Expanded access to phase II clinical trials in oncology: A step toward increasing scientific validity and compassion

Food and Drug Law Journal

Volumn 63, Issue 2, 2008, Pages 439-457

  Marcee, Alice K ^a  

^a SMU Dedman School of Law   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CETUXIMAB; PLACEBO; SULFANILAMIDE; THALIDOMIDE;

BIRTH DEFECT; CANCER PATIENT; CLINICAL TRIAL; COURT; DOCTOR PATIENT RELATION; DRUG APPROVAL; DRUG EFFICACY; DRUG INDUSTRY; DRUG LEGISLATION; DRUG SAFETY; DRUG SURVEILLANCE PROGRAM; FOOD AND DRUG ADMINISTRATION; GOVERNMENT REGULATION; HEAD AND NECK CARCINOMA; HEALTH CARE ACCESS; HEALTH PROMOTION; HUMAN; HUMAN RIGHTS; LAW SUIT; MEDICAL DECISION MAKING; MEDICAL ETHICS; MEDICOLEGAL ASPECT; NON PROFIT ORGANIZATION; ONCOLOGY; PATIENT DECISION MAKING; PHASE 2 CLINICAL TRIAL; REVIEW; RISK BENEFIT ANALYSIS; SQUAMOUS CELL CARCINOMA; TERMINALLY ILL PATIENT; VALIDITY;

CLINICAL TRIALS, PHASE II AS TOPIC; DRUG APPROVAL; EMPATHY; GOVERNMENT REGULATION; HEALTH SERVICES ACCESSIBILITY; HUMANS; MEDICAL ONCOLOGY; PUBLIC HEALTH PRACTICE; RANDOMIZED CONTROLLED TRIALS AS TOPIC; RESEARCH SUPPORT AS TOPIC; SCIENCE; TERMINAL CARE; UNITED STATES; UNITED STATES FOOD AND DRUG ADMINISTRATION;

EID: 44849096576     PISSN: 1064590X     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (186)

1. Steven Ginsberg, Cancer trial may be too late to save weakened student, FORT WAYNE J. GAZETTE (Ind.), June 7, 2001, available at 2001 WL 9686849.
2. Susan Okie, Perspective, Access before Approval - A right to take experimental drugs?, 355 NEW ENG. J. MED. 437, 438 (Aug. 3, 2006).
3. John Mendelsohn & Jose Baselga, Status of Epidermal Growth Factor Receptor Antagonists in the Biology and Treatment of Cancer, 21 J. CLINICAL ONCOLOGY 2787, 2789 (July 15, 2003).
4. Okie, supra note 2, at 438.
5. Id. at 438.
6. Ginsberg, supra note 1.
7. Id.
8. Id.
9. FDA News: FDA Approves First Head and Neck Cancer Treatment in 45 Years Data Shows Treatment with Erbitux Extends Survival, March 1, 2006, available at http://www.fda.gov/bbs/topics/NEWS/2006/NEW01329.html (last visited Sep. 12, 2007).
10. Abigail Alliance for Better Access to Investigational Drugs, The Abigail Story, at http://www.abigail-alliance.org/story.htm (last visited Sep. 26, 2007).
11. Abigail Alliance for Better Access to Investigational Drugs, Mission Statement, at http://www.abigail-alliance.org/mission.htm (last visited July 9, 2007).
12. Citizen Petition of the Abigail Alliance & Wash. Legal Found. to the FDA, U.S. Dept. Health Human Serv., In re Tier 1 Initial Approval Program to Expedite the Availability of Lifesaving Drugs, June 11. 2003, at http://www.abigail-alliance.org/WLF_FDA.pdf (last visited Sep. 20, 2007).
13. Id. at 7.
14. Abigail Alliance for Better Access to Developmental Drugs v. McClellan, No. 03-1601 (D.D.C. Aug. 30, 2004).
15. Id. at 9.
16. Id. at 9-10.
17. Abigail Alliance for Better Access to Developmental Drugs v. von Eschenbach, 495 F.3d 695, 697 (D.C. Cir. 2007) (en banc).
18. Id. at 697.
19. Abigail Alliance, 495 F.3d at 713 (en banc) (citing Rutherford, 444 U.S. 554 (1979)).
20. 495 F.3d 695 (2007), appeal docketed, No. 07-444 (U.S. Oct. 1, 2007), at http://www.supremecourtus.gov/docket/07-444.htm (last visited Oct. 8, 2007).
21. 495 F.3d 695 (2007), cert. denied, No. 07-444 (U.S. Jan. 14, 2008), available at http://www.supremecourtus.gov/orders/courtorders/ 011408pzr.pdf.
22. Jeremy Waldron, Essay, The Core of the Case Against Judicial Review, 115 YALE L.J. 1346, 1406 (2006) (arguing that judicial review of rights-based legislation is not appropriate in democratic societies).
23. See Abram Chayes, The Role of the Judge in the Political Law Litigation. 89 HARV. L. REV. 1281 (1976).
24. Frank Burroughs, Press Release, Abigail Alliance Supports ACCESS Act, (Nov. 10, 2005) at http://www.abigail-alliance.org/ AbigailAlliancesupportsACCESSAct_1_.pdf (last visited Sep. 15, 2007).
25. Thomas, Library of Congress, at http://thomas.loc.gov/cgi-bin/ bdquery/z?d109:SN 01956:@@@X (last visited Oct. 18, 2007).
26. Charging for Investigational Drugs, 71 Fed. Reg. 75168 (proposed December 14, 2006) (to be codified at 21 C.F.R. pt. 312).
27. 21 U.S.C. § 393 (2007).
28. 21 U.S.C. § 393 (b) (2007).
29. Robert M. Califf, Clinical Trials Bureaucracy: Unintended consequences of well-intended policy, 3 CLINICAL TRIALS 496-502 (2006) (arguing that the FDA's drug approval process is unnecessary complex, expensive and less efficient in answering questions that inform patients and physicians);
30. Melissa Marie Bean, Comment & Note, Fatal Flaws in the Food and Drug Administrations Drug-Approval Formula, 2003 UTAH L. REV. 881 (2003) (explaining that FDA is too cozy with the pharmaceutical industry which allowed the industry to abuse the expedited drug approval process);
31. Diedtra Henderson & Christopher Rowland, Once "Too Slow," FDA Approvals Called "Too Fast", BOSTON GLOBE, Apr. 10, 2005, at A1.
32. See infra p. 444.
33. U.S. Dep't Health Human Serv., Final Report of the Advisory Committee on the Food and Drug Administration, (Wash. D.C. May 1991).
34. Abigail Alliance, No. 03-1601, at 1-2 (D.D.C. Aug. 30, 2004).
35. Expanded Access to Investigational Drugs for Treatment Use, 71 Fed. Reg. 75147 (proposed December 16, 2006) (to be codified at 21 C.F.R. pt. 312).
36. Oxford English Dictionary (2nd ed. 1989), available at http://dictionary.oed.com
37. Tom L. Beauchamp & James F. Childress, PRINCIPLES OF BIOMEDICAL ETHICS, 115 (5th ed. 2001).
38. Steven H. Woolf et. al., Perspective, Promoting Informed Choice: Transforming Health Care to Dispense Knowledge for Decision Making, 143 ANNALS INTERNAL MED. 293, 294 (Aug. 16, 2005).
39. See infra p. 443.
40. Abigail Alliance, 445 F.3d 470 (D.C. Cir. 2006), vacated by 495 F.3d 695 (2007).
41. Washington v. Glucksberg, 521 U.S. 702, 720 (1997) (explaining that by extending constitutional protection to an asserted right the courts place the matter outside the arena of public debate and legislative action).
42. Abigail Alliance, 495 F.3d at 706 (en banc) (examining the history of Congress and the FDA in responding to risks from new drugs).
43. Id. at 715-716 (en banc) (Rogers, J., dissenting).
44. Abigail Alliance, 495 F.3d at 709 n.15 (en banc).
45. DCER Time Line: Chronology of Drug Regulation in the United States, at http://www.fda.gov/cder/about/history/time1.htm (last visited July 9, 2007).
46. Carol Ballentine, Taste of Raspberries, Taste of Death: The 1937 Elixir Sulfanilamide Incident. F.D.A CONSUMER MAG. (June 1981), at http://www.fda.gov/oc/history/elixir.html (last visited July 9, 2007).
47. 21 U.S.C. § 301 (2007).
48. Id.
49. DCER Time Line: Chronology of Drug Regulation in the United States, at http://www.fda.gov/cder/about/history/time1.htm (last visited July 9, 2007).
50. Id.
51. It is presently accepted in the scientific and medical community that thalidomide may be a safe and effective drug for use in patients with multiple myeloma. But it must not be used by pregnant women, a subgroup of the public. This highlights a theme that runs throughout this article. An unsafe drug or therapy for one group is not necessarily unsafe for other groups within the public. FDA recognizes this through its labeling requirements on what subgroups of the public the drug has not been proven safe for administration. See e.g. Seema Singhal et. al., Antitumor Activity of Thalidomide in Refractory Multiple Myeloma, 341 NEW ENG. J. MED. 1565-1571 (Nov. 18, 1999);
52. Paul G. Richardson et. al., New Drugs for Myeloma, 12 ONCOLOGIST 664-689 (2007);
53. Office of Oncolocy Drug Products, FDA Approves Thalomid (thalidomide) to Treat Multiple Myeloma, May 26, 2006, at http://www.fda.gov/cder/ Offices/OODP/whatsnew/thalidomide.htm (last visited Oct. 10, 2007).
54. DCER Time Line: Chronology of Drug Regulation in the United States, at http://www.fda.gov/cder/about/history/timel.htm (last visited July 9, 2007).
55. Paul Duggan, 1,000 Swarm FDA's Rockville Office to Demand Approval of AIDS Drugs, WASH. POST, Oct. 12, 1988, at B1.
56. Id.
57. 21 C.F.R. § 312.80-312.88 (2007).
58. 57 Fed. Reg. 13250 (Apr. 15, 1992) (final policy statement).
59. Brief of Amici Curiae American Society of Clinical Oncology et. al. at 19-20, Abigail Alliance, 495 F.3d 695 (en banc) (No. 04-5350).
60. Corrected En Banc Brief for the Appellees at 33, Abigail Alliance, 495 F.3d 695 (en banc) (No. 04-5350) (citing 21 U.S.C. § 355(a), (b), (d) (2007); 21 C.F.R. § 312.21(b)-(c) (2007)).
61. 21 C.F.R. § 312.21(a)(1) (2007).
62. Lawrence Friedman, Curt Furberg & David DeMets, FUNDAMENTALS OF CLINICAL TRIALS, 4 (3r ded. 1998).
63. Id.
64. Thomas G. Roberts et.al., Trends in the Risks and Benefits to Patients with Cancer Participating in Phase I Clinical Trials, 292 JAMA 2130, 2131 (Nov. 3, 2004).
65. Id.
66. Id.
67. Id.
68. Friedman, Furberg & DeMets, supra note 58, at 4.
69. 21 C.F.R. § 312.21 (b) (2007).
70. James J. Schlesselman & Isildinha M. Reis, Phase II Clinical Trials in Oncology: Strengths and Limitations of Two-Stage Designs, 24 CANCER INVESTIGATION 404, 405 (2006).
71. 21 C.F.R. § 312.21 (c) (2007).
72. Id.
73. 21 C.F.R. § 312.85 (2007).
74. 21 C.F.R. § 312.80-312.88 (2007).
75. 21 C.F.R. § 312.85 (2007).
76. Food and Drug Administration Amendments Act of 2007, Pub. L. No. 110-85, 121 Stat. 823 (2007).
77. Gen. Acct. Off., FDA Drug Review: Postapproval risks, 1976-85, (GAO/PEMD-90-15) (Apr 26, 1990).
78. 21 U.S.C. § 355(d)-(e) (2007).
79. Id.
80. 21 U.S.C. § 355 (a) (2007).
81. 21 U.S.C. § 355 (i) (2007).
82. 21 C.F.R. § 312 (2007).
83. 21 C.F.R. § 314 (2007).
84. Expanded Access to Investigational Drugs for Treatment Use, 71 Fed. Reg. 75148 (proposed December 14, 2006) (to be codified at 21 C.F.R. pt. 312) (explaining FDA's long history of permitting access to investigational drugs through informal means).
85. Id.
86. Food and Drug Modernization Act of 1997, Pub. L. No. 105-115, 111 Stat. 2296 (codified at 21 U.S.C. § 360bbb (2007)).
87. Id.
88. 21 U.S.C. § 360bbb (c)(2) (2007).
89. 21 U.S.C. § 360bbb (3)(A)-(B), (4) (2007).
90. 21 C.F.R. § 312.35 (b)(1) (2007).
91. Id.
92. Expanded Access to Investigational Drugs for Treatment Use, 71 Fed. Reg. 75165 (proposed December 14, 2006) (to be codified at 21 C.F.R. pt. 312) (estimating the reporting burden).
93. Id.
94. 21 C.F.R. § 312.34 (b) (2007).
95. 21 C.F.R. § 312.34 (a) (2007).
96. Corrected En Banc Brief for the Appellees, supra note 56, at 13-14 (quoting 71 Fed. Reg. 75153).
97. 21 C.F.R. § 312.34 (b)(3)(ii) (2007).
98. 21 C.F.R. § 312.34 (b)(3)(i) (2007).
99. Expanded Access to Investigational Drugs for Treatment Use, 71 Fed. Reg. 75147 (proposed December 14, 2006) (to be codified at 21 C.F.R. pt. 312).
100. Id.
101. Joel B. Finkelstein, News, FDA Clarifies Rules for Getting Experimental Drugs. 99 J. NAT'L CANCER INST. 584, 584 (Apr. 18, 2007).
102. Id.
103. Id.
104. Charging for Investigational Drugs, 71 Fed. Reg. 75168 (proposed December 14, 2006) (to be codified at 21 C.F.R. pt. 312).
105. 21 C.F.R. § 312.7 (d)(2) (2007).
106. See Expanded Access to Investigational Drugs for Treatment Use, 71 Fed. Reg. 75148 (proposed December 14, 2006) (to be codified at 21 C.F.R. pt. 312);
107. Charging for Investigational Drugs, 71 Fed. Reg. 75168 (proposed December 14, 2006) (to be codified at 21 C.F.R. pt. 312).
108. Corrected En Banc Brief for the Appellees, supra note 56, at 50-51.
109. 21 C.F.R. § 312.84 (a) (2007).
110. 21 U.S.C. § 360bbb (b)(3), (c)(5) (2007).
111. 21 U.S.C. § 360bbb (b)(3), (c)(5) (2007); 21 C.F.R. § 312.42 (b)(4)(ii) (2007).
112. Corrected En Banc Brief for the Appellees, supra note 56, at 14 (quoting 71 Fed. Reg. 75153).
113. See Donna St. George, Time in a Bottle; A new generation of precision cancer drugs is seducing patients with the possibility of adding months, even years, to their lives. If only they could get their hands on them, WASH. POST, Jan. 18, 2004, at W10;
114. Judy Foreman, A push for wider use of experimental drugs; Advocates are suing to ease the rules for seriously ill patients willing to risk taking unapproved medicines, LOS ANGELES TIMES, Sep. 29, 2003, at F1.
115. See Martha Minow, Symposium: Honoring Justice Thurgood Marshall, Choices and Constraints: For Justice Thurgood Marshall, 80 Geo. L.J. 2093 (1992).
116. Richard Delgado & Helen Leskovac, Article, Informed Consent in Human Experimentation: Bridging the Gap Between Ethical Thought and Current Practice, 34 UCLA L. Rev. 67, 93 (1986).
117. Corrected En Banc Brief for the Appellees, supra note 56, at 9-10.
118. Manish Agrawal & Ezekiel J. Emanuel, Special Communication, Ethics of Phase 1 Oncology Studies: Reexamining the Arguments and Data, 290 JAMA 1075, 1080 (2003).
119. Office of the Commissioner, FDA, Initiatives, Law Strengthens FDA, at http://www.fda.gov/oc/initiatives/advance/fdaaa.html (last visited Oct. 6, 2007) (announcing the signing of the Food and Drug Administration Amendments Act).
120. Corrected En Banc Brief for the Appellees, supra note 56, at 55-56.
121. Id. at 10-11.
122. Id. at 57-58.
123. Id. at 55-56.
124. U.S. v. Rutherford, 442 U.S. 455-456 (1979).
125. Abigail Alliance, 495 F.3d at 712 (en banc).
126. Beauchamp & Childress, supra note 35, at 59.
127. Id.
128. Corrected En Banc Brief for the Appellees, supra note 56, at 10.
129. Alan Meisel, Managed Care, Autonomy, and Decisionmaking at the End of Life, 35 HOUSTON LAW REVIEW. 1393, 1397-1398 (1999).
130. Beauchamp & Childress, supra note 35, at 79.
131. Nat'l Comm'n for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report, Apr. 18, 1979, available at http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm#xjust (last visited July 9, 2007).
132. Beauchamp & Childress, supra note 35, at 80-88.
133. Id. at 88-93.
134. Id. at 80.
135. Agrawal & Ezekiel J. Emanuel, supra note 112, at 1080.
136. Paul Appelbaum et. al., False Hopes and Best Data: Consent to Research and the Therapeutic Misconception, 17 HASTINGS CTR. REP. 20, 22 (Apr. 1987).
137. Elizabeth Horstmann et. al., Risks and Benefits of Phase 1 Oncology Trials, 1991 through 2002. 352 NEW ENG. J. MED. 895 (2005).
138. Id. at 899.
139. Id.
140. Corrected En Banc Brief for the Appellees, supra note 56, at 10.
141. Brief of Amici Curiae American Society of Clinical Oncology et. al. at 18, Abigail Alliance, 495 F.3d 695 (en banc) (No. 04-5350).
142. Corrected En Banc Brief for the Appellees, supra note 56, at 10-11.
143. Brief of Amici Curiae American Society of Clinical Oncology et. al. at 9-10, Abigail Alliance, 495 F.3d 695 (en banc) (No. 04-5350).
144. Id.
145. 21C.F.R. § 312.7 (d)(1) (2007).
146. Okie, supra note 2, at 440.
147. Charging for Investigational Drugs, 71 Fed. Reg. 75168 (proposed December 14, 2006) (to be codified at 21 C.F.R. pt. 312).
148. Marcia Angell, Excess in the Pharmaceutical Industry. 12 CAN. MED. ASS'N J.171 (Dec. 7, 2004).
149. John Simons, Big Pharma's Tough Medicine: Giant Drugmakers Have Announced a Record Number of Layoffs in 2007 as They Overhaul their Businesses in the Hopes of Reviving their Sluggish Share Prices, Dec. 13, 2007, FORTUNE, available at http://money.cnn.com/2007/12/10/news/ companies/pharmajayoffs.fortune/index.htm (last visited Jan. 21, 2007).
150. Id.
151. Peter Landers, Cost of Developing a New Drug Increases to About $1.7 Billion, WALL STREET JOURNAL, Dec. 8, 2003, at B4.
152. Marcia Angell, The Truth about Drug Companies, Interview by Peter Meredith. September 7, 2004. at http://www.motherjones.com/news/qa/2004/ 09/09_401.html (last visited July 9, 2007);
153. Jeff Gerth & Shryl Gay Stolberg, Medicine Merchants: Birth of a Blockbuster; Drug Makers Reap Profits on Tax-Backed Research, NEW YORK TIMES, Apr. 23, 2000, at 1.
154. Stuart A. Green, The Origins of Modern Clinical Research, 405 CLINICAL ORTHOPAEDICS RELATED RES. 311, 311-312 (2006).
155. Ezekiel Emanuel et.al., Special Communications, What Makes Clinical Research Ethical?, 283 JAMA 2701, 2708 (2000).
156. Sharona Hoffman, The Use of Placebos in Clinical Trials: Responsible Research or Unethical Practice?, 33 CONN. L. REV. 449 (2001).
157. See Richard Peto, Large Scale Randomized Evidence: Large, simple trials and overviews of trials, 48 J. CLINICAL EPIDEMIOLOGY 23 (1995);
158. Shivaani Kummar et. al., Opinion, Compressing Drug Development Timelines in Oncology Using Phase "0" Trials, 7 NATURE REV. CANCER 131 (2007);
159. Liam Smeeth et.al., Commentary: We Still Need Observational Studies - They Just Need to be Better, 35 INT'L J. EPIDEMIOLOGY 1310, 1310-1311 (2006).
160. Corrected En Banc Brief for the Appellees, supra note 56, at 9-10.
161. Id.
162. Id.
163. Expanded Access to Investigational Drugs for Treatment Use, 71 Fed. Reg. 75148 (proposed December 14, 2006) (to be codified at 21 C.F.R. pt. 312).
164. Id.
165. Corrected En Banc Brief for the Appellees, supra note 56, at 10.
166. David Casarett, Ethical Considerations in End-of-Life Care and Research, 8 J. PALLIATIVE MEDICINE 148, 157 (Supp. 2005) (advocating the selection of patients with treatment alternatives as an element of protecting voluntariness).
167. Beauchamp & Childress, supra note 35, at 93.
168. Manish Agrawal, Special Article, Voluntariness in Clinical Research at the End of Life, 25 J. PAIN SYMPTOM MGMT. 25, 28 (Supp. 2003).
169. Abigail Alliance, 445 F.3d 470, 480 (D.C. Cir. 2006), vacated by 495 F.3d 695 (2007).
170. Friedman, Furberg & DeMets, supra note 58, at 4.
171. Melissa Fazzari et.al., The Phase II/III Transition: Toward the Proof of Efficacy in Cancer Clinical Trials, 21 CONTROLLED CLINICAL TRIALS 360, 361 (2000).
172. 21 C.F.R. § 312.34 (b)(3)(ii) (2007) (defining immediately life threatening as a stage of a disease in which there is a reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment).
173. Jan Hoffman, Being a Patient, The Ethics of Hope, Doctors' Delicate Balance in Keeping Hope Alive, NEW YORK TIMES, Dec. 24, 2005, at A2.
174. Corrected En Banc Brief for the Appellees, supra note 56, at 14.
175. Friedman, Furberg & DeMets, supra note 58, at 5.
176. Id.
177. Corrected En Banc Brief for the Appellees, supra note 54, at 33 (citing 21 U.S.C. § 355(a), (b), (d) (2007); 21 C.F.R. § 312.21(b)-(c) (2007)).
178. Fazzari, supra note 162, at 363.
179. Mohammad I. Zia et. al., Comparison of Outcomes of Phase II Studies and Subsequent Randomized Control Studies Using Identical Chemotherapeutic Regimens, 23 J. CLINICAL ONCOLOGY 6982, 6985 (Oct. 1, 2005).
180. Fazzari, supra note 162, at 361.
181. Id.
182. Id. at 363.
183. FDA Media Teleconference, Food and Drug Administration Amendments Act of 2007 (Sept. 27, 2007), available at http://www.fda.gov/oc/initiatives/ advance/fdaa.html (last visited Oct. 6, 2007).
184. 42 U.S.C. § 282 (j)(2)(C)(ii) (2007).
185. Press Release, United States Senator Ted Kennedy, Kennedy on FDA Revitalization Act (Apr. 18, 2007), available at http://kennedy.senate. gov/newsroom/press_release.cfm?id=087B5657-0331-4A67-B7B6-97F80010504C (last visited Oct. 6, 2007).
186. Maurie Markman, Commentary, Ethical Conflict in Providing Informed Consent for Clinical Trials: A Problematic Example from the Gynecologic Cancer Research Community, 9 ONCOLOGIST 3, 7 (2004).