Download TREATMENT INDs: A FASTER ROUTE TO DRUG APPROVAL?

TREATMENT INDs: A FASTER ROUTE
TO DRUG APPROVAL?
MYRON L. MARLIN
INTRODUCTION
When a new virus plagues the nation, the public summons the
scientific community to devise innovative ways to mitigate the problem. 1 Although major victories invariably occur in the lab, progress
is also made by advancements in the law. 2 In many cases, medical
tragedies lead to the establishment of new laws and regulations for
3
the pharmaceutical industry.
The current Acquired Immune Deficiency Syndrome (AIDS)4 epidemic is one medical problem which has created controversy and
initiated legislative activity. 5 With thousands of patients facing imminent death 6 and no marketable drugs available, 7 the medical com1. See F. Young, Remarks at Treatment IND Conference, Washington, D.C. (Feb. 16,
1988) (available in FDA Medical Library) [hereinafter F. Young, Remarks] (explaining how
executive branch called upon medical and scientific communities to accelerate review and
availability of AIDS therapies).
2. See infra notes 41 & 49-51 and accompanying text (describing tragedies that resulted
in new drug legislation).
3. See P. TEMIN, TAKING YOUR MEDICINE: DRUG REGULATION IN THE UNITED STATEs 2743, 120-26 (1980) (describing incidents which spurred passage of new laws and regulations
within food and drug industry).
4. Current medical research postulates that infection with a human retrovirus causes
AIDS. AIDS in CorrectionalFacilities: Issues and Options, U.S. Department of Justice, National
Institute forJustice (3d ed. 1988). Id. The virus incorporates itself into genetic material and
disrupts the flow of genetic messages. Id. It begins to attack certain white blood cells which
are an integral part of the human immune system, thereby weakening an individual's ability to
ward off disease. Id.
5. See The AIDS Bill, NEWSWEEK, Oct. 24, 1988, at 10 (stating that 175 demonstrators
converged upon FDA headquarters to demand faster government approval of drugs for
AIDS); A CapitalOutlay, a Capital Outcry, U.S. NEws & WORLD REP., Oct. 24, 1988, at 14 (reporting on activists' protests against government's alleged delay in fighting AIDS).
6. Bishop, DesperateLives, Unknown Risks: AIDS Patientsand DrugManufacturers Fight FDA
Controlof Experimental Treatments, CAL. LAW., Sept. 1987, at 45 (revealing shocking numbers of
AIDS victims). Approximately 35 Americans are diagnosed with the AIDS virus every day. Id.
The Center for Disease Control anticipates that 324,000 cases will be diagnosed by 1991, as
compared with 38,160 as ofJuly 1987. Id. By 1991, as many as 179,000 people will have died
from AIDS. Id.; see also Chi. Tribune, Aug. 16, 1988, § 1, at 4, col. 1 (ranking AIDS disease
15th among all causes of death).
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munity recognized the need to expedite the drug approval process. 8
This process, described in the Federal Food, Drug, and Cosmetic
Act (FDCA), 9 requires that drugs be proven safe and effective
before they may be approved for commercial marketing.' 0 The road
to marketability, however, may take more than seven years, and thus
potential cures might not reach patients in time." Consequently, a
major debate concerning the FDCA resulted in the establishment of
a new route to drug approval. 12 This procedure, referred to as the
"Treatment Use of an Investigational New Drug,"1 or "treatment
IND," provides individuals with serious or immediately life-threatening diseases access to drugs still in the experimental or investiga7. The first drug to treat AIDS, zidovudine (AZT), was not approved for commercialization until 1987. Interim Rule, 53 Fed. Reg. 41,516 (1988) (supplementary information).
8. See Bishop, supra note 6, at 46 (describing network of medical facilities, called "guerilla clinics," specifically designed to circumvent lengthy drug approval process); see also Interim Rule, 53 Fed. Reg. 41,516 (1988) (codified at 21 C.F.R. §§ 312, 314) (indicating need to
expedite development, evaluation, and marketing procedure for certain new therapies).
9. Federal Food, Drug, and Cosmetic Act, ch. 675, §§ 1-902, 52 Stat. 1040 (1938) (current version at 21 U.S.C. §§ 301-392 (1982 & Supp. V 1987)).
10. See 21 U.S.C. § 355(d) (1982 & Supp. V 1987) (outlining approval criteria for application for interstate sale of new drugs). The relevant section of the Act states:
If the Secretary finds, after due notice to the applicant ...that (1) the investigations,
reports of which are required to be submitted to the Secretary ... do not include
adequate tests by all methods reasonably applicable to show whether or not such
drug is safe for use under the conditions prescribed, recommended, or suggested in
the proposed labeling thereof; (2) the results of such tests show that such drug is
unsafe for use under the such conditions or do not show that such drug is safe for
use under such conditions; (3) the methods used in, and the facilities and controls
used for, the manufacture, processing, and packing of such drug are inadequate to
preserve its identity, strength, quality, and purity; (4) upon the basis of the information submitted to him as part of the application, or upon the basis of any other information before him with respect to such drug, he has insufficient information to
determine whether such drug is safe for use under such conditions; or (5) evaluated
on the basis of the information submitted to him as part of the application and any
other information before him with respect to such drug, there is a lack of substantial
evidence that the drug will have the effect it purports or is represented to have under
the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof ... he shall issue an order approving the application.
Id.
11. Ballin, Regulation and Development of New Drugs,J.A.M.A.,June 4, 1982, at 2995, 299596 (acknowledging delay in drug approval process). The approval process for a new drug may
take between seven and ten years, and may cost a pharmaceutical company $70 million. Id. at
2995. This "drug lag" reduces pharmaceutical productivity and explains why drugs may be
approved much faster in a foreign country than in the United States. Id.; see F. Young, Remarks, supra note 1 (indicating that required three phases of clinical investigation could last as
long as seven years).
12. See Fast Track Approval For InvestigationalNew Drugs: Fire Out, Smoke Remains, HEALTnSPAN, Mar. 1988, at 2 [hereinafter Fast Track Approval] (noting that idea to expedite drug approval process generated heated discussions). After the FDA presented its proposal to revise
the drug approval process, it received over 300 comments from health professionals, research
institutions, pharmaceutical manufacturers, consumer groups, and other concerned individuals. Final Rule, 52 Fed. Reg. 19,466 (1987) (supplementary information); see also 21 C.F.R.
§ 312 (1989) (pronouncing expedited process by which drugs for life-threatening diseases
and serious illnesses may be made available).
13. 21 C.F.R. § 312.34 (1989).
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tional stage.'
Although the treatment IND procedure was codified in 1987,15
similar procedures allowing for the availability of investigational
drugs have existed in an ad hoc, unwritten form for two decades. 1 6
The treatment IND provision, however, is beset with ethical and
practical dilemmas and thus may not provide the only appropriate
route to drug approval.17
Whereas the 1987 regulation encouraged early availability of
drugs already on a route to marketability,' 8 a 1988 interim rule
shortens that route by allowing for a more flexible drug approval
standard.' 9 If this interim rule becomes finalized, it may decrease
reliance on the treatment IND process. 20 Yet, striking similarities
between the 1988 interim rule and earlier regulations have caused
skepticism regarding the interim rule's actual effect. 2 '
This Comment analyzes these provisions and explores the effects
they will have upon the medical profession and the pharmaceutical
industry. The Comment begins with a discussion in Part I of the
FDCA's history, focusing on those provisions related to the approval of new drugs. In Part II, it details the approval process for
drugs not otherwise granted treatment IND status. Part III explains
the treatment IND approval process and the intricacies of the 1987
treatment IND regulation. Part IV recognizes the importance of the
treatment IND regulation and also reveals the inherent flaws in the
process. Part V describes the 1988 interim rule and indicates its
limited effects upon prior legislation. Finally, this Comment offers
suggestions and recommendations for improving and expediting
the drug approval process.
14. See id. (outlining guidelines and circumstances for implementation of treatment IND
process).
15. See id. § 312 (providing guidelines for applications for investigational new drugs).
16. Young, The FDA's New Proceduresfor the Use of Investigational Drugs in Treatment, J.
A.M.A., Apr. 15, 1988, at 2267 [hereinafter Young, FDA's New Procedures](explaining that new
treatment IND regulation is built on past experience). Since the mid-1970s, there have been
several cases of patients, not enrolled in any clinical study, gaining access to investigational
new drugs for treatment purposes. Id. at 2267-68.
17. See infra notes 164-220 and accompanying text (discussing obstacles of treatment
IND route to drug approval).
18. See 21 C.F.R. § 312.34 (1989) (indicating that it may be appropriate to use investigational drug for treatment purposes).
19. See Interim Rule, 53 Fed. Reg. 41,516 (1988) (codified at 21 C.F.R. § 312.80 (1989))
(describing purpose of regulation as expediting marketing of new therapies).
20. See Booth, FDA Looks to Speed Up DrugApproval Process, 241 SCIENCE 1426, 1426 (1988)
(reporting that 1988 interim rule was intended to expedite drug approval after disappointing
results of treatment IND regulation).
21. See infra notes 246-58 and accompanying text (comparing 1988 regulation with older
regulations).
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I.
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AN HISTORICAL PERSPECTIVE
Although food and drug laws have existed in some form since the
beginning of civilization, 22 the United States government did not
pass legislation to protect consumers from dangerous drugs until
the nineteenth century. 23 One of the first laws, entitled "An Act to
prevent the Importation of adulterated and spurious Drugs and
Medicines," ' 24 required that imported drugs be labeled correctly and
be certified as having a medical use. 25 The Act, however, did not
require an objective safety standard and failed to regulate harmful
products manufactured in the United States. 2 6 Nevertheless, more
27
than fifty years passed before Congress took its next major step.
In 1906, despite strenuous opposition from food and drug manufacturers, 28 Congress passed the Pure Food and Drugs Act. 29 Con22. See Janssen, The U.S. Food and Drug Law: How it Came; How it Works, 35 FOOD DRUG
Cosm. L.J. 132, 132 (1980) (demonstrating that food and drug laws have been necessary since
beginning of civilization). Whether the food and drug regulations were those of the early
Hebrews and Egyptians, or the Greeks and Romans, the need to protect the consumer and
ensure safety clearly was recognized. Id. The Hebrews and Egyptians passed laws governing
the handling of meat, and the Romans and Greeks forbade adding water to wine and prohibited short measures for grain and cooking oil. Id. In the Middle Ages, trade guilds inspected
spices and drugs in order to combat adulteration. Id. Additionally, the Magna Carta unified
the measures of certain foods throughout the realm. Id.
23. See Hutt, Drug Regulations in the United States, 2 INTL. J. OF TEcH. ASSESSMrNT IN
HEALTH CARE 619, 619 (1986) [hereinafter Hutt, Drug Regulations] (describing Vaccine Act of
1813 as Congress' first regulatory legislation). This legislation was enacted following the discovery of a vaccine for smallpox. Id. Although repealed in 1822, the Act provided for the
appointment of a federal agent to "preserve the genuine vaccine matter and to furnish the
same to any citizen." Id. at 619-20; see also Comment, The Right of Privacy in ChoosingMedical
Treatment. Should Terminally Ill Persons Have Access to Drugs not yet Approved by the Food and Drug
Administration?, 20 J. MARSHALL L. REV. 693, 696-97 (1987) [hereinafter Comment, Privacy]
(implying that even though many state statutes were promulgated to address food and drug
issues, Congress was slow in passing legislation).
American colonists established many food laws to promote trade. Janssen, supra note 22, at
133. American merchants, concerned about rejection of their goods at foreign ports, instituted quality controls for their merchandise. Id. Although early colonial laws dealt largely
with foods rather than drugs, records of fines for bartering ineffective cures can be traced
back several centuries. Id.
24. Ch. 70, §§ 1-7, 9 Stat. 237 (1848). Congress passed this Act when it was commonly
believed that dangerous drugs were prepared in other countries for sale in the United States.
See Comment, Privacy, supra note 23, at 696 (describing 1848 Act).
25. Ch. 70, § 3, 9 Stat. 237, 238 (1848).
26. See Comment, Privacy, supra note 23, at 696 (indicating that objective standard would
help determine drug's safety and purity).
27. SeeJanssen, supra note 22, at 134 (describing emergence of Pure Food & Drugs Act);
Comment, Privacy, supra note 23, at 696 (noting that next significant legislation, Pure Food &
Drugs Act, did not appear for almost 60 years).
28. Janssen, supra note 22, at 134 (describing concerns of patent medicine manufacturers, then largest advertisers, that Act would severely curtail business). Medicines were touted
as being able to cure every disease and symptom, and lists of ingredients and warnings against
misuse were virtually nonexistent. Id. at 133-34. Instead, consumers discovered defects
through everyday use. Id. at 134.
29. Pure Food and Drugs Act of 1906, ch. 3915, §§ 1-13, 34 Stat. 768, repealed by Federal
Food, Drug, and Cosmetic Act of 1938, ch. 675, § 902(a), 52 Stat. 1040, 1059 (codified at 21
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gress overwhelmingly approved this Act because of national public
concern over commercial food preparation."0 The Act outlawed the
foreign and domestic drug manufacturers' practice of false and misleading labeling. 3 ' Additionally, the Act required a complete description of a drug's contents and ensured the monitoring of a
drug's strength, quality, and purity.3 2 This law, however, was difficult to enforce 3 3 due to the absence of pre-market review,3 4 the understaffing of scientific examiners to study the products,3 5 and the
fact that the government had the burden of proving the manufac36
turer's actual fraud.
The passage of the Federal Food, Drug, and Cosmetic Act
(FDCA) of 193837 addressed many of the shortcomings of the 1906
Act.3 8 Although industry pressure initially led to an overwhelming
U.S.C. § 301 (1982)). Twenty-seven years of congressional debate preceded its enactment.
Hutt, Drug Regulations, supra note 23, at 620.
30. SeeJanssen, supra note 22, at 134 (explaining that despite opposition from many in
business community, sponsor of bill had great support in Congress); see also P. TEMIN, supra
note 3, at 27-29 (detailing publicity effects of muckraking articles by Samuel Hopkins Adams
and Upton Sinclair's The Jungle); Yakowitz, The Evolution of the Drug Laws of the United States,
1906-1964, 19 FOOD DRUG CosM. LJ. 296, 297 (1964) (discussing progression of nation's
drug laws).
31. See Hutt, Development of Federal Law Regulating Slack Fill and Deceptive Packagingof Food,
Drugs, and Cosmetics, 42 FooD DRUG CosM. LJ. 1, 1-2 (1987) (describing congressional intent
behind new Act); Comment, Picking Your Poison: The Drug Efficacy Requirement and the Right of
Privacy, 25 UCLA L. REv. 577, 580 (1978) [hereinafter Comment, Picking Your Poison] (indicating that Act was intended to prevent unsubstantiated therapeutic claims).
32. Food and Drug Act, ch. 3915, §§ 1-13, 34 Stat. 768 (1906) (repealed 1938). The Act
empowered the Department of Agriculture's Bureau of Chemistry to conduct examinations of
food and drugs to determine compliance with the Act. Id. § 4. Upon finding violations, the
Secretary of Agriculture was to inform the parties involved and certify the issue to a U.S.
District Attorney for legal action. Id. §§ 4-5. Additionally, the Act provided for seizure and
disposal of violative substances shipped either interstate or from abroad. Id. § 10.
33. See Comment, Privacy, supra note 23, at 697 (describing deficiencies in 1906 Act); see
also infra notes 34-36 and accompanying text (providing specific examples of enforcement
difficulties).
34. See Comment, Privacy, supra note 23, at 697 (citing deficiencies in Act which made it
impossible to insure that consumers were protected from unsafe products).
35. See H. GRABOWSKI &J. VERNON, THE REGULATION OF PHARMACEUTICALS: BALANCING
THE BENEFITS AND RISKS 24-25 (1983) (providing evidence to prove that number of FDA new
drug examiners is disproportionately small and noting that numbers have remained virtually
unchanged for past decade).
36. See P. TEMIN, supra note 3, at 30-31 (detailing drug manufacturer's relatively small
obligations under law). The law banned "adulterated or misbranded" drugs. Id. The government, however, had a burden of proving misrepresentation. Id. at 30. The manufacturer
was not legally bound to disclose the contents of the drugs unless they contained alcohol or
narcotics, but the law compelled full disclosure if the manufacturer of it chose to list the
contents. Id. Even then, it remained the government's responsibility to monitor the manufacturer. Id.
37. Ch. 675, § 501, 52 Stat. 1040, 1049 (1938) (codified at 21 U.S.C. § 351 (1982 &
Supp. V 1987)).
38. See Janssen,supra note 22, at 135-37 (revealing problems that new legislation addressed); see also infra notes 42-45 and accompanying text (detailing provisions of new
regulation).
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congressional rejection in 1933,39 Congress eventually accepted a
40
final, compromise-ridden version of the legislation five years later.
This sudden change in congressional attitude resulted from the
poisoning of more than 100 people in 1937 by a product called
41
Elixir of Sulfanilamide.
In order to prevent the industry's practice of false claims, the Act
of 1938 eliminated the need to prove fraud and provided specific
authority for factory inspection. 4 2 A pre-marketing requirement for
scientific proof of safety, however, specifically distinguished this regulation from the 1906 Act. 43 Enforced by the Food and Drug
Administration (FDA),4 4 this law exempted those drugs being used
45
for investigational purposes from the Act's safety requirement.
39. SeeJanssen, supra note 22, at 135-36. In 1933, the Assistant Secretary of Agriculture
Rexford Tugwell received President Franklin D. Roosevelt's approval to introduce a bill to
revise the Food and Drug Act. Id. Opposition from industry and advertising interests, however, was overwhelming, and the "Tugwell bill" failed. Id.
40. See id. (describing how sponsors began five-year revision process that retained essential consumer protection elements of bill).
41. Id. at 135. Although no research was available and no tests were performed on the
drug's toxicity, the manufacturer nonetheless distributed it to the public. Cavers, The Food,
Drug, and Cosmetic Act of 1938: Its Legislative History and its Substantive Provisions, 6 LAw & CONTEMP. PROBS. 2, 20 (1939). After more than 100 people died from ingestion of this drug, the
FDA intervened. Id. The Agency's only legitimate basis for intervention, however, was product mislabeling. Id. Apparently, the lethal substance, diethylene glycol, was not listed, and
the product could not be considered an "elixir" because it did not contain alcohol. Id.
42. Janssen, supra note 22, at 136 (adding that although compromises were needed to
ensure passage, bill also provided for federal court injunctions against violations).
43. See Federal, Food, Drug, and Cosmetic Act, ch. 675, § 505, 52 Stat. 1040, 1052
(1938) (current version at 21 U.S.C. § 355 (1982 & Supp. V 1987)) (indicating criteria for
drug approval);Janssen, supra note 22, at 136-37 (showing how amendments made manufacturers responsible for proving safety). Although a law requiring pre-market safety testing of
new drugs existed, the FDA did not possess the resources to determine the safety of every
drug on the market. Janssen, supra note 22, at 136-37. Three amendments, subsequently
approved, required manufacturers to conduct their own research on drugs. Id. These amendments invaluably aided the FDA. Id. at 137.
44. See Janssen, supra note 22, at 134 (describing history of Food and Drug Administration). Prior to 1927, the Bureau of Chemistry enforced the food and drug laws. Id. The
Food, Drug, and Insecticide Administration was established in 1927, and was renamed the
Food and Drug Administration in 1931. Id. The Department of Agriculture oversaw the
Agency until 1940, when the Federal Security Agency, later known as the Department of
Health, Education, and Welfare, assumed control of the Food and Drug Administration. Id.
45. Federal Food, Drug, and Cosmetic Act, ch. 675, § 505(i), 52 Stat. 1040, 1052 (1938)
(current version at 21 U.S.C. § 355(i) (1982)). This section currently states in pertinent part:
The Secretary shall promulgate regulations for exempting from the operation of
the foregoing subsections of this section drugs intended solely for investigational use
by experts qualified by scientific training and experience to investigate the safety and
effectiveness of drugs...
Such regulations shall provide that such exemption shall be conditioned upon the
manufacturer, or the sponsor of the investigation, requiring that experts using such
drugs for investigational purposes certify to such manufacturer or sponsor that they
will inform any human beings to whom such drugs ... are being administered ...
that such drugs are being used for investigational purposes and will obtain the consent of such human beings ... except where they deem it not feasible or, in their
professional judgment, contrary to the best interests of such human beings. ...
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Therefore, the law enabled drug manufacturers to conduct clinical
safety tests before the drug reached the market.
Although the 1938 FDCA protected consumers from unsafe and
misbranded drugs, congressional hearings more than two decades
later highlighted the Act's failure to regulate safe yet ineffective
products. 46 Under the 1938 Act, the FDA could ban ineffective
drugs only if the product's labeling claims were misleading. 47 This
cumbersome monitoring procedure, which required a showing of
48
fraud, served as the only way to eliminate ineffective drugs.
In 1962, after the drug thalidomide caused over 1,000 birth defects in Europe, congressional hearings focused ever greater attention on the shortcomings of the FDCA.49 Believing that no drug
was truly safe until proven effective, Congress unanimously passed
the 1962 Drug Amendments. 50 In'addition to requiring that drugs
be proven safe, the amendments required that, prior to marketing,
all new drugs be proven effective for their intended use.5 1
Although the amended Act required both "safety" and "effectiveness," Congress declined to provide any precise definitions of these
terms. 5 2 Nevertheless, Congress explicitly rejected a pre-market approval system that would have deemed ineffective any drug shown
46. Drug Industry Act of 1962: Hearings on H.R. 11581 & 11582 Before the House Comm. on
Interstateand Foreign Commerce, 87th Cong., 2d Sess. 63-64 (1962) [hereinafter Hearings] (testimony of H.E.W. Secretary Abraham Ribicoff) (stating that public health was jeopardized because, although removal of drug was allowed if mislabeled, consumers could still gain access
to safe but ineffective drug).
47. Federal Food, Drug, and Cosmetic Act, ch. 675, § 301(b)(c), 52 Stat. 1040, 1042
(1938).
48. See Hearings, supra note 46, at 63 (testimony of H.E.W. Secretary Abraham Ribicoff)
(pointing out that FDA required accumulation of evidence of fraud, as well as legal action to
remove product).
49. P. TEMIN, supra note 3, at 123-24. Although pregnant women in Europe used the
sedative thalidomide, the FDA was not convinced of its safety and refused to grant the drug
approval in the United States on the ground of "insufficient information." Id. at 123. The
application for approval of thalidomide in the United States finally was withdrawn after it was
determined that the drug caused the birth defect known as phocomelia. Id. Phocomelia,
which causes babies to be born without hands or feet, appeared at an alarming rate in Europe.
Id. This tragedy, like the elixir tragedy that helped to pass the 1938 Act, led to the passage of
the 1962 Drug Amendments. Id.; see supra note 41 and accompanying text (describing legitimate basis for FDA intervention in elixir tragedy).
50. Drug Amendments of 1962, Pub. L. No. 87-781, § 102(b), 76 Stat. 780, 781 (codified
as amended at 21 U.S.C. § 355(b) (1982 & Supp. V 1987)); see P. TEMIN, supra note 3, at 124
(demonstrating that Congress passed amendments which focused primarily on efficacy). The
irony of Congress' action is that even though thalidomide played a substantial role in the
passage of the 1962 Amendments, the drug was effective, but not safe. Id. Thus, the Amendments would have done little to prevent the approval of thalidomide. Id.; see Janssen, supra
note 22, at 137 (describing apparent purpose of drug regulation amendments).
51. Drug Amendments of 1962, Pub. L. No. 87-781, § 102(b), 76 Stat. 780, 781 (codified
as amended at 21 U.S.C. § 355(b) (1982 & Supp. V 1987)). The amendments inserted the
words "and whether such drug is effective in use" following "is safe for use." Id.
52. See Knauer, The Regulation of Drugs on the Basis of Relative Effectiveness, 42 FOOD DRUG
CosM. LJ. 323, 323-25 (1987) (alluding to Congress' refusal to define adequately terms
178
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to be less effective than comparable drugs. 55 Despite the definitional confusion that the provision engendered, the FDCA's re54
quirements remain essential criteria in the drug approval process.
II.
DESTINATION:
MARKET APPROVAL
With few exceptions, 55 investigational drugs must follow a set
route to marketability.5 6> The drug must undergo a battery of tests
to prove its safety and effectiveness. 57 Until it passes those tests, the
drug remains virtually inaccessible to those for whom it is intended. 58 If that non-marketable drug is accorded treatment IND
status, however, it becomes available before it reaches its final destination. 5 9 Nevertheless, the drug must continue to be tested until
marketability is granted.6 0 The following section describes the criteria for marketability.
A.
The InvestigationalNew Drug Process
In order for a drug to meet the FDCA's safety and effectiveness
requirements, the drug's "sponsor"6 1 must conduct "adequate and
well-controlled" clinical studies. 6 2 These clinical trials must pro"safe" in FDCA of 1938 or "effective" in amendments of 1962). But see Comment, Piching Your
Poison, supra note 31, at 580 (arguing that safety requirement is well defined by FDCA).
53. See Knauer, supra note 52, at 323-25 (explaining that Congress did not believe drug
should be precluded from market on basis of relative effectiveness). Congress indicated that
medical professionals, not legislators, should make therapeutic decisions and that drug regulations should not absolutely bar drugs with therapeutic value from reaching the market. Id.
54. 21 U.S.C. § 355(d) (1982 & Supp. V 1987); see infra note 10 and accompanying text
(detailing method of ensuring safety and effectiveness of drug).
55. See infra notes 227-42 and accompanying text (explaining new legislation which
would expedite drug approval for serious or life-threatening diseases).
56. See generally 21 C.F.R. § 312 (1989) (providing route which drugs must take to be
granted approval).
57. Id. § 314.126 (insisting upon "adequate and well-controlled" investigations of drug
to determine safety and effectiveness as required by FDCA).
58. See 21 U.S.C. § 355(a) (1982 & Supp. V 1987) (requiring that drug be approved
before introduction into commerce). But see infra notes 103-17 and accompanying text (explaining testing procedures and opportunities for patients to obtain drug if they happen to be
part of investigational study group); infra notes 150-52 and accompanying text (describing
compassionite INDs, which enable patients to gain access to drugs).
59. 21 C.F.R. § 312.34 (1989). Although the FDA receives 2,000 applications for new
drugs every year, the Agency has received only 11 applications requesting treatment IND
status. B. Poet, Treatment INDs-FDA Position, Presentation on the Treatment IND Rule,
Twelfth International Good Manufacturing Practices Conference, at the University of Georgia
(Feb. 23, 1988) (available in FDA Medical Library) [hereinafter B. Poet, Presentation].
60. 21 C.F.R. § 312.34(b)(1)(iv) (1989) (listing fourth criteria of treatment IND status as
active pursuit of marketing approval by drug's sponsor).
61. "'Sponsor' means a person who takes responsibility for and initiates a clinical investigation." Id. § 312.3(b). "The sponsor may be an individual or pharmaceutical company, govermental agency, academic institution, private organization, or other organization." Id.
62. Id. § 314.126 (stating that purpose of conducting well-controlled and adequate studies is to determine whether there is "substantial evidence" that new drug is effective).
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ceed according to the Investigational New Drug (IND) regulations
that the FDA promulgated.6 3 These studies, which require the investigational use of the unapproved drug, may commence only after
sponsors of the drug have filed an "Investigational New Drug Application" with the Agency. 64
65
If prior tests on laboratory animals have yielded positive results
6
6
and previous human experience with similar drugs
has been
favorable, the FDA may accept the IND application. 6 7 The sponsors, however, must still agree to perform the additional responsibilities listed in the regulation. 68 These responsibilities include: 1)
selecting qualified "investigators ' 6 9 to perform studies on the
drug; 70 2) monitoring the progress of drug tests; 7 ' 3) ensuring that
the investigators comply with the regulations and with the signed
agreement for the experimental plan;7 2 4) evaluating the evidence
of the safety and efficacy of the drug being tested;7 3 and 5) discontinuing the investigation upon the discovery of unreasonable and
63. Id. § 312 (describing method of processing investigational new drug applications).
64. Id. § 312.23 (describing content and format of IND application). Documents submit-
ted with the application must describe the studies to be conducted, provide the identities of
those sponsoring the tests, include protocols detailing the course of the study, offer chemical,
physiological or biological character of the drug substance, list the previous human experience with the investigational drug, and furnish any other relevant information requested by
the FDA. Id.
65. Id. § 312.23(a)(8) (mandating that pharmacological and toxicological effects of drug
upon laboratory animals or in vitro must be revealed in IND application). The sponsor of the
drug must conclude from this information that it is reasonably safe to conduct the proposed
clinical investigation. Id.
66. Id. § 312.23(a)(9). The relevant parts of the required IND format state that:
A summary of previous human experience known to the applicant, if any, with the
investigational drug [must be submitted with the IND application]. The information
is required to include the following:
(i) If the investigational drug has been investigated or marketed previously, either
in the United States or other countries, detailed information about such experience
that is relevant to the safety of the proposed investigation or to the investigation's
rationale...
(ii) If the drug is a combination of drugs previously investigated or marketed, the
information required under paragraph (a)(9)(i) of this section should be provided for
each active drug component...
(iii) If the drug has been marketed outside the United States, a list of the countries
in which the drug has been marketed and a list of the countries in which the drug has
been withdrawn from marketing for reasons potentially related to safety or
effectiveness.
Id.
67. See id. § 312.23 (describing IND requirements).
68. Id. § 312.50.
69. Id. § 312.3 (defining investigators as physicians who administer drugs and track subjects' progress).
70. Id. § 312.53(a) (determining qualification on basis of training and experience).
71. Id. § 312.56(a).
72. Id. § 312.56(b) (outlining procedures for sponsor who discovers that investigator is
not complying with regulations). Upon the conclusion of the investigator's participation, the
sponsor must require that the investigator return or dispose of the investigational drug. Id.
73. Id. § 312.56(c).
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significant risk to the public. 7 4
Once the drug achieves IND status, the investigation may progress through three phases, 75 which often overlap or occur simultaneously. 76 In Phase I, investigators administer the new drug for the
first time to human patients or "normal volunteers. ' 7 7 By introducing small amounts of the drug into the subjects and then gradually
increasing the dosage, investigators determine the metabolic and
pharmacological effects of the drug. 78 Although each drug follows
an individual timetable, the initial phase usually takes one to two
years to complete 7 9 and generally involves between twenty and
80
eighty patients.
In Phase II, investigators conduct controlled clinical studies to determine the drug's effectiveness and assess the "common short-term
side effects and associated risks." ' This phase is usually closely
85
monitored,8 2 involves no more than several hundred individuals,
and lasts an additional one to two years.8 4 Studies have revealed
that investigators detect and reject virtually all drugs eventually
deemed unsafe during Phase 11.85
74. Id. § 312.56(d) (describing sponsor's responsibility upon discovering drug is unsafe).
Upon determining that the investigation should be terminated, the sponsor must discontinue
it as soon as possible. Id.
75. Id. § 312.21 (delineating investigational stages of drug testing).
76. B. Poet, Presentation, supra note 59 (arguing that, in practice, phases actually are
contemporaneous); see 21 C.F.R. § 312.21 (1989) (permitting overlap of investigational
stages).
77. 21 C.F.R. § 312.21(a)(1) (1989). The regulation uses the term "normal volunteer."
Id. The industry defines this term as meaning those not afflicted with the disease for which
the drug is being tested. Interview with Armond Welch, Consultant, in Washington, D.C.
(Oct. 25, 1988) [hereinafter Interview with Welch]; Telephone interview with Bill Jochimsen,
Clinical Pharmacologist (Oct. 15, 1988) [hereinafter Interview with Jochimsen].
78. 21 C.F.R. § 312.21(a)(1) (1989). The regulation also suggests that investigators
should use this phase to gain early evidence on effectiveness. Id.
79. F. Young, Remarks, supra note 1.
80. Id.; 21 C.F.R. § 312.21(a)(1) (1989). Phase I is designed to determine the target
organs of toxicity, the preferred route of administration, and a safe dosage range. See B. Poet,
Presentation, supra note 59 (stating that drug's metabolism, absorption, and elimination may
also be computed at this phase).
81. 21 C.F.R. § 312.21(b) (1989) (outlining purposes of Phase II); B. Poet, Presentation,
supra note 59 (describing investigators' examination of drug's safety and effectiveness).
82. 21 C.F.R. § 312.21(b) (1989).
83. Id.; see B. Poet, Presentation, supra note 59 (targeting between 100-200 patients with
disease for treatment by drug).
84. See F. Young, Remarks, supra note 1 (mentioning that three phases take six to seven
years, of which Phase II comprises one to two years).
85. See id. (disclosing existence of studies proving importance of Phase II). According to
FDA Commissioner Young, most of the drugs that reach Phase III ultimately are approved for
marketing. Id. Studies have shown that of 174 INDs submitted to the FDA in the late 1970s,
70% reached Phase II. Id. Only 33%, however, managed to make their way into Phase III,
while 27% were able to complete Phase III successfully. Id. Based on the results of these
phases, the FDA approved 20% of the 174 drugs. Id. But see B. Poet, Presentation, supra note
59 (revealing that almost 50% of drugs tested in Phase I are abandoned because they are
unsafe or ineffective).
19891
TREATMENT
INDs
Finally, Phase III studies are considered expanded trials.8 6 After
evidence of effectiveness has been accumulated from the research
conducted in Phases I and II, Phase III serves to gather additional
data, such as the drug's adverse effects, in order to evaluate the
drug's overall risks and benefits.8 7 Phase III involves several hundred to several thousand individuals8 8 and may last more than three
years.89
According to federal regulations, sponsors should submit thorough descriptions of the various phases to the FDA.90 These descriptions, called protocols, provide criteria for the selection of
patients to be included in investigational study groups. 91 Actual
testing of the drug may not commence until these protocols are submitted9 2 and an institutional review board is established. 93
B.
Clinical Studies: The Viable Routes to Drug Approval
A drug's sponsor must conduct clinical investigations to distinguish a drug's effects from the effects of other unrelated influences. 94 According to the regulations, such investigations must be
"well-controlled" and "adequately conducted." 9 5 A clinical study
satisfies these standards if it is characterized by: 1) a clear indication
of the objectives;9 6 2) a method of selecting the appropriate sub86. 21 C.F.R. § 312.21(c) (1989). This phase may be controlled (one group of patients
receives drug while other group does not) or, it may be uncontrolled (all patients in study
receive drug). Id.
87. See id. (describing assessment of "effectiveness" and "safety" for risk/benefit analysis
and for physician labeling); B. Poet, Presentation, supra note 59 (noting that evidence of effectiveness and adverse effects are weighed heavily at this stage).
88. See 21 C.F.R. § 312.21(c) (1989) (outlining wide range of patients to be included in
last phase).
89. See F. Young, Remarks, supra note I (describing extensiveness of Phase III research
both in terms of number of patients and length of time involved).
90. See 21 C.F.R. § 312.23(a)(6) (1989) (detailing process for submitting description of
Phases I-III, called protocols). Protocols for Phase I studies may be less detailed and more
flexible than protocols for Phase II and III studies. Id. Phase I protocols need only include an
outline of the investigation and information about safety considerations. Protocols in Phases
II and III require more detail and should include contingency plans to meet any anticipated
deviation from the study design as the investigation proceeds. Id.
91. See id. § 312.23(a)(6)(iii)(c) (indicating that estimate of numbers of patients to be
studied is also included in protocol).
92. See id. § 312.20 (enumerating requirements for IND application, including protocol
submission).
93. Id. § 56.103. The Institutional Review Board is an oversight committee established
to protect the rights and welfare of patients involved in the clinical trials. Id. § 56.102(g).
These boards are comprised of at least five experts from different professions who are qualified to review the later phases of the clinical studies. Id. § 56.107.
94. See id. § 314.126(a) (stating that other influences may be spontaneous change in
course of disease, placebo effect, or biased observation studies for drug testing).
95. Id. § 314.126(a).
96. Id. § 314.126(b)(1). A summary and description of the proposed methods of analysis
need to be included in the protocol. Id.
182
THE AMERICAN UNIVERSITY LAW REVIEW
[Vol. 39:171
jects; 9 7 3) an assurance that the different study groups are comparable with respect to pertinent variables such as age, sex, and severity
of the disease; 98 4) a procedure to protect against bias; 99 5) a
method to ensure well-defined responses from patients;10 0 6) an
analysis of results to assess adequately the effects of the drug;'10 and
7) a design that permits a valid comparison of the test group with a
10 2
control group in order to assess the drug's effects.
To ensure adherence to these rules, the federal regulation outlines five types of accepted "controls" or studies that may be implemented. 10 3 The first type of control that the regulation lists is the
placebo concurrent control.' 0 4 This most widely accepted study
method' 0 5 compares the progress of patients who have taken the
actual test drug to the progress of those who have taken an inactive
substance.' 0 6 By implementing a "double-blind" testing method,
which prevents both the patient and the investigator from knowing
which patient is receiving the actual test drug, researchers substantially curtail investigational bias and produce highly accurate results
0 7
of the drug's effectiveness.'
A second method of investigation compares the test drug to other
known effective therapies ' l0 8 This method, called the "active treat97. See id. § 314.216(b)(3) (noting that method of patient selection ensures that subjects
have disease or condition being studied, or present evidence of susceptibility and exposure to
condition for which investigational drug is being tested).
98. See id. § 314.126(b)(4) (indicating that method of assigning patients into different
control groups be conducted in manner to minimize bias). Random assignment of groups is
the standard method to accomplish this objective. Id.
99. See id. § 314.126(b)(5) (describing need to minimize bias on part of subjects, observers, and analysts of data).
100. See id. § 314.126(b)(6) (providing that report of results should explain variables measured, methods of observation, and criteria used to assess response).
101. Id. § 314.126(b)(7). The report of the study should describe the results and analytic
methods used to evaluate them. Id.
102. See id. § 314.126(b)(2) (stating that protocol should describe study design accurately
to substantiate quantitative assessment of drug effect).
103. See id. (delineating studies that FDA recognizes).
104. See id. § 314.126(b)(2)(i) (describing elements of placebo concurrent control).
105. See Frankel, INDINDA REWRITE, 35 FooD DRUG Cosm. LJ. 260, 265 (1980) (asserting that regulations should set forth hierarchy of types of studies as determined by scientific
merit). The placebo control study has the greatest scientific merit among clinical studies. Id.
The active control study and the historic control study follow in that order. Id.; see also AusT.
NEw ZEALAND J. PSYCHIATRY, June 23, 1989, at 181 (indicating that placebo-controlled trials
are conventionally preferred above all others, and that treatments not supported by such
studies are viewed skeptically).
106. See 21 C.F.R. § 314.126(b)(2)(i) (1989) (describing how test drug is compared with
preparation designed to resemble test drug). Inactive substances are referred to as placebos.
See Interview with Welch, supra note 77 (providing terminology within medical industry).
107. See 21 C.F.R. § 314.126(b)(2)(i) (1989) (noting that "blinding" is applied to patient
or investigator, or both); see also Frankel, supra note 105 (claiming that placebo studies are of
highest scientific merit); Interview with Welch, supra note 77 (mentioning that placebo concurrent control is most accurate method of testing drug effectiveness).
108. See 21 C.F.R. § 314.126(b)(2)(iv) (1989) (explaining that these studies usually involve
1989]
TREATMENT
INDs
ment concurrent control,"' 0 9 usually is favored in situations where
administering inactive substances to patients would be detrimental.110 The third type of study that the FDA accepts is the "historical
control.""' This control method compares the test drug's results
with the disease's natural progression based on historical experi-
ence."
2
Investigators consider the historical control to be the least
reliable testing method" 3 and, therefore, reserve it for special circumstances." 4 The remaining two accepted methods of investigation involve comparing results of varying doses of the drug ("dosecomparison concurrent control")," 5 and comparing the progres-
sion of a disease in patients receiving no treatment at all to those
actually using the control drug ("no treatment concurrent con-
trol").
6
These last two procedures are of limited value when used
alone and thus are generally accompanied by other accepted meth-
ods of clinical control to achieve better results."
7
C. The New Drug Application
Once the control drug has passed through the clinical studies, the
drug's sponsor submits a new drug application (NDA) to the
"blinding" of patients, investigators, or both from knowing who has received which
substance).
109.
Id.
110. Situations where active concurrent controls are beneficial include instances where a
patient requires some type of effective remedy to prevent increased mortality, serious morbidity, or major inconvenience. See Frankel, supra note 105, at 265 (stating that sponsor of active
control study must demonstrate why this method is in patient's interest).
111. 21 C.F.R. § 314.126(b)(2)(v) (1989).
112. See id. (stating that results of treatment with test drug are compared with adequately
documented natural history of disease in comparable patients or populations).
113. See Interview with Welch, supra note 77 (downplaying value of historical studies); see
also 21 C.F.R. § 314.126(2)(v) (1989) (explaining that historical control populations cannot
be as well assessed with respect to pertinent variables as can placebo concurrent control
populations); Frankel, supra note 105, at 265 (placing historical control at bottom of hierarchy
of acceptable study methods); Kopelman, Consent and Randomized ClinicalTrials: Are There Moral
or Design Problems?, 1IJ. MEDICINE & PHILOSOPHY 317, 346 (1986) (finding that use of historical controls offers less adequate assurances than concurrent controls); Levy, Ethical Dilemma of
Placebo-ControlledTrials in Life-ThreateningIllnesses, 2 J. CLINICAL RESEARCH DRUG DEv. 145, 148
(1988) (stating that historical controls are biased because of differences in collecting and recording data, circumstances of treatment delivery, subject inclusion criteria, placebo effects in
different settings, and changes in natural history of diseases).
114. 21 C.F.R. § 314.126(b)(2)(v) (1989) (explaining that historical controls are used in
special circumstances such as when there is high and predictable mortality or where effect of
drug is self-evident).
115. See id. § 314.126(b)(2)(ii) (stating that at least two doses of drug are compared for
relative effect).
116. See id. § 314.126(b)(2)(iii) (suggesting no treatment control when objective measurements of effectiveness are available and placebo effect is negligible).
117. See id. § 314.126(b)(2)(ii) (stating that dose-comparison study may include additional
treatment groups such as placebo control or active control); id. § 314.126(b)(2)(iii) (indicating
that no-treatment concurrent controls should be used where objective measurements of effectiveness have been obtained).
THE AMERICAN UNIVERSITY LAW REVIEW
[Vol. 39:171
FDA.'1 8 This application requires the sponsor to detail the results
of the concluded studies." 19 Next, before the drug may be introduced into interstate commerce, the FDA must approve the application.1 20 If the studies fail to show that the drug is safe, 12 ' lack
sufficient supporting data concerning the drug's safety, 122 or fail to
provide substantial evidence that the drug will have the effect it purports, 123 then the FDA will reject the NDA, and thereby deny marketability.' 24 By the time that the FDA approves the NDA, two years
may have passed since the application was first submitted. 2 5
Even if the drug clears all of these hurdles, another obstacle remains. Postmarketing reports revealing unanticipated effects or disclosing adverse reactions may lead to removal of the drug from the
market.' 26 Although extended pre-marketing clinical studies are
designed to guard against most of these adverse reactions, they do
not replace the postmarketing surveillance and the extensive statistical base that public marketing provides. 12 7 Furthermore, delaying
market approval of apparently safe and effective drugs in order to
conduct further pre-marketing studies may leave an entire population of terminally ill patients without any viable treatment.1 28 In
such a situation, the benefits of expediting a drug's accessibility are
self-evident.
118. See 21 U.S.C. § 355(a)-(b) (1982 & Supp. V 1987) (stating that application is required
before any new drug is introduced into interstate commerce). The Federal Food, Drug, and
Cosmetic Act requires that the application include: (1) full reports of investigations to show
whether the new drug is safe for the proposed use and whether the drug is effective in use; (2)
a full list of the articles used as components of the drug; (3) a full statement of the composition of the drug; (4) a full description of the methods used in, and the facilities and controls
used for, the manufacture, processing, and packing of the drug; (5) drug samples; and (6)
specimens of the proposed labels for the drug. Id.
119. Id.
120. Id.
121. Id. § 355(d)(1).
122. Id. § 355(d)(4).
123. Id. § 355(d)(5). "Substantial evidence" means evidence consisting of adequate and
well-controlled clinical investigations amassed by experts qualified to evaluate the drug's effectiveness. Id. § 355(d)(7).
124. See id. § 355(d)(7) (describing grounds for refusal of new drug application).
125. See Hutt, Drug Regulation, supra note 23, at 623 (explaining that-although statute requires FDA to consider NDA within six months, average approval time is three years and
median approval time is two years).
126. See 21 U.S.C. § 355(e) (1982 & Supp. V 1987) (stating that application may be suspended if drug is found to pose imminent hazard to public health). For a description of
postmarketing surveillance standard, see Faich, Postmarketing Surveillance of Prescription Drugs:
Current Status, FDA CLINICAL REAL LIFE STUDIES PROGRAM (1986).
127. See Knauer, supra note 52, at 339-41 (claiming pre-marketing clinical studies cannot
replace real-world experience).
128. See B. Poet, Presentation, supra note 59 (stating that many desperately ill patients
need expedited access to new drugs because no alternative treatment is available).
TREATMENT
1989]
III.
INDs
185
THE TREATMENT USE OF INVESTIGATIONAL NEW DRUGS
A.
The New Route to DrugApproval
The recently codified treatment IND procedure facilitates the
availability of promising drugs still in the clinical, pre-marketing
phase.1 2 9 Originally proposed in 1983,130 this regulation, authorizing the treatment use of investigational drugs, did not become effective until June 1987.13 l This procedure provides the only glimmer
of hope for desperately ill patients who do not have access to treat32
ment and who are not enrolled in a clinical study.'
Four criteria are required to assign a drug treatment IND status. 13 3 First, the drug must be intended to treat a serious or immediately life-threatening disease.1 34 Second, there may be no
comparable or satisfactory alternative drug or therapy available to
treat the disease in the intended patient population.' 35 Third, the
drug must be under investigation in a controlled clinical trial, or
have completed all clinical tests.13 6 Finally, the sponsor of the controlled clinical trial must actively pursue market approval of the in7
vestigational drug with due diligence.1
Nonetheless, the Commissioner of the FDA may deny a request
for treatment IND status if clinical tests have not yielded promising
results. 138 Such denial depends entirely on the degree of seriousness of the illness for which the drug is earmarked.' 3 9 In the case of
a serious illness, treatment IND status may be denied if there is in129. See generally 21 C.F.R. § 312.34 (1989) (increasing availability of investigational new
drugs to patients with life-threatening diseases before granting approval for marketing).
130. SeeJohnstone, Treatment IND Safety Assessment. PotentialLegal and Regulatory Problems, 43
FOOD DRUG CosM. L.J. 533, 534 (1988) (stating that FDA proposed revision of its investigational new drug regulations and set forth criteria authorizing use of investigational drugs for
treatment purposes).
131. Final Rule, 52 Fed. Reg. 19,466 (1987) (codified at 21 C.F.R. § 312 (1989)). The
FDA based its Final Rule on comments received from the public. Id.
132. See 0. Bowen, Remarks at The American Medical Association/Food and Drug Administration Conference, Washington, D.C. (Feb. 16, 1988) (available in FDA Medical Library) (describing several examples of life-threatening diseases to which treatment INDs may
successfully apply).
133. 21 C.F.R. § 312.34(b) (1989) (providing criteria that FDA shall use to determine
whether to grant treatment IND status).
134. Id. § 312.34(b)(1)(i). The provision defines an "immediately life-threatening" disease as one where there is a reasonable likelihood of death within a matter of months. Id.
§ 312.34(b)(3)(ii).
135. Id. § 312.34(b)(1)(ii).
136. Id. § 312.34(b)(1)(iii).
137. Id. § 312.34(b)(l)(iv).
138. See id. § 312.34(b)(2)-(3) (detailing reasons why Commissioner may deny treatment
IND status for new drug).
139. See id. § 312.34(b)(2)-(3) (listing reasons for denial of treatment IND based upon
whether disease is "serious" or "immediately life-threatening").
186
THE AMERICAN UNIVERSITY LAW REVIEW
[Vol. 39:171
sufficient evidence of safety and effectiveness to support such use. 140
Approval in the case of immediately life-threatening diseases, however, is more easily obtained. 14 1 When reviewing a treatment IND
application for an immediately life-threatening disease, the FDA
may deny a request only if the available clinical evidence fails to
prove the drug is effective or fails to show that patients would not be
exposed to an unreasonable and significant risk.142
Even after a drug has been deemed appropriate for treatment
IND status, the FDA conditions that decision upon additional compliance with certain safeguards. 43 Both the sponsor and the investigators administering the drug must comply with several of the
same safety measures required during the three phases of the IND
process. 144 These safeguards include obtaining the informed consent of all the participating patients gaining access to the investigational drug, establishing institutional review boards, distributing the
drug through qualified experts, maintaining adequate manufactur45
ing facilities, and submitting IND safety reports to the FDA.'
Additionally, this regulation permits the sponsor to charge patients for the use of the drug, provided the sponsor is not engaging
in commercialization. 14 6 The FDA defines commercialization as
charging a price higher than that necessary to recover costs of manufacture, research, development, and handling. 14 7 If the sponsor is
found to be commercializing its product, the FDA may withdraw au140. Id. § 312.34(b)(2). A person would be labeled as having a serious disease only if the
disease itself is classified as serious, or the disease has reached a "serious" stage. Final Rule,
52 Fed. Reg. 19,466, 19,467 (1987) (supplementary information). The diseases that the FDA
recognizes as serious include: Alzheimer's disease, advanced multiple sclerosis, advanced
Parkinson's disease, certain forms of epilepsy, transient ischemic attacks, and paroxysomal
supraventricular tachycardia. Id.
141. See 21 C.F.R. § 312.34(b)(3) (1989) (relaxing evidence requirements for treatment
IND for life-threatening diseases). An immediate life-threatening disease is defined as the
"stage of a disease in which there is a reasonable likelihood that death will occur within a
matter of months or in which a premature death is likely without early treatment." Id.
§ 312.34(b)(3)(ii). The following diseases are considered to be immediately life-threatening:
Herpes simplex encephalitis, advanced cases of AIDS, advanced congestive heart failure, most
advanced metastatic refractory cancers, and severe combined immunodeficiency syndrome.
Final Rule, 52 Fed. Reg. 19,466, 19,467 (1987) (supplementary information).
142. See 21 C.F.R. § 312.34(b)(3) (1989) (stating reasons Commissioner may deny request
for treatment IND).
143. Id. § 312.34(c).
144. Id.
145. Id. The informed consent requirements are governed by 21 C.F.R. § 50 (1989) and
the institutional review boards are governed by 21 C.F.R. § 56 (1989). Id. The requirements
regarding drug distribution, manufacturing, and safety reports are governed by 21 C.F.R.
§ 312 (1989).
146. See id. § 312.7(d)(2) (stating that sponsor may charge for drug provided there is adequate enrollment in clinical investigations, no commercial marketing or advertising of drug,
and active pursuit of market approval of drug); see also infra notes 209-20 and accompanying
text (discussing problems associated with charging provisions).
147. 21 C.F.R. § 312.7(d)(3) (1989).
1989]
TREATMENT
INDs
thorization to charge patients. 48 This pricing authorization is intended to encourage drug sponsors to follow the treatment IND
route and to continue to pursue diligently market approval.149
B.
The Treatment IND: Improving on the Past
Although only recently codified, the treatment IND procedure is
not new to the medical community. 15 0 In the 1970s, physicians administered investigational drugs to patients who were not involved
in any clinical study. 15 1 The FDA permitted physicians to provide
unapproved drugs to the seriously ill on an ad hoc basis under what
52
was referred to as the "compassionate IND."'
These physicians filed reports with the FDA, as do present day
"treatment IND" physicians, but they were not formally treated as
"investigators." 1 53 The physicians were not subject to the same
stringent monitoring requirements, and therefore, could not adequately assist in the study of the drug's effectiveness. 54 Thus, the
potential to gain important information from these real-world patients was never truly realized.' 55
The FDA conceived the treatment IND procedure as a way to save
15 6
lives and, concurrently, to obtain additional data on a new drug.
Consequently, the treatment IND is designed to rely upon the statistics derived from widespread use of a new drug by requiring the
investigators or physicians to report any adverse reactions found in
the treatment patient population.' 5 7 This information adds to the
148. Id. § 312.7(d)(4).
149. See id. § 312.7(d)(2) (requiring sponsor to actively pursue market approval with due
diligence).
150. See Young, FDA's New Procedures,supranote 16, at 2267 (citing prior example of drugs
administered to patients before FDA approval of new drug application).
151. See id. at 2267-68 (describing treatment use of drug prior to approval in 1976). The
first class of drugs to be expedited into use were cardioselective beta blockers. Id. at 2267.
Several thousand patients with bronchospastic lung disease obtained access to the drug
metaprolol while it was still in the investigational phase. Id. Additionally, patients with lifethreatening arrhythmias received the drug amiodarone prior to its approval in 1985. Id. Because at least 20,000 took advantage of this treatment IND, the FDA obtained a great deal of
data from the drug's wide use. Id. Other drugs used for treatment purposes include
nifedipine for patients with vasospastic angina, somatrem for hypoglycemia, etoposide and
streptozocin for cancer, and tetrahydrocannabinol for treating nausea and vomiting resulting
from cancer chemotherapy. Id. at 2267-68.
152. Johnstone, supra note 130, at 533 (noting that "compassionate INDs" were also referred to as treatment INDs). A "compassionate IND" made the drug Oraflex available after
it was removed from the market because of safety hazards. Id. at 533 n.2.
153. Id. at 533.
154. Id. at 533 n.3.
155. See id. (stating that there was no pretense of research expectation from use of investigational drugs).
156. Final Rule, 52 Fed. Reg. 19,466 (1987) (supplementary information).
157. See 21 G.F.R. § 312.34(c) (1989) (requiring submission of IND safety reports).
THE AMERICAN UNIVERSITY LAW REVIEW
[Vol. 39:171
sponsor's arsenal of evidence for its continuing battle to prove the
higher degree of safety and effectiveness required for general market approval.
Although it may appear to be burdensome to require a sponsor to
monitor all of the participating investigators, it is important to recall
that Phase III trials already may involve several thousand participants.' 5 8 Pharmaceutical companies, equipped to manage such extensive Phase III studies in a "controlled" setting, should naturally
be able to comply with the treatment IND procedure.' 59 Although
this procedure may involve a greater number of patients than a
Phase III study, the FDA does not expect the procedure to yield the
extensive data on each patient as in a Phase III investigation. 160
Moreover, the results yielded in the real-world therapeutic setting
highlight the importance and validity of treatment-use surveillance.' 6 ' The sponsor obtains an accurate assessment of the drug's
true effects by reviewing how the drug affects the general populace
162
after prolonged use.
IV.
A NEW RoUTE, BUT DETOURS EXIST
The 1987 treatment IND regulation provides for early availability
of certain drugs already on the road to marketability. 6 3 This new
treatment IND route to drug approval, however, contains several inherent flaws. 164 Although the FDA has issued an interim rule that
may minimize the problems associated with treatment INDs, flaws
16 5
within the process remain.
A.
Determining the ProperSafety and Effectiveness Threshold
Public health officials must be extremely careful when determining whether to grant a drug treatment IND status. 166 These officials
158. See supra notes 86-89 and accompanying text (discussing scope of Phase III studies).
159. Interview with Welch, supra note 77 (explaining that pharmaceutical companies have
great resources).
160. SeeJohnstone, supra note 130, at 538 (questioning whether physician can be expected
to keep as accurate and detailed case histories as are required in IND process).
161. See Knauer, supra note 52, at 339 (describing advantage of testing drug in real-world
environment to assess what effects result from prolonged use).
162. Id.
163. See 21 C.F.R. § 312.34(a) (1989) (describing early access of drug granted treatment
IND status).
164. See infra notes 166-220 and accompanying text (revealing problems associated with
treatment IND process).
165. See infra notes 246-58 and accompanying text (suggesting limited impact of newly
issued interim rule).
166. Young, ExperimentalDrugsfor the Desperately Ill, FDA CONSUMER, June 1987, at 2 (stating that AIDS has brought dilemma of balancing interests in granting treatment INDs to public scrutiny).
1989]
TREATMENT
INDs
must protect the public from possibly unsafe or useless drugs while
simultaneously attempting to provide access to drugs that may represent the last hope for a desperately ill person.' 6 7 Unfortunately,
vague standards for determining safety and effectiveness further
68
complicate this dilemma.'
The 1987 treatment IND regulation states that the Commissioner
may deny a request for treatment IND status if the scientific evidence fails to establish "a reasonable basis for concluding that a
drug may be effective."' 169 Although the word "reasonable" implies
that the Commissioner must use an objective standard when considering the request, the vague wording of the regulation provides the
Commissioner with much flexibility.' 70 Consequently, the FDA may
consider treatment IND proposals based on the prevailing philosophies or the demands of patient-activist groups, rather than granting approval upon specifications within the regulations.' 7'
Additionally, without an objective standard for the FDA guidelines,
there can be no oversight, accountability, or obvious recourse for
those who disagree with any given FDA decision.' 72 Thus, this nebulous standard used to determine whether to grant treatment IND
73
status may result in lawsuits challenging the procedure.
Nevertheless, the standards for determining what constitutes
safety and effectiveness have always been vague, as specific defini167. Id.; see also Eaglstein, Overview of the Reproposed and FinalIND Regulations Concernedwith
the Treatment Use and Sale of InvestigationalNew Drugs: The CongressionalPerspective, 43 FOoD DRUG
COSm. L.J. 435, 439 (1988) (suggesting that treatment IND may offer psychological relief).
168. See supra notes 169-77 and accompanying text (describing need to establish more
precise definitions of safety and effectiveness).
169. See 21 C.F.R. § 312.34(b)(3)(i) (1989) (providing standard for denying treatment
IND status for drug intended to treat immediately life-threatening disease); see also supra notes
140-42 and accompanying text (discussing treatment IND standard for drugs to treat such
diseases).
170. See W. Appler, FDA's Treatment IND Rule-A Glimpse into the Futureof Drug Regulation in
the U.S.?, Presentation on the Treatment IND Rule, at the University of Georgia (Feb. 22-25,
1988) (available in FDA Medical Library) [hereinafter W. Appler, Presentation] (claiming that
treatment IND standard is highly discretionary).
171. See Wittes, NoninvestigationalUses of InvestigationalDrugs: Some Implications of FDA's Revised Regulations, 80 J. NAT'L CANCER INST. 301, 303 (1988) (implying that authors intended to
leave uncodified as much regulation as possible, so that FDA could interpret statute liberally).
172. See W. Appler, Presentation, supra note 170 (adding that although one would expect
legal precedents to be established, confidential nature of NDA and IND submissions makes
case precedents unlikely). The courts, traditionally deferring to agency expertise, also are
unlikely to provide much guidance. See Rutherford v. American Medical Ass'n, 379 F.2d 641,
643 (7th Cir. 1967) (finding that initial approval or exemption of drug is within primary jurisdiction of FDA); Lemmon Pharmacal Co. v. Richardson, 319 F. Supp. 375, 377 (E.D. Pa.
1970) (holding that determination of actual safety and effectiveness of particular drug is one
of essential functions of FDA and that agency has primary jurisdiction to determine safety and
effectiveness of specified drug).
173. See W. Appler, Presentation, supra note 170 (stating that lack of standards in new
regulation provides substantial opportunity for lawsuits challenging IND procedures).
THE AMERICAN UNIVERsITY LAW REVIEW
[Vol. 39:171
tions of either term have consistently eluded drug regulations.' 74 In
fact, when the FDA issues treatment IND status, the Agency is not
necessarily claiming conclusively that the drug has met either criterion.17 5 Rather, after weighing the risks and benefits, the FDA simply classifies the drug as "promising."'' 76 The responsibility of
proving safety and effectiveness remains with the sponsor in its con77
tinuing studies to achieve market approval.'
B.
The Ethics of the Placebo Concurrent Study
The treatment IND regulation clearly states that a drug's sponsor
must diligently pursue market approval.1 78 Therefore, a drug that is
issued treatment IND status prior to the completion of Phase III of
the investigation is not precluded from continuing that phase. 179
Instead, the investigational drug, now being used for treatment purposes by patients across the nation, must undergo further tests for
safety and effectiveness before becoming marketable.' 80 Such marketability will ensure even greater use by patients because FDA-approved drugs may be advertised and promoted by its sponsor.' 8 '
Although drugs for "serious" illnesses will likely have progressed
into the later stages of Phase III before being granted treatment
IND status, treatment IND drugs for life-threatening diseases will, in
all probability, barely have begun that phase.' 8 2 Accordingly, the
method of clinical study which has yielded the most promising re174. Knauer, supra note 52, at 324-25 (describing Congress' unwillingness to define
"safety" and "effectiveness" in food and drug laws over past century).
175. See 21 C.F.R. § 312.34(b) (1989) (failing to list any requirement that drug be established as safe or effective before treatment IND status can be granted); see also Eaglstein, supra
note 167, at 440 (noting lower standard for treatment use of investigational drugs for immediately life-threatening diseases).
176. See 21 C.F.R. § 312.34(a) (1989) (stating that purpose is to make available "promising" drugs to desperately ill patients).
177. See id. § 312.34(b)(iv).
178. Id.
179. See id. § 312 (establishing criteria for granting treatment IND status and intimating
that it is not synonymous with marketing approval).
180. See id. § 312.34(b) (noting that drug must be under investigation and market approval must be pursued for treatment IND status to be granted); see also Interview with
Jochimsen, supra note 77 (replying that because clinical studies yield highly accurate results as
to drug's effectiveness and safety, those tests are required to be completed to satisfaction of
FDA in order to receive market approval).
181. See 21 C.F.R. § 312.7(d)(2) (1989) (forbidding commercial promotion and advertisement of treatment IND drtig for which sponsor is charging); see also Interview with Welch,
supra note 77 (stating that market-approved drug may be prescribed in many situations,
whereas treatment IND drug may only be used for purpose listed in treatment IND protocol).
182. Young, Remarks, supra note I (describing balancing that FDA undertakes). By balancing the risks of toxicity against the benefits of a potential cure, the FDA determines that
drugs for life-threatening diseases need not be tested for as high a degree of effectiveness and
safety as do drugs that are needed for serious illnesses. Id.
1989]
TREATMENT
INDs
suits thus far must be continued.' 8 3
Once treatment use of the investigational drug has been authorized, investigators must consider terminating the most accurate and
184
widely-used clinical study-the placebo concurrent study.
Although this method of study may yield promising results, it is no
longer moral or ethical to utilize. It provides only half of the patients with the actual drug and the other half with an ineffective
look-alike. 18 5 Enrollment in the study, therefore, means taking the
risk of receiving an inactive substance while knowing others are be18 6
ing treated with a potential cure.
The FDA recognized this issue when the drug AZT was being
tested as a treatment for the AIDS virus. 18 7 After producing very
favorable results in Phase I, investigators commenced a placebo
controlled clinical trial in February 1986.188 When they determined
that the patients receiving the placebo were dying at a faster rate
than those receiving the test drug, they immediately notified the
FDA. 18 9 Subsequently, the Agency prematurely terminated the investigation in mid-September of that year although it was expected
to last another two months. 90 Although the drug was not yet officially approved, AIDS patients received AZT on a treatment basis
183. See id. (arguing that pre-marketing studies should continue despite promising
results).
184. See infra notes 187-94 and accompanying text (noting how placebo concurrent study
was terminated after realizing that patients receiving placebos were dying at faster rate than
those receiving actual drug); Interview with Welch, supra note 77 (suggesting that physicians
face ethical dilemma when selecting which patients will receive potential cure and which will
receive placebo); Levy, supra note 112, at 145 n.1 (addressing argument that physician's first
obligation is not to gather objective clinical data, rather, it is to preserve life and well-being of
patient). Nevertheless, Levy concludes that placebo controlled studies are ethical despite the
problems. Levy, supra note 112, at 151.
185. See supra note 184 (contending that placebo concurrent control raises ethical debate
because 50%o of patients are left untreated).
186. See Fast Track Approval, supra note 12, at 3 (insisting that patients may become unwilling to volunteer for randomized clinical studies where they risk receiving placebo instead of
potential cure); see also N.Y. Times, Nov. 21, 1989, at 1, col. 1 (reporting that too few patients
with AIDS have volunteered to partake in clinical study of treatment IND drug DDI). Many
patients want more than a 50%o chance of getting the drug, and have thus opted against participating in any study. Id.
187. See Levy, supra note 112, at 149-50 (discussing success of AZT); see R. Windom, Address at American Medical Association/Food and Drug Administration Conference, Washington, D.C. (Feb. 16, 1988) (available in FDA Medical Library) (outlining AZT's expedited
approval procedure).
188. Levy, supra note 112, at 150. Burroughs Wellcome introduced the drug zidovudine,
which tested unsuccessfully as an anticancer agent. Id. at 149. Zidovudine, formerly known as
azidothymidine, or AZT, is also known as Retrovir. Young, FDA's New Procedures, supra note
16, at 2268.
189. See Levy, supra note 112, at 150 (noting favorable statistical results from use of AZT).
The study, initiated on February 18, 1986, involved 282 subjects with AIDS. Id. Nineteen of
the 137 patients who received the placebo died while only one of the 145 patients who received AZT died. Id.
190. Id.
192
THE AMERICAN UNIVERSITY LAW REVIEW [Vol. 39:171
until the drug was finally approved for commercialization in March
1987.191 In the period before approval, over 5,000 patients received the medication.' 92 Hailed as a major achievement,' 93 the
AZT experience is considered the primary motivation for the codification of the treatment IND process.' 94 Nevertheless, the AZT experiment also highlights the ethical dilemma of using the placebo
concurrent control.
C.
The Active Control Test Dilemma
Although AZT gained market approval soon after treatment IND
status was issued,' 9 5 drug sponsors, under the 1987 treatment IND
regulation, must prove to the FDA that general marketability is warranted.1 9 6 Because placebo concurrent studies on drugs for lifethreatening diseases are considered unethical, 9 7 especially when
another existing therapy exists, the active control study 9 8 is usually
relied upon to test the drug's effects.' 9 9
Like the placebo concurrent study, the active control study,
presents problems when used in context with treatment INDs. 20 0 As
previously noted, the active control study tests the effects of the investigational drug against those of an approved drug of a comparable nature. 20 1 One of the essential criteria for granting treatment
IND status, however, is that no comparable or satisfactory alterna191. Id. at 150. AZT is not a cure for AIDS, and few physicians anticipated a total remission. Id. at 145.
192. See Young, FDA's New Procedures, supra note 16, at 2268 (indicating that during 21
months of clinical evaluation and review, drug was available to physicians throughout country
through treatment INDs for six months, or about 30% of time required for clinical evaluation
and approval of NDA).
193. See R. Windom, Address, supra note 187 (noting success of then uncodified treatment
IND approach in case of AZT).
194. Young, FDA's New Procedures, supra note 16, at 2268. By the end of 1987, the FDA
had reviewed 164 IND applications for potential AIDS drugs and approved 146 of these applications. 0. Bowen, Remarks, supra note 132.
195. 0. Bowen, Remarks, supra note 132. Although AZT gained marketing approval at a
rapid pace, the new treatment IND procedure was not yet codified and thus not in effect at
that time. See id. (reporting that AZT was approved for treatment use in October 1986).
196. See 21 C.F.R. § 312.34(b)(iv) (1989) (requiring sponsor to continue to pursue actively marketing approval with due diligence).
197. See supra notes 184-90 and accompanying text (indicating that under placebo concurrent study patients with life-threatening illness may take inactive substance while potential
cure exists).
198. See supra notes 108-10 and accompanying text (discussing active treatment concurrent control study).
199. See 21 C.F.R. § 314.126(b)(2)(iv) (1989) (proposing that active treatment concurrent
control be used where placebos or no treatment would be contrary to interest of patient);
Interview with Welch, supra note 77 (indicating that this method allows for patients with lifethreatening diseases to continue to receive some form of treatment).
200. See supra notes 201-06 and accompanying text (noting deficiencies of active control
study).
201. 21 C.F.R. § 314.126(b)(2)(iv) (1989).
1989]
TREATMENT
INDs
193
tive drug is available. 20 2 Thus, by its very definition, an active control study is simply not feasible for a treatment IND drug.20 3
Furthermore, when Congress considered ways to measure a
drug's usefulness, it explicitly rejected the concept of "relative effectiveness," which compares one drug to another in order to measure
efficacy. 20 4 The FDA's reliance on the results of active control studies, therefore, appears to be contrary to congressional intent. 20 5
The FDA apparently has never fully accepted this congressional
judgment, and has continued in several instances to infuse relative
effectiveness criteria into its pre-market approval decision20 6
making.
In sum, despite the active control study's inherent flaws, investigators will likely continue to use this study method. The reason is
that placebo concurrent controls are unethical, and the remaining
three methods of study-the historical control, the dose-comparison
concurrent control, and the no treatment concurrent control-offer
20 7
minimal reliability in determining a drug's effects.
D. Motivating the Maker
Although treatment INDs provide a new route to approval that
202. See id. (stating that test drug is to be compared to "known effective therapy").
203. See Final Rule, 52 Fed. Reg. 19,466 (1987) (supplementary information) (stating that
one criterion for investigational drug use is that no comparable drug exists).
The FDA continues to believe that the absence of an alternative therapy should be a prerequisite to granting a treatment IND. Id. One of the major principles underlying the treatment
IND policy is that these drugs would be necessary to fill an existing gap in the medical therapies available. Id. The FDA agrees, however, that there should be flexibility in applying this
concept in order to serve effectively desperately ill patients. Id. at 19,468. For example, simply because an approved therapy already exists for a disease does not mean that the therapy is
appropriate for everyone inflicted with such a disease. Id.; Interview with Jochimsen, supra
note 77 (articulating view of FDA). Although the active control study compares the test drug
with other comparable, previously marketed drugs, those drugs do not necessarily have to
cure the same aspect of the disease as the test drug in order to be used in an active control
study. Id. Furthermore, the FDA does not interpret the "no comparable drug exists" clause
in a stringent manner. Id.; Interview with Welch, supra note 77 (indicating that if almost identical comparable drug existed, it might be classified as "me-too" drug). A "me-too" drug is a
drug extremely close in composition to another approved drug and would require a different
type of testing procedure. Interview with Welch, supra note 77.
204. See Knauer, supra note 52, at 323 (arguing that Congress neglected to grant unfettered authority to FDA to formulate operative definition of nebulous concept of
effectiveness).
205. See id. at 329 (stating that such regulatory action contravenes Congress' express
intent).
206. See id. at 329-36 (indicating that FDA engaged in relative effectiveness when deciding
upon cough suppressant-Benylin and antibiotic-erythromycin estolate).
207. See supra note 114 and accompanying text (discussing unreliability of historical control); see also Frankel, supra note 105, at 102 (ranking historical controls last on list of reliable
studies and not ranking either no treatment concurrent or dose-comparison concurrent controls); supra note 117 and accompanying text (describing limited value of no treatment concurrent and dose-comparison controls).
194
THE AMERICAN UNIVERSITY LAW REVIEW
[Vol. 39:171
yields greater drug availability, the drug sponsor must be willing to
follow that route. 20 8 With this in mind, the FDA inserted pricing
incentives into the regulation in order to coax the sponsors.2 0 9 As
previously indicated, 2 10 this provision, allowing sponsors to charge
in order to cover their costs, seeks to prevent sponsors from objecting to free extensive treatment use of their product. 21 1
Although the FDA recognizes its inability to monitor pricing practices adequately,2 12 some competitive pharmaceutical companies
still fail to take advantage of this provision. 21 3 Concerned about revealing their profit margins in the postmarketing period, these companies may choose to bypass the treatment IND route entirely. 21 4
Similarly, if the pharmaceutical companies believe that monitoring requirements are more burdensome under the treatment IND
route, their unwillingness will increase. 215 Instead of participating
in an extensive surveillance effort to test for adverse reactions while
continuing with clinical trials, these companies may opt against the
treatment IND process entirely.
If a pharmaceutical company believes that the FDA, through its
monitoring procedures, will not discover a drug's adverse reactions,
they may perpetually distribute their drug under a treatment
IND. 2 16 Recognizing the FDA's inability to supervise adequately
208. See Wittes, supra note 171, at 303 (outlining reasons why sponsor may decide against
participation in IND study).
209. See 21 C.F.R. § 312.7(d) (1989) (permitting sponsor to request FDA approval to
charge for investigation of drug). The regulation requires the sponsor to state why the costs
of distribution "should not be considered part of the normal cost of doing business." Id.; see
supra notes 146-49 and accompanying text (explaining pricing privilege during treatment
use).
210. See supra notes 146-49 and accompanying text (describing provision of treatment
IND regulation that allows drug manufacturers to charge to recover costs).
211. See Final Rule, 52 Fed. Reg. 19,466, 19,472 (1987) (supplementary information)
(stating that many pharmaceutical firms supported provisions allowing charging).
212. Telephone interview with Alan Kaplan, former trial attorney, Food and Drug Administration, currently FDA Specialist (Feb. 10, 1989) [hereinafter Interview with Kaplan] (concurring with view that supervision is difficult task).
213. See Wittes, supra note 171, at 303 (stating that establishment and administration of
treatment IND requires substantial commitment of resources).
214. Id. Because a company may only charge for actual costs during the treatment use of
its investigational drug, its profit margin eventually will be revealed. Id. This will occur when
the drug gets market approval, and the pharmaceutical company raises the price of the drug
in order to make a profit. See id. (stating potential concerns of drug company). But see Interview with Kaplan (stating that drug costs are greater in investigational stage than after marketing). A competitor, therefore, may not accurately estimate a drug company's profit margin
based upon a drug's cost while it is under a treatment IND. Id.
215. See Johnstone, supra note 130, at 537 (suggesting massive amount of paperwork for
pharmaceutical companies).
216. See Wittes, supra note 171, at 303 (stating that many anticancer agents have been in
clinical development for long time).
1989]
TREATMENT
INDs
overpricing,2 1 7 the pharmaceutical companies could exploit the system for economic gain.2 18 Such exploitation likely would occur
when drug efficacy is difficult to prove, but safety has already been
the
demonstrated.2 1 9 In such situations, any adverse reactions that 22
0
drug causes may remain unknown, as will its degree of efficacy.
V.
THE
1988
INTERIM RULE: SHORTENING THE TREATMENT
ROUTE BY GRANTING SWIFTER APPROVAL
IND
Obstacles confront an investigational drug from the moment it
begins the treatment IND route until it reaches its marketability destination. 22 1 As previously indicated, standards to determine safety
and effectiveness remain undetermined, 22 2 the required continuation of clinical studies pose ethical and legal dilemmas, 2 23 and necessary drug company participation is not assured. 2 24 Eliminating
the treatment IND process would avert the need to address these
dilemmas; unfortunately, it also would prevent investigational drugs
from gaining greater availability.2
25
Yet, shortening the drug ap-
proval process and granting marketability earlier in the investigaand
tional stages would minimize the treatment IND dilemmas
2 26
drugs.
needed
vitally
of
use
widespread
greater
ensure
Recognizing this fact, the FDA recently issued an interim rule that
217. See supra note 212 and accompanying text (confirming FDA's inability to monitor
adequately every investigator and sponsor).
218. See W. Appler, Presentation, supra note 170 (noting that smaller drug companies
might depend on recovering payments for use of their drugs).
219. Wittes, supra note 171, at 303. Once a drug has been granted treatment IND status,
the discovery of unsafe or adverse effects will cause it to be withdrawn from use. See generally
21 C.F.R. § 312 (1989) (outlining guidelines of treatment IND process). Thus, a company
still attempting to prove the efficacy of an otherwise ineffective drug may be slow in producing
the completed results from Phase III. Wittes, supra note 171, at 303.
220. See Wittes, supra note 171, at 303-04 (stating that lax monitoring requirements and
ability to charge may lead manufacturers to favor distribution of drug under treatment IND
when drug efficacy is difficult to prove).
221. See supra notes 164-220 and accompanying text (discussing problems with new treatment IND route to drug approval).
222. See supra notes 169-73 and accompanying text (revealing ambiguities in repulation
because of unspecified standards).
223. See supra notes 184-90 and accompanying text (explaining that ethical considerations
arise because patients in placebo concurrent studies may take inactive substance for lifethreatening disease although potential cure exists); supra notes 204-06 and accompanying text
(discussing FDA's reliance on concept of relative effectiveness despite congressional rejection
of that legal standard).
224. See supra notes 208-20 and accompanying text (arguing that treatment IND procedure fails to motivate sponsors sufficiently).
225. See W. Appler, Presentation, supra note 170 (noting that treatment IND process allows widespread use of drug, thereby expediting availability).
226. See Kessler, The Regulation of InvestigationalDrugs, 320 NEw ENG.J. MED. 281, 286-87
(1989) (advocating accelerated approval to facilitate availability of drugs for life-threatening
diseases).
THE AMERICAN UNIVERSITY LAW REVIEW
[Vol. 39:171
may address many of the flaws in the process. 2 2 7 This interim rule,
adopted in October 1988, seeks to accelerate NDA approval rather
than simply provide for treatment use of an otherwise non-marketable drug.2 28 Thus, the 1988 interim rule does not directly resolve
the problems of the treatment IND process; rather, it shortens or
possibly entirely eliminates the need for that process. 2 29
One major goal of the interim rule is to foster early consultation
between the FDA and the drug's sponsors. 23 0 By meeting with the
sponsor after Phase I, the FDA can determine the most appropriate
type of study to be conducted in Phase 11.231 The resulting study
consequently may yield sufficient data to warrant marketability,
thereby eliminating the need for Phase III and an extended treat23 2
ment IND process.
Second, the interim rule explicitly states that the FDA shall consider a risk-benefit analysis in deciding marketability. 233 Recognizing that the terms "safety" and "effectiveness" are not absolute, 23 4
227. Interim Rule, 53 Fed. Reg. 41,516 (1988) (supplementary information) (explaining
that regulation builds upon past attempts to expedite availability of promising new therapies).
Upon issuing the interim rule, the FDA deemed it effective immediately, while allowing for
public comment. Id.
228. Interim Rule, 53 Fed. Reg. 41,516 (1988) (codified at 21 C.F.R. § 312.80 (1989)).
The intended purpose of the rule is to "expedite the development, evaluation, and marketing
of new therapies intended to treat persons with life-threatening and severely-debilitating illnesses, especially where no satisfactory alternative therapy exists." Id. The purpose of this
new provision is considerably different from the treatment IND provision. Compare Final Rule,
52 Fed. Reg. 19,466 (1987) (supplementary information) (intending to facilitate availability of
promising investigational new drugs before marketing begins) with Interim Rule, 53 Fed. Reg.
41,516 (1988) (supplementary information) (claiming to expedite development, evaluation,
and marketing of otherwise investigational new drugs).
229. Although marketability would remove the need for the treatment IND process, the
new regulation encourages the continued use of the process. See Interim Rule, 53 Fed. Reg.
41,516 (1988) (supplementary information) (stating that new procedures focus on entire process, from early pre-clinical testing to postmarketing surveillance); see also infra notes 240-42
(indicating continued usefulness of treatment IND process).
230. See Interim Rule, 53 Fed. Reg. 41,516 (1988) (codified at 21 C.F.R. § 312.82 (1989))
(authorizing sponsors to meet with FDA reviewers early in development process in order to
design studies for drugs that treat life-threatening illnesses); see also U.S. REG. RVrR. 1, 2
(Dec. 1988) (describing FDA as "virtual paid consultant" to industry).
231. See Interim Rule, 53 Fed. Reg. 41,516 (1988) (codified at 21 C.F.R. § 312.82(b)
(1989)) (authorizing sponsor to request meeting with FDA after Phase I in order to design
Phase II to best provide data on safety and effectiveness). The sponsor also is permitted to
request a meeting with the FDA prior to the submission of the initial IND. Id. § 312.82(a).
The meeting's purpose would be to review the design of animal studies needed to initiate
human testing, and to discuss the design of Phase I. Id.
232. U.S. REG. Rrm. 1, 2 (Dec. 1988) (outlining primary purpose of post-Phase I meetings); see supra note 85 (explaining that most unsafe drugs are identified in Phase II). Because
this phase detects unsafe drugs, only the drug's effectiveness remains in doubt. See supra note
85. An individual suffering from a terminal illness, however, would not likely refuse to take a
potentially ineffective drug provided it had been proven safe. Id.
233. See Interim Rule, 53 Fed. Reg. 41,516 (1988) (supplementary information) (recognizing need for medical risk-benefit analysis when deciding upon marketability).
234. See Interim Rule, 53 Fed. Reg. 41,516, 41,517 (1988) (codified at 21 C.F.R. §§ 312,
314 (1989)) (agreeing that not all drugs are free of risk or have unequivocal benefits).
1989]
TREATMENT
INDs
197
the FDA seeks to determine whether a drug's benefits outweigh its
risks. 2 35 For drugs effective against life-threatening diseases, a
lower standard of safety will be allowed, thereby leading to more
23 6
immediate marketability.
A third provision addresses the importance of postmarketing surveillance. 23 7 This section of the proposal suggests a Phase IV study
as a way to obtain more data on the now marketable drug. 238 Unlike
the treatment IND process, the drug is no longer in the investigational stage at this point, and is commercially available to anyone. 2 39
Finally, the new proposal recognizes the usefulness, however limited, of the treatment IND process. 240 In situations where a drug
has not yet reached the new proposal's marketability standard, the
drug may nonetheless be granted treatment IND status. 24 ' Despite
the problems associated with the treatment IND process, the provision ensures the drug's availability until swift approval of the drug
242
can be granted.
235. Interim Rule, 53 Fed. Reg. 41,516 (1988) (codified at 21 C.F.R. § 312.84(a) (1989)).
The relevant portions of the risk-benefit provision states:
(a) FDA's application of the statutory standards for marketing approval shall recognize the need for a medical risk-benefit judgment in making the final decision on
approvability. As part of this evaluation .... FDA will consider whether the benefits
of the drug outweigh the known and potential risks of the drug and the need to
answer remaining questions about risks and benefits of the drug, taking into consideration the severity of the disease and the absence of satisfactory alternative therapy.
Id.
236. See id. § 312.80 (indicating that higher drug toxicity will be tolerated for drugs effective against life-threatening diseases).
237. Id. § 312.85. The relevant part of the regulation expediting drug approval states:
Concurrent with marketing approval, FDA may seek agreement from the sponsor to
conduct certain postmarketing (Phase IV) studies to delineate additional information
about the drug's risks, benefits, and optimal use. These studies could include, but
would not be limited to, studying different doses or schedules of administration than
were used in Phase II studies, use of the drug in other patient populations or other
stages of the disease, or use of the drug over a longer period of time.
Id.
238. Id. According to the regulation, when FDA approval is obtained on the basis of"limited, but sufficient, clinical trials," postmarketing clinical studies will be important. Interim
Rule, 53 Fed. Reg. 41,516,41,521 (1988) (supplementary information). These postmarketing
studies will assist physicians by providing more information about the drug's safety and efficacy. Id.
239. See Interim Rule, 53 Fed. Reg. 41,516, 41,521 (1988) (granting investigational drugs
swift marketing approval).
240. See Interim Rule, 53 Fed. Reg. 41,516 (1988) (codified at 21 C.F.R. § 312.83 (1989))
(citing continued usefulness of treatment INDs).
241. 21 C.F.R. § 312.83 (1989). The relevant regulatory provision states:
If the preliminary analysis of phase 2 test results appears promising, FDA may ask
the sponsor to [apply for Treatment IND status]. Such [status], if requested and
granted, would normally remain in effect while the complete data necessary for a
marketing application are being assembled by the sponsor and reviewed by FDA....
Id.
242. See id. §§ 312.34-.35 (noting treatment IND process that would be relied upon under
new regulations).
THE
VI.
AMERICAN UNIVERSITY LAW REVIEW
Is
IT REALLY A SHORTER
[Vol. 39:171
ROUTE?
Although the 1988 interim rule is intended to shorten the route to
drug approval, 24 3 it does not completely resolve the problems inherent in the treatment IND process. 244 Instead, the interim rule
minimizes dependence on the treatment IND process by accelerating marketability, thereby facilitating the greatest availability of potential cures. 24 5 These new provisions, however, actually add little
to already existing regulations and cause skepticism as to its pur2 46
ported effect.
First, the FDA has always encouraged consultation with the drug
sponsor.2 47 Pursuant to earlier regulations, and to the extent FDA
resources permitted, sponsors could request a conference to evaluate a drug more closely. 2 48 Although the 1988 interim rule explicitly recognizes the benefits of a conference following Phase 1,249 it is
premature to determine whether these consultations will be as valu2 50
able as the FDA claims.
Second, the 1988 interim rule addresses the appropriate standard
to be relied upon for granting marketability. 2 5 ' Whereas approval
under the FDCA requires substantial evidence of safety and effectiveness, 25 2 the 1988 regulation specifically recognizes a risk-benefit
243. See supra notes 221-42 and accompanying text (explaining procedures that decrease
obstacles to marketability).
244. See Interim Rule, 53 Fed. Reg. 41,516 (1988) (codified at 21 C.F.R. § 312.80 (1989))
(reporting expedition of marketability as primary purpose of new regulations).
245. Id. § 312.80.
246. U.S. REG. RvR. I, 1 (Dec. 1988) (quoting FDA staffers who argue that interim rule
will add little to existing procedures to expedite approval of badly needed drugs). Interview
with Kaplan, supra note 212 (stating that new regulation adds nothing new to existing
regulations).
247. See 21 C.F.R. § 312.47 (1989) (describing practical utility of meetings between sponsor and agency and encouraging such meetings to aid evaluating drug to extent that FDA
resources permit).
248. Id. Compare 21 C.F.R. § 312.47 (1989) (indicating that meetings to discuss drug studies are encouraged to extent that FDA resources permit) with Interim Rule, 53 Fed. Reg.
41,516 (1988) (codified at 21 C.F.R. § 312.82 (1989)) (suggesting Agency will honor request
for meetings to extent FDA resources permit).
249. Interim Rule, 53 Fed. Reg. 41,516 (1988) (codified at 21 C.F.R. § 312.82(b)(1989)).
Compare id. (detailing sponsor's opportunity to request FDA meeting prior to submission of
IND application and prior to Phase II) with 21 C.F.R. § 312.47(b) (1989) (indicating importance of post-Phase II meetings to determine safety of proceeding to expanded Phase III).
250. Interview with Kaplan, supra note 212 (indicating that, in past, sponsors could always
request such meetings, but that perhaps new regulatory provisions will mandate certain FDA
conduct helpful to sponsors).
251. See Interim Rule, 53 Fed. Reg. 41,516 (1988) (codified at 21 C.F.R. § 312.84 (1989))
(basing decision of marketability on risk-benefit judgment incorporating advice of outside expert consultants or advisory committees).
252. 21 U.S.C. § 355(d) (1982 & Supp. V 1987); see supra note 10 (citing substantial portion of Federal Food, Drug, and Cosmetic Act).
1989]
TREATMENT
INDs
analysis in determining whether that standard has been met. 253
However, the FDA has always willingly accepted less evidence of
25 4
safety if improvement in patient survival could be demonstrated.
In effect, this provision simply recognizes a previous FDA practice.
Finally, the 1988 provision requesting the sponsor's consent in
conducting postmarketing studies contributes little to the process. 25 5 The FDA had already used postmarketing surveillance techniques to reveal a drug's unanticipated effects. 25 6 Thus, the new
regulation does little more than emphasize the utility of what it refers to as a Phase IV investigation.
Considering the slight modifications that it actually creates,
the
FDA may have established the interim rule merely for public relations and political purposes. 257 After all, the interim rule emerged
during the fall election campaign at the urging of a Presidential
Task Force, and addressed a major political, as well as medical problem.2 5 8 Thus, the true value of the new interim rule remains in
doubt.
VII.
THE BEST
RouTE
IF THE
FDA
GOES ALONG
Although the 1988 interim rule theoretically allows the FDA to
accelerate the drug approval process, what it does in practice ultimately will determine whether the route to marketability is shortened. The ethical, legislative, and motivational dilemmas associated
253. Interim Rule, 53 Fed. Reg. 41,516 (1988) (codified at 21 C.F.R. § 312.84 (1989))
(outlining risk-benefit procedure).
254. Interim Rule, 53 Fed. Reg. 41,516,41,518 (1988) (supplementary information) (noting that risk-benefit criteria is consistent with flexibility granted to Agency in determining
safety and effectiveness of drugs); see Interview with Kaplan, supra note 212 (agreeing that
drug's risks are always measured against its discovered benefits). Mr. Kaplan suggested that
the FDA's infusion of risk-benefit analysis into the standard to determine marketability. may
signal a greater willingness to approve drugs for life-threatening diseases earlier in the investigational process. Id
255. See Interim Rule, 53 Fed. Reg. 41,516 (1988) (codified at 21 G.F.R. § 312.85 (1989)).
Compare id. (proposing Phase IV studies to obtain additional data about drug's risks, benefits
and optimal use) with 21 U.S.C. § 355(e) (1982 & Supp. V 1987) (indicating usefulness of
postmarketing surveillance).
256. See 21 U.S.C. § 355(e) (1982 & Supp. V 1987) (instituting surveillance technique to
continue monitoring drug's effects).
257. See Booth, FDA Looks to Speed Up Drug Approval Process, 241 SCIENCE 1426, 1426
(1988) (critiquing interim rule); Interview with Kaplan, supra note 212 (acknowledging that
some individuals within industry feel that FDA may have been politically motivated in issuing
interim rule).
258. See FDA Expedites Approval Processfor Drugs FightingLife-Threatening Diseases, AMERICAN
PHARMACY, Jan. 1989, at 14 (reporting that thrust of new rule came at request of President's
Task Force on Regulatory Relief); Interim Rule, 53 Fed. Reg. 41,516 (1988) (supplementary
information) (referring to then-Vice President Bush's request to expedite marketing of new
therapies). Vice-President Bush was then the chairman of the President's Task Force. Interim
Rule, supra, at 41,516.
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[Vol. 39:171
with treatment INDs might not be directly resolved, 259 but a concerted effort to implement the 1988 interim rule will minimize the
need to rely upon the treatment IND process. If the 1988 interim
rule proves to eliminate Phase III, or compresses it into Phase II and
thus provides for faster marketability, the detours of the treatment
IND route will be avoided. 2 60 Pharmaceutical companies would be
quick to provide their product, 26 ' and new drugs would gain greater
26 2
availability for those in dire need of them.
Furthermore, if new drug application aiproval is granted, data
obtained from a real-world setting would reveal a drug's true effects. 263 There would no longer be any need to continue unethical
placebo concurrent trials, 26 4 unreliable historical controls, 2 65 or potentially unauthorized active controlled studies. 2 66 Instead, better
planned studies in Phases I and II, coupled with the results from this
postmarket surveillance, would yield the necessary data on the drug.
Even though the 1988 provisions concerning consultation, risk26 7
benefit analysis, and postmarketing studies are not entirely new,
the very fact that the FDA promulgated this interim rule could signal a greater willingness to make vitally needed drugs marketable. 268 This willingness, however, must be applied in practice,
259. See supra notes 164-220 and accompanying text (discussing flaws in treatment IND
regulation).
260. See infra notes 261-66 and accompanying text (explaining how marketability eliminates need for unethical placebo concurrent studies, minimizes reliance on active control
tests, and financially motivates sponsors).
261. See supra notes 208-20 and accompanying text (recognizing financial interest of pharmaceutical companies); see also Final Rule 52 Fed. Reg. 19,466, 19,467 (1987) (supplementary
information) (explaining that FDA understands sponsors' desire to charge for their product);
W. Appler, Presentation, supra note 170 (recognizing that current treatment IND process does
not adequately inform those who might benefit from new drug). Additionally, once the drug
reaches the market, commercialization may commence. See 21 C.F.R. § 312.7 (1989) (stating
that sponsor shall not commercially promote or distribute investigational drug). When advertising begins, patients who may not have known of the investigational drug will more likely be
able to learn that a possible cure exists. See W. Appler, Presentation, supra note 170 (stating
that little information is publicly available regarding investigational drugs).
262. See supra note 181 and accompanying text (indicating that wider use of drug will result from promotion and advertisement of drug granted marketability).
263. See supra notes 161-62 and accompanying text (recognizing greater value of realworld monitoring). See also Chadha, Phase IV Studies: An Introduction, 38 CURRENT THERAPEUTIC REs. 353, 353 (1985) (discussing opportunities for creative research that Phase IV drug
testing would provide).
264. See supra notes 184-90 and accompanying text (suggesting that under placebo concurrent study, patients with life-threatening diseases may be required to take inactive substances when potential cure exists).
265. See supra notes I11-14 and accompanying text (doubting historical control study's
reliability).
266. See supra notes 204-06 and accompanying text (describing FDA's reliance on relative
effectiveness technique despite congressional rejection of such method).
267. See supra notes 247-56 (revealing that new regulation is very similar to prior
legislation).
268. Interview with Kaplan, supra note 212 (suggesting that although FDA may have been
1989]
TREATMENT
INDs
otherwise the interim rule will have only limited effect and the obstacles associated with the treatment IND process will be
unavoidable.
CONCLUSION
The 1987 treatment IND regulation enables drugs to be accessible to patients as potential cures for their illnesses. The procedure,
however, contains many obstacles. For instance, appropriate standards of safety and effectiveness remain elusive, the required continuation of clinical studies pose ethical and legislative dilemmas, and
the needed participation by drug companies is not assured.
By attempting to shorten the drug approval route, the 1988 interim rule seeks to avoid these obstacles. Although its specific provisions may not be new to the drug industry, the 1988 interim rule
reflects an attitude that is conducive to expediting the drug approval
process. With the FDA's willingness, it can. For patients with serious and life-threatening diseases, it must.
politically motivated to promulgate interim rule, issuance may signal FDA's willingness to
accelerate approval of certain potential cures).