salbu, supra note 137, at 428.
154. Expanded Access to Investigational Drugs, 71 Fed. Reg. at 75,150.
155. Id. at 75,150-51.
156. See, e.g., ClinicalTrials.gov, Clinical Studies of Gemcitabine-Oxaliplatin, http://www.clinicaltrials.gov/ct/show/NCT00407433? order=5 (listing requirements for participation in study on mellublastomas in children as allowing prior chemotherapy or radiation but not requiring these therapies).
157. See Salbu, supra note 137, at 428.
158. See id. at 435.
159. See supra notes 140-41 and accompanying text.
160. See discussion infra section IV.B.2.b.
161. Expanded Access to Investigational Drugs, 71 Fed. Reg. 75,147, 75,151 (Dec. 14, 2006) (to be codified at 21 C.F.R. pt. 312); see also U.S. Dep't of Health and Human Servs., Food and Drug Admin., Guidance for Industry: Available Therapy, July 2004, available at http://www.fda.gov/cber/gdlns/availther.htm.
162. See STEPHEN J. CECCOLI, PILL POLITICS: DRUGS AND THE FDA 158-159 (2004).
163. David Loughnut, Potential Interactions of the Orphan Drug Act and Pharmacogenomics: A Flood of Orphan Drugs and Abuses?, 31 AM. J.L. & MED. 365, 371 (2005).
164. See Steven R. Salbu, The FDA and Public Access to New Drugs: Appropriate Levels of Scrutiny in the Wake of HIV, AIDS, and the Diet Drug Debacle, 79 B.U. L. REV. 93, 123 (1999) (citing criticisms of provisions of the FDAMA that loosened restrictions on promotion of off-label uses because the absence of approval means there is "'no credible scientific evidence of the safety and effectiveness for that use ... or no one has bothered to present the information to the FDA"'); see also Horwin, supra note 82, at 706 (stating that most chemotherapy treatments for brain cancer have not been FDA approved for use on children).
165. Most drugs used in experimental access have completed Phase I testing in which basic safety and toxicology information is gained along with preliminary evidence on effectiveness; furthermore, many drugs are undergoing or have completed Phase II or III testing where more data on safety and effectiveness is gathered. See supra notes 33-37 and accompanying text.
166. Expanded Access to Investigational Drugs, 71 Fed. Reg. at 75,151.
167. See Beyond the FDA, supra note 82, at 46-76, 81-93 (cataloguing testimony of patients who believed available therapies were not satisfactory or comparable to potential experimental therapies for their conditions).
168. Expanded Access to Investigational Drugs, 71 Fed. Reg. at 75,158.
169. See id. at 75,154 (explaining use of experimental drugs in larger patient populations usually requires more clinical experience than for individual use).
170. Id. at 75,150 ("FDA may place an ongoing expanded access IND... on clinical hold if it is determined that the pertinent criteria... are no longer satisfied (e.g., a satisfactory alternative therapy becomes available." (emphasis added)).
171. Id.
172. Groopman, supra note 1, at 40-41.
173. See generally MATHIEU, supra note 6, at 179-205 (describing the possible delays and pitfalls of the long and complicated NDA review process).
174. Charging for Investigational Drugs, 71 Fed. Reg. 75,168, 75,170 (Dec. 15, 2006) (to be codified at 21 C.F.R. pt. 312).
175. Id. at 75,169.
176. Id.
177. Id. at 75,172.
178. Id.
179. See supra notes 104-09 and accompanying text.
180. See Nelson, supra note 77, at 484 (mentioning possibility of extending companies' patents without further detail).
181. Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. 1585 (codified in scattered sections of 21 U.S.C.) [hereinafter Hatch-Waxman Act].
182. Orphan Drug Act, Pub. L. No. 97-414, § 527 96 Stat. 2049, 2050 (1982) (codified as amended at 21 U.S.C. §360cc).
183. David Duffield Rohde, The Orphan Drug Act: An Engine or Innovation? At What Cost?, 55 FOOD & DRUG L.J. 125, 133 (2000) ("[T]he expectation of market exclusivity and the ability to obtain a limited monopoly encourage innovation.").
184. See Ashlee B. Mehl, Note & Comment, The Hatch-Waxman Act and Market Exclusivity for Generic Drug Manufacturers: An Entitlement or an Incentive?, 81 CHI.-KENT L. REV. 649,651 (2006).
185. See Rebecca S. Eisenberg, The Problem of New Uses, 5 YALE J. HEALTH POL' Y. L. & ETHICS 717, 730 (2005) (stating that Hatch-Waxman market exclusivity rewards firms for investing in clinical trials); Rohde, supra note 183, at 133 (suggesting that without market exclusivity many orphan drugs would not exist).
186. Orphan Drug Act § 527.
187. Hatch-Waxman Act, Pub. L. No. 98-417, 98 Stat. 1585 (1984) (codified in scattered sections of 21 U.S.C.).
188. Best Pharmaceuticals for Children Act, Pub. L. No. 107-109, § 4, 115 Stat. 1408, 1411-12 (2002) (codified at 21 U.S.C. § 355a(d)) [hereinafter BPCA]. The market exclusivity extension for children's testing was originally authorized under section 505A of the FDAMA in 1997. Food and Drug Administration (FDA) Modernization Act of 1997, Pub. L. No. 105-115, 111 Stat. 2296 § 505A (codified in scattered sections of 21 U.S.C.). Section 505A had a sunset provision, and the BPCA was passed to renew the market extension with only minor changes and to add new incentives for child testing. Glenn Cohen, Therapeutic Orphans, Pediatric Victims? The Best Pharmaceuticals for Children Act and Existing Pediatric Human Subject Protection, 58 FOOD & DRUG L.J. 661,667-70 (2003).
189. See Robert A. Bohrer & John T. Prince, A Tale of Two Proteins: The FDA's Uncertain Interpretations of the Orphan Drug Act, 12 HARV. J.L. & TECH. 365, 372 (1999) ("[A]warding a monopoly to an innovative product is generally economically justified - despite the monopoly output restrictions and the correspondingly higher prices - when the investment in innovation would be unlikely without market protection."); Eisenberg, supra note 185, at 730 (stating that Hatch-Waxman market exclusivity rewards firms for investing in clinical trials); Rohde, supra note 183, at 133 (suggesting that without the market exclusivity many orphan drugs would not exist).
190. See Orphan Drug Act § 527. For a full summary of the Orphan Drug Act's provision and impact, see Rohde, supra note 183.
191. See Eisenberg, supra note 185, at 726.
192. See id. at 727.
193. Hatch-Waxman Act, Pub. L. No. 98-417, 98 Stat. 1585 (2002) (codified in scattered sections of 21 U.S.C.). For a full discussion of the Hatch-Waxman Act and its impact, see Mehl, supra note 184.
194. See supra notes 183-85 and accompanying text.
195. See Rohde, supra note 183, at 133.
196. See Bohrer & Prince, supra note 189, at 372.
197. FDA approval requires rigorous clinical testing and no expanded access program may interfere with the "initiation, conduct, or completion of clinical investigations that could support marketing approval." Expanded Access to Investigational Drugs, 71 Fed. Reg. 75,147, 75,166 (Dec. 14, 2006) (to be codified at 21 C.F.R. pt. 312).
198. BPCA, Pub. L. No. 107-109, § 4 115 Stat. 1407, 1411-12 (2002) (codified at 21 U.S.C. § 355a(d)).
199. Id.; see also Eisenberg, supra note 185, at 729-30.
200. See Cohen, supra note 188, at 664.
201. See id.; see also Sujatha Vathyam, Note, No More "Hand-Me-Dawns" Please!: Children Deserve Medical Devices Specifically Designed for and Tested on Children, 58 RUTGERS L. REV. 719, 732 (2006) (stating that adult purchases make up most of the drug sales).
202. See Vathyam, supra note 201, at 733 (explaining that the six-month exclusivity forces consumers to pay more for their drugs).
203. See supra notes 86-91 and accompanying text.
204. Presumably, the FDA restricts manufacturers to recovering only direct costs for expanded access in pan because the company will eventually make a large profit on some drugs undergoing testing. See Charging for Investigational Drugs, 71 Fed. Reg. 75,168, 75,170-71 (Dec. 14, 2006) (to be codified at 21 C.F.R. pt. 312) (explaining the FDA's motives for providing a cost-recovery provision).
205. See supra notes 86-91 and accompanying text.
206. See Eisenberg, supra note 185, at 730 (describing BPCA exclusivity extension as extending "any existing market exclusivity ... whether under a patent, the Orphan Drug Act, or Hatch-Waxman...").
207. See supra notes 86-91 and accompanying text.
208. See Rohde, supra note 183, at 131 (describing the market exclusivity of the Orphan Drug Act as a success in encouraging drug companies to bring drugs treating rare diseases to market); Vathyam, supra note 201, at 733 (stating that the exclusivity extension under the BPCA provided invaluable information and encouraged new labeling for children).
209. See Rohde, supra note 183, at 130 ("[P]harmaceutical manufacturers cite the grant of seven years marketing exclusivity as the most important incentive to orphan drug research and development." (quoting John J. Flynn, The Orphan Drug Act: An Unconstitutional Exercise of the Patent Power, 2 UTAH L. REV. 389, 395 (1992))).
210. Bohrer & Prince, supra note 189, at 381.
211. See Cohen, supra note 188, at 666 ("[S]ince enactment of the pediatric exclusivity provision, both the numbers of drugs studied in children and the therapeutic classes they represent have substantially increased." (quoting Janet Heinrich, GAO Director for Health Care)).
212. Patents are usually granted at the initial discovery of a chemical or process, and the 20-year patent term runs throughout animal testing, clinical trials, and FDA approval, which can take up to ten years. See CECCOLI, supra note 162, at 87 (stating drugs average 6.5 years prior to marketing after initial submission to the FDA for clinical testing approval); MATHIEU, supra note 6, at 6 (stating that pre-clinical animal testing lasts an average of 3.5 years).
213. See Nelson, supra note 77, at 481 (stating that sponsors allowed to sell experimental drugs will have less incentive to pursue New Drug Applications because they can recoup costs).
214. See, e.g., Bohrer & Prince, supra note 189, at 374 (explaining that Orphan Drug Act market exclusivity only attaches for the "first manufacturer to receive full FDA drug approval").
215. See Vathyam, supra note 201, at 732 (discussing how companies stood to gain high profits from exclusivity extensions under the BPCA, which caused companies to accept FDA requests to shoulder the costs of testing children).
216. See Charging for Investigation Drugs, 71 Fed. Reg. 75,168, 75,178 (Dec. 15, 2006) (to be codified at 21 C.F.R. pt. 312) (describing the "significant concern... [of] the potential affect [sic] on access to investigational therapies for economically disadvantaged individuals and the uninsured" when companies are allowed to charge for investigational drugs); Expanded Access to Investigational Drugs, 71 Fed. Reg. 75,147, 75,149 (Dec. 14, 2006) (to be codified at 21 C.F.R. pt 312) (describing concern that "patients treated outside of academic medical centers are less likely to have access to investigational drugs for treatment use").
217. See, e.g., Vathyam, supra note 201, at 733.
218. See id
219. See id. (explaining that companies try to lower costs of pediatric testing by conducting less rigorous testing in order to gain a higher profit margin).
220. See Mark D. Shtilerman, Pharmaceutical Inventions: A Proposal for Risk-Sensitive Rewards, 46 IDEA 337, 338 (2006) (discussing how companies have financial incentives to produce imitations of drugs already on the market over novel drugs with complicated chemistry or smaller patient populations).
221. See id. at 361-62.
222. See id. at 363 (showing that expected returns for copycat drugs are much higher than for novel or orphan drugs).
223. See Salbu, supra note 137, at 436-39 (discussing how allowing more experimental drug access can provide "valuable information," "feedback on the use of experimental drugs" for patients, and "secondary quality statistical findings," while not replacing the gold standard of double-blind placebo studies). Since clinical trials are explicitly protected by the expanded access regulations, expanded access will simply be providing additional information.
224. See id. at 435-36.
225. See Shulman & Brown, supra note 75, at 508.
226. See Salbu, supra note 137, at 435.
227. See Shulman & Brown, supra note 75, at 508 (suggesting that "limitations on the use of... data submitted in marketing applications" may have created company skepticism in treatment INDs).
228. See supra notes 80-82 and accompanying text.
229. See U.S. FOOD & DRUG ADMIN., FAST TRACK, ACCELERATED APPROVAL & PRIORITY REVIEW, (2006), available at http://www.fda.gov/oashi/ fast.html (stating that getting data on "clinical outcomes" such as living longer or feeling better can take a long time" and using surrogate endpoint[s] "can considerably shorten the time required prior to receiving FDA approval").
230. Salbu, supra note 137, at 432.
231. See Ralph F. Hall, The Risk of Risk Reduction: Can Postmarket Surveillance Pose More Risk than Benefit?, 62 FOOD & DRUG L.J. 473,474 (2007).
232. CTR. FOR DRUG EVALUATION, FOOD & DRUG ADMIN., GUIDANCE DRUG SAFETY INFO.-FDA's COMM'N TO THE PUB. 4, (Mar. 2007), http://www.fda.gov/cder/guidance/7477fnl.pdf. [hereinafter GANCE DRUG SAFETY].
233. Id. at 4.
234. See id.
235. Hall, supra note 231, at 474.
236. See supra notes 134-44 and accompanying text.
237. Expanded Access to Investigational Drags, 71 Fed. Reg. 75,147, 75,154 (Dec. 14, 2006) (to be codified at 21 C.F.R. pt. 312).
238. See id.
239. See id. at 75,160.
240. See id. at 75,162.