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Guidance for Industry

Referencing Discontinued Labeling

for Listed Drugs in Abbreviated New

Drug Applications

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 90 days of

publication of the Federal Register notice announcing the availability of the draft guidance. Submit

comments to Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers

Lane, rm. 1601, Rockville, MD 20857. All comments should be identified with the docket number

listed in the notice of availability that publishes in the Federal Register.

For questions on the content of the draft document contact Cecelia M. Parise, 301-827-5845.

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

October 2000

OGD
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Guidance for Industry

Referencing Discontinued Labeling

for Listed Drugs in Abbreviated New

Drug Applications

DRAFT GUIDANCE

Additional copies of this Draft Guidance are available from:

 Office of Training and Communications

 Division of Communications Management

Drug Information Branch, HFD-210

Center for Drug Evaluation and Research

Food and Drug Administration

 5600 Fishers Lane, Rockville, MD 20857

(Tel) 301-827-4573

(Internet) http://www.fda.gov/cder/guidance/index.htm.

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

October 2000

OGD
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TABLE OF CONTENTS

I. INTRODUCTION.........................................................................................................................................................................1

II. BACKGROUND............................................................................................................................................................................1

III. PROPOSED APPROACH..........................................................................................................................................................3

IV. SUBMISSION OF ANDAS ........................................................................................................................................................3

A. STATUTORY REQUIREMENTS....................................................................................................................................................3

B. REGULATORY REQUIREMENTS.................................................................................................................................................4

C. PAST PRACTICE...........................................................................................................................................................................5

V. REFERENCING DISCONTINUED LABELING FOR A LISTED DRUG IN AN ANDA .....................................5

A. EXISTENCE OF EXCLUSIVITY OR PATENT PROTECTION........................................................................................................5

B. IDENTIFYING APPROPRIATE LABELING...................................................................................................................................6

C. SUBMISSION OF PETITION REQUESTING DETERMINATION OF REASONS FOR CHANGE TO LABELING...........................6

D. FDA DETERMINATION ON SAFETY AND EFFECTIVENESS.....................................................................................................6

E. THERAPEUTIC EQUIVALENCE RATINGS...................................................................................................................................6

F. EXPIRATION OF EXCLUSIVITY OR PATENT PROTECTION......................................................................................................7
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GUIDANCE FOR INDUSTRY11

2

3 Referencing Discontinued Labeling

4 for Listed Drugs in Abbreviated

5 New Drug Applications

6

7

8

9

10

11

12

13

14

15 If you plan to submit comments on this draft guidance, to expedite FDA review of your comments, please:

16

17 • Clearly explain each issue/concern and, when appropriate, include a proposed revision and the

18 rationale/justification for the proposed changes.

19 • Identify specific comments by line number(s); use the PDF version of the document, whenever possible.

20

21

22 I. INTRODUCTION

23

24 This document is intended to provide guidance to applicants on referencing discontinued

25 labeling for listed drugs in abbreviated new drug applications (ANDAs) submitted for

26 approval under section 505(j) of the Federal Food, Drug, and Cosmetic Act (the Act).

27 This issue is not addressed directly in the regulations governing the approvals of ANDAs

28 at 21 CFR 314 subpart C. The Office of Generic Drugs (OGD) is proposing the most

29 appropriate response to this regulatory question, and is making its current thinking on the

30 matter available to the public through this guidance.

31

32 II. BACKGROUND

33

34 The Drug Price Competition and Patent Term Restoration Act of 1984 (the Hatch35 Waxman amendments) established the generic drug approval program used today to

36 ensure that lower price generic drugs are made available to the public promptly upon the

37 expiration of patent and exclusivity protections covering the innovator products. The

38 generic drug approval process generally depends on the ANDA applicant establishing

39 that the generic drug is the same as an approved innovator product (the listed drug) with

40 respect to active ingredient, dosage form, strength, route of administration, conditions of

41 use, and labeling.

 

1

This draft guidance has been prepared by the Office of Generic Drugs in the Center for

Drug Evaluation and Research (CDER).

This draft guidance, when finalized, will represent the Food and Drug Administration=s current thinking

on this topic. It does not create or confer any rights for or on any person and does not operate to bind

FDA or the public. An alternative approach may be used if such approach satisfies the requirements of

the applicable statutes and regulations.
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42

43 During the period when an innovator drug is being marketed, it may undergo a number of

44 changes that are approved through new drug application (NDA) supplements. Such

45 changes can include the addition of new indications, changes to the product formulation,

46 and labeling changes. In the past, when ANDAs have been submitted, they have

47 referenced only the innovator drug product labeling as it appears at the time of ANDA

48 submission. However, recently a question has been raised as to whether, in certain

49 circumstances, an ANDA can refer to discontinued labeling for the listed drug.

50

51 The issue of referencing discontinued labeling for the listed drug arises when the sponsor

52 of the innovator drug product has obtained exclusivity or patent protection for a new

53 aspect of product labeling and has removed the previous unprotected labeling for reasons

54 other than safety or effectiveness. When the holder of the innovator drug obtains

55 approval and market protection for a change to the drug and removes the corresponding

56 unprotected information from the current labeling, there is no current complete labeling

for the ANDA applicant to reference.257 For example, the NDA holder may obtain

58 approval and market protection for a new dosing regimen and remove the previous

59 dosing regimen(s) from the labeling. In this situation, the ANDA applicant, which must

60 include information regarding dosing regimen in its application, is blocked by the NDA

61 holder's exclusivity from referencing the new dosing regimen contained in the innovator

62 drug labeling, and all the previous dosing regimen information has been removed from

63 the current labeling. This raises the question of whether applicants will be barred from

64 obtaining approval for any ANDA for that innovator drug until the protection for the new

65 dosing regimen expires, because relevant labeling is either protected or has been removed

from the currently marketed product.366

67

68 In FDA's view, the appropriate approach to the situation depends on whether the previous

69 labeling was withdrawn from the drug product for reasons of safety or effectiveness, and

70 whether omission of the protected information will render the drug unsafe. This is the

71 same approach taken by the Agency when an entire product, rather than just a portion of

72 the labeling, is withdrawn from the market, and when a portion of the innovator labeling

73 must be omitted from a generic drug label because of patent or exclusivity protection.

74

75 FDA’s proposed approach creates a process intended to assure that labeling removed

76 from an innovator drug product for reasons of safety or effectiveness cannot be

77 referenced in an ANDA. At the same time, this process will permit approval of ANDAs

 

2 Contrast this with the situation in which an innovator has obtained approval for a new indication

and patent or exclusivity protection that extends beyond the protection for other indications that remain on

the labeling. The ANDA applicant may cite the innovator labeling that includes all of the approved

indications, and only the protected indication will be omitted from the ANDA labeling when it is approved.

See Bristol-Myers Squibb v. Shalala, 91 F.3d 1493 (D.C.Cir. 1996).

3

In theory, the innovator could delay generic competition indefinitely by continuing to make

minor — but protectable — changes to the drug, and removing unprotected labeling. If this approach were

effective, the Agency also could expect to review many more labeling supplements, possibly for changes

that, although sufficiently innovative to warrant patent or exclusivity protection, do not necessarily

represent significant improvements in the currently marketed drug.
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78 that reference labeling that, although removed from the currently marketed innovator

79 product, nonetheless describes the safe and effective use of the drug. This approach will

80 make safe and effective generic drug products available to the public as promptly as

81 possible when relevant market protections have expired.

82

83 III. PROPOSED APPROACH

84

85 The Agency has determined that in certain circumstances an ANDA should be permitted

86 to reference discontinued labeling for a listed drug. This generally should occur when:

87

88 1. The holder of the NDA for the innovator drug has obtained approval for a change in

89 the drug labeling.

90

91 2. That change has received either a patent listed in Approved Drug Products with

92 Therapeutic Equivalence Evaluations (the Orange Book) or market exclusivity under

93 the Act.

94

95 3. The NDA sponsor has removed or revised the labeling describing the corresponding

96 unprotected aspects of the drug.

97

98 4. The change to the drug product is not one for which a suitability petition may be filed

99 (21 CFR 314.93).

100

101 5. The sponsor wishing to reference the discontinued labeling has submitted a petition

102 requesting that the Agency determine whether the previous labeling was withdrawn

103 for reasons of safety or effectiveness, or the Agency has undertaken its own inquiry

104 regarding the withdrawal of the previous labeling.

105

106 6. The Agency has determined that the previous innovator labeling was not withdrawn

107 for reasons of safety or effectiveness.

108

109 7. The Agency has determined that omission of the protected information will not render

110 the drug product less safe or effective than the currently marketed innovator product.

111

112

113 IV. SUBMISSION OF ANDAS

114

115 A. Statutory Requirements

116

117 The generic drug approval process is based on the ANDA applicant establishing that its

118 product is the same as a drug previously approved by FDA. Among other things, an

119 ANDA must provide information to show that the conditions of use, route of

120 administration, dosage form, and strength of the proposed product have been previously

121 approved for a listed drug (section 505(j)(2)(A) of the Act). If an ANDA applicant wants

122 approval of a change to the route of administration, dosage form, strength, or the

123 substitution of an active ingredient in a combination drug product, it can obtain approval
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124 for this change through a suitability petition (section 505(j)(2)(C)). The ANDA also must

125 include information to show that the labeling for the proposed drug is the same as the

126 labeling approved for the listed drug, except for differences approved through a petition,

127 or because the proposed drug and listed drug are produced by different manufacturers

128 (section 505(j)(2)(A)(v)).

129

130 A listed drug is a drug included on a list published by FDA of drugs approved for safety

131 and effectiveness under section 505(c) (section 505(j)(7)) of the Act. This list is

132 published in the Orange Book. A drug whose approval was withdrawn or suspended

133 under section 505(e) for reasons of safety or effectiveness, or that has been withdrawn

134 from sale for reasons of safety or effectiveness, cannot serve as a listed drug for approval

135 and is removed from the Orange Book (section 505(j)(4)(I) and (j)(7)(C)).

136

137 B. Regulatory Requirements

138

139 Identification of a listed drug is a crucial component of the ANDA approval process. An

140 ANDA must refer to a listed drug (21 CFR 314.94(a)(3)). The characteristics and

141 labeling of the listed drug generally will be duplicated in the characteristics and labeling

142 of the product proposed in the ANDA (21 CFR 314.94(a)(3)-(9)). A drug approved in an

143 ANDA must be the same as the listed drug in terms of active ingredient(s), dosage form,

144 strength, route of administration, and conditions of use, except for conditions of use for

145 which approval cannot be granted because of exclusivity or an existing patent (21 CFR

146 314.92(a)(1)). Certain differences will be permitted for products for which a suitability

147 petition has been approved, or because the drug proposed in the ANDA and the listed

148 drug are produced or distributed by different manufacturers. These differences can

149 include omission of an indication or other aspect of labeling that is protected by patent or

150 exclusivity (21 CFR 314.94(a)(8)(iv)). Aspects of a listed drug's labeling that are

151 protected by patent or exclusivity may be omitted from the labeling proposed in an

152 ANDA if the resulting differences in the labeling do not render the proposed drug product

153 less safe or effective for all the remaining, unprotected conditions of use (21 CFR

154 314.127(a)(7)).

155

156 An ANDA may refer to a listed drug that is an approved product currently being

157 marketed, or that is an approved product which has been withdrawn from the market by

the sponsor.4 158 If an ANDA applicant references a listed drug that the sponsor has ceased

159 to market, the FDA must determine whether the drug was removed from the market for

160 reasons of safety or effectiveness before the ANDA can be approved (21 CFR 314.161).

161 If the Agency has not made such a determination on its own initiative, the ANDA relying

 

4

 FDA regulations define listed drug at 21 CFR 314.3(b) as "a new drug product that has an

effective approval under section 505(c) of the act for safety and effectiveness or under 505(j) of the act,

which has not been withdrawn or suspended under section 505(e)(1) through (e)(5) or (j)(5) of the act, and

which has not been withdrawn from sale for what FDA has determined are reasons of safety or

effectiveness. Listed drug status is evidenced by the drug product's identification as a drug with an

effective approval in the current edition of [the Orange Book], or any current supplement thereto." Note:

section 505(j)(5) of the Act has been renumbered as 505(j)(6).
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162 on the discontinued drug must be accompanied by a petition requesting FDA to

163 determine whether the drug was withdrawn from the market for reasons of safety or

164 effectiveness (21 CFR 314.122).

165

166 C. Past Practice

167

168 In the past, when an applicant submitted an ANDA, the only labeling available for the

169 listed drug has been labeling on the currently marketed form of the listed drug. The

170 regulations require an ANDA to include a copy of the "currently approved labeling for

171 the listed drug" (21 CFR 314.94(a)(8)). If the generic product will have labeling that is

172 different from that of the listed drug, the ANDA applicant should state the reason for

173 such differences and explain why such differences are permitted. As described above,

174 certain differences from the innovator labeling are permitted.

175

176 The question of whether an ANDA could refer to previously approved but subsequently

177 altered labeling had not arisen previously. Therefore, until recently, the Agency had not

had a reason to develop a policy on the appropriate response to this situation. 5178 Now, with

179 what could be a growing practice among innovator sponsors of substituting protected

180 labeling for unprotected labeling, the Agency has determined that in certain situations, it

181 may approve an ANDA for a drug product with labeling that was previously approved for

182 the listed drug, but which the listed drug is no longer carrying.

183

184

185 V. REFERENCING DISCONTINUED LABELING FOR A LISTED DRUG IN

186 AN ANDA

187

188 For an ANDA applicant to refer to discontinued labeling for a listed drug, the following

189 conditions should exist.

190

191 A. Existence of Exclusivity or Patent Protection

192

193 An ANDA generally should refer to discontinued labeling for the listed drug only when,

194 at the time the ANDA is submitted (or while it is pending), an essential part of the

195 labeling for the currently marketed innovator drug is protected by exclusivity or a patent,

196 and the corresponding unprotected labeling has been removed. This approach is based on

197 the desire to minimize confusion in the marketplace arising from the availability of drugs

that are the same in many respects, but have slightly different labeling.6 198

 

5

 In 1998, the Office of Generic Drugs provided an informal opinion to an innovator company that

had removed unprotected dosing information from its label stating that the Agency would not approve an

ANDA that does not contain the same dosing and administration information as the listed drug. That

opinion, however, was given in a case in which the discontinued labeling information was determined by

the Agency to have been removed from the innovator drug for reasons of safety or effectiveness. To

address any concern that the approach described in this guidance can be considered a change from past

interpretation, the guidance is being released in draft for public comment prior to implementation.

6

 There are already situations in which ANDAs will be approved for drug products that are
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199

200 B. Identifying Appropriate Labeling

201

202 The ANDA applicant should identify the discontinued labeling for the listed drug to

203 which it will refer. Generally, this will be the labeling as approved in the innovator

204 application just prior to the addition of the protected part labeling and deletion of the

205 unprotected part of labeling.

206

207 C. Submission of Petition Requesting Determination of Reasons for Change to

208 Labeling

209

210 Once the ANDA applicant has identified the discontinued labeling for the listed drug to

211 which it will refer, the applicant should submit a petition as described in 21 CFR

212 314.122, seeking a determination by FDA that the discontinued labeling was not

213 withdrawn from the listed drug for reasons of safety or effectiveness. An ANDA for the

214 drug may be submitted at the same time the petition is submitted, but the ANDA will not

215 be approved until the Agency has determined that the discontinued labeling for the listed

216 drug was not withdrawn for reasons of safety or effectiveness. FDA also may, on its own

217 initiative, begin the process of determining whether labeling was discontinued for reasons

218 of safety or effectiveness.

219

220 D. FDA Determination on Safety and Effectiveness

221

222 The Agency will determine whether the labeling was discontinued for reasons of safety

223 or effectiveness. If the labeling was discontinued for reasons of safety or effectiveness, it

224 cannot be referred to by the ANDA applicant. Such a determination will be based on the

225 same factors and information FDA considers when determining whether a product

226 withdrawn entirely from the market was withdrawn for reasons of safety or effectiveness

227 (see 54 FR 28872, 28907-08; July 10, 1989). In addition, the Agency will determine

228 whether omission of protected information from the labeling would render the proposed

drug product less safe or effective for all the remaining, unprotected conditions of use.7 229 

230 The Agency will publish its determination in the Federal Register, as described in 21 CR

231 314.161.

232

233 E. Therapeutic Equivalence Ratings

234

235 Whether a drug approved in an ANDA that refers to discontinued labeling for the listed

236 drug will be rated therapeutically equivalent to the currently marketed innovator product

237 will depend upon the differences in the labeling.

238

 

different from the marketed innovator drug. For example, an ANDA may be approved for fewer than all of

the indications approved for the innovator drug. There can also be differences in labeling related to

excipients, handling and administration of the drug related to excipient differences, and differences arising

from revisions in labeling guidelines (21 CFR 314.94(a)(8)(iv)).

7 New labeling will not be protected by exclusivity if it describes new risks or warnings (54 FR

28872, 28899, July 10, 1989; 59 FR 50338, 50356-57, October 3, 1994).
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239 F. Expiration of Exclusivity or Patent Protection

240

241 Once the exclusivity or patent protecting the current innovator labeling has expired, the

242 ANDA applicant whose product references the discontinued labeling should file a

243 supplement to its ANDA to make the labeling conform to the labeling of the marketed

244 innovator product.