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FDA Guidances

FDA Guidances

All Information was adapted from the Food and Drug Administration website as a service to our readers. The most current versions can be found on the FDA Website.

Microbiology Data for Systemic Antibacterial Drugs — Development, Analysis, and Presentation Guidance for Industry

Microbiology Data for

Systemic Antibacterial

Drugs — Development,

Analysis, and Presentation Guidance for Industry

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

August 2016 Clinical/Antimicrobial

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Microbiology Data for

Systemic Antibacterial

Drugs — Development,

Analysis, and Presentation Guidance for Industry

Additional copies are available from:

Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: 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)

August 2016 Clinical/Antimicrobial

I. II.

A.

1. 2. 3. 4.

B.

1. 2. 3. 4.

C.

1. 2. 3. 4. 5. 6. 7.

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1 MICROBIOLOGY DEVELOPMENT PROGRAM ..................................................... 1 Early Development Nonclinical Considerations ..........................................................................2

Antibacterial Spectrum of Activity....................................................................................................2 Mechanism of Action ........................................................................................................................2 Intracellular Antimicrobial Concentration Assessment ...................................................................2 Resistance Studies ............................................................................................................................3 In Vitro Antimicrobial Susceptibility Test Methods During Drug Development.....................3

Early Clinical Development .............................................................................................................3 Provisional Antibacterial Susceptibility Test Interpretive Criteria .................................................4 Establishing In Vitro Antibacterial Susceptibility Test Interpretive Criteria...................................5 Quality Control Parameters.............................................................................................................5 Other Considerations .....................................................................................................................6

First and Second Lists of Target Bacteria in Labeling ....................................................................6 Antibacterial Interactions and Fixed Combination Studies .............................................................6 Additional Nonclinical Studies of Antibacterial Drugs....................................................................7 Animal Models of Infection ..............................................................................................................7 Microbiology Information Collected in Clinical Trials ...................................................................7 Electronic Submission of Microbiology Information .......................................................................8 Postmarketing Microbiology Information........................................................................................8

REFERENCES............................................................................................................................ 10 APPENDIX A: GUIDELINES FOR BACTERIAL ISOLATE SELECTION
FOR STUDIES OF IN VITRO ANTIBACTERIAL ACTIVITY .......................................... 11 APPENDIX B: STUDY REPORTS OF SPECTRUM OF ACTIVITY AND

RESISTANCE ............................................................................................................................. 13 APPENDIX C: DATABASE FOR FINAL IN VITRO ANTIBACTERIAL SUSCEPTIBILITY TEST INTERPRETIVE CRITERIA ..................................................... 15 APPENDIX D: EXAMPLE FORMAT FOR SECTIONS OF LABELING

THAT PERTAIN TO MICROBIOLOGY ............................................................................... 18

APPENDIX E: INFORMATION REGARDING THE SECOND BACTERIA LIST
IN THE MICROBIOLOGY SUBSECTION OF LABELING............................................... 23

Contains Nonbinding Recommendations

Microbiology Data for Systemic Antibacterial Drugs — Development, Analysis, and Presentation Guidance for Industry1

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

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I. INTRODUCTION

The purpose of this guidance is to assist sponsors in the development, analysis, and presentation of microbiology data during antibacterial drug development.2 Specifically, this guidance addresses the Food and Drug Administration’s (FDA’s) current thinking regarding the overall microbiology development program needed to support clinical development and approval of antibacterial drugs administered systemically as well as microbiology information collected after approval.3

In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

II. MICROBIOLOGY DEVELOPMENT PROGRAM

Microbiology data provide important information to guide clinical development of an investigational new drug. Microbiology data guide clinicians on the use of an antibacterial drug for its intended indications.

1 This guidance has been prepared by the Division of Anti-Infective Products in the Center for Drug Evaluation and Research at the Food and Drug Administration.

2 For the purposes of this guidance, all references to drugs include both human drugs and therapeutic biological products unless otherwise specified.

3 This guidance addresses the types of microbiology information that should be provided to support an investigational new drug application (IND), a new drug application (NDA), a biologics license application (BLA), and a supplemental NDA or BLA. The term sponsor is used in this guidance and refers to sponsors submitting an IND as well as applicants submitting an NDA or BLA.

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A. Early Development Nonclinical Considerations

1. Antibacterial Spectrum of Activity

Sponsors should evaluate the activity of an antibacterial drug, including its active components and major circulating metabolites, against a test panel of relevant bacteria early in clinical development. Sponsors should provide data on a sufficient range of clinically relevant bacteria to allow an assessment of the potential clinical efficacy of the antibacterial drug for the intended indication. Appendix A provides the suggested number of genera and species that should be tested, and recommended characteristics and diversity of the test isolates.

When conducting studies of the spectrum of activity, sponsors should test in parallel FDA- approved antibacterial drugs, especially those with the same mechanism of action as the investigational drug. In the case of a drug that acts by a new mechanism of action, we recommend that sponsors include FDA-approved antibacterial drugs with a spectrum of activity similar to the investigational drug. In the event there is no FDA-approved antibacterial drug with a similar spectrum of activity, we recommend that sponsors discuss with the FDA the approved drugs to include in these studies.

Sponsors should evaluate the minimum inhibitory concentrations (MICs) in the relevant target bacteria and provide the rationale for an estimate of the epidemiologic cutoff (EC) of the investigational drug against target bacteria.

Appendix B provides an example of the recommended elements of the study reports on antibacterial spectrum of activity.

2. Mechanism of Action

Sponsors should evaluate the mechanism of action of an investigational drug (e.g., inhibition of cell wall synthesis, lysis of cell membrane, protein synthesis). Information about the drug’s chemical structure and a description of any structural or biological similarities to known antibacterial drugs should be provided. Data to substantiate both physiological and morphological effects on the microbial cells can provide a basis for understanding the development of resistance through alterations in the drug’s target sites. Studies evaluating microbial killing (e.g., microbial kill curves) should also be provided.

3. Intracellular Antimicrobial Concentration Assessment

The ability of an antibacterial drug to achieve significant intracellular concentrations may have clinical importance when the target organism can reside within the cell (e.g., Listeria, Chlamydophila, Legionella). In situations where the antibacterial drug is intended to treat infections caused by microorganisms that reside within the cell, sponsors should provide data on the drug’s ability to penetrate into host cells and demonstrate the drug’s activity against target microorganisms inside the cell (e.g., assessment of viable intracellular microorganisms following exposure of the cells to various concentrations of an antibacterial drug).

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4. Resistance Studies

Characterization of the resistance mechanisms and their distribution within the proposed target bacteria may delineate the potential clinical usefulness of the drug. Mechanisms include alterations of the drug by production of enzymes (e.g., beta-lactamases, extended spectrum beta- lactamases), inability to reach the target, and changes in the affinity of the antibacterial drug for the target site. To determine if there may be a proportion of bacteria in the overall population that are resistant to the antibacterial drug (i.e., hetero-resistance), testing should be done to evaluate for the presence of such bacteria. When possible, we recommend that sponsors provide the genotypic characteristic of resistance mechanisms.

Sponsors should compare the activity of an investigational antibacterial drug to the activity profile of approved and other existing antibacterial drugs with the same mechanism of action to assess the possibility of cross-resistance.

Under some circumstances, tentative inferences can be drawn about cross-resistance between antibacterial drugs within a specific population of isolates from regression analyses (i.e., MIC versus MIC or zone diameter versus zone diameter) of one drug compared to another drug. If cross-resistance exists between both the investigational and control drug, a strong correlation between the MICs of both drugs would be expected to be observed; with a majority of the MICs clustered on a 45-degree diagonal. If resistance affects the activity of one drug over the other, the cluster is usually skewed in the direction of one drug or the other and away from the expected diagonal.

Detailed information on the mechanism of action, resistance, or cross-resistance for an antibacterial drug with a novel mechanism of action may not be available for sponsors to include in the initial investigational new drug application. This information should be provided early in drug development, and ideally before initiation of phase 2 clinical development.

Appendix B provides an example of the recommended elements of study reports evaluating resistance.

B. In Vitro Antimicrobial Susceptibility Test Methods During Drug Development

1. Early Clinical Development

Before conducting clinical trials, sponsors should describe the methods used for generating susceptibility data. Sponsors can reference a standard method,4 or evaluate susceptibility by other methods including modification of the method. Sponsors should provide a detailed description of the method, including the justification for the modification of the method, the effect on susceptibility results, and performance characteristics of the method (i.e., sensitivity, specificity, precision, linearity). Sponsors should discuss any modification of an established in

4 Standard methods for susceptibility testing are developed by organizations such as the Clinical and Laboratory Standards Institute; information can be found at http://clsi.org. Sponsors can describe the standard method that they have used by referencing a recognized testing methodology.

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vitro susceptibility test method with the FDA before implementation in the drug development program.

Modifications can include the addition of any substance (e.g., blood, body fluids, polysorbate). In some cases, isolates obtained during clinical trials may need to be tested for their susceptibility in the presence and absence of the substance and the results of both methods correlated with clinical and microbiological results. Sponsors also should conduct studies to address the influence of the growth medium (e.g., pH, divalent cations), inoculum density, incubation conditions (e.g., concentration of CO2), and additives (e.g., polysorbate), in both broth and agar medium on in vitro susceptibility test results.

If sponsors propose to use freeze-dried panels to assess the MIC of clinical isolates, they should conduct a comparative study to demonstrate comparability of MIC results for the frozen and freeze-dried panels. Sponsors should discuss this proposed study with the FDA to ensure that appropriate data are developed for the equivalency assessment. The data should be submitted to the FDA before initiating phase 2 trials.

2. Provisional Antibacterial Susceptibility Test Interpretive Criteria

Provisional antibacterial susceptibility test (AST) interpretive criteria usually are based on the limited information available before the initiation of phase 3 clinical trials. In vitro microbiology data include distributions of MICs or zone diameters that are obtained by testing the antibacterial drug against a population of recent clinical isolates that represent the target bacteria for the indications being sought (see Appendix A for guidelines in the selection of target bacteria). Sponsors should provide testing data on a sufficient range of clinically relevant bacteria for the intended indications. Sponsors should identify the prominent genotypes, serotypes, biotypes, and isolates with known mechanisms of resistance and include these in the test panel. In addition, the mechanism of action of the investigational antibacterial drug and other drugs with the same mechanism of action should be considered when establishing susceptibility testing methods and provisional AST interpretive criteria.

When an investigational drug has a similar mechanism of action to an approved drug, the data justifying provisional AST interpretive criteria for the investigational drug should be presented as regressions of MIC versus MIC and zone diameter versus zone diameter. These data should be examined for clusters of isolates that are substantially different from those clusters near the expected regression line of MIC versus MIC or zone versus zone plots. For example, a cluster in a position away from the expected regression line suggests that one of the drugs is affected by a resistance mechanism that does not affect the other drug. Therefore, the two drugs are not interchangeable and provisional AST interpretive criteria of the investigational drug may not be similar to the AST interpretive criteria of an approved drug with a similar mechanism of action. When developing an antibacterial drug with a specific mechanism of action for the treatment of bacteria resistant to other antibacterial drugs with the same mechanism of action, these types of analyses can be extremely useful in demonstrating the activity of the investigational drug.

The data should be analyzed in terms of frequency distributions (e.g., histograms) of AST results. Frequency distribution analyses can help define which populations of isolates harbor

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specific resistance mechanisms that sponsors should identify. Frequency distributions can be analyzed for both dilution and diffusion susceptibility testing methods. Frequency distributions call for evaluation for each target bacteria, especially if there is no clear demarcation between the resistant and susceptible populations. EC values should be estimated for each targeted species or bacterial group.

Additional considerations to the provisional AST interpretive criteria include the methodological variability between diffusion and dilution susceptibility testing methods. Sponsors can suggest adjustments to the provisional AST interpretive criteria by evaluating scattergrams of dilution testing results compared with diffusion testing results of the same isolates tested with both methods. This evaluation can be performed by the Error Rate Bounding method that compares diffusion testing to dilution testing. The computational algorithm generates AST interpretive criteria that minimize the number of isolates with diffusion testing results that fall outside these criteria.

Finally, evaluation of the frequency distribution analyses relative to the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of the investigational antibacterial drug can further refine the provisional AST interpretive criteria.

3. Establishing In Vitro Antibacterial Susceptibility Test Interpretive Criteria

Sponsors should perform an analysis of the correlation between the clinical cure and microbiologic eradication rates in the clinical trials with the provisional AST interpretive criteria results to determine their clinical relevance. When appropriate, the clinical response and microbiologic eradication rates should be assessed as overall rates and as individual rates against bacteria with resistance to other antibacterial drugs as well as specific virulence factors. The available human PK/PD information, including target attainment analyses, assists in the selection of AST interpretive criteria. These analyses help to form the basis for the final selection of the AST interpretive criteria.

The purpose of establishing AST interpretive criteria is to guide the selection of appropriate antibacterial therapy. The accuracy and clinical relevance of such tests depend on adherence to standardized methods and appropriate consideration of the test results.

Consideration should also be given to the time it takes to develop a susceptibility test. The coordination of susceptibility test development with drug development is encouraged so that susceptibility testing is available to inform use of the drug after it is marketed.

Appendix C provides the recommended electronic database format for the data from clinical trials as it pertains to AST interpretive criteria.

4. Quality Control Parameters

Quality control (QC) parameters for AST should be established before determining the activity of the antibacterial drug to ensure the generation of precise, accurate, and reproducible results. Routine QC procedures involve performance testing of designated QC strains that are genetically

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stable and have well-characterized susceptibility characteristics. Generally, the establishment of QC parameters should involve the use of 3 different lots of test medium, frozen panels in the case of MICs, 2 different lots of disks in the case of disk diffusion, and 10 replicates of each QC strain over 3 days in at least 7 different laboratories. This testing is done to generate enough data points to determine appropriate QC parameters.

Sponsors should obtain reference bacteria recognized from a reputable source such as the American Type Culture Collection (ATCC). In the event that sponsors do not use these recommended QC bacteria, they should justify the use of other well-characterized bacteria. If a QC bacterium is chosen that is different from these recommended QC bacteria, it should be deposited in a recognized culture collection (e.g., ATCC).

The use of established methods and concomitant use of QC strains lends confidence to the in vitro susceptibility data generated from the testing of bacteria. Therefore, QC data should be provided with all susceptibility test results done on bacteria at each facility that is conducting susceptibility testing for clinical trials. Alternatively, if in vitro susceptibility tests are performed by a central laboratory, we recommend that sponsors provide the QC data generated by the central laboratory. In addition, we recommend that sponsors analyze the QC data generated during the conduct of clinical trials to determine whether adjustments to the QC ranges are necessary.

C. Other Considerations

1. First and Second Lists of Target Bacteria in Labeling TheMicrobiologysubsectionoflabelingcontainstwolistsofbacteria. Sponsorsshouldformat

this section as described in Appendix D.

The first list is based on bacteria evaluated during clinical trials that are included in the INDICATIONS AND USAGE section of labeling (21 CFR 201.57(c)(2)(i)(C)).

The second list is based on the relevance of the bacteria to the indication and its susceptibility to concentrations of the antibacterial drug that can be achieved using the proposed dosage. Appendix E provides a summary of the information needed to support the inclusion of bacteria in the second list. The inclusion of bacteria in the second list is not based on results from adequate and well-controlled clinical trials. Sponsors should provide information in support of the second list for each species proposed for inclusion by indication.

2. Antibacterial Interactions and Fixed Combination Studies

Drug interaction studies may provide information (e.g., synergy, antagonism, indifference) on the effects one antibacterial drug may have on another. Potential for interaction usually can be determined by qualitative or quantitative in vitro studies when the activity cannot be accurately anticipated from general knowledge of the drug characteristics. The preferred methods for the characterization of antibacterial interaction are kill curves. Another method is the checkerboard titration analyzed by fractional inhibitory concentration.

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For fixed combination drug products, including drugs that contain an antibacterial drug and a component that counteracts a resistance mechanism (e.g., beta-lactam and beta-lactamase inhibitor combination), we recommend that sponsors provide the in vitro and/or in vivo data to support the contribution of each of the drugs (separately and in combination) to the activity.

3. Additional Nonclinical Studies of Antibacterial Drugs

Antibacterial drugs may have various effects on target bacteria and/or interactions with the host. These phenomena include, but are not limited to, postantibiotic effect, postantibiotic leukocyte effect, sub-MIC effects, effects on endotoxin, effects on virulence factors, and interactions with the host immune system. The sponsor should provide data from studies that are designed to investigate these effects of the investigational antibacterial drug.

Some antibacterial drugs may be inactive when protein bound, or there may be insufficient free active drug at trough concentrations. Therefore, we recommend that sponsors characterize the effects of human serum proteins and other human body fluids (e.g., lung surfactant), when appropriate, on the in vitro and in vivo activity of the drug. The effects of human serum proteins and human body fluids on activity of the drug should be evaluated over the range of clinically relevant concentrations of the antibacterial drug.

4. Animal Models of Infection

The goal of the animal models is to investigate the antibacterial activity of the investigational drug. Ideally, the animal model of infection should be similar to the infection of interest in humans and the bacteria used in the animal model should be similar in character (e.g., antibacterial resistance, virulence factors) to bacteria that cause human disease.

In addition to measuring survival, bacterial burden in blood and relevant affected organs should be measured. For example, an evaluation of antibacterial activity in relevant issue sites can be important to characterize the drug’s potential in the treatment of particular body site infections in humans. Animal models can provide preliminary information on PK/PD parameters as they pertain to microbiology data (e.g., area under the unbound plasma concentration time cure over the MIC, time above MIC).

Sponsors can conduct comparative studies of the investigational antibacterial drug with other antibacterial drugs exhibiting the same mechanism of action or drugs with the same spectrum of activity. Results can be reported as 50 percent effective dose (ED50), 50 percent protective dose (PD50), or 50 percent curative dose (CD50). The bacterial burden data at baseline and various time points should also be provided.

5. Microbiology Information Collected in Clinical Trials

We recommend that a central laboratory be used for microbiologic testing (including confirmation of bacteria identification and AST) during clinical trials. We recommend that sponsors provide clinical trial protocols and laboratory procedure manuals (including details of

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specimen collection, isolate/specimen transport, isolate characterization and identification, isolate preservation, and susceptibility testing methods) to the FDA for review before trial initiation.

6. Electronic Submission of Microbiology Information

Sponsors should provide microbiology information in the electronic common technical document (eCTD) as described in the guidance for industry Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications.5 Generally, the information on microbiology should be provided in two sections of the eCTD as follows:

  • Module 2, Section 2.7, Clinical Summary, subsection 2.7.2.4, Special Studies. This section should contain the microbiology summary reports and the information used to justify the microbiology information included in the labeling.

  • Module 5, Clinical Study Reports, subsection 5.3.5.4, Other Study Reports. This section should contain the nonclinical study and clinical trial reports used in the construction of the summary information provided in subsection 2.7.2.4. All of the study and trial reports used to construct the summary report presented in section 2.7.2.4 should be cross- linked to the summary report. Both of these sections should be cross-referenced to each other.

7. Postmarketing Microbiology Information

Over time after approval, additional information may become available regarding the methods for in vitro AST and/or the QC parameters used to monitor the performance of the test as well as how the susceptibility test results should be interpreted. Changes in AST interpretative criteria may translate into a lack of efficacy and/or safety concerns when out-of-date AST information leads to failure to appropriately treat the infectious disease. Consequently, it is important that the in vitro AST methods, the QC parameters, and the AST interpretive criteria be reviewed on a regular basis and updated to reflect the most current information. The rationale for any changes in the in vitro AST methods, QC parameters, spectrum of activity, or AST interpretive criteria, as well as new information regarding emergence of resistance, should be indicated in an applicant’s annual report under the new drug application. The procedures for updating microbiology labeling information can be found in the guidance for industry Updating Labeling for Susceptibility Test Information in Systemic Antibacterial Drug Products and Antimicrobial Susceptibility Testing Devices.

For applicants submitting a labeling supplement with supporting data to update or change the method of determining the AST, we recommend the description of the old and new methods with the changes noted, as well as validation data and QC parameters of the new method. Any change to a test method (e.g., microbroth dilution) should be accompanied by data to show that the

5 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

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results correlate with other methods (e.g., agar dilution, disk diffusion testing) by which susceptibility testing can be done. The results of validation studies should be included when information to change the QC parameters is provided.

We recommend including the following information when providing changes to the existing AST interpretive criteria:

  • Rationale for change

  • The MIC and zone diameter distributions against the genera and species of interest; data

    should be from isolates collected in the preceding 3 years of the submission

  • Susceptibility to the antibacterial drug to determine microbiologically supported cutoffs (e.g., histograms)

  • Categorical agreement between MIC and zone diameter breakpoints in graphical form

  • Error-rate bounded method of Metzler and DeHaan (Metzler and DeHaan 1974) to determine discrepancies between the two methods; the Metzler and DeHaan method usually needs to be modified because two MIC values are normally described to define an intermediate category (Bruden, Zurenko, et al. 1992)

  • Relevant human PK data

  • Clinical data from adequate and well-controlled trials and literature reports

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REFERENCES

Bruden, MN, GE Zurenko, et al., 1992, Modification of the Error-Bounded Classification Scheme for Use With Two MIC Breakpoints, Diagn Microbiol Inf Dis, 15:135-140.

Clinical and Laboratory Standards Institute (CLSI), 1999, Methods for Determining Bactericidal Activity of Antimicrobial Agents; Approved Guideline, CLSI document M26A, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.

CLSI, 2008, Development of In Vitro Testing Criteria and Quality Control Parameters; Approved Guideline-Third Edition, CLSI document M23-A3, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA

CLSI, 2012, Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard – Eighth Edition, CLSI document M11-A8, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.

CLSI, 2015, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard – Tenth Edition, CLSI document M07-A10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.

CLSI, 2015, Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition, CLSI document M02-A12, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.

CLSI, 2015, Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fifth Informational Supplement, CLSI document M100-S25, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.

Metzler, DM and RM DeHaan, 1974, Susceptibility Tests of Anaerobic Bacteria: Statistical and Clinical Considerations, J Infect Dis, 130:588-594.

Turnidge, J and DL Paterson, 2007, Setting and Revising Antibacterial Susceptibility Breakpoints, Clinical Microbiology Reviews, Vol. 20, pp. 391-408.

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APPENDIX A:
GUIDELINES FOR BACTERIAL ISOLATE SELECTION FOR STUDIES OF IN VITRO ANTIBACTERIAL ACTIVITY

For the purposes of determining the antibacterial activity of a new molecular entity and for establishing correlation of test methods (i.e., minimum inhibitory concentration (MIC) and disk diffusion), we recommend that the sponsor provide antibacterial susceptibility test (AST) data for bacterial isolates intended for inclusion in labeling. The sponsor should consult with the division to determine an adequate number of tested isolates in those situations, as well as for special types of studies where significant information may be obtained using few isolates (e.g., bactericidal studies, time-kill studies).

Table A lists the suggested number of bacterial isolates of each species or bacterial group that should be tested in nonclinical studies, when those species will be included in labeling for the antibacterial drug (i.e., in either the first or second list of target bacteria).

We recommend that sponsors identify the prominent genotypes, serotypes, biotypes, and isolates with known mechanisms of resistance and include these in the test panel. When appropriate, the spectrum of activity against hetero-resistant bacteria should be determined (e.g., vancomycin hetero-resistant Staphylococcus aureus). The organisms tested should be recent clinical isolates that have been collected within the last 3 years of the new drug application with susceptibility profiles that are representative of antibacterial drugs used to treat infections caused by the target bacteria for the indication being sought. Summary data by subset of organisms demonstrating resistance should be provided (e.g., methicillin-resistant S. aureus (MRSA), extended spectrum beta-lactamases).

We recommend that at least 75 percent of isolates analyzed in these studies be collected in the United States. Sponsors who include isolates from outside the United States should compare the characteristics of those isolates with the same species found in the United States (e.g., phenotype, genotype, serotype, susceptibility profile, and virulence factors).

Susceptibility testing should be performed using a range of drug dilutions that will minimize reporting greater than or equal to or less than or equal to MIC values (e.g., 16 mcg/mL,
0.012 mcg/mL). All AST data should be determined using standard reference methods, unless modifications of the standard methods are needed. Sponsors should present a summary of susceptibility testing results as MIC histograms or other frequency distributions displaying any proposed in vitro AST interpretive criteria. All susceptibility test data should be accompanied by appropriate quality control data.

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Table A: Suggested Number of Isolates for Determination of In Vitro Antibacterial Activity and for Correlation of MIC and Disk Diffusion Methods

Organism Group

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Number of Isolates

Enterobacteriaceae

300

Pseudomonas aeruginosa

100

Acinetobacter spp.

100

Staphylococcus spp.1,2

100

Enterococcus spp.1,2

100

Haemophilus influenzae and H. parainfluenzae

100

Neisseria gonorrhoeae

100

Streptococcus pneumoniae

100 (prefer > 300)

Beta-hemolytic streptococci1

100 (prefer > 300)

Alpha-hemolytic streptococci (other than S. pneumoniae)1

100 (prefer > 300)

Other single species

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100

1 Bacterial isolates in these genera or bacterial groups should be identified to species level (or, in some cases, to more specific groups (e.g., Streptococcus anginosus group)). In these cases, the recommended number of isolates applies to the particular species or group.
2 When a particular phenotype (e.g., MRSA, vancomycin-resistant Enterococcus faecalis) will be included in labeling, the recommended number of isolates applies to that phenotype.

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APPENDIX B:
STUDY REPORTS OF SPECTRUM OF ACTIVITY AND RESISTANCE

Study Reports of Spectrum of Activity

We recommend that study reports of spectrum of activity include the following elements:

  • The name and location of each investigator conducting or contributing to the study

  • The standardized methods for bacterial identification and antibacterial susceptibility test (AST) used to determine the activity of the antibacterial drug; details of the method and the performance characteristics of the assay in the actual laboratory where such testing is done should be included if a nonstandard method is used

  • A description of all susceptibility testing quality control (QC) measures; all AST results should be accompanied by QC data

  • The number of isolates tested in each laboratory, the specimen source, and the geographical region from which the isolates were obtained

  • A description of the spectrum of activity by all regions and individual geographic regions

  • The phenotypic and/or genotypic characterization of isolates relative to their resistance to other antibacterial drugs; the methodology and the criteria used to characterize isolates as resistant should be described

  • The phenotypic and/or genotypic characterization of isolates relative to virulence characteristics

    Results from studies evaluating antibacterial activity should be presented in tabular form under appropriate sections as described below:

    • Genera and species tested — species with unique mechanisms of resistance should be grouped separately; serotype, phenotype, and/or genotype should be included if known

    • Drug name

    • The minimum inhibitory concentration (MIC) range and the number of isolates tested

    • The values for the MIC required to inhibit growth of 50 percent of bacteria (MIC50) and the MIC required to inhibit growth of 90 percent of bacteria (MIC90)

    • Minimum bactericidal concentration (MBC)

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Study Reports of Resistance

Results from studies evaluating resistance should be presented in tabular form under appropriate sections as described below:

  • Genera and species tested — species with unique mechanisms of resistance should be grouped separately; if serotype, phenotype, and/or genotype are known then that information should be included

  • Drug name

  • MIC range — for each group of organisms and the number of isolates tested in each

    laboratory

  • MIC50 and MIC90 values

  • MBC

    The complete study report should include stability and lot numbers of the drug used for microbiology testing. In addition, reproducibility of test results should be submitted. If the data are derived from a publication, a copy of the publication should be included in the submission.

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APPENDIX C:
DATABASE FOR FINAL IN VITRO ANTIBACTERIAL SUSCEPTIBILITY TEST INTERPRETIVE CRITERIA

We recommend a single electronic database for the clinical trial with the subject level data presented in columns. Each column heading should identify the scope of information below it. For instance, a subject identification (ID) number can include a coding arrangement that differentiates the trial center as well as the individual subject. Sponsors should discuss the format of the microbiology datasets with the FDA at the time of the pre-new drug application or pre-biologics license application meeting. We recommend that the following information be provided in the database under appropriate columnar headings:

  • Clinical trial center number

  • Subject ID number

  • Treatment group

  • Sample source

  • Species of bacterial isolate

  • Indication

  • Subject-by-subject clinical evaluations including separate rows for each subject, the subject’s status of microbiological eradication, and the subject’s overall clinical response (e.g., cure, failure)

  • Antibacterial susceptibility test (AST) results by diffusion methods for the investigational drug and the comparator drug

  • AST results by dilution methods for the investigational drug and the comparator drug

    Sponsors should provide an interpretation of the data described below for the investigational drug and comparator drugs. Because of possible geographic differences in antibiograms and the clonal nature of bacteria, data should be presented in both combined and separate formats (e.g., United States and non-United States in separate tables). Where appropriate, we recommend that U.S. data be broken down into regions (e.g., Northeast, Southeast, Midwest, Northwest, Southwest), and that non-U.S. data be broken down by region (e.g., Asia, Europe, Africa) and within region by country (e.g., France, Germany).

    We recommend that the following be included in the database:

1. Minimum inhibitory concentration (MIC) values and subject microbiological responses for each baseline bacterium within each proposed indication; all subsets of bacteria demonstrating unique mechanisms of resistance (e.g., methicillin-resistant

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Staphylococcus aureus, beta-lactamase-positive Haemophilus influenzae) and virulence should be listed separately.

  1. MIC values and subject clinical response for each baseline bacterium for each proposed indication; all subsets of bacteria demonstrating unique mechanisms of resistance and virulence should be listed separately.

  2. Zone diameter values and subject microbiological responses for each bacterium for each proposed indication; all subsets of bacteria demonstrating unique mechanisms of resistance and virulence should be listed separately.

  3. Zone diameter values and subject clinical responses for each bacterium for each proposed indication; all subsets of bacteria demonstrating unique mechanisms of resistance and virulence should be listed separately.

  4. For each subset of bacteria requiring defined AST interpretive criteria, all individual isolates in the range of MICs from two dilutions below the susceptible and two dilutions above the resistant provisional AST interpretive criteria.

  5. For each subset of bacteria requiring defined zone diameter AST interpretive criteria, all individual isolates in the range of zone diameters from 4 to 6 millimeters above the susceptible and 4 to 6 millimeters below the resistant provisional AST interpretive criteria.

  6. By indication and bacteria relevant to the indication, all MICs for isolates associated with microbiological failures. The bacteria should be identified to the species level.

  7. By indication and bacteria relevant to the indication, all zone diameters for isolates associated with microbiological failures. The bacteria should be identified to the species level.

  8. For each bacterium (e.g., nonfastidious, fastidious, and anaerobic), the MIC value indicating the number and percent of isolates at that MIC associated with each microbiological response. MIC values should be grouped by bacterial type.

  9. For each bacterium (e.g., nonfastidious, fastidious), the zone diameter indicating the number and percent of isolates at the zone diameter associated with each microbiological response. Zone diameter information should be grouped by bacterial type.

  10. For each group of bacteria, a histogram showing the number of isolates at each MIC from clinical trials overlaying isolates from nonclinical studies. Sponsors should present bacteria with characterized phenotypic resistance and virulence markers as a subset.

  11. For each group of bacteria, a histogram showing the number of isolates at each zone diameter from clinical trials overlaying isolates from nonclinical studies. Sponsors

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should present bacteria with characterized phenotypic resistance and virulence markers as a subset.

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APPENDIX D:
EXAMPLE FORMAT FOR SECTIONS OF LABELING THAT PERTAIN TO MICROBIOLOGY

Recommended language for and organization of the microbiology information that is discussed in the CLINICAL PHARMACOLOGY section of labeling are provided below along with additional recommendations in italics.6 For additional information concerning this section of labeling, see the draft guidance for industry Clinical Pharmacology Labeling for Human Prescription Drug and Biological Products — Considerations, Content, and Format.7 Also included are recommended citations for the REFERENCES section of labeling. We recommend a consistent formatting approach for headings and subheadings in the CLINICAL PHARMACOLOGY section and the other sections of labeling to help organize the information (e.g., underlining for headings and italics for subheadings). We recommend the use of title case for headings and subheadings.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action

X is an anti- (e.g., bacterial, as appropriate) drug [see Microbiology (12.4)].8
Recommendation: The antimicrobial mechanism of action should be described in subsection

12.4 Microbiology.

12.4 Microbiology

Mechanism of Action
Resistance
Interaction With Other Antimicrobials
[Heading Title] [Other relevant information to be determined on a case-to-case basis]

Recommendation: Additional relevant microbiological information that provides characterization of the antimicrobial drug should be placed under another appropriately named heading.

6 As provided for in the final rule “Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products” (71 FR 3922, January 24, 2006), the microbiology portion of labeling should be added as subsection 12.4 under the CLINICAL PHARMACOLOGY section.

7 When final, this guidance will represent the FDA’s current thinking on this topic. For the most recent version of a guidance, check the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

8 Note that this is an exception to the preferred presentation of cross-referencing in the Full Prescribing Information, which is to use the section heading followed by the numerical identifier.

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Antimicrobial Activity
[Name of drug] has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections
[see Indications and Usage (1)]:

Recommendation: Each organism in this list must be associated with an indication in the INDICATIONS AND USAGE section (e.g., acute bacterial skin and skin structure infections caused by susceptible isolates of Staphylococcus aureus) (21 CFR 201.57(c)(2)(i)(C)).

[Microorganisms should be listed under the following categories in alphabetical order] Aerobic bacteria

Gram-positive bacteria

Gram-negative bacteria Anaerobic bacteria

Gram-positive bacteria

Gram-negative bacteria
Other microorganisms (as applicable)

The following in vitro data are available, but their clinical significance is unknown.9 At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for [name of drug] against isolates of similar genus or organism group. However, the efficacy of [name of drug] in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.

[Microorganisms should be listed under the following categories in alphabetical order] Aerobic bacteria

Gram-positive bacteria

Gram-negative bacteria Anaerobic bacteria

Gram-positive bacteria

Gram-negative bacteria
Other microorganisms (as applicable)

Recommendation: For an organism to be included in the above list (i.e., the second list), the organism at a minimum should: (1) be relevant to an indication granted in the labeling; and (2) have an MIC90 below the concentration of the antimicrobial achievable in the plasma or at the infection site using the dosing regimen approved in the labeling as determined from in vitro testing of the targeted species or organism group. See Appendix A for the recommended number and characteristics of test isolates. See Appendix E for a summary of information for microorganisms to be included on the second list as well as additional information.

9 This statement must be included for the second list of bacteria; see 21 CFR 201.57(c)(13)(ii)(A). 19

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Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide cumulative reports of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid in the selection of an appropriate antibacterial drug for treatment.

Recommendation: If standardized susceptibility test methods are not used, information and unusual characteristics of the antibacterial susceptibility test procedure can be placed under the susceptibility test method that is pertinent.

Dilution Techniques

Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method1,2 (broth and/or agar). The MIC values should be interpreted according to criteria provided in Table [insert table number].

Recommendation: Proposed references, as denoted by the numbers 1, 2, 3, and 4 in superscript, are listed below in the example for the REFERENCES section.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.2,3 This procedure uses paper disks impregnated with [x] mcg [name of drug] to test the susceptibility of bacteria to [name of drug]. The disc diffusion breakpoints are provided in Table [insert table number].

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to [name of drug] can be determined by a standardized test method.4 The MIC values obtained should be interpreted according to the criteria provided in Table [insert table number].

Recommendation: An example of the table referenced in dilution, diffusion, and anaerobic techniques is provided below.

Table [insert table number]. Susceptibility Test Interpretive Criteria for [name of drug]

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Minimum Inhibitory Concentrations (mcg/mL)

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Disk Diffusion (zone diameters in mm)

Pathogen

S

I

R

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S

I

R

Pathogen #1

<#

#-#

>#

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>#

#-#

<#

Pathogen #2

<#

#-#

>#

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>#

#-#

<#

etc.

etc.

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etc.

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A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of the drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the infection site; other therapy should be selected.

Recommendation: If there are no resistant criteria (R) because of the lack of data on resistant microorganisms, the following should be noted in the labeling: “The current absence of data on resistant isolates precludes defining any category other than ‘Susceptible.’ If isolates do not yield MIC results that are Susceptible, they should be submitted to a reference laboratory for additional testing.” If the drug is approved at one dosage, the paragraph above should not contain the statement “ . . . or in situations where a high dosage of the drug can be used.”

Quality Control
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.
1,2,3,4 Standard [name of drug] powder should provide the following range of MIC values noted in Table [insert table number]. For the diffusion technique using the [disk content of antimicrobial] mcg disk, the criteria in Table [insert table number] should be achieved.

Recommendation: An example of the table referenced in Quality Control is provided below. This table should be included when appropriate quality control parameters should be provided for both broth and agar MIC tests.

Table [insert table number]. Acceptable Quality Control Ranges for [name of drug]

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Minimum Inhibitory Concentrations (mcg/mL)

Disk Diffusion (zone diameters in mm)

QC strain #1

#-#

#-#

QC strain #2

#-#

#-#

etc.

etc.

etc.

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15 REFERENCES

Recommendation: We propose that the following references, as denoted above by the numbers 1, 2, 3, and 4 in superscript, be included in the REFERENCES section.

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard – [Edition]. CLSI document M07-[Edition number]. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087, USA, [Year].

2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; [Supplement Edition]. CLSI document M100-[Supplement Edition number]. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087, USA, [Year].

3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests: Approved Standard – [Edition]. CLSI document M02- [Edition number]. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087, USA, [Year].

4. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Testing of Anaerobic Bacteria; [Edition]. CLSI document M11-[Edition number]. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087, USA, [Year].

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APPENDIX E:
INFORMATION REGARDING THE SECOND BACTERIA LIST IN THE MICROBIOLOGY SUBSECTION OF LABELING

Factors to Consider When Developing the Lists

The following factors should be considered when developing the bacteria lists:

  • Certain bacteria are disease-specific and therefore can be properly placed only in the first list. Examples of such pathogens are Mycobacterium tuberculosis, Bacillus anthracis, Mycobacterium leprae, Yersinia pestis, Neisseria meningitidis, Neisseria gonorrhoeae, and Brucella species.

  • There should be scientific evidence demonstrating that the bacteria are frequently associated with an indication for which approval is being sought.

  • Sponsors should support the species included in the second list with antibacterial susceptibility test (AST) results of recent clinical isolates (minimum inhibitory concentrations (MICs)) correlated with the achievable concentrations of the antibacterial drug using the recommended dosing regimen.

  • Bacteria included in the second list should have MIC90 values less than or equal to the clinically relevant AST interpretive criteria established for the particular genera, species, or group of bacteria related to a specific indication or indications.

    Summary Information for the Second List

    The summary should include the following information for the bacteria on the second list:

    • A discussion of the relevance of the bacteria to a specific clinical indication

    • The frequency in which the bacteria is shown to cause disease in the general population

    • Relevant literature references and/or laboratory test data summary tabulations of susceptibility data (e.g., range, MIC50, MIC90 for relevant antibacterial drugs) and annotated supporting literature for the listed bacteria

    • In vitro susceptibility information for (e.g., MIC, MIC range, MIC50, MIC90) of the bacteria proposed for the second list (see Appendix C for the suggested number of isolates and characteristics of pathogens that should be included for testing), accompanied by appropriate quality control (QC) data

    • A discussion of the methods used and their comparability to assess susceptibility as described in the supporting literature

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  • Comparisons of U.S. and foreign data analyzed separately and together

  • Susceptibility data that are accompanied by the appropriate QC data

24

 

Bacterial Vaginosis: Developing Drugs for Treatment Guidance for Industry

Bacterial Vaginosis:

Developing Drugs for

Treatment 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 Edward Weinstein, M.D., Ph.D. at 301-796- 1400.

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

July 2016 Clinical/Antimicrobial

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50759dft.doc 06/28/16

Bacterial Vaginosis:

Developing Drugs for

Treatment Guidance for Industry

Additional copies are available from:

Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: 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)

July 2016 Clinical/Antimicrobial

I. II.

A.

1. 2. 3.

B.

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1 DEVELOPMENT PROGRAM ....................................................................................... 2 General Considerations .................................................................................................................2

Drug Development Population.........................................................................................................2 Efficacy Considerations ...................................................................................................................2 Safety Considerations.......................................................................................................................2 Specific Efficacy Trial Considerations .........................................................................................3

1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

a.

b.

Clinical Trial Designs ......................................................................................................................3 Clinical Microbiology Considerations .............................................................................................3 Enrollment Criteria ..........................................................................................................................3 Randomization and Blinding ............................................................................................................4 Specific Populations.........................................................................................................................4 Dose Selection ..................................................................................................................................5 Choice of Comparators ....................................................................................................................5 Efficacy Endpoints............................................................................................................................6 Trial Procedures and Timing of Assessments ..................................................................................6

Statistical Considerations ............................................................................................................6

Analysis populations..................................................................................................................7

Sample size................................................................................................................................7

C. Other Considerations .....................................................................................................................7

1. Ethical Considerations .....................................................................................................................7 2. Relevant Nonclinical Considerations...............................................................................................8 3. Pharmacokinetic/Pharmacodynamic Considerations ......................................................................8

Contains Nonbinding Recommendations

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  1. 1 Bacterial Vaginosis: Developing Drugs for Treatment

  2. 2 Guidance for Industry1

3 4 5

6 7 8 9

10 11 12

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I. INTRODUCTION 17

  1. 18  The purpose of this guidance is to assist sponsors in the overall clinical development program

  2. 19  and clinical trial designs to support drugs for the treatment of bacterial vaginosis (BV).2 This

  3. 20  draft guidance is intended to serve as a focus for continued discussions among the Division of

  4. 21  Anti-Infective Products, pharmaceutical sponsors, the academic community, and the public.3

22

  1. 23  This guidance focuses only on developing antibacterial drugs for the treatment of symptomatic

  2. 24  BV. There are epidemiological associations between BV and other adverse health outcomes,

  3. 25  such as sexually transmitted infections including human immunodeficiency virus, postoperative

  4. 26  infections, preterm birth, and other gynecological infections. Sponsors are encouraged to discuss

  5. 27  with FDA the trial designs and drug development issues related to the development of drugs to

  6. 28  address epidemiogically associated adverse health outcomes.

29

  1. 30  This guidance does not contain discussion of the general issues of clinical trial design or

  2. 31  statistical analysis. Those topics are addressed in the ICH guidances for industry E8 General

  3. 32 Considerations for Clinical Trials and E9 Statistical Principles for Clinical Trials, respectively.4

33

1 This guidance has been prepared by the Division of Anti-Infective Products in the Center for Drug Evaluation and Research at the Food and Drug Administration.

2 For the purposes of this guidance, all references to drugs include both human drugs and therapeutic biological products unless otherwise specified.

3 In addition to consulting guidances, sponsors are encouraged to contact the division to discuss specific issues that arise during the development of drugs for the treatment of BV.

4 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

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

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1

DEVELOPMENT PROGRAM
A. General Considerations
1. Drug Development Population

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 34  In general, FDA’s guidance documents do not establish legally enforceable responsibilities.

  2. 35  Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only

  3. 36  as recommendations, unless specific regulatory or statutory requirements are cited. The use of

  4. 37  the word should in Agency guidances means that something is suggested or recommended, but

  5. 38  not required.

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II. 42
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  1. 47  FDA considers postmenarchal females with a clinical and microbial diagnosis of BV (see

  2. 48  sections II.B.2 and II.B.3) to be eligible for enrollment.

49
50
2. Efficacy Considerations 51

  1. 52  In general, two adequate and well-controlled trials are recommended (see 21 CFR 314.126). If

  2. 53  the drug is being developed for other infectious disease indications in addition to BV, sponsors

  3. 54  should discuss with FDA the potential situations in which one trial would provide evidence of

  4. 55  effectiveness, supported by evidence of effectiveness for the other infectious disease

  5. 56  indications.5

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3. Safety Considerations 59

  1. 60  The recommended size of the safety database depends on whether the drug is administered

  2. 61  systemically or topically, and the level of systemic absorption. In general, for a systemically

  3. 62  administered drug, we recommend a preapproval safety database for BV of approximately 500

  4. 63  patients. A topically administered drug without significant systemic absorption may need fewer

  5. 64  patients. If the same or greater dose and duration of therapy for treatment of BV were used in

  6. 65  clinical trials for other infectious disease indications, the safety information from those clinical

  7. 66  trials typically should be included in the overall preapproval safety database. Sponsors should

  8. 67  discuss the appropriate size of the preapproval safety database with FDA during clinical

  9. 68  development.

69

  1. 70  For drugs administered topically, human safety evaluations should focus on local toxicities of the

  2. 71  cervicovaginal area in addition to systemic toxicities.

72

5 See the guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products.

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B. Specific Efficacy Trial Considerations

1. Clinical Trial Designs

Trials should be randomized, double-blinded, and either placebo-controlled or active-controlled, with the hypothesis that the investigational drug is superior to the control treatment. Trials can be multicenter and multinational in scope; however, particular considerations may apply to such trial designs. These issues are addressed in the ICH guidance for industry E5 Ethnic Factors in the Acceptance of Foreign Clinical Data and the guidance for industry and FDA staff FDA Acceptance of Foreign Clinical Studies Not Conducted Under an IND Frequently Asked Questions.

2. Clinical Microbiology Considerations

An appropriate vaginal swab clinical specimen should be obtained for microbiologic evaluation. Specimens should be collected, processed, and transported according to appropriate methods.6

The following tests should be performed on specimens collected to aid in the diagnosis of BV: (1) the addition of a drop of 10-percent solution of potassium hydroxide (KOH) to evaluate for the presence of a characteristic fishy amine odor; (2) the examination for the presence of clue cells using a microscope at 400-times magnification of a normal saline wet mount; and (3) the examination by Gram stain for specific bacterial morphologic types (e.g., large gram-positive rods suggestive of Lactobacillus species, small gram-variable rods suggestive of Bacteroides species, curved gram-variable rods suggestive of Mobiluncus species, and gram-positive cocci).

3. Enrollment Criteria

The recommended enrollment criteria are outlined as follows:

Inclusion criteria: postmenarchal females should have the presence of all four Amsel criteria:7

(1) Off-white (milky or gray), thin, homogeneous discharge with minimal or absent pruritus and inflammation of the vulva and vagina

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6 See, for example, the American Society for Microbiology, 2010, Clinical Microbiology Procedures Handbook, 3rd Edition.

7 Amsel R, PA Totten, CA Spiegel, KC Chen, D Eschenbach, and KK Holmes, 1983, Nonspecific Vaginitis: Diagnostic Criteria and Microbial and Epidemiologic Associations, Am J Med, 74(1):14-22.

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  1. (2)  The presence of clue cells greater than 20 percent of the total epithelial cells on microscopic examination of the saline wet mount8

  2. (3)  Vaginal secretion pH of greater than 4.5

  3. (4)  A fishy odor (i.e., a positive whiff test) of the vaginal discharge with the addition of a drop of KOH

To enhance the reliability for the diagnosis of BV at enrollment, the Gram stain of the vaginal specimen should have a Nugent score of greater than or equal to 7.9

The following exclusion criteria are recommended:

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  1. 132  Eligible patients should be randomized to treatment groups at enrollment. Treatment assignment

  2. 133  should be blinded to the patient, investigator, and microbiologist performing assessments.

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5. Specific Populations 136

  1. 137  The trials should include patients of all races, as well as geriatric patients.10 Patients with renal

  2. 138  or hepatic impairment can be enrolled, provided pharmacokinetics of a drug with systemic

  3. 139  absorption have been evaluated in these patients and appropriate dosing regimens have been

  4. 140  defined, or pharmacokinetics of a drug administered topically demonstrated minimal or no

  5. 141  systemic absorption.

    8 Diagnostic clue cells should have Gardnerella-like organisms (small, nonmotile, coccobacilli) covering not only the surface of the squamous epithelial cells, but also spreading out past the cell boundaries, obscuring the cytoplasmic margins and thus creating a shaggy appearance. The entire cell need not be covered with bacteria, but cells with organisms simply sticking to the surface without extending past the cytoplasmic margins should not be considered clue cells. Both the saline mount and the Gram stain can be easily and accurately used to determine clue cells.

    9 Nugent RP, MA Krohn, and SL Hillier, 1991, Reliability of Diagnosing Bacterial Vaginosis Is Improved by a Standardized Method of Gram Stain Interpretation, J Clin Micro, 29(2):297-301.

    10 See the ICH guidances for industry E7 Studies in Support of Special Populations: Geriatrics and E7 Studies in Support of Special Populations: Geriatrics; Questions and Answers.

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Patients with other infectious causes of vulvovaginitis (e.g., vulvovaginal candidiasis, Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, Herpes simplex, or human papilloma virus)

Patients with another vaginal or vulvar condition, which would confound the interpretation of clinical response

Patients who are currently receiving antibacterial therapy unrelated to BV

4. Randomization and Blinding

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142

  1. 143  Sponsors are encouraged to begin discussions about their pediatric clinical development plan as

  2. 144  early as is feasible because pediatric studies are a required part of the overall drug development

  3. 145  program and sponsors are required to submit pediatric study plans no later than 60 days after an

  4. 146  end-of-phase 2 meeting or such other time as may be agreed upon by FDA and the sponsor.11

  5. 147  BV is unlikely to occur in healthy premenarchal girls. Postmenarchal adolescent girls with BV

  6. 148  should be included in phase 3 trials, if appropriate. Inclusion of adolescents in phase 3 trials may

  7. 149  be capable of fulfilling the required pediatric clinical development plans.

150

  1. 151  In general, safe and effective treatments are available for pregnant patients with BV. Therefore,

  2. 152  it is generally appropriate to complete phase 3 clinical trials that establish safety and efficacy in

  3. 153  nonpregnant patients before trials in pregnant patients are initiated. However, if current effective

  4. 154  treatments are unavailable, such as a pregnant patient who has allergy to all available therapies

  5. 155  for BV, it may be appropriate to characterize safety and pharmacokinetics of the investigational

  6. 156  drug in pregnant patients who have the potential to benefit from the investigational drug. Before

  7. 157  sponsors consider clinical evaluations of an investigational drug in pregnant women, nonclinical

  8. 158  toxicology studies, reproductive and developmental toxicology studies, and phase 1 and phase 2

  9. 159  clinical trials should be completed. Infants born to women who received the investigational drug

  10. 160  should be followed for an appropriate period of time based on available nonclinical and clinical

  11. 161  data.

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6. DoseSelection 164

  1. 165  Sponsors should integrate findings from nonclinical studies, pharmacokinetics, and safety

  2. 166  information from earlier stages of clinical development to select the dose or doses to be

  3. 167  evaluated in phase 3 clinical trials. Information regarding pharmacokinetics in specific

  4. 168  populations (e.g., adolescent patients, patients with renal or hepatic impairment) should be

  5. 169  evaluated before initiation of phase 3 to determine whether dose adjustments are necessary and

  6. 170  may prevent the exclusion of these patients from the phase 3 clinical trials.

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7. Choice of Comparators 173

  1. 174  The control group for superiority trials can be a placebo or another antibacterial drug. If a

  2. 175  vehicle control is used as the placebo for a drug administered topically, then the vehicle control

  3. 176  should not influence the safety or efficacy evaluations (e.g., the vehicle control should not cause

  4. 177  irritation and should not have an antibacterial effect). Appropriate active comparators can be

  5. 178  used as a control provided superiority is demonstrated.

179

11 See the Pediatric Research Equity Act (Public Law 108-155; section 505B of the Federal Food, Drug, and Cosmetic Act; 21 U.S.C. 355c), as amended by the Food and Drug Administration Safety and Innovation Act of 2012 (Public Law 112-144), and the draft guidance for industry Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Pediatric Study Plans. When final, this guidance will represent FDA’s current thinking on this topic.

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8. Efficacy Endpoints

The recommended primary efficacy endpoint is characterized as follows:

Clinical cure: resolution of the abnormal vaginal discharge, negative whiff test, and the presence of clue cells at less than 20 percent of the total epithelial cells on microscopic examination of the saline wet mount.12

Sponsors also can consider the following supportive secondary endpoints for BV:

 

Nugent score of less than 4
Responder outcome defined as clinical cure plus Nugent score of less than 4

9. Trial Procedures and Timing of Assessments

The following points outline the recommended trial procedures and the timing of assessments:

Entry visit: Appropriate demographic information, history and physical examination findings, a microbiological specimen, and pregnancy and safety laboratory tests should be collected at this visit; patients should be randomized and receive the clinical trial treatment at this visit.

Visit at approximately 7 to 14 days after randomization: This visit should assess the primary efficacy endpoint and should be the test-of-cure visit. Adverse event information and, if appropriate, safety laboratory tests should also be collected.

Visit at 21 to 30 days after randomization: This visit should assess the continued clinical response to treatment and adverse events. Contact with the patient by telephone may be sufficient for this visit.

A patient diary is recommended for the collection of information regarding investigational drug administration, assessment of symptoms, and adverse events. Patients who have continued or worsening symptoms before the test-of-cure visit can be assigned as a treatment failure and offered rescue therapy for BV .

10. Statistical Considerations

In general, a detailed statistical analysis plan stating the trial hypotheses and the analysis methods should be submitted before trial initiation. The primary efficacy analysis should be based on a comparison of the proportions of patients achieving a successful efficacy outcome.

12 Note that there are four entry criteria, yet only three of the four criteria are used as the primary efficacy endpoint. The pH inclusion criteria is included for the purpose of enrichment of a clinical trial population most likely to have a true diagnosis of BV. Vaginal pH is not included as a component of the clinical cure for BV.

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221 a. Analysispopulations
222
223 Sponsors should consider the following definitions of analysis populations: 224
225

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  1. 240  The mITT population should be considered the primary analysis population. In general,

  2. 241  sponsors should not consider analyses of the per-protocol populations as primary because after-

  3. 242  randomization events or characteristics could potentially bias results in this population.

  4. 243  However, consistency of the results should be evaluated in all patient populations. Every attempt

  5. 244  should be made to limit the loss of patients from the trial and to follow all randomized patients

  6. 245  for the study outcome so that the ITT analysis can be performed. If any missing patient outcome

  7. 246  data is anticipated, there should be plans for handling that in the protocol.

247
248 b. Sample size 249

  1. 250  The sample size is influenced by several factors including the prespecified type I and type II

  2. 251  error, the heterogeneity of the success rate, and the amount by which the investigational drug is

  3. 252  superior to the control in a superiority trial. A two-sided type I error rate of 0.05 and a type II

  4. 253  error rate between 0.10 and 0.20 are usually specified. Expected success rates are typically

  5. 254  based upon results obtained in phase 2 trials or other information.

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C. Other Considerations 257
258
1. Ethical Considerations 259

  1. 260  The occurrence of adverse events from antibacterial drugs can be relevant in assessing the risk-

  2. 261  benefit to patients in a placebo-controlled trial. Rescue therapy can be incorporated into the trial

  3. 262  design so that individual patients are treated at the time when a failure outcome is assigned: this

  4. 263  may serve to mitigate concerns regarding inclusion of a placebo group in a trial. All trials should

  5. 264  provide appropriate provisions for patient safety.

265

Safety population — All patients who received at least one dose of the investigational drug during the trial

Intent-to-treat population — All patients who were randomized

Modified intent-to-treat (mITT) — All randomized patients excluding those who subsequently demonstrate a positive test result for other concomitant vaginal or cervical infections at baseline (e.g., C. trachomatis, N. gonorrhoeae), which may interfere with the efficacy assessment for BV or who have a baseline Nugent score less than 7.

Per-protocol population — The population of patients who qualify for the mITT population and who follow important components of the trial (important components of the trial include patients who adhere to the treatment and follow up for the efficacy assessment within the prescribed time frame)

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266 2. Relevant Nonclinical Considerations 267

  1. 268  Investigational drugs being studied for BV should have nonclinical data documenting activity

  2. 269  against the implicated pathogens associated with BV (e.g., Gardnerella vaginalis, Mycoplasma

  3. 270 hominis). Guidances for industry provide information for sponsors on nonclinical considerations

  4. 271  for drug development in general and also nonclinical considerations for drugs administered

  5. 272  topically.13

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3. Pharmacokinetic/PharmacodynamicConsiderations 275

  1. 276  Pharmacokinetic/pharmacodynamic approaches typically used to identify appropriate dosing

  2. 277  regimens for evaluation in phase 2 and phase 3 clinical trials for systemic bacterial infections

  3. 278  may not be appropriate for drugs used for the treatment of BV. However, the following

  4. 279  pharmacokinetic evaluations should be considered for such drugs used for the treatment of BV.

280

  1. 281  For a drug administered topically into the vagina and/or the area surrounding the vagina, it is

  2. 282  important to determine systemic drug exposure as part of the safety assessment. Evaluation of

  3. 283  systemic exposure following topical vaginal administration can be performed in females with BV

  4. 284  or in healthy females without BV because it is deemed that the extent of systemic drug

  5. 285  absorption is not related to the presence or absence of BV.

286

  1. 287  For a drug administered systemically for treatment of BV (e.g., oral), the systemic exposure and

  2. 288  other relevant clinical pharmacology aspects of the drug (e.g., drug-drug interactions, QT

  3. 289  prolongation,14 dosage adjustment in renal and/or hepatic impairment, food effect) should be

  4. 290  adequately characterized. Sponsors should discuss with FDA the need to evaluate pertinent

  5. 291  drug-drug interactions, particularly with oral contraceptives. In addition, dose-ranging studies in

  6. 292  BV patients can be considered as an option in the early stages of development to help determine

  7. 293  an adequate dosage regimen to bring forth in later trials.

294

13 See the Pharmacology/Toxicology guidance Web Page at: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065014.htm. For example, see the guidance for industry Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products. Given the unique characteristics of a topical administration, sponsors also may wish to refer to the guidance for industry Nonclinical Pharmacology/Toxicology Development of Topical Drugs Intended to Prevent the Transmission of Sexually Transmitted Diseases (STD) and/or for the Development of Drugs Intended to Act as Vaginal Contraceptives.

14 See the ICH guidance for industry E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs.

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Updating ANDA Labeling After the Marketing Application for the Reference Listed Drug Has Been Withdrawn

Updating ANDA Labeling

After the Marketing Application

for the Reference Listed Drug

Has Been Withdrawn 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 60 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 (CDER) Emily Helms Williams, 301-796- 3600.

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

July 2016 Generics

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Updating ANDA Labeling

After the Marketing Application

for the Reference Listed Drug

Has Been Withdrawn Guidance for Industry

Additional copies are available from:
Office of Communications, Division of Drug Information Center for Drug Evaluation and Research

Food and Drug Administration th 10001 New Hampshire Ave., Hillandale Bldg., 4

Floor

Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: 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

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U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) July 2016
Generics

I. II. III. IV.

A. B. C.

1. 2.

Contains Nonbinding Recommendations

Draft — Not for Implementation

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1 BACKGROUND ............................................................................................................... 2 SCOPE OF GUIDANCE .................................................................................................. 4 UPDATING LABELING OF ANDAs THAT RELY ON WITHDRAWN RLDs ...... 4 Examples of Labeling Updates for ANDAs That Rely on Withdrawn RLDs........................... 5 Process for Labeling Updates ....................................................................................................... 7 Relationship of this Guidance to Existing Authorities and Processes ....................................... 7

Safety Labeling Changes Under Section 505(o)(4) of the FD&C Act ............................................. 7 Section 409I of the Public Health Services Act................................................................................ 8

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 1 Updating ANDA Labeling After the Marketing Application for the

  2. 2 Reference Listed Drug Has Been Withdrawn

34 Guidance for Industry1

5 6 7 8 9

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I. INTRODUCTION 16

  1. 17  This guidance describes a process for updating labeling for abbreviated new drug applications

  2. 18  (ANDAs) in cases where FDA has withdrawn approval of the new drug application (NDA)2 for

  3. 19  the ANDA’s reference listed drug (RLD)3 for reasons other than safety or effectiveness. Where

  4. 20  approval of the NDA for the RLD has been withdrawn by FDA under these circumstances

  5. 21  (referred to in this guidance as a “withdrawn RLD”), and ANDAs are pending or generic drugs

  6. 22  continue to be marketed under one or more ANDAs that rely on the withdrawn RLD, the

  7. 23  labeling of those pending or marketed ANDA products may need to be updated to reflect

  8. 24  changes that would have been necessary had the NDA for the RLD not been withdrawn.

25

  1. 26  This guidance sets forth ways in which FDA may seek to facilitate the revision of labeling to

  2. 27  reflect updated information for ANDAs that rely on withdrawn RLDs. This guidance will be of

  3. 28  interest to the holders of pending or approved ANDAs that rely upon a withdrawn RLD, as well

  4. 29  as to applicants seeking to submit ANDAs relying on withdrawn RLDs. We anticipate that this

  5. 30  guidance will help facilitate labeling updates for approved ANDAs as well as the approval of

  6. 31  certain pending ANDAs where the NDA for the RLD has been withdrawn.

32

  1. 33  In general, FDA’s guidance documents do not establish legally enforceable responsibilities.

  2. 34  Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only

  3. 35  as recommendations, unless specific regulatory or statutory requirements are cited. The use of

    1 This guidance has been prepared by the Office of Regulatory Policy, the Office of Generic Drugs, the Office of New Drugs, and the Office of Surveillance and Epidemiology in the Center for Drug Evaluation and Research at the Food and Drug Administration.
    2 For purposes of this guidance, we use the phrase “new drug application” or “NDA” to refer to an application approved under section 505(c) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(c)), including applications based on a finding of effectiveness under the Drug Efficacy Study Implementation (DESI) review process.
    3 See 21 CFR 314.3 (defining reference listed drug and listed drug); see also “Abbreviated New Drug Applications and 505(b)(2) Applications” (Proposed Rule), 80 FR 6802 at 6814 (February 6, 2015).

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

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  1. 36  the word should in Agency guidances means that something is suggested or recommended, but

  2. 37  not required.

38 39

40 II. BACKGROUND 41

  1. 42  A generic drug is required to have the same labeling as the RLD at the time of approval, except

  2. 43  for changes required because of differences approved under a suitability petition (see section

  3. 44  505(j)(2)(C) of the FD&C Act and 21 CFR 314.93) or because the generic drug and the RLD are

  4. 45  “produced or distributed by different manufacturers” (see section 505(j)(2)(A)(v) of the FD&C

  5. 46  Act). FDA regulations provide examples of permissible differences in labeling that may result

  6. 47  where a proposed generic drug and the RLD are “produced or distributed by different

  7. 48  manufacturers,” including the omission of an indication or other aspect of labeling protected by

  8. 49  patent or exclusivity and “labeling revisions made to comply with current FDA labeling

  9. 50  guidelines or other guidance.” 21 CFR 314.94(a)(8)(iv).

51

  1. 52  As a general matter, all holders of marketing applications for drug products (both NDAs and

  2. 53  ANDAs) have an ongoing obligation to ensure their product labeling is accurate, and not false or

  3. 54  misleading. When new information becomes available that causes the labeling to become

  4. 55  inaccurate, false or misleading, the application holder must take steps to update its labeling (see,

  5. 56  e.g., 21 CFR 201.56(a)(2)). Any drug is misbranded if its labeling is false or misleading, or does

  6. 57  not provide adequate directions for use and adequate warnings (sections 301(a) and (b), and

  7. 58  502(a), (f), and (j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 331(a)

  8. 59  and (b), and 352(a), (f), and (j))).

60

  1. 61  Where the NDA for the RLD has not been withdrawn, RLD holders often propose changes to the

  2. 62  labeling by submitting them to the NDA. ANDA holders are expected to update their labeling

  3. 63  after FDA has approved relevant changes to the labeling for the corresponding NDA RLD. FDA

  4. 64  may withdraw approval of an ANDA if it finds that the labeling for the drug product that is the

  5. 65  subject of the ANDA is no longer consistent with that for the RLD (section 505(e) of the FD&C

  6. 66  Act and 21 CFR 314.150(b)(10)).

67

  1. 68  FDA believes ANDA applicants are familiar with the mechanisms for updating labeling for

  2. 69  pending and marketed ANDAs where the NDAs for the RLDs have not been withdrawn.

  3. 70  However, there has been confusion regarding the process for updating labeling for ANDAs

  4. 71  referencing RLDs where the NDAs have been withdrawn.

72

  1. 73  NDAs for RLDs may be withdrawn voluntarily, at the NDA holder’s request, for reasons other

  2. 74  than safety and effectiveness. Specifically, FDA will withdraw approval of an NDA at the

  3. 75  applicant’s request where the drug that is the subject of the application is no longer being

  4. 76  marketed, and if certain other conditions are satisfied, including the absence of any FDA finding

  5. 77  that the drug is unsafe or ineffective for its approved conditions of use (see, e.g., § 314.150(c)

2

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 78  (21 CFR 314.150(c))).4 As noted above, withdrawal of an NDA RLD under these circumstances

  2. 79  is referred to in this guidance as a “withdrawn RLD.”5

80

  1. 81  Where an RLD has been withdrawn, ANDA products that were approved in reliance on the

  2. 82  withdrawn RLD may continue to be marketed, and new ANDAs must refer to the withdrawn

  3. 83  RLD as the basis for ANDA submission (provided that there has been a determination that the

  4. 84  NDA RLD was not withdrawn for reasons of safety or effectiveness) (see § 314.122(c) (21 CFR

  5. 85  314.122(c))).

86

  1. 87  Under these circumstances, where approval of the NDA for an RLD has been withdrawn, the

  2. 88  NDA holder can no longer update labeling for the withdrawn RLD.6 Yet as a drug is used over

  3. 89  time, the scientific community’s understanding of the drug may evolve based on data from

  4. 90  various sources, including published literature and postmarketing data. Therefore, the labeling

  5. 91  of ANDAs that rely on the withdrawn RLD might eventually become inaccurate and outdated,

  6. 92  resulting in labeling that is false and/or misleading, for example. Likewise, new original

  7. 93  ANDAs that rely on the withdrawn RLD might include proposed labeling based on the last

  8. 94  approved RLD labeling that includes outdated information that is false and/or misleading.

95

  1. 96  If an NDA for a certain drug has been withdrawn, there may be other drugs that contain the same

  2. 97  active ingredient (or an active ingredient in the same pharmacologic or therapeutic class) for

  3. 98  which approval of the NDA has not been withdrawn. The labeling of those other drugs, as well

  4. 99  as the labeling of any corresponding ANDAs, may have been updated to reflect any new

  5. 100  scientific information that is needed for the safe and effective use of the drug. This creates a

  6. 101  situation in which certain NDAs and ANDAs for a given active ingredient have up-to-date

  7. 102  labeling, while other ANDAs do not, simply because those other ANDAs rely on an RLD for

  8. 103  which approval of the NDA has been withdrawn. In such cases the labeling of pending ANDAs

  9. 104  or marketed ANDAs products may need to be updated to reflect changes that would have been

  10. 105  necessary had the NDA for the RLD not been withdrawn.

106

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4 If the NDA for the RLD has been withdrawn for reasons other than safety or effectiveness, a therapeutically equivalent drug product approved under an ANDA may be designated as the reference standard for use in conducting an in vivo study to demonstrate bioequivalence.
5 Withdrawal of approval of an NDA is considered effective upon the date specified in the notice of withdrawal published in the Federal Register. Until that date, an NDA holder that has submitted a request under 21 CFR 314.150 to withdraw the approval of an NDA will continue to be responsible for ensuring that the labeling of the drug product approved under the NDA remains accurate and up to date.

6 In cases where marketing of the RLD product has been discontinued but approval of the NDA has not been withdrawn under § 314.150 or section 505(e) of the FD&C Act (referred to in this guidance as a “discontinued RLD”), the NDA holder must still comply with applicable statutory and regulatory requirements. These requirements include, for example, proposing any necessary revisions to update product labeling for the discontinued RLD (see, e.g., § 201.56(a)(2)). ANDA products approved in reliance on a discontinued RLD may continue to be marketed, and new ANDAs must refer to the discontinued RLD as the basis for ANDA submission (see § 314.122(c)). The Agency will continue to list discontinued RLD drug products on the “Discontinued Drug Product List” in FDA’s “Approved Drug Products With Therapeutic Equivalence Evaluations” (the “Orange Book”), unless FDA determines that the drug product was withdrawn from sale for reasons of safety or effectiveness, in which case the drug product will be removed from the Orange Book.

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Draft — Not for Implementation

  1. 107  In this guidance, FDA clarifies that consistent with the statute, where the RLD is withdrawn, 7

  2. 108  certain labeling changes may continue to be made for pending ANDAs and marketed ANDAs.

109 110

111 III. SCOPE OF GUIDANCE 112

  1. 113  This guidance is limited to labeling updates for generic drugs that are the subject of new original,

  2. 114  pending ANDAs or approved ANDAs that rely on an RLD for which approval of the NDA has

  3. 115  been withdrawn for reasons other than safety or effectiveness.

116

  1. 117  Consistent with this guidance, FDA may seek to facilitate certain updates to the labeling for a

  2. 118  new original, pending ANDA or an already-approved ANDA that relies on a withdrawn RLD

  3. 119  when the previously approved labeling for the withdrawn RLD has become outdated and such

  4. 120  changes would have been necessary had the RLD not been withdrawn.

121

  1. 122  The process described in this guidance is intended to complement existing Agency authorities

  2. 123  and processes, including FDA’s authority under the Food and Drug Administration Amendments

  3. 124  Act of 2007 (FDAAA) to require certain safety labeling changes (SLCs) to the labeling of certain

  4. 125  prescription drug products. The relationship of this guidance to certain existing FDA authorities

  5. 126  and processes is further discussed in section IV.C below.

127
128
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IV. UPDATING LABELING OF ANDAs THAT RELY ON WITHDRAWN RLDs 130

  1. 131  ANDA holders are responsible for reviewing postmarketing data and published literature as

  2. 132  appropriate to satisfy applicable reporting requirements (e.g., 21 CFR 314.81, 314.98).

  3. 133  However, FDA (as well as ANDA holders and applicants) may be aware of data relevant to

  4. 134  labeling updates in a variety of situations. For example, relevant data may already be reflected in

  5. 135  the updated labeling of other drugs in the same pharmacologic or therapeutic class (e.g., class

  6. 136  labeling); in non-product specific literature; or in postmarketing information. The updates

  7. 137  contemplated by this guidance generally would not involve reliance on product-specific,

  8. 138  proprietary information about another drug. Any changes proposed under this guidance must be

  9. 139  consistent with the requirement that an ANDA include sufficient information to show that the

  10. 140  conditions of use have been previously approved for the RLD (section 505(j)(2)(A)(i)).

141

7 The approach proposed in this guidance is consistent with FDA statements made in the context of determinations that certain drug products that have been withdrawn from sale were not withdrawn for reasons of safety or effectiveness, including statements to the effect that “[i]f FDA determines that labeling for these drug products should be revised to meet current standards, the Agency will advise ANDA applicants to submit such labeling.” See, e.g., 80 FR 27320 at 27321 (May 13, 2015) (determining that SODIUM SULAMYD (sulfacetamide sodium) Ophthalmic Solution and Ophthalmic Ointment were not withdrawn from sale for reasons of safety or effectiveness).

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Contains Nonbinding Recommendations

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A. Examples of Labeling Updates for ANDAs That Rely on Withdrawn RLDs

In general, the labeling changes contemplated under this guidance include changes necessary to ensure that labeling adequately describes information essential for safe and effective use; that labeling is accurate and meets current standards; and that labeling is not false or misleading under section 502 of the FD&C Act. Revisions described by this guidance may include changes based on data that have become available since the RLD was withdrawn, including published literature and other data that emerge after products have entered the market.

More specifically, the labeling changes contemplated under this guidance may be needed:

• •

To achieve consistency with the labeling of other products that have the same active ingredient or an active ingredient in the same pharmacologic or therapeutic class, or with the labeling of other products approved for the same indication, where appropriate;
To correct outdated information related to a previously approved indication; and/or
To achieve consistency with applicable regulations and current FDA labeling guidelines or other guidance (as already contemplated under § 314.94(a)(8)(iv)).

Examples of the updates contemplated by this guidance might include the following (this list is not intended to be exhaustive):8

• •

Updating the indication statement in the INDICATIONS AND USAGE section to reflect current disease terminology (e.g., changing “Juvenile Rheumatoid Arthritis” to “Juvenile Idiopathic Arthritis”) or to modify the description of an outdated restriction on the use of the drug in specific situations.

For systemic antibacterial drug products, including the required statement about antimicrobial resistance in the INDICATIONS AND USAGE section (see 21 CFR 201.24(b)).

For parenteral products, including the following required statement or appropriate modification in the DOSAGE AND ADMINISTRATION section: “Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit” (see 21 CFR 201.57(c)(3)(iv)).

Removing a risk from the CONTRAINDICATIONS section if the benefit outweighs the risk of use in the situation or subpopulation (e.g., the risk is theoretical) (see 21 CFR 201.57(c)(5)).

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8 FDA intends to use the process outlined in section IV.B to address these types of labeling changes, unless, in particular circumstances, such changes fall within FDA’s authority to require SLCs pursuant to section 505(o)(4) of the FD&C Act. As noted above in section III, the process described in this guidance is intended to complement existing Agency authorities and processes, including FDA’s authority to require SLCs.

5

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Revising the WARNINGS AND PRECAUTIONS section to include current steps to prevent, mitigate, monitor for, or manage a clinically significant adverse reaction or risk.

Revising the ADVERSE REACTIONS section to include a new adverse reaction based on postmarketing experience.

Revising the ADVERSE REACTIONS section to include the following recommended statement or appropriate modification before the presentation of adverse reactions from spontaneous reports:

The following adverse reactions have been identified during postapproval use of drug X. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

See FDA guidance for industry, Adverse Reactions Section of Labeling for Human Prescription Drug and Biological Products — Content and Format. 9

Adding a new clinically significant drug interaction in the DRUG INTERACTIONS section based on postmarketing data showing that a newly approved product interacts with the active ingredient in the ANDA product or with products in the ANDA product’s class.

Revising the OVERDOSAGE section to include overdose management strategies that are consistent with current Poison Control recommendations.

For systemic antibacterial drug products, updating susceptibility test interpretive criteria, susceptibility test methods, and quality control parameters in the Microbiology subsection of the CLINICAL PHARMACOLOGY section. See FDA guidance for industry, Updating Labeling for Susceptibility Test Information in Systemic Antibacterial Drug Products and Antimicrobial Susceptibility Testing Devices;10 see also section 1111 of FDAAA.

Making changes to keep up to date with class Medication Guides (e.g., if there is a class Medication Guide for nonsteroidal anti-inflammatory drugs (NSAIDs), all ANDA NSAID products -- including those with withdrawn NDA RLDs -- should have the current version of the class NSAID Medication Guide).

Making changes requested by FDA prior to withdrawal of an NDA RLD that are determined to be necessary for safe and effective use.

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9 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
10 Available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

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  1. 228  ANDA holders have the ability to submit any of the labeling updates contemplated by this

  2. 229  guidance, i.e. those changes needed to ensure that labeling is accurate and meets current

  3. 230  standards for an ANDA whose RLD is withdrawn, through the submission of a prior approval

  4. 231  supplement (PAS). If FDA determines that a change proposed in this manner is appropriate and

  5. 232  approves the supplement, the Agency may request that other ANDA holders and any ANDA

  6. 233  applicants relying on the same withdrawn RLD make the same updates, where appropriate. This

  7. 234  latter step is intended to ensure that labeling remains uniform across generic drugs that rely on

  8. 235  the same RLD.

236

  1. 237  FDA may also request a changes being effected (CBE-0) supplement from ANDA holders (see

  2. 238  21 CFR 314.70(c)(6)(iii)(E)) if FDA becomes aware of labeling updates that are needed to

  3. 239  ensure that labeling is accurate and meets current standards for an ANDA or ANDAs whose

  4. 240  RLD is withdrawn.11 Under these circumstances, the Agency would also solicit an amendment

  5. 241  reflecting the needed updates from any ANDA applicants seeking initial approval that rely on the

  6. 242  same RLD. Such an amendment would be necessary prior to ANDA approval.

243
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C. Relationship of This Guidance to Existing Authorities and Processes 245

  1. 246  The process described in this guidance is intended to complement existing Agency authorities

  2. 247  and processes. Two of these are described below.

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1. Safety Labeling Changes Under Section 505(o)(4) of the FD&C Act 250

  1. 251  The Food and Drug Administration Amendments Act of 2007 (FDAAA) gave FDA explicit

  2. 252  authority to require certain safety labeling changes (SLCs) to the labeling of prescription drug

  3. 253  products marketed under NDAs and under ANDAs whose RLD is not currently marketed (i.e.,

  4. 254  ANDAs with a “withdrawn RLD” or “discontinued RLD” as described in the Background

  5. 255  section of this guidance). If FDA becomes aware of “new safety information”12 that it believes

    11 FDA has issued a proposed rule that would allow ANDA holders to independently submit CBE-0 supplements making certain safety-related updates to their labeling, based on newly acquired information. See 78 FR 67985 (November 13, 2013). That proposed rule, along with comments received, remains under review. If the proposed rule is finalized, the final rule will govern the process for carrying out labeling updates that are within the scope of the rule. The process described in this guidance would not alter ANDA holders’ obligation to maintain up-to-date labeling, whether under the current regulatory framework or a future scenario at such time as the proposed rule is finalized.

    12 See 21 U.S.C. 355-1(b)(3). The term “new safety information” includes certain information about a serious risk or an unexpected serious risk associated with the use of a drug that FDA has become aware of since the drug was approved, since a risk evaluation and mitigation strategy (REMS) was required, or since the last assessment of the approved REMS for the drug.

Making changes or updates described in Agency regulations, guidance, or Federal Register notices even if they do not specifically address the labeling of ANDAs where the NDA RLD is withdrawn.

B. Process for Labeling Updates

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  1. 256  should be included in labeling, FDA issues a safety labeling change notification letter, which

  2. 257  may include proposed labeling changes, to the affected application holder(s) (see section

  3. 258  505(o)(4) of the FD&C Act). Application holders must then submit either a supplement with the

  4. 259  proposed labeling changes, or a rebuttal statement explaining why the proposed changes are not

  5. 260  warranted, within 30 days. FDA reviews and acts on these supplements and rebuttal statement

  6. 261  within defined time frames (see FDA guidance for industry, Safety Labeling Changes –

  7. 262 Implementation of Section 505(o)(4) of the FD&C Act.13

  8. 263  The FDAAA SLC process is separate and distinct from the process described in this guidance.

  9. 264  FDA will continue to use its FDAAA SLC authorities where appropriate in situations where

  10. 265  FDA becomes aware of “new safety information” about a serious risk or an unexpected serious

  11. 266  risk that the Agency believes should be included in product labeling.

  12. 267  This guidance addresses certain situations in which needed updates to the labeling of ANDAs

  13. 268  that rely on withdrawn RLDs may not be captured by the FDAAA SLC process. For example:

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290 291

  1. 292  Under section 409I of the Public Health Service Act (42 U.S.C. § 284m), the National Institutes

  2. 293  of Health (NIH) and FDA implement a program for pediatric studies of drugs. NIH may under

  3. 294  certain circumstances award funds to an entity with appropriate expertise for the conduct of

  4. 295  studies needed to provide safety and efficacy information for pediatric labeling. Upon

    13 Available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 8

The FDAAA SLC authorities apply only to approved NDAs and ANDAs. When new original ANDAs are submitted that rely on a withdrawn RLD, the FDAAA SLC authorities do not extend to the draft labeling submitted as part of those pending applications. Under this guidance, FDA will consider the FDAAA SLC notification that is sent to the holders of approved applications to be “FDA labeling guidelines or other guidance” within the meaning of § 314.94(a)(8)(iv). Applicants with pending ANDAs will be able to submit amendments to their applications with labeling that reflects the safety labeling change made by the holders of approved ANDAs relying on the same RLD, and this will be considered a change made to comply with “current FDA labeling guidelines or other guidance” within the meaning of the regulation.

Before FDAAA came into effect on March 25, 2008, certain labeling updates had been accomplished through other regulatory procedures, including class labeling changes. Those updates were typically carried out in the first instance by updates to NDA RLD labeling that would then have been reflected in the labeling of ANDAs relying on that RLD. Where an RLD affected by the update was withdrawn, however, the corresponding ANDAs may have never adopted these updates. Where appropriate under the process described in this guidance (for example where labeling changes are not implemented through the FDAAA SLC process), FDA will ask ANDA holders that rely on withdrawn RLDs to make these updates to their labeling consistent with this guidance.

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  1. 296  completion of these pediatric studies, a study report that includes all data generated in connection

  2. 297  with the studies is placed in a public docket assigned by FDA. FDA will review the data

  3. 298  generated, and if labeling changes are determined to be appropriate, FDA may request CBE-0

  4. 299  supplements from the affected application holders to reflect those changes. Affected application

  5. 300  holders may include holders of ANDAs that rely on withdrawn RLDs.

301
302 The section 409I process will not be affected by this guidance. 303
304

9

 

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

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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

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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

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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

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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
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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

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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.

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INTRODUCTION AND SCOPE

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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))

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  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.

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  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
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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).

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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,

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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.

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  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.

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  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.

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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)

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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).

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  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.

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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

 

Osteoporosis: Nonclinical Evaluation of Drugs Intended for Treatment Guidance for Industry

Osteoporosis:

Nonclinical Evaluation

of Drugs Intended for

Treatment 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 60 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 Samantha Bell at 301-796-9687.

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

June 2016 Pharmacology/Toxicology

page1image9320

15004dft.doc 06/01/16

Osteoporosis:

Nonclinical Evaluation

of Drugs Intended for

Treatment Guidance for Industry

Additional copies are available from:

Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: 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)

June 2016 Pharmacology/Toxicology

I. II. III.

A. B.

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1 BACKGROUND ............................................................................................................... 2 NONCLINICAL STUDIES.............................................................................................. 2 Toxicology Studies ......................................................................................................................... 2 Bone Quality Studies...................................................................................................................... 2

1. Animal Species and Models ............................................................................................................. 2

  1. Two-species requirement .......................................................................................................... 2

  2. Osteoporosis models ................................................................................................................. 3

  3. Studies to support other osteoporosis indications ..................................................................... 3

2. Study Design .................................................................................................................................... 3

  1. Dose selection ........................................................................................................................... 3

  2. Dosing regimen and administration route.................................................................................3

  3. Study duration ........................................................................................................................... 4

  4. Data analysis ............................................................................................................................. 4

3. Evaluations ...................................................................................................................................... 4

  1. Bone turnover ............................................................................................................................ 4

  2. Bone mass and density..............................................................................................................4

  3. Bone structure and architecture................................................................................................. 4

  4. Bone strength ............................................................................................................................ 5

  5. Additional evaluations .............................................................................................................. 5

Biopharmaceuticals ....................................................................................................................... 6

REGULATORY ASPECTS............................................................................................. 6

C. IV.

V. REFERENCES.............................................................................................................................. 8

ANABOLIC AGENTS...................................................................................................... 6

1 2

3 4 5 6

7 8 9

10 11 12 13

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Osteoporosis: Nonclinical Evaluation of Drugs Intended for Treatment Guidance for Industry1

page4image9976

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

page4image23232

I. INTRODUCTION

The purpose of this guidance is to provide recommendations to industry for designing nonclinical studies to support the approval of drugs intended for the treatment of osteoporosis.2 Specifically, this guidance addresses the Food and Drug Administration’s (FDA’s) current thinking regarding the nonclinical development program for biopharmaceuticals to treat osteoporosis.

We recommend sponsors review the following guidances for industry before initiating clinical trials of drugs intended to treat osteoporosis:3

General Considerations for the Clinical Evaluation of Drugs
Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products Study of Drugs Likely to be Used in the Elderly

In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

1 This guidance has been prepared by the Division of Bone, Reproductive, and Urologic Products in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.

2 For the purposes of this guidance, drugs refers to drug and biological products regulated in CDER.

3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

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38
39
II. BACKGROUND 40

  1. 41  In addition to the pharmacology and toxicology studies required for all new drugs,4 long-term

  2. 42  nonclinical pharmacology studies (bone quality studies) should be conducted for drugs intended

  3. 43  to treat osteoporosis. These studies are warranted because of concerns about long-term adverse

  4. 44  effects of pharmaceutical agents on the quality of bone (Harris, Watts, et al. 1993; Kleerekoper

  5. 45  1996; Van der Meulen and Boskey 2012) and because there are no validated and reliable

  6. 46  methods for the noninvasive assessment of bone quality in humans. Bone quality refers to those

  7. 47  structural and material properties of bone that determine its biomechanical behavior in ways that

  8. 48  are not accounted for by bone quantity or mass (Hernandez and Keaveny 2006). Although bone

  9. 49  quality cannot be easily assessed directly, nonclinical studies offer the opportunity to provide

  10. 50  indirect information about bone quality through the measurement of bone strength, which is

  11. 51  determined by both bone mass and bone quality. An adverse effect on bone quality can be

  12. 52  identified by a change in the correlation between bone mass (i.e., bone mineral density (BMD) or

  13. 53  bone mineral content (BMC)) and bone strength. However, clinical trials must still establish that

  14. 54  increases in BMD are associated with reductions in the incidences of bone fractures.5

55
56
57
III. 58
59
60

  1. 61  Pharmacology and toxicology studies are needed to support clinical development of new drugs

  2. 62  and biologics for osteoporosis indications.6 In addition to these standard pharmacology and

  3. 63  toxicology studies, bone quality studies should be conducted for drugs intended to treat

  4. 64  osteoporosis.

65
66
B. 67
68
1. 69
70
71

  1. 72  Various animal species and models are available for the study of osteoporosis (Turner 2001;

  2. 73  Jerome and Peterson 2001). Species and models selected should be relevant to the specific

  3. 74  clinical indication for which the drug is being developed. Bone quality studies to support

  4. 75  osteoporosis indications generally should be conducted in two different animal species.

  5. 76  However, biopharmaceuticals may be exempted from this recommendation (see section III.C.,

  6. 77  Biopharmaceuticals).

    4 21 CFR 312.23(a)(8)
    5 21 CFR 314.50(d)(2) and 21 CFR 314.50(d)(5)

    6 See the ICH guidances for industry S7A Safety Pharmacology Studies for Human Pharmaceuticals, M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals, and S6(R1) Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals.

NONCLINICAL STUDIES A. Toxicology Studies

Bone Quality Studies

Animal Species and Models

a. Two-species requirement

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78
79 b. Osteoporosis models 80

  1. 81  For postmenopausal osteoporosis, one of the bone quality studies should be conducted in the

  2. 82  ovariectomized rat, and the other study should be done in a larger ovariectomized nonrodent

  3. 83  species with more extensive cortical remodeling (e.g., nonhuman primate, sheep, pig, or dog).

  4. 84  The age of the animals at ovariectomy should be adequate to evaluate the effects of the

  5. 85  investigational drug on already formed bone rather than bone growth. Treatment initiation time

  6. 86  after ovariectomy should be determined by the intended clinical use of the drug and the expected

  7. 87  time course of bone loss in the species used. For other forms of osteoporosis, appropriate animal

  8. 88  models (such as the mature orchidectomized rodent for male osteoporosis and the glucocorticoid-

  9. 89  treated rabbit for glucocorticoid-induced osteoporosis) and transgenic animal models may

  10. 90  provide relevant information (see section III.C., Biopharmaceuticals).

91
92 c. Studies to support other osteoporosis indications 93

  1. 94  When a drug has been approved for a specific osteoporosis indication and the approval was

  2. 95  supported by bone quality studies in indication-specific animal models, the nonclinical

  3. 96  recommendation to support another osteoporosis indication for the drug may be limited to a

  4. 97  short-term study (less than or equal to 6 months) in a relevant animal model that can serve to

  5. 98  bridge to the original bone quality studies. The recommendation for additional animal studies

  6. 99  depends on the level of scientific concern about the skeletal effects of the drug in other forms of

  7. 100  osteoporosis.

101
102
2. StudyDesign
103
104 a. Dose selection 105

  1. 106  Nonclinical bone quality studies generally should be conducted with three doses, including a

  2. 107  dose that induces an optimal pharmacological effect on bone mass, a high dose that is an

  3. 108  adequate multiple of the optimally effective dose, and a low dose intended to produce a

  4. 109  suboptimal response. The optimally effective dose should be determined in dose range-finding

  5. 110  studies and should be based on BMD and biochemical markers of bone turnover. The high dose

  6. 111  should be used to optimize the identification of adverse bone effects and the low dose can be

  7. 112  useful in establishing a no observable adverse effect level for adverse bone effects. The dose

  8. 113  selection may be influenced by nonskeletal toxicities.

114
115 b. Dosing regimen and administration route 116

  1. 117  The dosing regimen and administration route in the nonclinical studies should reflect the

  2. 118  intended clinical use. Dosing interval should be selected based on the pharmacokinetic profile of

  3. 119  the investigational drug and the respective bone remodeling cycle durations in animals and

  4. 120  humans. For follow-up indications with different clinical dosing regimens or dose

  5. 121  administration routes, the need for additional nonclinical studies should be based on scientific

  6. 122  rationale.

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124 c. Studyduration 125

  1. 126  The treatment duration of the long-term bone quality studies should consist of a number of

  2. 127  remodeling cycles equivalent to approximately 3 years of human exposure. Assuming that the

  3. 128  duration of the bone turnover cycle in humans is 16 to 26 weeks (2 to 3 cycles per year) (Eriksen

  4. 129  2010), approximately 6 weeks in rats (8 cycles per year) (Baron, Tross, et al. 1984) and

  5. 130  approximately 10 weeks in monkeys (5 cycles per year) (Schock, Noyes, et al. 1972), a treatment

  6. 131  duration of 9 to 14 months in rats and 14 to 22 months in primates would be comparable to

  7. 132  approximately 3 years of treatment in humans. Because of their relatively short life-span, studies

  8. 133  in rats and mice can be limited to 12 months. In monkeys, a study duration of 16 to 24 months is

  9. 134  generally adequate. Study duration also can be affected by other species-specific considerations.

135
136 d. Data analysis 137

  1. 138  Studies should be sufficiently powered to demonstrate statistically significant effects on BMD

  2. 139  and biomechanical strength parameters at the optimal dose.

140
141
3. Evaluations 142
143
144

  1. 145  Biochemical markers of bone resorption and formation should be measured in the bone quality

  2. 146  studies to provide information on bone turnover. Resorption markers include serum or urine

  3. 147  cross-linked telopeptides of type I collagen, such as NTx or CTx, and urinary pyridinium cross-

  4. 148  links of collagen, such as PYD or DPD. Formation markers include serum OC, PICP, PINP, and

  5. 149  BSAP. Data on bone turnover should be collected at interim time points (e.g., at 3, 6, 12, and 18

  6. 150  months) and at end of study. Bone turnover markers do not by themselves provide information

  7. 151  on bone quality, but may help to explain or interpret changes in other bone parameters.

152
153 b. Bone mass and density 154

  1. 155  Established noninvasive techniques for the assessment of BMD and BMC, such as dual energy

  2. 156  X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT), should

  3. 157  be used in the bone quality studies. Both axial (spine) and appendicular (long bone) skeletal

  4. 158  sites should be examined. The pQCT data should be collected for both cancellous and cortical

  5. 159  bone. Geometrical bone properties also should be estimated by densitometric techniques. Ex

  6. 160  vivo measurements can be carried out at end of study, but in vivo measurements in anesthetized

  7. 161  animals can be performed at interim time points as well.

162
163 c. Bone structure and architecture 164

  1. 165  A qualitative histological evaluation of the microscopic bone structure, with optional histological

  2. 166  staining, should be performed to identify bone cell and matrix components. In addition, static

  3. 167  and dynamic histomorphometry of cortical and cancellous bone at axial and appendicular

  4. 168  skeletal sites should be employed to obtain quantitative information on bone architecture and

  5. 169  remodeling dynamics (Parfitt, Drezner, et al. 1987; Dempster, Compston, et al. 2013). Other

a. Bone turnover

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  1. 170  imaging or spectroscopic techniques (micro-computed tomography, high-resolution pQCT,

  2. 171  magnetic resonance imaging, Raman or infrared spectroscopy, polarized light microscopy, small-

  3. 172  and wide-angle X-ray scattering, or advanced forms of computed tomography) can be used to

  4. 173  provide additional information on bone structure at different hierarchical levels. Evaluations

  5. 174  should be carried out at the end of the study, but data also can be collected at interim time points.

175
176 d. Bone strength 177

  1. 178  Biomechanical testing of both axial and appendicular sites should be performed in the bone

  2. 179  quality studies. Tests can include compression tests of vertebrae or vertebral bodies, bending

  3. 180  tests of long bones, and femoral neck loading tests. Both extrinsic (e.g., ultimate force, stiffness,

  4. 181  work-to-failure) and intrinsic mechanical parameters (e.g., ultimate strength, yield strength,

  5. 182  elastic modulus) should be determined (Turner and Burr 1993). Characterization of pre-yield as

  6. 183  well as post-yield bone mechanical properties is recommended. The choice of the biomechanical

  7. 184  parameter(s) used to describe the bone’s mechanical properties and demonstrate an effect of the

  8. 185  therapeutic drug should be adequately justified. Geometric and densitometric parameters of the

  9. 186  mechanically tested bone types should also be evaluated.

187

  1. 188  An analysis of the correlation between densitometric parameters (BMC, BMD) and mechanical

  2. 189  parameters (e.g., ultimate force, stiffness, work-to-failure, ultimate strength, yield strength, or

  3. 190  toughness) is essential and should be carried out to provide information about the value of BMD

  4. 191  as a strength predictive parameter for the investigational drug. BMD can be correlated to mass-

  5. 192  normalized strength parameters, but BMC should be associated with whole bone (extrinsic)

  6. 193  mechanical properties. Importantly, potential differences in the relationship between bone mass

  7. 194  and strength parameters between control and treatment groups should be resolved by adequate

  8. 195  statistical analysis. Finite element analysis based on computed tomography images can be

  9. 196  carried out, but currently is not considered to be a substitute measure of bone strength.

  10. 197  Biomechanical assessments should be carried out in animals sacrificed at end of study, but also

  11. 198  can be performed in animals sacrificed at interim time points.

199
200 e. Additional evaluations 201

  1. 202  The evaluation of bone quality is a continually evolving field that seeks to characterize bone

  2. 203  tissue properties and their relationship to the bone’s mechanical behavior using the latest

  3. 204  scientific advances. As described above, bone quality is not captured by the measurement of one

  4. 205  particular bone parameter but is, in part, reflected by the relationship between specific bone

  5. 206  strength and densitometric parameters. Measurement of additional determinants of the bone’s

  6. 207  mechanical behavior (e.g., fatigue life, fracture toughness, hardness) can be included in animal

  7. 208  studies. Other assessments such as histologic evaluation of target organs of toxicity also can be

  8. 209  recommended for long-term bone quality studies based on drug- and indication-specific safety

  9. 210  concerns. Pharmacokinetic parameters (Cmax, area under the curve (AUC)) should be evaluated

  10. 211  in the bone quality studies to determine human exposure multiples.

212

  1. 213  Skeletal endpoints in long-term toxicology studies can be used to provide additional nonclinical

  2. 214  support for the bone safety and efficacy of therapeutic drugs.

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216 C. Biopharmaceuticals 217

  1. 218  Biopharmaceuticals (e.g., recombinant proteins and monoclonal antibodies) are typically selected

  2. 219  based upon their high specificity for their human target receptor/antigen. This target may be

  3. 220  absent in common animal test species, or the nonhuman target (the ortholog) may not

  4. 221  productively interact with the biopharmaceutical. Species selection for nonclinical bone quality

  5. 222  studies of biopharmaceuticals should be guided by pharmacological responsiveness. The test

  6. 223  agent should be pharmacologically active in the selected species. The immunogenicity of the

  7. 224  biopharmaceutical and the effect of the immune response on systemic exposure,

  8. 225  pharmacodynamic response, and toxicity of a drug should be characterized. As a result of these

  9. 226  potential limitations, bone quality as well as toxicology studies in a single responsive animal

  10. 227  species may be appropriate. In cases where no relevant test species exists, consideration should

  11. 228  be given to the use of alternative models, such as the use of an analogous drug (surrogate)

  12. 229  against the orthologous target, or the use of a transgenic model in which the animal is made to

  13. 230  express the human target. For biopharmaceuticals to be used for the treatment of osteoporosis,

  14. 231  sponsors should also consult the ICH guidance for industry S6(R1) Preclinical Safety Evaluation

  15. 232 of Biotechnology-Derived Pharmaceuticals.

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234
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IV. REGULATORY ASPECTS 236

  1. 237  Sponsors are encouraged to consult with the Division of Bone, Reproductive, and Urologic

  2. 238  Products regarding the design of the nonclinical bone quality studies as early in development as

  3. 239  possible. Study protocols with detailed description of testing procedures should be submitted for

  4. 240  review by the division. Data from dose-range finding studies of relatively short-term duration

  5. 241  (3 to 4 months in rodents, 6 months in large animals) can be used to support the initiation of

  6. 242  phase 2 or phase 3 clinical trials and inform the design of the long-term studies. Final reports of

  7. 243  nonclinical bone quality studies generally should be submitted by the end of phase 3 or at the

  8. 244  time of submission of the new drug application or biologics license application. Modification of

  9. 245  study timing and requirements can be considered for some drugs according to the level of

  10. 246  concern and the availability of relevant animal models. If appropriate, data from short-term dose

  11. 247  range-finding studies may be needed to evaluate drug-specific bone safety concerns and support

  12. 248  long-term clinical trials.

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250
251
V . ANABOLIC AGENTS 252

  1. 253  A toxicological issue for the development of bone anabolic agents for the treatment of

  2. 254  osteoporosis is the potential for carcinogenicity. In previous nonclinical studies, rats and mice

  3. 255  dosed with parathyroid hormone (PTH) or parathyroid hormone-related peptide (PTHrP) drugs

  4. 256  for 4 to 24 months developed bone tumors including osteosarcomas. In rats given daily PTH

  5. 257  injections, tumors occurred at low multiples of human exposure (AUC). As a result of the

  6. 258  concern about carcinogenicity, studies to evaluate carcinogenic potential generally should be

  7. 259  conducted with PTH drugs developed for the treatment of osteoporosis. Relevant drugs include

  8. 260  PTH- and PTHrP-related peptides and other drugs stimulating osteoblastic bone formation.

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Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 261  These studies may entail unique design features. Therefore, study protocols should be discussed

  2. 262  with the division before study initiation.

263

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Contains Nonbinding Recommendations

Draft — Not for Implementation

264 REFERENCES 265

  1. 266  Baron, R, Tross, R, and Vignery, A, 1984, Evidence of Sequential Remodeling in Rat Trabecular

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269

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  2. 271  PJ, Ott, SM, Recker, RR, and Parfitt, AM, 2013, Standardized Nomenclature, Symbols, and

  3. 272  Units for Bone Histomorphometry: A 2012 Update of the Report of the ASBMR

  4. 273  Histomorphometry Nomenclature Committee, J Bone Miner Res, (28)(1):1-16.

274

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277

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282

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285

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289 Kleerekoper, M, 1996, Fluoride and the Skeleton, Crit Rev Clin Lab Sci, (33)(2):139-161. 290

  1. 291  Parfitt, AM, Drezner, MK, Glorieux, FH, Kanis, JA, Malluche, H, Meunier, PJ, Ott, SM, and

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  3. 293  Units, J Bone Miner Res, (2)(6):595-610.

294

  1. 295  Schock, CC, Noyes, FR, and Villanueva, AR, 1972, Measurement of Haversian Bone

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  3. 297  Med J, (20)(3):131-144.

298

  1. 299  Turner, AS, 2001, Animal Models of Osteoporosis — Necessity and Limitations, Eur Cell Mater,

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301

  1. 302  Turner, CH and Burr, D, 1993, Basic Biomechanical Measurements of Bone: A Tutorial, Bone

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304

  1. 305  Van der Meulen, MC and Boskey, AL, 2012, Atypical Subtrochanteric Femoral Shaft Fractures:

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