596
GENERAL GUIDELINES FOR THE EVALUATION OF NEW ANTI-INFECTIVE DRUGS FOR THE TREATMENT OF SEXUALLY TRANSMITTED DISEASES
Special Issues in Clinical Trials of New Anti-Infective Drugs for the Treatment of Sexually Transmitted Diseases H. Hunter Handsfield, J. Allen McCutchan, Lawrence Corey, and Allan R. Ronald
From the Departments ofMedicine and Laboratory Medicine. University of Washington School of Medicine, and the Seattle-King County Department of Public Health, Seattle, Washington; the Department of Medicine. University of California, San Diego, California; and the Departments ofInternal Medicine and Medical Microbiology, University ofManitoba and St. Boniface General Hospital. Winnipeg. Manitoba. Canada
I. INCLUSION OF ADOLESCENTS IN 0............. CLINICAL TRIALS II. INCLUSION OF PREGNANT AND NONPREGNANT WOMEN IN CLINICAL TRIALS........................................ III. USE OF UNAPPROVED CONTROL REGIMENS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. ANTIMICROBIAL SUSCEPTIBILITY TESTING V. CLINICAL SYNDROMES OF OBSCURE OR POLYMICROBIAL ETIOLOGY .. VI. SPECIAL CONSIDERATIONS WITH REGARD TO SINGLE-DOSE REGIMENS .. VII. MANAGEMENT OF SEXUAL PARTNERS OF SUBJECTS IN CLINICAL TRIALS VIII. PRESENTATION AND ANALYSIS OF DATA .... IX. SEXUAL REEXPOSURE DURING A CLINICAL TRIAL ....... X. ASSURANCE OF COMPLIANCE AND ETHICAL CONDUCT 0
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S97 S97 S97 S98 S98 S98
The treatment of sexually transmitted diseases (STDs) raises several special issues. Although these issues are not Financial support: This work was supported by a contract to the Infectious Diseases Society of America from the u.s. Food and Drug Administration (no. HHS 223-88-130 I). Correspondence: Dr. H. Hunter Handsfield, Harborview Medical Center ZA-89, 325 Ninth Avenue. Seattle, Washington 98104. Clinical Infectious Diseases
1992;15(Suppll):S96-8
© 1992 by The University of Chicago. All rights reserved.
unique to STDs, they arise more frequently in clinical trials of treatment for STDs than they do in treatment of most other infectious diseases. I. INCLUSION OF ADOLESCENTS IN CLINICAL TRIALS A substantial minority of STD cases occur in adolescents
< 18 years old-the usual age of consent for medical care. It is theoretically possible for an agent to have different profiles of efficacy or safety in adolescents than in adults. Moreover, the rates of some STDs (e.g., gonorrhea, chlamydial infection, pelvic inflammatory disease) and of some serious complications of STDs (e.g., infertility, ectopic pregnancy) are highest among adolescents. Because a requirement for the consent ofparents or guardians would inhibit both the access of adolescents to medical care and the control ofSTDs, most states have lowered the age of consent (typically to 12 or 14 years) for the diagnosis and treatment of patients with STDs. In some jurisdictions, the authority of minors to give consent for routine diagnosis and treatment may apply to participation in clinical trials. The age of consent for participation in studies ofSTD therapy is determined by local laws and regulations applicable to each study center. Where these statutes permit, adolescents < 18 years old should be actively recruited for participation in trials of treatment for STDs.
II. INCLUSION OF PREGNANT AND NONPREGNANT WOMEN IN CLINICAL TRIALS Women and their newborn infants bear the brunt of the adverse short-term and long-term consequences of STDs.
Downloaded from http://cid.oxfordjournals.org/ at University of Birmingham on June 4, 2015
Several special issues arise in relation to clinical trials of therapy for sexually transmitted diseases. These issues include the desirability of including adolescents and both pregnant and nonpregnant women in the trial, the use of unapproved control regimens, problems with antimicrobial susceptibility testing due to inadequate methodology and the need for prompt treatment, the need to assess agents for treatment of syndromes of unknown microbial etiology, toxicity considerations related to the use of single-dose regimens, management of the sexual partners of the participants in the trial, analysis of data despite the high frequency of minor protocol violations, sexual reexposure to infection during the trial, and the potential for loss, alteration, or falsification of data because of the relative simplicity of the usual protocol design and the diagnostic reliance on specimens that are routinely discarded.
CIO 1992;15 (Suppl I)
Special Issues in STD Treatment Trials
should be aware of the prevalence ofantimicrobial resistance among STD pathogens in the community.
V. CLINICAL SYNDROMES OF OBSCURE OR POLYMICROBIAL ETIOLOGY
The specific microbial etiology of some STD syndromes is unknown. In other STDs the suspected pathogens may not be detectable by available technology, the true role ofputative pathogens may be unknown, or multiple potential pathogens are present but their individual roles in pathogenesis are unknown. Examples include bacterial vaginosis; genital ulceration not due to genital herpes, chancroid, or syphilis; and nonchlamydial, nongonococcal urethritis and cervicitis. In clinical trials of therapy for such conditions, clinical criteria may be the paramount determinants of efficacy. Therefore, in some instances it may be unnecessary to isolate putative pathogens or to conduct susceptibility testing of isolates in clinical trials.
III. USE OF UNAPPROVED CONTROL REGIMENS
Some regimens (including some recommended by the Centers for Disease Control) have become standard for treatment of STDs despite lack of approval by the FDA for such use. The selection of these regimens as control regimens in therapeutic studies may be acceptable under certain circumstances. (See General Guidelines, section X.B.) This choice may be especially appropriate when no FDA-approved therapy exists for the STD under study or when no FDA-approved regimen meets the standards for efficacy or safety fulfilled by available but unapproved regimens. The rationale for the use of an unapproved control regimen must be stringently documented. Before initiating a study, sponsors should review with the FDA any planned protocols that use an unapproved regimen as a control. IV. ANTIMICROBIAL SUSCEPTIBILITY TESTING
There are no reproducible methods for in vitro susceptibility testing of certain pathogens causing STDs (e.g., Treponema pallidum); for other STD pathogens (e.g., Chlamydia trachomatis), the available methods are technically demanding and results may correlate poorly with clinical outcome. Furthermore, in the management of many STDs, public health requirements preclude susceptibility testing before treatment but nonetheless require high levels of clinical efficacy regardless of the prevalence of antimicrobial resistance. For example, it is widely recommended as a public health measure that routine treatment for gonorrhea be effective in ;;?;95% of cases. When such standards exist, licensure of an agent for the treatment of infection "due to susceptible strains" is irrelevant. Investigators initiating a clinical trial
VI. SPECIAL CONSIDERATIONS WITH REGARD TO SINGLE-DOSE REGIMENS
Single-dose antimicrobial regimens are used commonly for the treatment of certain STDs. When a single dose of a short-acting agent is used, posttreatment screening for biochemical, hematologic, or other types of toxicity may not be required. The necessity for such screening is especially unlikely when a single follow-up visit is scheduled for several days after treatment and when substantial data about the safety of equal or larger doses ofthe drug have been accumulated. Pretreatment testing nonetheless should be routine so that baseline data will be available if clinical evidence of toxicity is documented and so that conditions with a potential impact on the assessment of therapeutic efficacy will be detected. If adverse reactions are documented in other clinical trials, such effects may be subjected to a focused evaluation, and expanded data on population-specific adverse reactions may be requested by the FDA.
VII. MANAGEMENT OF SEXUAL PARTNERS OF SUBJECTS IN CLINICAL TRIALS
For most STDs clinical standards require that patients' sexual partners be informed and given the opportunity to obtain clinical care. While the management of sexual partners is not required for the conduct of clinical trials, investigators should routinely provide these individuals with medical services or help them arrange for care at a referral site.
Downloaded from http://cid.oxfordjournals.org/ at University of Birmingham on June 4, 2015
The U.S. Food and Drug Administration (FDA) encourages the inclusion of women in clinical trials evaluating the diagnosis and treatment ofSTDs. This policy affords women and men equal access to the benefits of participation in trials and assures the accrual of clinically applicable, gender-specific results. In the case of some STDs (e.g., chlamydial infection, gonorrhea), pregnant women may respond less well than nonpregnant women to standard regimens of treatment. In other STDs (e.g., syphilis) the efficacy of treatment in curing fetal infection or preventing the transmission of infection to the fetus is poorly documented. Therefore, pregnant women in the second or third trimester may be appropriate subjects for trials of investigational antimicrobial drugs for the treatment of some STDs, especially when experience suggests that the investigational and control drugs are safe for both the mother and the fetus. Researchers are encouraged to make concerted efforts to include women, including pregnant women in the second and third trimesters, in clinical trials of therapy for STDs. (See General Guidelines, sections VI.B and VI.c.)
S97
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Handsfield et al.
VIII. PRESENTATION AND ANALYSIS OF DATA An intent-to-treat analysis should be routine in controlled clinical trials of therapy for STDs. This design permits the retention of subjects despite minor violations ofthe protocol and assures evaluability for efficacy. Minor protocol violations (e.g., sexual reexposure or return for test-of-cure outside the protocol-designated follow-up period) are common in this setting. Methods for the calculation of sample sizes, the presentation of data, and statistical evaluation are presented in the General Guidelines (section XVI and appendix).
Sexual reexposure is a common event among subjects in clinical trials of treatment for STDs, often confounding the distinction between treatment failure and reinfection. Ideally, subjects will avoid sexual contact until their participation in the study ends and the outcome oftheir treatment can be assessed. Sexual reexposure should be discouraged particularly strongly in trials ofshort duration (e.g., 1-2 weeks). For longer studies, sexual reexposure is undesirable during the first 1-2 weeks but may be permitted thereafter provided that sexual contact is limited to treated partners, partners known to be uninfected, or partners with little or no risk for STDs. The use of condoms should be encouraged or even required for sexual contact during the follow-up period. Sexual reexposures during the study should be reported; it may be appropriate to require the subjects to keep records ofreexposures. When a trial with a concurrent-control regimen is analyzed on an intent-to-treat basis, sexual reexposure should not preclude evaluation for efficacy. When trials do not in-
elude concurrent controls or when an intent-to-treat analysis is not planned, the decision to retain or exclude reexposed subjects should be made before initiation of the study and must be implemented uniformly at all study sites. It is permissible to distinguish between reexposures that require exclusion and those that do not-for example, exposure with a condom vs. that without a condom or exposure to a treated or uninfected partner vs. that to an untreated or infected partner. Diagnosis and treatment ofthe partner by the investigators can assist in making such distinctions. Under no circumstance should the apparent response to treatment-or lack thereof-be a factor in the decision to retain or exclude a sexually reexposed subject. X. ASSURANCE OF COMPLIANCE AND ETHICAL CONDUCT In clinical trials oftreatment for STDs, the relative simplicity of some protocol designs (e.g., a brief, directed physical examination or a single follow-up visit) and the diagnostic reliance on specimens that are routinely discarded (e.g., wet mounts, dark-field preparations) may create opportunities for the loss, alteration, or falsification of data. Careful selection of investigators and institutions, rigorous monitoring, and meticulous completion and retention of research and clinical records are of paramount importance. In selected circumstances, diagnostic tests, although within the capability of the investigator, should be performed or confirmed by a laboratory or an individual not directly involved in the trial. Whenever possible, pathogenic isolates should be retained for external review for at least 2 years. Other permanent materials that support the documentation of infection (e.g., gram-stained smears, slides used for fluorescent antibody testing) should also be retained as part of the case record.
Downloaded from http://cid.oxfordjournals.org/ at University of Birmingham on June 4, 2015
IX. SEXUAL REEXPOSURE DURING A CLINICAL TRIAL
CID 1992; 15 (Suppl 1)
GENERAL GUIDELINES FOR THE EVALUATION OF NEW ANTI-INFECTIVE DRUGS FOR THE TREATMENT OF SEXUALLY TRANSMITTED DISEASES
Special Issues in Clinical Trials of New Anti-Infective Drugs for the Treatment of Sexually Transmitted Diseases H. Hunter Handsfield, J. Allen McCutchan, Lawrence Corey, and Allan R. Ronald
From the Departments ofMedicine and Laboratory Medicine. University of Washington School of Medicine, and the Seattle-King County Department of Public Health, Seattle, Washington; the Department of Medicine. University of California, San Diego, California; and the Departments ofInternal Medicine and Medical Microbiology, University ofManitoba and St. Boniface General Hospital. Winnipeg. Manitoba. Canada
I. INCLUSION OF ADOLESCENTS IN 0............. CLINICAL TRIALS II. INCLUSION OF PREGNANT AND NONPREGNANT WOMEN IN CLINICAL TRIALS........................................ III. USE OF UNAPPROVED CONTROL REGIMENS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. ANTIMICROBIAL SUSCEPTIBILITY TESTING V. CLINICAL SYNDROMES OF OBSCURE OR POLYMICROBIAL ETIOLOGY .. VI. SPECIAL CONSIDERATIONS WITH REGARD TO SINGLE-DOSE REGIMENS .. VII. MANAGEMENT OF SEXUAL PARTNERS OF SUBJECTS IN CLINICAL TRIALS VIII. PRESENTATION AND ANALYSIS OF DATA .... IX. SEXUAL REEXPOSURE DURING A CLINICAL TRIAL ....... X. ASSURANCE OF COMPLIANCE AND ETHICAL CONDUCT 0
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S96
S96 S97 S97
S97 S97 S97 S98 S98 S98
The treatment of sexually transmitted diseases (STDs) raises several special issues. Although these issues are not Financial support: This work was supported by a contract to the Infectious Diseases Society of America from the u.s. Food and Drug Administration (no. HHS 223-88-130 I). Correspondence: Dr. H. Hunter Handsfield, Harborview Medical Center ZA-89, 325 Ninth Avenue. Seattle, Washington 98104. Clinical Infectious Diseases
1992;15(Suppll):S96-8
© 1992 by The University of Chicago. All rights reserved.
unique to STDs, they arise more frequently in clinical trials of treatment for STDs than they do in treatment of most other infectious diseases. I. INCLUSION OF ADOLESCENTS IN CLINICAL TRIALS A substantial minority of STD cases occur in adolescents
< 18 years old-the usual age of consent for medical care. It is theoretically possible for an agent to have different profiles of efficacy or safety in adolescents than in adults. Moreover, the rates of some STDs (e.g., gonorrhea, chlamydial infection, pelvic inflammatory disease) and of some serious complications of STDs (e.g., infertility, ectopic pregnancy) are highest among adolescents. Because a requirement for the consent ofparents or guardians would inhibit both the access of adolescents to medical care and the control ofSTDs, most states have lowered the age of consent (typically to 12 or 14 years) for the diagnosis and treatment of patients with STDs. In some jurisdictions, the authority of minors to give consent for routine diagnosis and treatment may apply to participation in clinical trials. The age of consent for participation in studies ofSTD therapy is determined by local laws and regulations applicable to each study center. Where these statutes permit, adolescents < 18 years old should be actively recruited for participation in trials of treatment for STDs.
II. INCLUSION OF PREGNANT AND NONPREGNANT WOMEN IN CLINICAL TRIALS Women and their newborn infants bear the brunt of the adverse short-term and long-term consequences of STDs.
Downloaded from http://cid.oxfordjournals.org/ at University of Birmingham on June 4, 2015
Several special issues arise in relation to clinical trials of therapy for sexually transmitted diseases. These issues include the desirability of including adolescents and both pregnant and nonpregnant women in the trial, the use of unapproved control regimens, problems with antimicrobial susceptibility testing due to inadequate methodology and the need for prompt treatment, the need to assess agents for treatment of syndromes of unknown microbial etiology, toxicity considerations related to the use of single-dose regimens, management of the sexual partners of the participants in the trial, analysis of data despite the high frequency of minor protocol violations, sexual reexposure to infection during the trial, and the potential for loss, alteration, or falsification of data because of the relative simplicity of the usual protocol design and the diagnostic reliance on specimens that are routinely discarded.
CIO 1992;15 (Suppl I)
Special Issues in STD Treatment Trials
should be aware of the prevalence ofantimicrobial resistance among STD pathogens in the community.
V. CLINICAL SYNDROMES OF OBSCURE OR POLYMICROBIAL ETIOLOGY
The specific microbial etiology of some STD syndromes is unknown. In other STDs the suspected pathogens may not be detectable by available technology, the true role ofputative pathogens may be unknown, or multiple potential pathogens are present but their individual roles in pathogenesis are unknown. Examples include bacterial vaginosis; genital ulceration not due to genital herpes, chancroid, or syphilis; and nonchlamydial, nongonococcal urethritis and cervicitis. In clinical trials of therapy for such conditions, clinical criteria may be the paramount determinants of efficacy. Therefore, in some instances it may be unnecessary to isolate putative pathogens or to conduct susceptibility testing of isolates in clinical trials.
III. USE OF UNAPPROVED CONTROL REGIMENS
Some regimens (including some recommended by the Centers for Disease Control) have become standard for treatment of STDs despite lack of approval by the FDA for such use. The selection of these regimens as control regimens in therapeutic studies may be acceptable under certain circumstances. (See General Guidelines, section X.B.) This choice may be especially appropriate when no FDA-approved therapy exists for the STD under study or when no FDA-approved regimen meets the standards for efficacy or safety fulfilled by available but unapproved regimens. The rationale for the use of an unapproved control regimen must be stringently documented. Before initiating a study, sponsors should review with the FDA any planned protocols that use an unapproved regimen as a control. IV. ANTIMICROBIAL SUSCEPTIBILITY TESTING
There are no reproducible methods for in vitro susceptibility testing of certain pathogens causing STDs (e.g., Treponema pallidum); for other STD pathogens (e.g., Chlamydia trachomatis), the available methods are technically demanding and results may correlate poorly with clinical outcome. Furthermore, in the management of many STDs, public health requirements preclude susceptibility testing before treatment but nonetheless require high levels of clinical efficacy regardless of the prevalence of antimicrobial resistance. For example, it is widely recommended as a public health measure that routine treatment for gonorrhea be effective in ;;?;95% of cases. When such standards exist, licensure of an agent for the treatment of infection "due to susceptible strains" is irrelevant. Investigators initiating a clinical trial
VI. SPECIAL CONSIDERATIONS WITH REGARD TO SINGLE-DOSE REGIMENS
Single-dose antimicrobial regimens are used commonly for the treatment of certain STDs. When a single dose of a short-acting agent is used, posttreatment screening for biochemical, hematologic, or other types of toxicity may not be required. The necessity for such screening is especially unlikely when a single follow-up visit is scheduled for several days after treatment and when substantial data about the safety of equal or larger doses ofthe drug have been accumulated. Pretreatment testing nonetheless should be routine so that baseline data will be available if clinical evidence of toxicity is documented and so that conditions with a potential impact on the assessment of therapeutic efficacy will be detected. If adverse reactions are documented in other clinical trials, such effects may be subjected to a focused evaluation, and expanded data on population-specific adverse reactions may be requested by the FDA.
VII. MANAGEMENT OF SEXUAL PARTNERS OF SUBJECTS IN CLINICAL TRIALS
For most STDs clinical standards require that patients' sexual partners be informed and given the opportunity to obtain clinical care. While the management of sexual partners is not required for the conduct of clinical trials, investigators should routinely provide these individuals with medical services or help them arrange for care at a referral site.
Downloaded from http://cid.oxfordjournals.org/ at University of Birmingham on June 4, 2015
The U.S. Food and Drug Administration (FDA) encourages the inclusion of women in clinical trials evaluating the diagnosis and treatment ofSTDs. This policy affords women and men equal access to the benefits of participation in trials and assures the accrual of clinically applicable, gender-specific results. In the case of some STDs (e.g., chlamydial infection, gonorrhea), pregnant women may respond less well than nonpregnant women to standard regimens of treatment. In other STDs (e.g., syphilis) the efficacy of treatment in curing fetal infection or preventing the transmission of infection to the fetus is poorly documented. Therefore, pregnant women in the second or third trimester may be appropriate subjects for trials of investigational antimicrobial drugs for the treatment of some STDs, especially when experience suggests that the investigational and control drugs are safe for both the mother and the fetus. Researchers are encouraged to make concerted efforts to include women, including pregnant women in the second and third trimesters, in clinical trials of therapy for STDs. (See General Guidelines, sections VI.B and VI.c.)
S97
S98
Handsfield et al.
VIII. PRESENTATION AND ANALYSIS OF DATA An intent-to-treat analysis should be routine in controlled clinical trials of therapy for STDs. This design permits the retention of subjects despite minor violations ofthe protocol and assures evaluability for efficacy. Minor protocol violations (e.g., sexual reexposure or return for test-of-cure outside the protocol-designated follow-up period) are common in this setting. Methods for the calculation of sample sizes, the presentation of data, and statistical evaluation are presented in the General Guidelines (section XVI and appendix).
Sexual reexposure is a common event among subjects in clinical trials of treatment for STDs, often confounding the distinction between treatment failure and reinfection. Ideally, subjects will avoid sexual contact until their participation in the study ends and the outcome oftheir treatment can be assessed. Sexual reexposure should be discouraged particularly strongly in trials ofshort duration (e.g., 1-2 weeks). For longer studies, sexual reexposure is undesirable during the first 1-2 weeks but may be permitted thereafter provided that sexual contact is limited to treated partners, partners known to be uninfected, or partners with little or no risk for STDs. The use of condoms should be encouraged or even required for sexual contact during the follow-up period. Sexual reexposures during the study should be reported; it may be appropriate to require the subjects to keep records ofreexposures. When a trial with a concurrent-control regimen is analyzed on an intent-to-treat basis, sexual reexposure should not preclude evaluation for efficacy. When trials do not in-
elude concurrent controls or when an intent-to-treat analysis is not planned, the decision to retain or exclude reexposed subjects should be made before initiation of the study and must be implemented uniformly at all study sites. It is permissible to distinguish between reexposures that require exclusion and those that do not-for example, exposure with a condom vs. that without a condom or exposure to a treated or uninfected partner vs. that to an untreated or infected partner. Diagnosis and treatment ofthe partner by the investigators can assist in making such distinctions. Under no circumstance should the apparent response to treatment-or lack thereof-be a factor in the decision to retain or exclude a sexually reexposed subject. X. ASSURANCE OF COMPLIANCE AND ETHICAL CONDUCT In clinical trials oftreatment for STDs, the relative simplicity of some protocol designs (e.g., a brief, directed physical examination or a single follow-up visit) and the diagnostic reliance on specimens that are routinely discarded (e.g., wet mounts, dark-field preparations) may create opportunities for the loss, alteration, or falsification of data. Careful selection of investigators and institutions, rigorous monitoring, and meticulous completion and retention of research and clinical records are of paramount importance. In selected circumstances, diagnostic tests, although within the capability of the investigator, should be performed or confirmed by a laboratory or an individual not directly involved in the trial. Whenever possible, pathogenic isolates should be retained for external review for at least 2 years. Other permanent materials that support the documentation of infection (e.g., gram-stained smears, slides used for fluorescent antibody testing) should also be retained as part of the case record.
Downloaded from http://cid.oxfordjournals.org/ at University of Birmingham on June 4, 2015
IX. SEXUAL REEXPOSURE DURING A CLINICAL TRIAL
CID 1992; 15 (Suppl 1)
