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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.

Recurrent Herpes Labialis: Developing Drugs for Treatment and Prevention Guidance for Industry

Recurrent Herpes

Labialis: Developing

Drugs for Treatment

and Prevention 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DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.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be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance.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 Regina Alivisatos, MD, at 301-796-1500.

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

July 2016 Clinical/Medical

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16857dft.doc 06/29/16

Recurrent Herpes

Labialis: Developing

Drugs for Treatment

and Prevention 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/Medical

I. II. III.

A. B.

1. 2.

3.

C.

1. 2.

3. 4.

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1 BACKGROUND ............................................................................................................... 2 DEVELOPMENT PROGRAM ....................................................................................... 3 General Considerations .................................................................................................................3 Nonclinical Development Considerations.....................................................................................3

Pharmacology/Toxicology Considerations ......................................................................................3 Virology Considerations...................................................................................................................4

D.

1. 2. 3. 4. 5.

Risk Management Considerations..................................................................................................16 Relevant Nonclinical Safety Considerations ..................................................................................17 Pharmacokinetic/Pharmacodynamic Considerations ....................................................................17 CMC Considerations......................................................................................................................17 Labeling Considerations ................................................................................................................18

a.
b.
c.
d.
e.
f.
Early Phase Clinical Considerations ...............................................................................................6

  1. Investigational drugs..................................................................................................................6

  2. Previously approved drugs with a new formulation and/or route of administration .................7

Phase 2 and Phase 3 Clinical Development..................................................................................7

Mechanism of action .................................................................................................................4 Antiviral activity in cell culture.................................................................................................4 Cytotoxicity and mitochondrial toxicity ....................................................................................4 Combination antiviral activity ...................................................................................................5 Activity in animal models..........................................................................................................5 Resistance and cross-resistance..................................................................................................5

Drug Development Population.........................................................................................................7 Efficacy Considerations ...................................................................................................................7

  1. Treatment indication..................................................................................................................8

  2. Prevention indication.................................................................................................................8

Safety Considerations.......................................................................................................................8 Specific Efficacy Trial Considerations.............................................................................................9

a.
b.
c.
d.
e.
f.
g.
h.
i.
j.
k.
l.
m.
n.
Other Considerations ...................................................................................................................16

Study design ..............................................................................................................................9 Study population......................................................................................................................10 Inclusion and exclusion criteria ...............................................................................................10 Randomization, stratification, and blinding ............................................................................11 Special populations..................................................................................................................11 Dose selection ..........................................................................................................................12 Choice of comparators.............................................................................................................12 Efficacy endpoints...................................................................................................................12

Study procedures and timing of assessments ...........................................................................14 Endpoint adjudication ..............................................................................................................14 Statistical considerations .........................................................................................................14 Clinical virology considerations...............................................................................................15 Accelerated approval (subpart H) considerations...................................................................16 Risk-benefit considerations .....................................................................................................16

REFERENCES............................................................................................................................ 19

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 1 Recurrent Herpes Labialis:

  2. 2 Developing Drugs for Treatment and Prevention

  3. 3 Guidance for Industry1

4 5 6

7 8 9

10 11 12 13

14
15
16
17
I. INTRODUCTION 18

  1. 19  The purpose of this guidance is to assist sponsors in the development of drugs for the treatment

  2. 20  and prevention of recurrent herpes labialis (RHL). Specifically, this guidance addresses the

  3. 21  Food and Drug Administration’s (FDA’s) current thinking regarding the overall development

  4. 22  program and clinical trial designs to support the development of drug products with an antiviral

  5. 23  mechanism of action used to prevent and/or treat RHL caused by either herpes simplex virus

  6. 24  type 1 or 2 (HSV-1 or HSV-2) in immunocompetent subjects. This draft guidance is intended to

  7. 25  serve as a focus for continued discussions among the Division of Antiviral Products (DAVP),

  8. 26  pharmaceutical sponsors, the academic community, and the public.2 This guidance does not

  9. 27  address the development of drug products used to treat systemic, genital, or disseminated herpes

  10. 28  virus infections, or herpes labialis in immunosuppressed subjects.

29

  1. 30  This guidance does not contain discussions of the general issues of statistical analysis or clinical

  2. 31  trial design. Those topics are addressed in the ICH guidances for industry E9 Statistical

  3. 32 Principles for Clinical Trials and E10 Choice of Control Group and Related Issues in Clinical

  4. 33 Trials, respectively.3

34

  1. 35  In general, FDA’s guidance documents do not establish legally enforceable responsibilities.

  2. 36  Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only

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

    2 In addition to consulting guidances, sponsors are encouraged to contact the division to discuss specific issues that arise during the development of drugs used to treat or prevent RHL.

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

  2. 38  the word should in Agency guidances means that something is suggested or recommended, but

  3. 39  not required.

40

41
42
II. BACKGROUND 43

  1. 44  Infections caused by viruses of the herpes virus family are increasingly frequent. One of the

  2. 45  more common forms of such infections is RHL, which is primarily caused by HSV-1 but also

  3. 46  caused by HSV-2, which is more commonly associated with genital herpes (Harmenberg, Öberg,

  4. 47  et al. 2010; Cunningham, Griffiths, et al. 2012). From 2005 to 2010, the seroprevalence of HSV­

  5. 48  1 was 53.9 percent, and the seroprevalence of HSV-2 was 15.7 percent in the United States

  6. 49  (Bradley, Markowitz, et al. 2014). It is estimated that 20 to 40 percent of adults in the U.S.

  7. 50  population experience RHL (Bader, Crumpacker, et al. 1978; Lowhagen, Bonde, et al. 2002).

51

  1. 52  The presentation of a primary herpes labialis episode in adults can vary from an asymptomatic

  2. 53  presentation to an acute self-limiting gingivostomatitis often associated with posterior

  3. 54  pharyngitis and tonsillitis (Arduino and Porter 2006). Fever, malaise, headache, and sore throat

  4. 55  are presenting features and can be associated with vesicles on the tonsils and the posterior

  5. 56  pharynx. These vesicles if present can rupture to form ulcerative lesions with grayish exudates.

  6. 57  This type of primary infection that is associated with oral and labial lesions occurs in less than 10

  7. 58  percent of patients. Acute herpetic gingivostomatitis usually lasts 5 to 7 days, and the symptoms

  8. 59  subside in 2 weeks. The virus then establishes latency in the sensory ganglia and, when

  9. 60  reactivated, virus particles travel along sensory neurons to the skin and other mucosal sites and

  10. 61  cause RHL (Harmenberg, Öberg, et al. 2010). A variety of stimuli can lead to reactivation,

  11. 62  including exposure to ultraviolet light, fever, psychological stress, and menstruation. These

  12. 63  recurrent episodes can be associated with lesions or asymptomatic viral shedding. When

  13. 64  symptomatic, the episodes can be painful and disfiguring.

65

  1. 66  The outer edge of the vermilion border is the most common site of reactivation; on average three

  2. 67  to five lesions are present. Episodes typically progress through sequential phases, including a

  3. 68  prodromal stage followed by stages characterized by papules, or pustules (vesicles), and/or

  4. 69  ulcers. The prodromal stage, comprised of sensory symptoms occurring in the absence of

  5. 70  cutaneous lesions, generally resolves in 4 to 5 days.

71

  1. 72  Approximately 25 to 50 percent of RHL episodes do not progress beyond the prodromal or

  2. 73  papule stage; these are referred to as aborted lesions (Spruance, Overall, et al. 1977). In the

  3. 74  immunocompetent host, episodes that progress beyond the prodromal stage are self-limited and

  4. 75  generally heal spontaneously within 8 to 10 days.

76

  1. 77  Herpes labialis recurrences are diagnosed primarily on the basis of clinical presentation.

  2. 78  Diagnostic testing for HSV-1 or HSV-2, while available, is not used routinely in the clinical

  3. 79  setting. Diagnostic confirmation, if needed, can be provided by isolation of HSV in tissue

  4. 80  culture, indirect immunofluorescent staining of skin scrapings with monoclonal antibodies, or

  5. 81  polymerase chain reaction.

82

2

DEVELOPMENT PROGRAM A. General Considerations

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 83  There are a number of prescription topical and systemic drugs approved for the treatment of

  2. 84  RHL. For antiviral drugs, the goal of therapy is to block viral replication in order to shorten the

  3. 85  duration of symptoms and accelerate the healing of lesions leading to a return to normal skin.

  4. 86  Because episodes of RHL are self-limited with an expected duration of 5 to 10 days, if treatment

  5. 87  is either warranted or requested, it should be initiated as soon as possible to ensure an optimal

  6. 88  and beneficial therapeutic effect. To date, no antiviral drug has been approved for the prevention

  7. 89  of RHL.

90
91
92
III. 93
94
95

  1. 96  General considerations pertinent to nonclinical development and early clinical development are

  2. 97  outlined in this section. Sponsors can also obtain regulatory advice early in the development

  3. 98  program, before submitting an investigational new drug application (IND), through the pre-IND

  4. 99  consultation program.4

100
101
B. Nonclinical Development Considerations 102
103
1. Pharmacology/ToxicologyConsiderations 104

  1. 105  Pharmacology/toxicology development for HSV antivirals should follow existing guidances for

  2. 106  nonclinical drug development with regard to study requirements, study duration, timing, and

  3. 107  local tolerance, as well as fixed-drug combinations.5

108

  1. 109  If it is anticipated that a subject may be exposed to an HSV antiviral for prevention of

  2. 110  recurrences, or for 26 weeks or longer (cumulative dosing over a calendar year), chronic toxicity

  3. 111  and carcinogenicity studies are generally needed to support chronic dosing in subjects.

112

  1. 113  Nonclinical studies to support a change in the route of administration (e.g., oral to topical) or

  2. 114  reformulation of an already approved drug substance may be needed if existing data do not

  3. 115  support trials in subjects.6 Similarly, if systemic absorption following a change in the route of

  4. 116  administration is higher than previously observed, additional pharmacology/toxicology studies

  5. 117  may be needed. The need for such studies can be further discussed with the DAVP.

118

4 See the FDA Web site at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplicati ons/InvestigationalNewDrugINDApplication/Overview/ucm077546.htm.

5 See the ICH guidance for industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals.

6 See the guidance for industry and review staff Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route.

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119 2. VirologyConsiderations 120

  1. 121  Nonclinical virology studies can facilitate dose selection and study design to provide proof of

  2. 122  concept and data supporting an antiviral claim. Additional recommendations for general

  3. 123  antiviral drug development can be found in the guidance for industry Antiviral Product

  4. 124 Development — Conducting and Submitting Virology Studies to the Agency. Sponsors can seek

  5. 125  advice regarding the appropriate nonclinical virology assays through the pre-IND program

  6. 126  mentioned previously.

127
128 a. Mechanism of action 129

  1. 130  The mechanism by which an anti-HSV investigational drug specifically inhibits HSV-1 and/or

  2. 131  HSV-2 replication or a virus-specific function should be investigated using cell culture,

  3. 132  biochemical, structural, and/or genetic studies that include evaluation of the effect of the drug on

  4. 133  relevant stages of the virus life cycle. Mechanism-of-action studies should include appropriate

  5. 134  controls for assessing the specificity of anti-HSV activity, which may include assessments of

  6. 135  activity against HSV-1 and/or HSV-2 proteins that are targeted by the investigational drug,

  7. 136  relevant host proteins, and other viruses.

137
138 b. Antiviral activity in cell culture 139

  1. 140  HSV-1 and HSV-2 are closely related but distinct viruses and both cause RHL. The antiviral

  2. 141  activity of oral, parenteral, and topical drugs should be characterized in cell culture to assess the

  3. 142  anti-HSV-1 and/or HSV-2 activity and to identify a target plasma concentration for evaluation of

  4. 143  oral- or parenteral-administered drug products in HSV-infected subjects. Anti-HSV activity

  5. 144  studies should include assessments against several (greater than or equal to 20 each)

  6. 145  geographically and temporally distinct isolates of HSV-1 and HSV-2, the vast majority of which

  7. 146  should be U.S. isolates. Additional isolates should be obtained from relevant countries if non­

  8. 147  U.S. sites will be used in clinical studies. The effective concentration at which virus replication

  9. 148  is inhibited by 50 and 90 percent (EC50 and EC90 values) should be determined for each isolate

  10. 149  using a quantitative assay. Sponsors should consider and discuss with the DAVP the merits of

  11. 150  developing an investigational drug showing significantly greater activity for HSV-2 compared to

  12. 151  HSV-1 given the relative proportions of each in the U.S.-infected population.

152
153 c. Cytotoxicity and mitochondrial toxicity 154

  1. 155  The cytotoxic effects of the drug should be quantified directly in the cells used for assessing anti­

  2. 156  HSV activity, and a 50 percent cytotoxic concentration (CC50) and a therapeutic index (CC50

  3. 157  value/EC50 value) should be calculated. Cytotoxicity should also be assessed using various cell

  4. 158  lines and primary cells cultured under proliferating conditions for several cell divisions and

  5. 159  nonproliferating conditions. Deoxynucleoside/deoxynucleotide analogs should be assessed for

  6. 160  bone marrow precursor cell toxicity with appropriate controls.

161

  1. 162  Mitochondrial toxicity for all drugs should be evaluated in glucose-containing medium and

  2. 163  galactose-containing medium (Marroquin, Hynes, et al. 2007). Mitochondrial toxicity

  3. 164  assessments should be evaluated with drug exposures for several cell divisions. Positive controls

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Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 165  for mitochondrial toxicity studies should be relevant to the class of the investigational drug

  2. 166  whenever possible. The active triphosphate of nucleoside analog inhibitors also should be

  3. 167  evaluated in biochemical assays with mitochondrial DNA and RNA polymerases (Arnold,

  4. 168  Sharma, et al. 2012).

169

  1. 170  These biochemical and cell-based assessments for potential cellular and mitochondrial toxicity

  2. 171  should be conducted as a complement to in vivo toxicology assessments and not in lieu of in

  3. 172  vivo studies. Results from these studies should be interpreted in the context of the in vivo

  4. 173  toxicology, nonclinical, and clinical pharmacokinetic data to help assess clinical risk.

174
175 d. Combination antiviral activity 176

  1. 177  Early in development, combination antiviral activity relationships of the investigational drug and

  2. 178  approved drugs for HSV should be characterized in cell culture to identify any combinations

  3. 179  where the antiviral activity is antagonistic if future combination therapy is anticipated. Each

  4. 180  component of a combination drug that will contain at least one novel drug substance should be

  5. 181  assessed for antagonism between the components.7 For all combination antiviral activity

  6. 182  assessments, sponsors should provide combination index values or synergy scores when the two

  7. 183  drugs are combined at their individual EC50 values, and studies should include controls for

  8. 184  cytotoxicity. Combination antiviral activity relationships for nucleos(t)ide and

  9. 185  deoxynucleos(t)ide HSV investigational drugs for which there will be systemic exposure should

  10. 186  also be assessed with approved drugs for hepatitis B virus, hepatitis C virus, and human

  11. 187  immunodeficiency virus-1, as appropriate, before testing combinations of the drugs in co­

  12. 188  infected subjects.

189
190 e. Activity in animal models 191

  1. 192  Demonstration of HSV-1 and HSV-2 antiviral activity in an animal model is not needed for drug

  2. 193  approval. However, if such studies are conducted and provided in support of an HSV therapy

  3. 194  program, we recommend including the HSV type, time course plots of viral load data for each

  4. 195  animal, and an assessment of resistance development.

196
197 f. Resistance and cross-resistance 198

  1. 199  Amino acid substitutions associated with the development of resistance to the investigational

  2. 200  drug can be identified by genotyping the target gene and the conferred fold-shift in susceptibility

  3. 201  determined using appropriate cell culture assays. Results from these studies can be used to: (1)

  4. 202  identify resistance pathways; (2) validate resistance assays for use in clinical trials; (3) determine

  5. 203  whether the genetic barrier for resistance development is high or low; (4) predict whether the

  6. 204  genetic barrier for resistance may vary as a function of concentration of the investigational drug;

  7. 205  (5) assess the potential for cross-resistance with other anti-HSV drugs, particularly acyclovir;

  8. 206  and (6) support the drug’s hypothesized mechanism of action. Resistant viruses selected in cell

  9. 207  culture provide important controls for phenotypic assessment of clinical isolates.

    7 See the guidance for industry Antiviral Product Development — Conducting and Submitting Virology Studies to the Agency.

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208

  1. 209  Resistance studies can include evaluation of the potential for cross-resistance, both to approved

  2. 210  drugs and also to drugs in development when possible, particularly focusing on those in the same

  3. 211  drug class and other classes targeting the same protein or protein complex. The antiviral activity

  4. 212  of the investigational drug can be assessed against mutant viruses that are resistant to drugs

  5. 213  within the same drug class as the investigational drug as well as against a representative sample

  6. 214  of viruses resistant to other approved anti-HSV drugs.

215

  1. 216  Deoxynucleoside analogs for the treatment of herpes viruses have been found to have antiviral

  2. 217  activity against human immunodeficiency virus-1 (HIV-1) and can select for resistant variants

  3. 218  (Tachedjian, Hooker, et al. 1995; McMahon, Siliciano, et al. 2008; Lisco, Vanpouille, et al.

  4. 219  2008). Developers of such drugs for HSV should determine the cell culture antiviral activity of

  5. 220  the active moiety against HIV-1. If the drug demonstrates antiviral activity, development of

  6. 221  resistance to the investigational drug should be determined genotypically and phenotypically by

  7. 222  selecting resistant HIV-1 variants. Resistance studies should include evaluation of cross­

  8. 223  resistance to approved nucleo(t)side reverse transcriptase inhibitors for HIV-1.

224
225
3. Early Phase Clinical Considerations 226

  1. 227  The extent of this development phase depends on whether the treatment under study is a new

  2. 228  molecular entity or a previously approved drug seeking a new indication with or without a new

  3. 229  route of administration or a new formulation. In all cases, DAVP will consult with the Division

  4. 230  of Dermatology and Dental Products to assess the need for dermatologic safety studies for drugs

  5. 231  being developed for topical administration.

232
233 a. Investigational drugs 234

  1. 235  The development program for orally or topically administered investigational drugs should

  2. 236  include the standard phase 1 safety studies as specified in the guidance for industry,

  3. 237  investigators, and reviewers Exploratory IND Studies. Following phase 1, progression to proof­

  4. 238  of-concept and dose-ranging phase 2 trials is strongly advised to establish a sufficiently well­

  5. 239  tolerated and active dose for phase 3 trials. The phase 2 trials can be of similar design to phase 3

  6. 240  trials, albeit smaller. The primary objective should be a reduction in the duration of the episode

  7. 241  of RHL by at least 1/2 day. The number of phase 2 trials needed to proceed to phase 3 clinical

  8. 242  development depends on the treatment under study, and the safety and efficacy results observed

  9. 243  in at least one such trial.

244

  1. 245  Of note, a phase 2 dose-response trial is one type of adequate and well-controlled trial that, if

  2. 246  measuring appropriate endpoints in appropriate populations, can contribute to substantial

  3. 247  evidence of effectiveness (21 CFR 314.126). In addition, dose- or exposure-response analyses

  4. 248  within trials can provide additional support for approval of different doses or dosing regimens.

249

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250 b. Previously approved drugs with a new formulation and/or route of

251 252

  1. 253  The early clinical development program for previously approved drugs with a new formulation

  2. 254  and/or route of administration should be discussed with the FDA. A drug previously approved

  3. 255  for oral administration and now being developed for a new indication and/or dosage likely will

  4. 256  not need an extensive phase 1 development program. However, as discussed previously, an oral

  5. 257  drug product now being developed as a topical drug product may need to undergo dermatologic

  6. 258  safety testing. A proof-of-concept phase 2 clinical trial may be needed depending on the

  7. 259  formulation, route of administration, and dose under study.

260
261
C. Phase 2 and Phase 3 Clinical Development 262
263
1. Drug Development Population
264

  1. 265  The drug development population should include immunocompetent adults or adolescents at risk

  2. 266  for developing recurrent episodes of herpes labialis, defined as individuals experiencing at least

  3. 267  four recurrent episodes per year. Enrollment of a population that has experienced multiple

  4. 268  recurrences is preferred for the treatment indication to allow early initiation of treatment at the

  5. 269  first symptoms or signs of recurrence. For a prevention indication, the enrollment of a

  6. 270  population with a greater likelihood of recurrence is critical to demonstrate a preventative effect.

  7. 271  It may be possible to enroll children 12 years of age or younger (ages 6 to 12) depending on the

  8. 272  formulation under development and its safety profile (i.e., a drug product for topical use) in

  9. 273  either the adult trials or in separate concurrently run trials. Sponsors are advised to discuss this

  10. 274  possibility with the FDA.

275

  1. 276  Given estimates of disease prevalence in the United States, we recommend that there be adequate

  2. 277  representation of U.S. subjects within the application to support approval. If trials are conducted

  3. 278  outside the United States, sponsors are strongly encouraged to refer to the recommendations

  4. 279  outlined in the guidance for industry Acceptance of Foreign Clinical Studies and the

  5. 280  requirements in the final rule “Human Subject Protection; Foreign Clinical Studies Not

  6. 281  Conducted Under an Investigational New Drug Application” for the relevant considerations.8

282
283
2. Efficacy Considerations 284

  1. 285  For investigational drugs, sponsors are strongly encouraged to conduct two adequate and well-

  2. 286  controlled phase 3 trials (superiority) to support the intended indication. However, a single

  3. 287  persuasive and clinically meaningful study for each indication (treatment and prevention)

  4. 288  submitted together may provide substantial evidence of effectiveness sufficient for approval of

  5. 289  both indications. In circumstances where a drug previously approved for RHL treatment is being

  6. 290  developed for the prevention indication, a single superiority study may be considered to provide

  7. 291  substantial evidence of effectiveness for the intended indication. In addition if a drug was

  8. 292  previously approved for a disease caused by HSV-1 or HSV-2 and is now being developed for

  9. 293  RHL, one adequate and well-controlled trial may suffice. For a prevention-only indication, data

    8 73 FR 22800, April 28, 2008

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  1. 294  from two phase 3 trials is strongly recommended. See section III.C.4., Specific Efficacy Trial

  2. 295  Considerations, for details. Sponsors should also refer to the guidance for industry Providing

  3. 296 Clinical Evidence of Effectiveness for Human Drug and Biologic Products.

297

298 a. Treatment indication 299

  1. 300  In general, treatment trials should be designed to demonstrate a decrease in the duration of

  2. 301  episode (DOE) of RHL by at least 1/2 day relative to a control. Spontaneous resolution of RHL

  3. 302  can occur in 5 to 10 days and approved antiviral drugs that reduce the duration of RHL episodes

  4. 303  by at least 1/2 day are considered clinically beneficial. Sponsors can consider secondary

  5. 304  endpoints, such as a reduction in the number of ulcerative lesions, pain reduction, or an increase

  6. 305  in the number of aborted lesions for labeling claims; however, discussion with the FDA and

  7. 306  agreement before designing pivotal trials is strongly encouraged. See the guidance for industry

  8. 307 Providing Clinical Evidence of Effectiveness for Human Drug and Biologic Products for details

  9. 308  on the number of controlled clinical efficacy studies needed to support the effectiveness of a new

  10. 309  treatment.

310

  1. 311  In general, as noted above, trials for the RHL treatment indication should be placebo-controlled

  2. 312  superiority trials although an actively controlled superiority trial also can be considered.

313
314 b. Prevention indication 315

  1. 316  Prevention of RHL denotes no recurrences or less-frequent recurrent episodes in at-risk

  2. 317  individuals. Currently, no drug is approved for the prevention of RHL; therefore, a trial for this

  3. 318  indication should be a placebo-controlled superiority trial.

319

  1. 320  While designing a prevention trial(s), consideration should be given to the duration of

  2. 321  observation (preferably 12 months) and the determination of the primary endpoint. An

  3. 322  appropriate primary endpoint for prevention studies is either the number of confirmed

  4. 323  recurrences observed in subjects on suppressive therapy over a 12-month period or the time to

  5. 324  first recurrence, defined as the time from randomization until the onset of an episode of RHL.

  6. 325  However, it is strongly recommended that the number of recurrences over a 12-month period be

  7. 326  provided.

327

  1. 328  Drugs in development for the treatment and/or prevention of RHL in immunocompetent hosts

  2. 329  are not eligible for consideration under 21 CFR part 312, subpart E, Drugs Intended to Treat

  3. 330  Life-Threatening and Severely-Debilitating Illnesses, breakthrough therapy designation, fast

  4. 331  track, or priority review because of the non-life-threatening and self-limited nature of the

  5. 332  disease.

333
334
3. SafetyConsiderations 335

  1. 336  Generally, sponsors are advised to discuss the size of an appropriate safety database for their

  2. 337  drug product at the end-of-phase 2 meeting. Consideration should also be given to the route of

  3. 338  administration in determining the size of the safety database for either the treatment or the

  4. 339  prevention indication. The safety database can include both adults and pediatric subjects.

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340

  1. 341  For topical treatments, the safety database may need topical safety studies. Sponsors are advised

  2. 342  to discuss the need for such studies with the DA VP .

343

  1. 344  The number of subjects that should be studied to have an acceptable safety database for a new

  2. 345  previously unapproved drug product that will be used chronically for a prevention indication

  3. 346  should be discussed with the DAVP. We anticipate that a minimum of 1,000 subjects treated

  4. 347  with the proposed dose for oral drugs or topicals with systemic absorption will be studied.

  5. 348  However, a topical drug with no systemic absorption may have a safety database between 500

  6. 349  and 1,000 subjects.

350

  1. 351  Sponsors should provide a toxicity grading scheme for clinical trials. Commonly used schemata

  2. 352  can be used (e.g., AIDS Clinical Trials Group, National Cancer Institute, or World Health

  3. 353  Organization), with the understanding that toxicities with a relatively low grade assignment may

  4. 354  be less acceptable in healthy populations commonly enrolled in RHL clinical trials compared to

  5. 355  populations in clinical trials of drugs for diseases such as cancer or human immunodeficiency

  6. 356  virus.

357
358
4. 359
360
361

  1. 362  Study designs appropriate for the study of the treatment or prevention of RHL can be found

  2. 363  below:

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385

Specific Efficacy Trial Considerations

a. Study design

Treatment trials

To date, the most successful applications for a treatment indication of RHL have included double-blinded, placebo-controlled trials that focused on early treatment intervention by prospectively dispensing the investigational drug (or placebo) for subject-initiated treatment at the first sign or symptom of a recurrent episode. Given the self-limited nature of RHL, such placebo-controlled superiority trials are considered the most direct route to providing evidence of efficacy.

Noninferiority trials have not been considered feasible for an RHL treatment indication because of the modest and variable treatment effects observed to date with available treatments (1/2 day difference in the duration of episode endpoint). Expected outcomes cannot be predicted well enough to support an adequate noninferiority margin.

In addition to placebo-controlled trials, superiority trials against an active control (i.e., an approved antiviral drug for RHL) could also be considered. A single-arm, open-label trial design is not considered appropriate for a treatment indication.

Duration of treatment depends on the formulation under study and can range from single to multiple doses.

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389

398 III.C.4.e., Special populations, for discussion of pediatric and adolescent subjects. 399
400 c. Inclusion and exclusion criteria
401

  1. 402  Generally, trials to assess the treatment (or prevention) of RHL should be conducted in a

  2. 403  population of subjects highly experienced with the disease under study. This enables subjects to

  3. 404  rapidly identify recurrences and to self-initiate treatment as soon as possible during the prodrome

Currently no drug is approved for the prevention of RHL; therefore, a trial for this indication should be a placebo-controlled superiority trial. A placebo-controlled trial is considered feasible given the self-limited nature of RHL. Similar to trials designed for a treatment indication, a single-arm, open-label trial design is not considered an appropriate alternative for evaluating prevention of RHL.

390
391
392
393
394
395
  1. 396  As mentioned above, RHL affects a substantial percentage of the U.S. population. Phase 3 trials

  2. 397  should focus on RHL in healthy immunocompetent adults and adolescents. See section

405 phase. 406
407
408

409
410
411
412
413
414
415

  1. 416  Note: Culture or serologic documentation is not needed for the RHL indication. The diagnosis

  2. 417  is a clinical one based on previous history of recurrences. However, HSV-1 and HSV-2 could

  3. 418  respond differently to an investigational drug product, which could affect efficacy results (see

  4. 419  section III.C.4.l., Clinical virology considerations, for further discussion).

420

  1. 421  Subjects who have received even one dose of any treatment active against HSV (current episode)

  2. 422  should be excluded. This includes both nonprescription as well as prescription medications.

423

  1. 424  Also subjects should be excluded if they have evidence of active malignancy or

  2. 425  immunodeficiency disease, require chronic use of immunosuppressive drugs (e.g., systemic

  3. 426  steroids) or topical steroids, or chronically use antiviral medication with activity against HSV.

  4. 427  Subjects who cannot be reliably expected to comprehend or satisfactorily assess a herpetic

  5. 428  lesion, who have abnormal skin conditions (e.g., acne, eczema, rosacea, psoriasis, albinism, or

  6. 429  chronic vesiculo-bullous disorders) that occur in the area ordinarily affected by RHL, or who

  7. 430  have had a vaccine for HSV-1 (typically oral herpes) or HSV-2 (typically genital herpes) should

  8. 431  also be excluded.

The inclusion criteria should specify:

Enrollment of experienced subjects with a history of at least 4 episodes of RHL in the previous 12-month period

At least half of these episodes should be vesicular in nature
At least half of the episodes should be preceded by prodromal symptoms Immunocompetent subjects

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432
433 d. Randomization, stratification, and blinding 434

  1. 435  It is important for sponsors to consider double-blinding, if possible, given the self-limited nature

  2. 436  of RHL and the subjectivity of a number of the endpoints, such as time to pain resolution, or

  3. 437  symptom improvement.

438
439 e. Special populations
440
441 Special populations in which RHL can be studied are listed below: 442
443
Pediatrics
444

  1. 445  Decisions regarding pediatric development may vary depending on various issues

  2. 446  including, but not limited to, formulation and safety profile. Therefore, sponsors are

  3. 447  encouraged to begin discussions about their pediatric formulation and clinical

  4. 448  development plan early because sponsors are required to submit pediatric study plans

  5. 449  under the Pediatric Research Equity Act (PREA).9 The following discussion is based on

  6. 450  situations where the antiviral drug is expected to act similarly in adults and pediatric

  7. 451  patients. Other situations should be discussed with the FDA on a case-by-case basis.

452

  1. 453  Because the course and pathophysiology of RHL is similar in adults and pediatric

  2. 454  patients (ages 6 to younger than 18 years), and the effect of the antiviral drug product is

  3. 455  expected to be the same in adults and children, extrapolation of efficacy from adults to

  4. 456  children is generally acceptable. In this situation, pharmacokinetic (if systemically

  5. 457  absorbed) and safety studies may be considered adequate to extend the indications to

  6. 458  these pediatric age groups.

459

  1. 460  The annual prevalence of RHL in children from 8 to 11 years has been estimated to be 12

  2. 461  percent in some studies. The annual prevalence of RHL in adolescents between 12 and

  3. 462  17 years of age has been estimated to be 17 percent in some studies. Therefore, studies in

  4. 463  the pediatric population are required under PREA.10 Herpes labialis in children younger

  5. 464  than 6 years of age is generally a primary infection, and not recurrent in nature (Rioboo­

  6. 465  Crespo Mdel R, Planells-del Pozo P, et al. 2005; Arduino, Porter, et al. 2008). Therefore,

  7. 466  a partial waiver to conduct studies in subjects younger than 6 years of age generally will

  8. 467  be granted. Pediatric studies should evaluate subjects aged 6 to 17 years as described

  9. 468  below:

469

9 See PREA (Public Law 108-155; section 505B(e)(2)(A) of the Federal Food, Drug, and Cosmetic Act (FD&C Act); 21 U.S.C. 355B) as amended by the Food and Drug Administration Safety and Innovation Act (FDASIA) (Public Law 112-144). See also 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 the FDA’s current thinking on this topic.

10 See PREA (Public Law 108-155; section 505B(e)(2)(A) of the FD&C Act; 21 U.S.C. 355B) as amended by FDASIA (Public Law 112-144).

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Antiviral drugs with favorable risk-benefit assessment should be evaluated in pediatric patients aged 6 to 11 years. A minimum of 50 pediatric patients (aged 6 to 11 years) should be studied to adequately characterize dosing and safety of the drug product.

Antiviral drugs with favorable risk-benefit assessment should be evaluated in adolescent subjects aged 12 to younger than 18 years. A minimum of 50 adolescent subjects (subjects aged 12 to younger than 18 years) should be studied to adequately characterize dosing and safety of the drug product.

Other special populations

The determination of the efficacy and safety of the treatment under study in other special populations should be discussed with the DAVP. The route of administration and the degree of systemic absorption for a topical drug product will be factors in determining the need for further assessment.

f. Dose selection

482
483
484
485
486
487
488
  1. 489  Animal studies and human dose-ranging trials can contribute to dose selection for phase 3

  2. 490  clinical trials. Exposure-response relationships can be used to help guide dose selection.

  3. 491  Various pharmacodynamic parameters, such as those relating to viral clearance and healing time,

  4. 492  should be explored. As previously noted, sponsors should conduct adequate phase 2 trials before

  5. 493  designing the phase 3 trials.

494

  1. 495  For some drugs, more than one route of administration can be considered. Different dosing,

  2. 496  safety, and efficacy issues may arise with different routes of administration. For example,

  3. 497  certain drugs may be available for both oral and topical use and appropriate dosing should be

  4. 498  established for both routes.

499
500 g. Choice of comparators 501

  1. 502  RHL is a self-limited disease. Therefore, a placebo comparator arm is considered ethical and

  2. 503  most appropriate in a superiority trial design for either the treatment or the prevention indication.

  3. 504  Other approved treatments for RHL also can be used as comparators in a superiority trial for the

  4. 505  treatment indication.

506
507 h. Efficacy endpoints
508
509 Efficacy endpoints for both the treatment and prevention indications are discussed below: 510
511

512
513
514
515

For the treatment indication

The DOE endpoint provides the most accurate assessment of the effectiveness of RHL treatments to date because it measures the effect of the treatment under study on the full spectrum of the RHL episode (i.e., all stages of lesion evolution).

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516

  1. 517  DOE is defined as the time from treatment initiation to the healing of primary lesions

  2. 518  (loss of crust) for subjects who experienced a vesicular lesion. For subjects whose

  3. 519  primary lesions were not vesicular in nature, DOE is the time from the treatment

  4. 520  initiation to the return to normal skin or to the cessation of symptoms, whichever occurs

  5. 521  last.

522
523 524
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531
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533 534
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539 540
541
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558

For the DOE endpoint, the protocol should provide:

How often the acute episodes will be assessed

Daily investigator follow-up during the acute episodes until complete healing has occurred

Subject diary where subjects can record their lesion status at least twice daily, so that time of assessment and lesion or disease status can be accurately documented

For the DOE endpoint, the mean and median values should be provided. A study evaluating treatment of RHL should show clinically meaningful as well as statistically significant results to make a claim of decreased episode duration. A clinically meaningful difference in DOE has been determined to be a difference between treatment arms of at least 1/2 day for both mean and median values.

Secondary endpoints can include:

Investigator-assessed prevention of progression to a classical lesion (aborted lesions)

  • Subject-assessed duration of lesion pain

  • Subject-assessed severity of lesion pain

  • The incidence of recurrence and time to recurrence following treatment

For labeling claims based on secondary endpoints, the results should be clinically meaningful and statistically significant. A testing strategy should be included a priori in the protocol and statistical analysis plan (SAP) to control the overall type I error rate.

Note: For incidence of recurrence, all enrolled subjects should continue to be followed for the prespecified time period and the follow-up population should be defined a priori.

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For the prevention indication

The recommended primary endpoint should be either the number of confirmed recurrences observed in subjects on suppressive therapy over a 12-month period or the time to first recurrence defined as the time from randomization until the onset of an episode of RHL. It should be stressed that for this indication the duration of observation is paramount. Shorter observation periods, such as 6 months, may be inadequate to collect an appropriate amount of clinically meaningful events.

563
564
565
566
567
568
569
  1. 570  Enrolled and randomized subjects should be provided with study treatment and directions to start

  2. 571  treatment as soon as possible after the appearance of their prodromal symptoms.

i. Study procedures and timing of assessments

572

  1. 573  Of primary importance for the treatment indication is the frequency of clinical assessments and

  2. 574  by whom assessments are made. For the treatment indication, subjects should be assessed by the

  3. 575  investigator within 12 to 24 hours of the start of the prodromal symptoms and treatment initiation

  4. 576  (self-initiation) and then observed daily thereafter (or as often as possible) by the investigator or

  5. 577  a subinvestigator until healing of the primary vesicular lesion or return to normal skin for those

  6. 578  subjects without a vesicular lesion. In addition, subjects should be provided with a subject diary

  7. 579  in which they should record, at a minimum of twice daily, their symptoms, such as pain,

  8. 580  tenderness, tingling, itching, and discomfort and the stage of their herpes lesions (e.g., normal

  9. 581  lip, erythema, papule, vesicle, ulcer, crust).

582

  1. 583  For the prevention indication, subjects should be assessed within 24 to 48 hours of the

  2. 584  development of prodromal symptoms or an active lesion. Consideration should be given to the

  3. 585  treatment of such subjects. One option is to continue the drug under study and to assess the

  4. 586  duration of episode as well as other secondary endpoints. The treatment of subjects who develop

  5. 587  a recurrence should be discussed with the DAVP at the time of protocol development.

588
589 j. Endpoint adjudication 590

  1. 591  Generally, the drug development of RHL treatment has been straightforward with a well-defined

  2. 592  primary endpoint and it is unlikely that adjudication will be necessary. The same is expected for

  3. 593  the prevention indication.

594
595 k. Statistical considerations 596

  1. 597  Sponsors should provide a protocol with a detailed SAP stating the trial hypotheses and the

  2. 598  analysis methods before trial initiation.

599
600
601
602
603
604

Treatment studies

The primary endpoint in RHL treatment studies in adults should be the decrease in DOE. The primary efficacy analysis should be based on the differences in the time to DOE among groups, and appropriate statistical methods for event-time data should be

14

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employed. Both the mean and median DOE should be assessed. Minimizing missing data is paramount, and there should be an explicit plan to handle missing data. A strategy should be included a priori in the SAP to control the overall type I error rate for any secondary endpoints that may form the basis of labeling claims.

The primary efficacy analysis should be performed on the intent-to-treat (ITT) population defined as all randomized subjects who initiated treatment. Safety analyses should be conducted on all randomized subjects. It should be noted that all subjects with RHL should be assessed and not only those subjects who develop vesicular lesions.

Prevention studies

617
618
619
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621
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623
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629
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633
  1. 634  HSV-1 and HSV-2 have distinct viral proteins and may exhibit differential responses to an

  2. 635  investigational drug, which could affect efficacy results in clinical trials if the drug is only

  3. 636  effective against one type of HSV and the clinical study population was infected with both types.

  4. 637  Therefore, sponsors may want to consider determining the type of HSV infection present at

In prevention studies the primary endpoint should be either the number of confirmed recurrences observed in subjects on suppressive therapy over a 12-month period or the time to first recurrence defined as the time from randomization until the onset of an episode of RHL. However, as noted in section III.C.2.b, Prevention indication, it is strongly recommended that the number of recurrences over a 12-month period be provided.

Minimizing missing data is important, and investigators should be diligent in obtaining the final status of subjects either on or off the assigned treatment, either in the study or if terminated from the study. The primary analysis should be performed on the ITT population and all subjects lost to follow-up/missing and drop outs should be considered to have had a recurrence (i.e., a treatment failure). Appropriate sensitivity analyses should be performed to assess the robustness of the results to the strategy for handling missing data.

l. Clinical virology considerations

  1. 638  baseline to determine if the investigational drug exhibits antiviral activity against both HSV

  2. 639  types. The assay used to genotype the HSV type in enrolled subjects should be included with the

  3. 640  clinical trial protocol and the performance characteristics of the assay provided. However, the

  4. 641  diagnosis of RHL is clinical; therefore, virologic confirmatory studies are not considered

  5. 642  mandatory.

643

  1. 644  In general, the HSV-1 or HSV-2 present in recurrent lesions is not likely to persist at the site of

  2. 645  the lesion in a latent state; therefore, resistance analysis of virus from immunocompetent subjects

  3. 646  is considered optional. Sponsors may want to consider performing resistance analysis in a subset

  4. 647  of subjects who failed treatment (failure of lesions to heal) to determine if baseline or emergent

  5. 648  substitutions that occur in the targeted genome region correlate with resistance.

649

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  1. 650  For resistance analyses, any changes, including mixtures, in the amino acid sequence of the

  2. 651  target protein present in on-treatment or follow-up samples, but not in the baseline sample, can

  3. 652  be reported as having developed during therapy. In addition, baseline samples should be

  4. 653  analyzed to identify HSV genetic polymorphisms that are associated with differential antiviral

  5. 654  activity against the investigational drug. The DAVP should be consulted for the most current

  6. 655  format for submission of resistance data.

656

  1. 657  For virologic assessments in clinical trials, the use of FDA-approved assays, when available, and

  2. 658  a central laboratory are recommended. Sponsors can collect results from local lab tests,

  3. 659  identifying the assay(s) used. If investigational assay(s) are used, performance characteristics

  4. 660  with geographically and temporally distinct isolates should be provided.

661
662 m. Accelerated approval (subpart H) considerations 663

  1. 664  The regulations in 21 CFR part 314, subpart H (accelerated approval based on a surrogate

  2. 665  endpoint considered reasonably likely to predict clinical benefit in subjects with a serious or life­

  3. 666  threatening disease), have not been used for approval of antivirals used to treat RHL, and are

  4. 667  unlikely to be appropriate in most instances, because RHL is not considered a serious or life­

  5. 668  threatening disease.

669
670 n. Risk-benefitconsiderations 671

  1. 672  The overall risk-benefit assessment should be considered in the context of disease, which in this

  2. 673  case is a nonserious and self-limited condition. RHL in immunocompetent individuals is also

  3. 674  not associated with life-threatening complications and several approved antivirals are available

  4. 675  for treatment. For the treatment indication, clinically meaningful benefits should outweigh

  5. 676  toxicity risks. As discussed previously, demonstrating large efficacy improvements over

  6. 677  currently approved drugs is challenging. A favorable safety and tolerability profile is critical for

  7. 678  the target population. In addition, other advantages over current standard of care, such as shorter

  8. 679  duration dosing, or convenient administration resulting in improved adherence are considerations

  9. 680  in the overall assessment.

681

  1. 682  Likewise for the prevention indication, a favorable drug safety profile is critical because the

  2. 683  target population consists of immunocompetent individuals with a relatively benign recurrent

  3. 684  condition. For a chronic suppressive drug, safety with cumulative or chronic dosing should be

  4. 685  emphasized. Because there are no approved drugs for prevention of RHL, the overall assessment

  5. 686  should rely on the level of clinical benefit the drug offers in reducing the frequency of

  6. 687  recurrences or the recurrence-free period.

688
689
D. Other Considerations
690
691
1. Risk Management Considerations 692

  1. 693  Given the self-limited nature of RHL, risk minimization strategies usually are not considered

  2. 694  necessary.

695

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696 2. Relevant Nonclinical Safety Considerations 697

  1. 698  In general, it is anticipated that the nonclinical toxicology studies for drugs active against RHL

  2. 699  will be similar to studies for other antimicrobial drugs. One question that can be asked is

  3. 700  whether animal toxicology data to support chronic administration are needed. Although RHL

  4. 701  treatment is usually for 5 to 10 days, the possibility of multiple courses of treatment or long-term

  5. 702  prevention should be taken into account in determining the nature and duration of nonclinical

  6. 703  safety studies.

704

  1. 705  For instance, if the indication for a drug is treatment of RHL, long-term carcinogenicity studies

  2. 706  in rodents usually are not needed. If, on the other hand, the drug is indicated for the prevention

  3. 707  of RHL, carcinogenicity studies in rats and mice as well as 6-month toxicology studies in a

  4. 708  rodent and a nonrodent species should be conducted before approval. Longer duration studies

  5. 709  may be needed when the duration of life time exposures to drugs used frequently in an

  6. 710  intermittent manner in the treatment and prevention of chronic or recurrent conditions generally

  7. 711  exceed 6 months. The ICH guidance for industry S1A The Need for Long-Term Rodent

  8. 712 Carcinogenicity Studies of Pharmaceuticals provides detailed information concerning the

  9. 713  conditions under which carcinogenicity studies should be conducted. The sponsor should also

  10. 714  refer to the ICH guidance for industry M3(R2) Nonclinical Safety Studies for the Conduct of

  11. 715 Human Clinical Trials and Marketing Authorization for Pharmaceuticals when designing its

  12. 716  studies.

717
718
3. Pharmacokinetic/PharmacodynamicConsiderations 719

  1. 720  Various administration routes have been considered for RHL drugs: oral, topical, and buccal.

  2. 721  For oral administration, plasma drug concentrations are presumed to be correlated with

  3. 722  concentrations at the site of action, although prediction of clinical effect cannot be assumed.

  4. 723  However, for topical and buccal administration, drug concentrations at the dermal layer of the

  5. 724  skin may better correlate with the antiviral activity. Generally, comparing concentrations in a

  6. 725  targeted organ to cell culture EC50 values or antiviral activity data from animals with similar

  7. 726  concentrations in a targeted organ may help select doses for initial clinical trials.

727

  1. 728  Clinical endpoints can be used as response metrics in the exposure-response evaluations. For

  2. 729  prevention trials, the clinical endpoint should be used. Relationships between each of these

  3. 730  assessments and the principal efficacy endpoints should be assessed based on all available data.

731

  1. 732  Any drug exposure-related toxicity should be explored to assess the relationship between drug

  2. 733  concentration and the adverse event, to identify the highest tolerable dose, and to determine the

  3. 734  probability of an adverse event with a given drug exposure. This information can also guide

  4. 735  dose adjustments for specific populations and drug interactions.

736
737
4. CMCConsiderations 738

  1. 739  We anticipate that the chemistry, manufacturing, and controls (CMC) data for RHL drugs will be

  2. 740  comparable to the CMC data for other drugs with similar uses and administration.

741

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742 5. Labeling Considerations 743

744 745

There are no specific labeling considerations for the RHL indications.

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746 REFERENCES 747

  1. 748  Arduino PG and Porter SR, 2006, Oral and Perioral Herpes Simplex Virus Type 1 (HSV-1)

  2. 749  Infection: Review of Its Management, Oral Dis., May;12(3):254-70.

750

  1. 751  Arduino PG and Porter SR, 2008, Herpes Simplex Virus Type 1 Infection: Overview on

  2. 752  Relevant Clinico-Pathological Features, J Oral Pathol Med, 37:107-21.

753

  1. 754  Arnold JJ, Sharma SD, Feng JY, Ray AS, Smidansky ED et al., 2012, Sensitivity of

  2. 755  Mitochondrial Transcription and Resistance of RNA Polymerase II Dependent Nuclear

  3. 756  Transcription to Antiviral Ribonucleosides, PLoS Pathog, 8(11):e1003030.

757

  1. 758  Bader C, Crumpacker CS, Schnipper LE et al., 1978, The Natural History of Recurrent Facial­

  2. 759  Oral Infection With Herpes Simplex Virus, J. Infect. Dis., 138:897-905.

760

  1. 761  Bradley H, Markowitz LE, Gibson T, and McQuillan GM, 2014, Seroprevalence of Herpes

  2. 762  Simplex Virus Types 1 and 2 — United States, 1999-2010, J Infect Dis., 209(3):325-33.

763

  1. 764  Cunningham A, Griffiths P, Leonec P, Mindeld A, Patel R, Stanberry L, and Whitley R, 2012,

  2. 765  Current Management and Recommendations for Access to Antiviral Therapy of Herpes Labialis,

  3. 766  Journal of Clinical Virology, 53:6-11.

767

  1. 768  Harmenberg J, Öberg B, and Spruance S, 2010, Prevention of Ulcerative Lesions by Episodic

  2. 769  Treatment of Recurrent Herpes Labialis: A Literature Review, Acta Derm Venereol, 90:122­

  3. 770  130.

771

  1. 772  Lisco A, Vanpouille C, Tchesnokov EP, Grivel JC, Biancotto A, Brichacek B, Elliott J,

  2. 773  Fromentin E, Shattock R, Anton P, Gorelick R, Balzarini J, McGuigan C, Derudas M, Götte M,

  3. 774  Schinazi RF, and Margolis L, 2008, Acyclovir Is Activated Into a HIV-1 Reverse Transcriptase

  4. 775  Inhibitor in Herpesvirus-Infected Human Tissues, Cell Host Microbe, 4(3):260-270.

776

  1. 777  Lowhagen GB, Bonde E, Eriksson B, Nordin L, Tunback P, and Krantz I, 2002, Self-Reported

  2. 778  Herpes Labialis in a Swedish Population, Scand. J. Infect. Dis., 34:664-667.

779

  1. 780  Marroquin LD, Hynes J, Dykens JA, Jamieson JD, and Will Y, 2007, Circumventing the

  2. 781  Crabtree Effect: Replacing Media Glucose With Galactose Increases Susceptibility of HepG2

  3. 782  Cells to Mitochondrial Toxicants, Toxicol. Sci., 97(2):539-547.

783

  1. 784  McMahon MA, Siliciano JD, Lai J, Liu JO, Stivers JT, Siliciano RF, and Kohli RM, 2008, The

  2. 785  Antiherpetic Drug Acyclovir Inhibits HIV Replication and Selects the V75I Reverse

  3. 786  Transcriptase Multidrug Resistance Mutation, J Biol Chem., 283(46):31289-31293.

787

  1. 788  Rioboo-Crespo Mdel R, Planells-del Pozo P, and Rioboo-García R, 2005, Epidemiology of the

  2. 789  Most Common Oral Mucosal Diseases in Children, J Med Oral Patol Oral Cir Bucal, Nov­

  3. 790  Dec;10(5):376-87.

791

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Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 792  Spruance SL, Overall Jr JC, Kern ER, Krueger GG, Pliam V, and Miller W, 1977, The Natural

  2. 793  History of Recurrent Herpes Simplex Labialis: Implications for Antiviral Therapy, N Engl J

  3. 794  Med, 297:69-75.

795

  1. 796  Tachedjian G, Hooker DJ, Gurusinghe AD, Bazmi H, Deacon NJ, Mellors J, Birch C, and Mills

  2. 797  J, 1995, Characterisation of Foscarnet-Resistant Strains of Human Immunodeficiency Virus

  3. 798  Type 1, Virology, 212(1):58-68.

799

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Vulvovaginal Candidiasis: Developing Drugs for Treatment Guidance for Industry

Vulvovaginal

Candidiasis: 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 Shrimant Mishra, MD, 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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15051dft.doc 06/28/16

Vulvovaginal

Candidiasis: 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............................................................................................................................5 Trial Procedures and Timing of Assessments ..................................................................................5

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

Analysis populations..................................................................................................................6

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

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

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

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 1 Vulvovaginal Candidiasis:

  2. 2 Developing Drugs for Treatment

  3. 3 Guidance for Industry1

4 5 6

7 8 9

10 11 12 13

14
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17
I. INTRODUCTION 18

  1. 19  The purpose of this guidance is to assist sponsors in the overall clinical development program

  2. 20  and clinical trial designs to support drugs for the treatment of vulvovaginal candidiasis (VVC).2

  3. 21  This draft guidance is intended to serve as a focus for continued discussions among the Division

  4. 22  of Anti-Infective Products, pharmaceutical sponsors, the academic community, and the public.3

23

  1. 24  In general, this guidance focuses only on developing antifungal drugs for the treatment of

  2. 25  uncomplicated VVC, generally defined as a single episode of vaginal inflammation caused by

  3. 26 Candida yeast in an otherwise healthy female. For complicated VVC (e.g., patients who have

  4. 27  recurrent VVC, defined as having four or more episodes of VVC in a 1-year time frame), the

  5. 28  dose, duration, or formulation of antifungal treatment may be different in comparison to

  6. 29  uncomplicated VVC. Sponsors should discuss with FDA the clinical development programs for

  7. 30  treatment of complicated VVC.

31

  1. 32  This guidance does not discuss trial designs for development programs for nonprescription

  2. 33  treatments of VVC. This guidance also does not contain discussion of general issues in drug

  3. 34  development or general issues of statistical analysis or clinical trial design. Those topics are

    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 VVC.

page4image22432

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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Contains Nonbinding Recommendations

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  1. 35  addressed in the ICH guidances for industry E9 Statistical Principles for Clinical Trials and E10

  2. 36 Choice of Control Group and Related Issues in Clinical Trials, respectively.4

37

  1. 38  In general, FDA’s guidance documents do not establish legally enforceable responsibilities.

  2. 39  Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only

  3. 40  as recommendations, unless specific regulatory or statutory requirements are cited. The use of

  4. 41  the word should in Agency guidances means that something is suggested or recommended, but

  5. 42  not required.

43
44
45
II. 46
47
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49
50

  1. 51  Sponsors should enroll postmenarchal females with a clinical diagnosis of uncomplicated VVC.

  2. 52  Sponsors should discuss with FDA if the trial population plans to include patients who have

  3. 53  HIV/AIDS or diabetes mellitus.

54
55
2. Efficacy Considerations 56

  1. 57  In general, two adequate and well-controlled trials are recommended for the demonstration of

  2. 58  efficacy (see 21 CFR 314.126). If the drug is being developed for other infectious disease

  3. 59  indications, sponsors should discuss with FDA the potential situations in which one trial would

  4. 60  provide evidence of effectiveness, supported by evidence of effectiveness for the other infectious

  5. 61  disease indications.5

62
63
3. Safety Considerations 64

  1. 65  The recommended size of the safety database depends on whether the drug is administered

  2. 66  systemically or topically, and the level of systemic absorption. If the same therapy for treatment

  3. 67  of VVC were used in clinical trials for other infectious disease indications, the safety information

  4. 68  from those clinical trials typically can be included in the overall preapproval safety database.

  5. 69  Sponsors should discuss the appropriate size of the preapproval safety database with FDA during

  6. 70  clinical development.

71

  1. 72  For drugs administered topically, human safety evaluations should focus on local toxicities of the

  2. 73  cervicovaginal area in addition to systemic toxicities.

74

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.

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

DEVELOPMENT PROGRAM
A. General Considerations
1. Drug Development Population

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Contains Nonbinding Recommendations

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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, using a superiority design.

2. Clinical Microbiology Considerations

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

Specimens collected to aid in the diagnosis of VVC should be examined microscopically for the presence of yeast (e.g., a wet mount prepared in a potassium hydroxide solution (KOH)), and should be cultured using standard fungal media.7 Yeast grown in culture should be identified to species level and tested for susceptibility to appropriate antifungal drugs, using standard methods such as those recommended by the Clinical and Laboratory Standards Institute (CLSI).8

3. Enrollment Criteria

Inclusion criteria for VVC trials should include postmenarchal females who have a clinical diagnosis of VVC, defined as having a white or creamy vaginal discharge plus the following findings:

Two or more of the following signs and symptoms of VVC that are characterized as moderate or severe: itching, burning, irritation, edema, redness, or excoriation9

KOH or saline preparation from the inflamed vaginal mucosa or secretions revealing yeast forms (hyphae or pseudohyphae) or budding yeasts

Normal vaginal pH (greater than or equal to 4.5)
6 See, for example, the American Society for Microbiology, 2010, Clinical Microbiology Procedures Handbook, 3rd

Edition.

7 Clinical and Laboratory Standards Institute (CLSI), 2008, Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard — Third Edition, CLSI document M27-A3, Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898, USA.

8 CLSI, 2012, Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Fourth Informational Supplement, CLSI document M27-S4, Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.

9 There should be at least two signs or symptoms are of at least moderate severity. Signs and symptoms can be rated on a scale and evaluated using a score based on a numerical rating of severity (absent=0; mild=1; moderate=2; severe=3) for each symptom. The purpose of the qualitative evaluation of signs and symptoms at baseline is to establish a patient population with sufficient severity of uncomplicated VVC for trial enrollment. See the guidance for industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims.

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Contains Nonbinding Recommendations

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106
107 The following patients should be excluded from VVC trials: 108
109

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113

114
115

116
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118

  1. 119  Eligible patients should be randomized to treatment groups at enrollment. All trials should be

  2. 120  multicenter and double-blinded to control for potential biases.

121
122
5. Specific Populations 123

  1. 124  The trials should include patients of all races, as well as geriatric patients.10 Patients with renal

  2. 125  or hepatic impairment can be enrolled if appropriate dosing regimens have been defined.

126

  1. 127  Sponsors are encouraged to begin discussions about their pediatric clinical development plan as

  2. 128  early as is feasible because pediatric studies are a required part of the overall drug development

  3. 129  program and sponsors are required to submit pediatric study plans no later than 60 days after an

  4. 130  end-of-phase 2 meeting or such other time as may be agreed upon by FDA and the sponsor.11

  5. 131  Uncomplicated VVC is unlikely to occur in healthy premenarchal girls. Postmenarchal

  6. 132  adolescent girls with VVC should be included in phase 3 trials, if appropriate. Inclusion of

  7. 133  adolescents in phase 3 trials is capable of fulfilling the required pediatric clinical development

  8. 134  plans.

135

  1. 136  In general, safe and effective treatments are available for pregnant patients with VVC.

  2. 137  Therefore, it is generally acceptable to complete phase 3 clinical trials that establish safety and

  3. 138  efficacy in nonpregnant patients before trials in pregnant patients are initiated. However, if

  4. 139  current effective therapy is unavailable, such as a pregnant patient who is allergic to all available

  5. 140  drugs for treatment of VVC, it may be appropriate to offer the investigational drug in the

  6. 141  pregnant patient. Before sponsors consider use of an investigational drug in pregnant women,

  7. 142  nonclinical toxicology studies, reproductive and developmental toxicology studies, and phase 1

  8. 143  and phase 2 clinical trials should be completed. Infants born to mothers who received the

    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.

    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.

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

Patients who were treated for VVC within the past month
Patients who are currently receiving antifungal therapy unrelated to VVC
4. Randomization and Blinding

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Contains Nonbinding Recommendations

Draft — Not for Implementation

investigational drug should be followed for an appropriate period of time based on available nonclinical and clinical data.

6. DoseSelection

Sponsors should integrate findings from nonclinical studies, pharmacokinetics, and safety information from earlier stages of clinical development to select the dose or doses to be evaluated in phase 3 clinical trials. The pharmacokinetics of the drug in specific populations (e.g., adolescent patients, patients with renal or hepatic impairment) should be understood before initiation of phase 3 trials to determine whether dose adjustments are necessary. This evaluation may prevent the exclusion of such patients from the phase 3 clinical trials.

7. Choice of Comparators

For most superiority trials, the control group for VVC should be an oral placebo or a vehicle control for a drug administered topically. The vehicle control should not influence the safety or efficacy evaluations (e.g., the vehicle control should not cause irritation and should not have an antifungal effect). Appropriate active comparators can be used as a control provided superiority is demonstrated.

8. Efficacy Endpoints

The primary efficacy endpoint should be clinical cure, defined as the absence of all signs and symptoms of VVC.

Sponsors should consider the following secondary endpoints:

Vaginal swab culture negative for growth of Candida species

Responder outcome, defined as absence of signs and symptoms plus vaginal swab culture negative for growth of Candida species

9. Trial Procedures and Timing of Assessments

The following bullet 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 safety laboratory tests (including pregnancy testing) should be collected at this visit; patients should be randomized and receive the investigational drug or control treatment at this visit.

On-therapy assessment: Telephone calls or diary card entries should be used to assess for adverse effects.

5

Contains Nonbinding Recommendations

Draft — Not for Implementation

Test-of-cure visit, approximately 7 to 14 days after randomization: This visit should assess the primary efficacy endpoint. Adverse effect information and, if appropriate, safety laboratory tests should also be collected. The timing of this visit depends on the total duration of antifungal therapy.

193
194
195
196
197

  1. 198  A patient diary is recommended for the collection of information regarding investigational drug

  2. 199  administration, assessment of symptoms, and adverse events. Patients who have continued or

  3. 200  worsening symptoms before the test-of-cure visit can be assigned as a treatment failure and

  4. 201  offered rescue therapy for VVC.

202
203
10. Statistical Considerations 204

  1. 205  In general, a detailed statistical analysis plan stating the trial hypotheses and the analysis

  2. 206  methods should be submitted before trial initiation. The primary efficacy analysis should be

  3. 207  based on a comparison of the proportions of patients achieving a successful efficacy outcome.

208
209 a. Analysispopulations
210
211 Sponsors should consider the following definitions of analysis populations: 212
213

214
215
216

217
218

219
220
221

222
223
224
225

  1. 226  The mITT population should be considered the primary analysis population. In general,

  2. 227  sponsors should not consider analyses of the per-protocol populations as primary because

  3. 228  postrandomization events or characteristics could potentially bias results in this population.

  4. 229  However, consistency of the results should be evaluated in all patient populations. Every attempt

  5. 230  should be made to limit the loss of patients from the trial. The method for handling missing data

  6. 231  should be specified in the protocol.

232

189 190
191
192

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.

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 who have Candida species isolated on culture of vaginal specimen at baseline

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)

6

Contains Nonbinding Recommendations

Draft — Not for Implementation

233 b. Sample size 234

  1. 235  The sample size is influenced by several factors including the prespecified type I and type II

  2. 236  error, the expected success rate, and the amount by which the investigational drug is expected to

  3. 237  be superior to the control. A two-sided type I error rate of 0.05 and a type II error rate between

  4. 238  0.10 and 0.20 are usually specified. Expected success rates are typically based upon results

  5. 239  obtained in phase 2 trials or other information.

240
241
C. Other Considerations 242
243
1. Ethical Considerations 244

  1. 245  Rescue therapy can be incorporated into the placebo-controlled trial design so that individual

  2. 246  patients are treated at the time a failure outcome is assigned: this may serve to mitigate ethical

  3. 247  concerns regarding inclusion of a placebo group in a trial. All trials should provide appropriate

  4. 248  provisions for patient safety.

249
250
2. Relevant Nonclinical Considerations 251

  1. 252  Investigational drugs being studied for VVC should have nonclinical data documenting activity

  2. 253  against Candida species. Guidance for industry provides information for sponsors on nonclinical

  3. 254  considerations for drug development in general and also nonclinical considerations for drugs

  4. 255  administered topically.12

256
257
3. Pharmacokinetic/PharmacodynamicConsiderations 258

  1. 259  Pharmacokinetic/pharmacodynamic approaches typically used to identify appropriate dosing

  2. 260  regimens for evaluation in phase 2 and phase 3 clinical trials for systemic infections may not be

  3. 261  appropriate for drugs used for the treatment of VVC. However, the following pharmacokinetic

  4. 262  evaluations should be considered.

263

  1. 264  For a drug administered topically into the vagina and/or the area surrounding the vagina, it is

  2. 265  important to determine systemic drug exposure as part of the safety assessment. Evaluation of

  3. 266  systemic exposure following topical vaginal administration can be performed in females with

  4. 267  VVC or in healthy females without VVC because it is deemed that the extent of systemic drug

  5. 268  absorption is not related to the presence or absence of VVC.

269

12 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; and, given the unique characteristics of a topical administration, sponsors of a topical drug may want to refer to the discussions of nonclinical safety evaluations in 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. See also the guidance for industry Vaginal Microbicides: Development for the Prevention of HIV Infection on the Clinical/Antimicrobial guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064980.htm.

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Contains Nonbinding Recommendations

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  1. 270  For a drug administered systemically for treatment of VVC (e.g., oral), the systemic/vaginal

  2. 271  exposure and other relevant clinical pharmacology aspects of the drug (e.g., drug-drug

  3. 272  interactions, QT prolongation,13 dosage adjustment in renal and/or hepatic impairment, food

  4. 273  effect) should be adequately characterized. Sponsors should discuss with FDA the need to

  5. 274  evaluate pertinent drug-drug interactions, particularly with oral contraceptives. In addition,

  6. 275  dose-ranging studies in VVC patients can be considered as an option in the early stages of

  7. 276  development to help determine an adequate dosage regimen to bring forth in later trials.

277

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

8

 

Elemental Impurities in Drug Products Guidance for Industry

Elemental Impurities in

Drug Products 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) John Kauffman 314–539–2168, or (CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010.

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

June 2016 Pharmaceutical Quality/CMC

page1image9536 page1image9696

Elemental Impurities in

Drug Products 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 and/or
Office of Communication, Outreach and Development
Center for Biologics Evaluation and Research

Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, Room 3128
Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010
Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it
http://www.fda.gov/BiologicsBloodVaccines/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) Center for Biologics Evaluation and Research (CBER)

June 2016 Pharmaceutical Quality/CMC

 

Contains Nonbinding Recommendations

Draft — Not for Implementation

TABLE OF CONTENTS

  1. INTRODUCTION............................................................................................................. 1

  2. BACKGROUND ............................................................................................................... 2

    1. ICH Q3D............................................................................................................................2

    2. USP General Chapters <232> and <233>.......................................................................3

  3. RECOMMENDATIONS.................................................................................................. 4

    1. New Compendial NDA or ANDA Drug Products .......................................................... 4

    2. New Noncompendial NDA and ANDA Drug Products ................................................. 4

    3. Compendial Drug Products Not Approved Under an NDA or ANDA ........................ 4

    4. Noncompendial Drug Products Not Approved Under an NDA or ANDA .................. 5

    5. Changes to Approved NDAs and ANDAs....................................................................... 5

    6. Documentation Related to the Control of Elemental Impurities..................................6

    7. Quantitative Analytical Procedures for Elemental Impurities ..................................... 7

    8. Validation of Analytical Procedures ............................................................................... 8

    9. Early Adoption..................................................................................................................8

      CLICK HERE FOR FULL GUIDANCE

 

Product-Specific Recommendations for Generic Drug Development

Product-Specific Recommendations for Generic Drug Development

 

To successfully develop and manufacture a generic drug product, an applicant should consider that their  product is expected to be:  pharmaceutically equivalent to its reference listed drug (RLD), i.e., to have the same active ingredient, dosage form, strength, and route of administration under the same conditions of use,  bioequivalent to the RLD, i.e., to show no significant difference in the rate and extent of absorption of the active pharmaceutical ingredient;  and, consequently,  therapeutically equivalent, i.e., to be substitutable for the RLD with the expectation that the generic product will have the same safety and efficacy as its reference listed drug.

According 21 CFR 320.24, different types of evidence may be used to establish bioequivalence for pharmaceutically equivalent drug products, including in vivo or in vitro testing, or both. The selection of the method used to demonstrate bioequivalence depends upon the purpose of the study, the analytical methods available, and the nature of the drug product.  Under this regulation, applicants must conduct bioequivalence testing using the most accurate, sensitive, and reproducible approach available among those set forth in 21 CFR 320.24.  As the initial step for selecting methodology for generic drug product development, applicants are referred to the following draft guidance: Draft Guidance for Industry on Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted Under an Abbreviated New Drug Application (ANDA) (Dec. 2013).

To further facilitate generic drug product availability and to assist generic pharmaceutical industry with identifying the most appropriate methodology for developing drugs and generating evidence needed to support ANDA approval, FDA publishes product-specific recommendations describing  the Agency’s current thinking and expectations on how to develop generic drug products therapeutically equivalent to specific reference-listed drugs.

These recommendations are published in an incremental manner and listed below in alphabetical order according to RLD’s name. The most recently published recommendations (new and revised) are listed below.

The Agency is seeking feedback and considers comments to the docket on these recommendations. The comments should be submitted to the Division of Dockets Management (DDM) under Docket FDA-2007-D-0369-0015. For electronic comments, refer to the website http://www.regulations.gov OR mail your written comments to DDM (HFA-305), FDA, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. Please contact the Regulations.gov Help Desk at 1-877-378-5457 (toll free) for assistance regarding submissions.

For additional information on development of generic drug products refer to Biopharmaceutics

Bioequivalence Recommendations for Specific Products Arranged by Active Ingredient [Total count 1523]
A B C D E F G H I J  K L M N O P Q R S T U V W X  Y  Z

Newly Added Recommendations since Oct. 1, 2016 (34 New; 33 Revisions) updated 10/4/2016

CLICK FOR FULL GUIDANCE

 

Quality Attribute Considerations for Chewable Tablets Guidance for Industry

Quality Attribute

Considerations for

Chewable Tablets 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) Nallaperumal Chidambaram 301- 796-1339.

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

June 2016 Pharmaceutical Quality/CMC

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17051dft.doc

Quality Attribute

Considerations for

Chewable Tablets Guidance for Industry

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

June 2016 Pharmaceutical Quality/CMC

 

I. II. III.

A. B. C. D. E.

IV. A.

INTRODUCTION............................................................................................................. 1 BACKGROUND ............................................................................................................... 2 DISCUSSION .................................................................................................................... 2 Hardness ......................................................................................................................................... 3 Disintegration ................................................................................................................................. 3 Dissolution ...................................................................................................................................... 3 Performance in Simulated Physiological Media ......................................................................... 4 Biowaiver and Postapproval Considerations .............................................................................. 4 RECOMMENDATIONS.................................................................................................. 4 Critical Quality Attributes ............................................................................................................ 5 Nomenclature and Labeling .......................................................................................................... 7

Contains Nonbinding Recommendations

Draft — Not for Implementation

TABLE OF CONTENTS

B.
APPENDIX I: CHEWING DIFFICULTY INDEX.................................................................. 8 FIGURES....................................................................................................................................... 9 APPENDIX II: SIMULATED SALIVARY FLUID COMPOSITION .................................10

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