Warning: Creating default object from empty value in /home4/sspccco/public_html/pharmafacts.com/plugins/system/J2top.php on line 78
Compounded Drug Products That Are Essentially Copies of a Commercially Available Drug Product Under Section 503A of the Federal Food, Drug, and Cosmetic Act - PharmaFacts
gototopgototop
If you don't find what you're looking for, please let us know.

Compounded Drug Products That Are Essentially Copies of a Commercially Available Drug Product Under Section 503A of the Federal Food, Drug, and Cosmetic Act

Compounded Drug Products That Are Essentially Copies of a Commercially Available Drug Product Under Section 503A of the Federal Food, Drug, and Cosmetic Act

Guidance for Industry

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.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be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to http://www.regulations.gov. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.

For questions regarding this draft document contact Sara Rothman (CDER) at 301-796-3110.

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) Office of Compliance/OUDLC

July 2016 Compounding and Related Documents

page1image9960

1

Compounded Drug Products That Are Essentially Copies of a Commercially Available Drug Product Under Section 503A of the Federal Food, Drug, and Cosmetic Act

Guidance for Industry

Additional copies are available from:
Office of Communications
Division of Drug Information, WO51, Room 2201
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Silver Spring, MD 20993
Phone: 301-796-3400; Fax: 301-847-8714 This e-mail address is being protected from spambots. You need JavaScript enabled to view it
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) Office of Compliance/OUDLC

July 2016 Compounding and Related Documents

page2image7144

2

I. II.

INTRODUCTION AND SCOPE .................................................................................... 1 BACKGROUND ............................................................................................................... 2 Section 503A of the FD&C Act ..................................................................................................... 2 Compounding, Generally .............................................................................................................. 2 Risks Associated with Compounded Drug Products .................................................................. 3 Compounded Drugs That Are Essentially Copies of Commercially Available Drug

Contains Nonbinding Recommendations

Draft — Not for Implementation

TABLE OF CONTENTS

A.
B.
C.
D. Products................................................................................................................................................... 3

III. POLICY ............................................................................................................................ 4

  1. Commercially Available Drug Product........................................................................................ 5

  2. Essentially a Copy of a Commercially Available Drug Product................................................5

3

Contains Nonbinding Recommendations

Draft — Not for Implementation

Guidance for Industry1

Compounded Drug Products That Are Essentially Copies of a Commercially Available Drug Product Under Section 503A of the Federal Food, Drug, and Cosmetic Act

14
15
16
I. 17

  1. 18  To qualify for exemptions under section 503A of the Federal Food, Drug, and Cosmetic Act

  2. 19  (FD&C Act or the Act), a drug product must be compounded by a licensed pharmacist or

  3. 20  physician who does not compound regularly or in inordinate amounts any drug products that are

  4. 21  essentially copies of a commercially available drug product, among other conditions. This

  5. 22  guidance sets forth the FDA’s policies regarding this provision of section 503A, including the

  6. 23  terms commercially available, essentially a copy of a commercially available drug product, and

  7. 24 regularly or in inordinate amounts.2

25

  1. 26  In general, FDA’s guidance documents do not establish legally enforceable responsibilities.

  2. 27  Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only

  3. 28  as recommendations, unless specific regulatory or statutory requirements are cited. The use of

  4. 29  the word should in Agency guidances means that something is suggested or recommended, but

  5. 30  not required.

31

1 This guidance has been prepared by multiple offices in the Center for Drug Evaluation and Research, in consultation with the Office of Regulatory Affairs at the Food and Drug Administration.

2 This guidance does not apply to drugs compounded for use in animals, to biological products subject to licensure in a biologics license application, or to repackaged drug products. For proposed policies pertaining to compounding drug products from bulk drug substances for use in animals, see FDA’s draft guidance, Compounding Animal Drugs from Bulk Drug Substances. For proposed policies pertaining to mixing, diluting, and repackaging biological products, see FDA’s draft guidance, Mixing, Diluting, and Repackaging Biological Products Outside the Scope of an Approved Biologics License Application. For proposed policies pertaining to repackaged drug products, see FDA’s draft guidance, Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities.

All FDA guidances are available on the FDA guidance web page. FDA updates guidances regularly. To make sure you have the most recent version of a guidance, always consult the guidance web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

1 2 3 4

56

7 8 9

10 11 12 13

page4image25768

This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or the Agency) on this topic. It does not create any rights for any person and is not binding on FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed in the title page.

page4image39264

INTRODUCTION AND SCOPE

page4image41208 page4image41368

1

Contains Nonbinding Recommendations

Draft — Not for Implementation

32 II. BACKGROUND
33
34
A. Section 503A of the FD&C Act 35

  1. 36  Section 503A, added to the FD&C Act by the Food and Drug Administration Modernization Act

  2. 37  in 1997 and amended by the Drug Quality and Security Act in 2013, describes the conditions that

  3. 38  must be satisfied for human drug products compounded by a licensed pharmacist in a State-

  4. 39  licensed pharmacy or Federal facility, or by a licensed physician, to qualify for exemptions from

  5. 40  the following three sections of the FD&C Act3:

41
42
43

  1. 44

  2. 45

46 47

  1. 48  One of the conditions that must be met for a compounded drug product to qualify for the

  2. 49  exemptions under section 503A of the FD&C Act is that it must be compounded by a licensed

  3. 50  pharmacist or a licensed physician that “does not compound regularly or in inordinate amounts

  4. 51  (as defined by the Secretary) any drug products that are essentially copies of a commercially

  5. 52  available drug product.”4

53

  1. 54  The statute further states that “[t]he term ‘essentially a copy of a commercially available drug

  2. 55  product’ does not include a drug product in which there is a change, made for an identified

  3. 56  individual patient, which produces for that patient a significant difference, as determined by the

  4. 57  prescribing practitioner, between the compounded drug and the comparable commercially

  5. 58  available drug.”5

59

  1. 60  A complete list of the conditions that must be met for a compounded drug product to qualify for

  2. 61  the exemptions in section 503A appears in the FDA’s guidance, Pharmacy Compounding of

  3. 62 Human Drug Products Under Section 503A of the Federal Food, Drug, and Cosmetic Act.

63
64
B. Compounding,Generally 65

  1. 66  Compounded drug products serve an important role for patients whose clinical needs cannot be

  2. 67  met by an FDA-approved drug product, such as a patient who has an allergy and needs a

  3. 68  medication to be made without a certain dye, an elderly patient who cannot swallow a pill and

  4. 69  needs a medicine in a liquid form that is not otherwise available, or a child who needs a drug in a

  5. 70  strength that is lower than that of the commercially available product. Drug products for

  6. 71  identified individual patients can be compounded by licensed pharmacists in state-licensed

    3 In addition, under section 581(13) of the FD&C Act, the term “product,” for purposes of pharmaceutical supply chain security requirements, does not include a drug compounded in compliance with section 503A.

    4 See section 503A(b)(1)(D). 5 See section 503A(b)(2).

Section 501(a)(2)(B) (concerning current good manufacturing practice (CGMP) requirements)
Section 502(f)(1) (concerning the labeling of drugs with adequate directions for use) Section 505 (concerning the approval of drugs under new drug applications (NDAs) or abbreviated new drug applications (ANDAs))

page5image29384

2

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 72  pharmacies and Federal facilities and by licensed physicians operating under section 503A of the

  2. 73  FD&C Act. Drug products can also be compounded by outsourcing facilities under section 503B

  3. 74  of the FD&C Act for identified individual patients pursuant to prescriptions or for distribution to

  4. 75  health care practitioners without first receiving a prescription.6 Both sections 503A and 503B

  5. 76  restrict compounding drug products that are essentially a copy of a commercially available drug

  6. 77  product (section 503A) or an approved drug product (section 503B).

78
79
C. Risks Associated with Compounded Drug Products

80

  1. 81  Although compounded drugs can serve an important need, they also pose a higher risk to patients

  2. 82  than FDA-approved drugs. Compounded drug products are not FDA-approved, which means

  3. 83  they have not undergone FDA premarket review for safety, effectiveness, and quality. In

  4. 84  addition, licensed pharmacists and licensed physicians who compound drug products in

  5. 85  accordance with section 503A are not required to comply with CGMP requirements.

  6. 86  Furthermore, FDA does not interact with the vast majority of licensed pharmacists and licensed

  7. 87  physicians who compound drug products and seek to qualify for the exemptions under section

  8. 88  503A of the FD&C Act for the drug products that they compound because these compounders

  9. 89  are not licensed by FDA and generally do not register their compounding facilities with FDA.

  10. 90  Therefore, FDA is often not aware of potential problems with their compounded drug products

  11. 91  or compounding practices unless it receives a complaint such as a report of a serious adverse

  12. 92  event or visible contamination.

93

  1. 94  FDA has investigated numerous serious adverse events associated with compounded drug

  2. 95  products that were contaminated or otherwise compounded improperly, including the adverse

  3. 96  events associated with the 2012 fungal meningitis outbreak in which contaminated injectable

  4. 97  drug products resulted in more than 60 deaths and 750 cases of infection. FDA has also

  5. 98  identified many pharmacies that compounded drug products under insanitary conditions whereby

  6. 99  the drug products may have been contaminated with filth or rendered injurious to health and that

  7. 100  shipped the compounded drug products made under these conditions to patients and health care

  8. 101  practitioners across the country, sometimes in large amounts.

102

  1. 103 D. Compounded Drugs That Are Essentially Copies of Commercially Available

  2. 104 Drug Products

105

  1. 106  Section 503A provides exemptions from new drug approval, labeling with adequate directions

  2. 107  for use, and CGMP requirements of the FD&C Act, so that drug products can be compounded as

  3. 108  customized therapies for identified individual patients whose medical needs cannot be met by

  4. 109  commercially available drug products. The restrictions on making drugs that are essentially

  5. 110  copies ensure that pharmacists and physicians do not compound drug products under the

  6. 111  exemptions for patients who could use a commercially available drug product. Such a practice

  7. 112  would create significant public health risks because patients would be unnecessarily exposed to

    6 Section 503B of the FD&C Act describes the conditions that must be met for a human drug product compounded by an outsourcing facility to qualify for exemptions from sections 505, 502(f)(1), and 582 (concerning drug supply chain security requirements) of the FD&C Act. The conditions applicable to outsourcing facilities are discussed in separate guidances applicable to those facilities.

page6image32480

3

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 113  drug products that have not been shown to be safe and effective and that may have been prepared

  2. 114  under substandard manufacturing conditions. FDA has investigated serious adverse events in

  3. 115  patients who received contaminated compounded drugs when a comparable approved drug, made

  4. 116  in a facility subject to CGMP requirements, was available.

117

  1. 118  In addition to these immediate public health risks, section 503A’s limitations on producing a

  2. 119  drug product that is essentially a copy of a commercially available drug product protects the

  3. 120  integrity and effectiveness of the new drug and abbreviated new drug approval processes that

  4. 121  Congress put in place to protect patients from unsafe, ineffective, or poor quality drugs.

  5. 122  Furthermore, sponsors may be less likely to invest in and seek approval of innovative, life-saving

  6. 123  medications if a compounder could, after a drug is approved, compound “substitutes” that have

  7. 124  not had to demonstrate safety and effectiveness and are not produced in accordance with CGMP

  8. 125  requirements or labeled with adequate directions for use.

126

  1. 127  Sponsors might also be less likely to seek approval of an ANDA for a generic drug if

  2. 128  compounders were permitted to compound drugs that are essentially copies of commercially

  3. 129  available drugs without going through the ANDA process. An ANDA must include data to

  4. 130  demonstrate that the drug has the same active ingredient and is bioequivalent to an approved

  5. 131  drug. FDA also conducts a premarketing inspection of proposed manufacturing facilities before

  6. 132  approving the application.

133

  1. 134  The copies restriction also protects FDA’s drug monograph process. FDA has an ongoing

  2. 135  process for evaluating the safety and effectiveness of certain over-the-counter (OTC)

  3. 136  medications, and if the Agency determines that an OTC drug meets certain conditions and is

  4. 137  generally recognized as safe and effective, it will publish a final monograph specifying those

  5. 138  conditions. Products that comply with a final monograph may be marketed, but manufacturers

  6. 139  are required to meet CGMP standards. Restrictions in section 503A prevent compounders from

  7. 140  producing drugs without having to comply with monograph standards, or CGMP requirements.

141
142
III. POLICY 143

  1. 144  As stated above, to qualify for the exemptions under section 503A of the FD&C Act, a drug must

  2. 145  be compounded by a licensed pharmacist or a licensed physician that does not compound

  3. 146  regularly or in inordinate amounts (as defined by the Secretary) any drug products that are

  4. 147  essentially copies of a commercially available drug product.7 In other words, a compounded

  5. 148  drug product is not eligible for the exemptions in section 503A if it is both 1) essentially a copy

  6. 149  of a commercially available drug product, and it is 2) compounded regularly or in inordinate

  7. 150  amounts. Accordingly, and as discussed below, when evaluating whether a drug product meets

  8. 151  the condition in section 503A regarding essentially copies, FDA intends to determine first

  9. 152  whether a compounded drug product is essentially a copy of a commercially available drug

  10. 153 product, and if it is, FDA intends to determine second whether the drug product was

  11. 154  compounded regularly or in inordinate amounts.

155

7 See section 503A(b)(1)(D).

page7image31688

4

156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192

Contains Nonbinding Recommendations

Draft — Not for Implementation

FDA’s policies with regard to the terms (1) commercially available drug product, (2) essentially a copy of a commercially available drug product, and (3) regularly or in inordinate amounts, are as follows:

A. Commercially Available Drug Product

For purposes of this guidance, a drug product is commercially available if it is a marketed drug product.

We do not consider a drug product to be commercially available if

• •

8
the drug product has been discontinued and is no longer marketed ) or

the drug product appears on the FDA drug shortage list in effect under section 506E of the FD&C Act.9 A drug “appears on the drug shortage list in effect under section 506E” if the drug is in “currently in shortage” status (and not in “resolved” status) in FDA’s drug shortage database.

Commercially available drugs are available on the market, and they are generally subject to FD&C Act requirements relating to approval, labeling, and CGMP requirements, and the copies restriction applies to all such drugs because section 503A is not intended to provide a means for compounders to produce compounded drugs exempt from the Act’s requirements that are essentially copies of commercially available drug products.

B. Essentially a Copy of a Commercially Available Drug Product

1. What is Essentially a Copy?

FDA intends to consider a compounded drug product to be essentially a copy of a commercially available drug product if:

• •

the compounded drug product has the same active pharmaceutical ingredient(s) (API) as the commercially available drug product;
the API(s) have the same, similar, or an easily substitutable dosage strength; and
the commercially available drug product can be used by the same route of administration as prescribed for the compounded drug,

page8image24016

8 FDA maintains a list of approved drug products that sponsors have indicated are not marketed in the discontinued section of the list of Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book). See http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm. Specifically, the list includes approved drug products that have never been marketed, are for exportation, are for military use, have been discontinued from marketing and we have not determined that they were withdrawn for safety or effectiveness reasons, or have had their approvals withdrawn for reasons other than safety or effectiveness subsequent to being discontinued from marketing.

9 See http://www.accessdata.fda.gov/scripts/drugshortages/default.cfm.

page8image29120 page8image29280

5

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 193  unless a prescriber determines that there is a change, made for an identified individual patient,

  2. 194  which produces for that patient a significant difference from the commercially available drug

  3. 195  product.

196

  1. 197  The limitations in section 503A(b)(1)(D) apply to the compounding of drug products that are

  2. 198 essentially copies of a commercially available drug product – not only to drugs that are exact

  3. 199  copies or even to drugs that are nearly identical. This is to ensure that compounders do not evade

  4. 200  the limits in this section by making relatively small changes to a compounded drug product and

  5. 201  then offering the drug to the general public without regard to whether a prescribing practitioner

  6. 202  has determined that the change produces for the patient a significant difference. For example,

  7. 203  Congress contemplated that a compounded drug may be essentially a copy of a commercially

  8. 204  available drug if “minor changes in strength (such as from .08% to .09%) are made that are not

  9. 205  known to be significant . . .” for the patient for whom the drug was prescribed.10

206
207 a. Same API 208

  1. 209  With regard to the characteristics listed above, an API is the substance in a drug product that

  2. 210  is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure,

  3. 211  mitigation, treatment, or prevention of disease or to affect the structure or function of the

  4. 212  body.11 When a compounded drug product offers the same API as a commercially available

  5. 213  drug product, in the same, similar, or easily substitutable dosage strength and for use through

  6. 214  the same route of administration, we generally intend to consider such a drug product

  7. 215 essentially a copy, unless a prescriber determines that there is a change, made for an

  8. 216  individual patient, that will produce a significant difference for that patient.

217

  1. 218  We recognize that, for some patients, a drug product that has the same API, strength, and

  2. 219  route of administration may include a change that produces a significant difference for a

  3. 220  particular patient. For example, a drug product compounded without a particular inactive

  4. 221  ingredient may produce a significant difference for a patient who has an allergy to the

  5. 222  inactive ingredient in the commercially available drug product. However, for other patients,

  6. 223  this change may produce no difference at all. Congress did not intend for compounders to

  7. 224  use, for example, the fact that some patients may have allergies as a basis to compound a

  8. 225  drug without the inactive ingredient for other patients who do not have the allergy under the

  9. 226  exemptions in section 503A (i.e., without meeting requirements for premarket approval,

  10. 227  labeling with adequate directions for use, or CGMP requirements).12 In the context of

  11. 228  compounding and consistent with the statute, we intend to consider such a drug essentially a

    10 U.S. House. Food and Drug Administration Modernization Act of 1997, Conference Report (to Accompany S. 830). (105 H. Rpt. 399).

    11 Section 503A refers to bulk drug substances. A bulk drug substance is defined as any substance that is represented for use in a drug and that, when used in the manufacturing, processing, or packaging of a drug, becomes an active ingredient or finished dosage form of the drug, but the term does not include intermediates used in the synthesis of such substances (21 CFR 207.3(4)).

    12 See note 10.

page9image32784

6

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 229  copy, unless a prescriber determines that there is a change that will produce a significant

  2. 230  difference for the patient for whom it is prescribed.

231
232 b. Same, Similar or Easily Substitutable Strength

233

  1. 234  FDA generally intends to consider two drugs to have a similar dosage strength if the dosage

  2. 235  strength of the compounded drug is within 10% of the dosage strength of the commercially

  3. 236  available drug product.

237

  1. 238  With regard to the concept of easily substitutable strength, in some cases, the same or similar

  2. 239  dosage strength can be achieved by administration of fractional or multiple doses of a drug

  3. 240  product. For example, if FDA-approved Drug X tablets have a dosage strength of 25 mg and

  4. 241  a patient needs 50 mg of Drug X, FDA would generally consider a compounded Drug X 50

  5. 242  mg tablet to have an easily substitutable strength because the patient could take two Drug X

  6. 243  25 mg tablets to achieve the required dose.

244
245 c. Same Route of Administration 246

  1. 247  Route of administration is a way of administering a drug to a site in a patient (e.g., topical,

  2. 248  intravenous, oral).13 In general, FDA does not intend to consider a compounded drug

  3. 249  product with the same API and similar or easily substitutable strength to be essentially a copy

  4. 250  of a commercially available drug product if the compounded drug product and the

  5. 251  commercially available drug product have different routes of administration (e.g., if the

  6. 252  commercially available drug product is oral and the compounded drug product is topical).

  7. 253  However, if the compounded drug product has the same API and similar or easily

  8. 254  substitutable strength as the commercially available drug product and the commercially

  9. 255  available drug product can be used (regardless of how it is labeled) by the route of

  10. 256  administration prescribed for the compounded drug, FDA generally intends to consider the

  11. 257  compounded drug to be essentially a copy of the commercially available drug. In this case,

  12. 258  the compounded drug product generally would not produce a significant difference for an

  13. 259  identified individual patient relative to the commercially available drug product.

260

  1. 261  For example, if the commercially available drug is an injectable drug sold in a vial that is

  2. 262  labeled for intra-muscular use, but the drug also can be drawn from the vial by a smaller

  3. 263  needle for subcutaneous administration, a compounded drug product with the same API and

  4. 264  similar or easily substitutable strength prescribed for sub-cutaneous administration would

  5. 265  generally be considered to be essentially a copy, unless the prescriber documents on the

  6. 266  prescription that the compounded drug product produces a significant difference for the

  7. 267  identified individual patient.

268
269 Same Characteristics as Two or More Commercially Available Drug Products

13 See

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/D ataStandardsManualmonographs/ucm071667.htm.

page10image29288 page10image29448 page10image29608

7

Contains Nonbinding Recommendations

Draft — Not for Implementation

270

  1. 271  FDA intends to consider a compounded drug product to be essentially a copy of a

  2. 272  commercially available drug product if the compounded drug product contains the same APIs

  3. 273  as two or more commercially available drug products in the same, similar, or easily

  4. 274  substitutable strength and if the compounded drug product and the commercially available

  5. 275  drug products have the same route of administration, unless there is documentation as

  6. 276  described in section III.B.2. Such drug products present the same kinds of concerns as drug

  7. 277  products that have a single API and in some respects may be more dangerous because of the

  8. 278  potential for unintended drug interactions. For example, if drug X and drug Y are

  9. 279  commercially available oral drug products, FDA intends to consider a compounded oral drug

  10. 280  product that combines drug X and drug Y in strengths that are within 10% of the strengths of

  11. 281  the respective commercially available products to be essentially a copy of the commercially

  12. 282  available drug product, unless a prescriber determination of a significant difference has been

  13. 283  documented.

284
285
2. Statement of Significant Difference 286

  1. 287  Pursuant to section 503A(b)(2) of the FD&C Act, a compounded drug product is not essentially a

  2. 288  copy of a commercially available drug product if a change is made for an identified individual

  3. 289  patient, and the prescribing practitioner has determined that the change will produce a significant

  4. 290  difference for that patient. If a compounder intends to rely on such a determination to establish

  5. 291  that a compounded drug is not essentially a copy of a commercially available drug product, the

  6. 292  compounder should ensure that the determination is documented on the prescription.

293

  1. 294  FDA does not believe that a particular format is needed to document the determination, provided

  2. 295  that the prescription makes clear that the prescriber identified the relevant change and the

  3. 296  significant difference produced for the patient. For example, the following would be sufficient:

297

  1. 298

  2. 299

  3. 300

301

  1. 302  However, if a prescription identifies only a patient name and drug product formulation, this

  2. 303  would not be sufficient to establish that the prescriber made the determination described by

  3. 304  section 503A(b)(2). Note also that the significant benefit that the prescriber identifies must be

  4. 305  produced by the change the compounder will make to a commercially available drug product

  5. 306  (i.e., a change in drug product formulation). Other factors, such as a lower price, are not

  6. 307  sufficient to establish that the compounded drug product is not essentially a copy of the

  7. 308  commercially available drug product.14

    14 Congress noted that “where it is readily apparent, based on the circumstances, that the ‘significant difference’ is a mere pretext to allow compounding of products that are essentially copies of commercially available products, such compounding would be considered copying of commercially available products and would not qualify for the compounding exemptions if it is done regularly or in inordinate amounts. Such circumstances may include, for example, minor changes in strength (such as from .08% to .09%) are made that are not known to be significant or instances in which the prescribing physician is receiving financial remuneration or other incentives to write

“No Dye X, patient allergy” (if the comparable drug contains the dye)
“Liquid form, patient can’t swallow tablet” (if the comparable drug is a tablet)
“6 mg, patient needs higher dose” (if the comparable drug is only available in 5 mg dose)

page11image34448

8

Contains Nonbinding Recommendations

Draft — Not for Implementation

309

  1. 310  If a prescription does not make clear that the prescriber made the determination required by

  2. 311  section 503A(b)(2), or a compounded drug is substituted for the commercially available drug

  3. 312  product, the compounder can contact the prescriber and if the prescriber confirms it, make a

  4. 313  notation on the prescription that the compounded drug product contains a change that makes a

  5. 314  significant difference for the patient. The notations should be as specific as those described

  6. 315  above, and the date of the conversation with the prescriber should be included on the

  7. 316  prescription.

317

  1. 318  It is not possible to offer comprehensive guidance about when a difference will be “significant”

  2. 319  to an identified individual patient. FDA generally does not intend to question prescriber

  3. 320  determinations that are documented in a prescription or notation. However, we do intend to

  4. 321  consider whether a prescription or notation relied upon by a compounder to establish that a drug

  5. 322  is not essentially a copy documents that the determination was made.

323
324
3. Documentation of shortage 325

  1. 326  If the drug was compounded because the approved drug product was not commercially available

  2. 327  because it was on the FDA drug shortage list, the prescriber or compounder should include a

  3. 328  notation on the prescription that it was on the drug shortage list and the date the list was checked.

329
330
4. Regularly or in Inordinate Amounts 331

  1. 332  A drug product is not eligible for the exemptions in section 503A if it is prepared by a

  2. 333  pharmacist or physician who compounds “regularly or in inordinate amounts (as defined by the

  3. 334  Secretary)” any drug products that are essentially copies of a commercially available drug

  4. 335  product.15 FDA interprets this to mean that to be compounded in accordance with section 503A,

  5. 336  a drug product that is essentially a copy of a commercially available drug product cannot be

  6. 337  compounded regularly – i.e., it cannot be compounded at regular times or intervals, usually, or

  7. 338  very often. Nor can the amounts compounded be inordinate, in light of the purpose of section

  8. 339  503A.

340

  1. 341  Section 503A is intended to protect patients from the public health risks of providing

  2. 342  compounded drugs to patients whose medical needs could be met by commercially available

  3. 343  drug products and to protect the integrity and efficiency of the drug approval process. Under the

  4. 344  statutory scheme, only very rarely should a compounded drug product that is essentially a copy

  5. 345  of a commercially available drug product be offered to a patient. For example, a compounded

  6. 346  drug product that has the same API, dosage strength, and route of administration as a drug

  7. 347  product on FDA’s shortage list would not be considered essentially a copy of a commercially

  8. 348  available drug because a drug product is not considered commercially available if it is on FDA’s

  9. 349  drug shortage list. In addition, a compounded drug product is not essentially a copy of a

    prescriptions for compounded products.” See the U.S. House. Food and Drug Administration Modernization Act of 1997, Conference Report (to Accompany S. 830). (105 H. Rpt. 399).

15 See section 503A(b)(1)(D).

page12image31512

9

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 350  commercially available drug product if a prescriber has determined that the compounded drug

  2. 351  has a change that produces a significant difference for a patient. We conclude, therefore, that a

  3. 352  drug product that is essentially a copy of a commercially available drug product is compounded

  4. 353  regularly or in inordinate amounts if it is compounded more frequently than needed to address

  5. 354  unanticipated, emergency circumstances or in more than the small quantities needed to address

  6. 355  unanticipated, emergency circumstances.

356

  1. 357  Once it has been determined that a compounded drug is essentially a copy of a commercially

  2. 358  available drug product as described above, the following are examples of factors that may be the

  3. 359  basis for concluding that it has been compounded regularly or in inordinate amounts:

360
361
362
363
364
365
366
367
368
369
370
371
372

  1. 373  The foregoing list is not intended to be exhaustive. Other factors may be appropriate for

  2. 374  consideration in a particular case.

375

  1. 376  To focus enforcement on the most significant cases, as a matter of policy, at this time FDA does

  2. 377  not intend to take action against a compounder for compounding a drug product that is

  3. 378  essentially a copy of a commercially available drug product regularly or in inordinate amounts if

  4. 379  the compounder fills four or fewer prescriptions for the relevant compounded drug product in a

  5. 380  calendar month.16 Be aware that a prescription would not be considered to be for a drug that is

  6. 381  essentially a copy of a commercially available drug product and would not be counted towards

  7. 382  the four prescriptions if the prescription documents that the compounded drug product makes a

  8. 383  significant difference for the patient as described above.

384
385
5. Recordkeeping 386

  1. 387  A licensed pharmacist or physician seeking to compound a drug product under section 503A

  2. 388  should maintain records to demonstrate compliance with section 503A(b)(1)(D). For example,

  3. 389  records should be kept of notations on prescriptions for identified individual patients that a

  4. 390  prescriber has determined that the compounded drug has a change that produces a significant

  5. 391  difference for the identified patient.

    16 For purposes of this policy, a prescription does not include additional refills. FDA intends to consider each refill of a prescription as an additional prescription.

The compounded drug product amounts to more than a small number of prescriptions or a small percentage of the compounded drug products that a physician or prescriber prepares or provides to patients.
The compounder routinely substitutes compounded drugs that are essentially copies of commercially available drugs upon receiving prescriptions for patients.

The compounder offers pre-printed prescription pads that a prescriber can use to write a prescription for the drug product that is essentially a copy without making a determination that there is a change that will produce a significant difference for a patient.

The compounded drug product is not compounded on an as-needed basis, but on a routine or pre-set schedule.

page13image31472

10

 

Contains Nonbinding Recommendations

Draft — Not for Implementation

392

  1. 393  Compounders under section 503A should also maintain records of the frequency in which they

  2. 394  have compounded drug products that are essentially copies of commercially available drug

  3. 395  products and the number of prescriptions that they have filled for compounded drug products that

  4. 396  are essentially copies of commercially available drug products to document that such

  5. 397  compounding has not been done regularly or in inordinate amounts.

11