FDA addresses unmet need in drug development guidance for female sexual dysfunction

On Oct. 25, 2016, the Food and Drug Administration issued a draft guidance document titled “Low Sexual Interest, Desire, and/or Arousal in Women: Developing Drugs for Treatment.” The document outlines FDA’s current thinking about how best to design phase III trials for drugs to treat these problems. The purpose of this guidance is to provide pharmaceutical companies with a road map of what the FDA recommends should be addressed in clinical trials designed for new drug approval.

The FDA makes it clear that this guidance is only a “recommendation,” reflecting the agency’s current thinking on this important issue, and is not a requirement (unless specific regulatory or statutory requirements are cited). That may well be, but this puts me in mind of my graduate school days when my advisor used to tell me that his suggestions for my dissertation were only “recommendations.” I knew, of course, that to ignore these recommendations was folly.

We need to acknowledge that this guidance reflects tremendous progress in the field of sexual medicine. We have come a long way since the first draft guidance was made available in May 2000. The guidance from 16 years ago was never finalized and was eventually withdrawn. So this is progress. We should applaud the FDA for using the most up-to-date, expert opinion and evidence-based recommendations in this 2016 guidance. Also of note is that these recommendations are likely informed by the agency’s 2-day “Patient-Focused Drug Development Public Meeting and Scientific workshop on Female Sexual Dysfunction” held in October 2014.

Specifically, I would like to highlight several remarkable advances in this document. First, the guidance document acknowledges that there is a medical need for drugs to treat women with sexual dysfunction. Second, the guidance supports retaining the disorders of Hypoactive Sexual Desire Disorder (HSDD) and Female Sexual Arousal Disorder (FSAD) from the DSM-IV as treatment indications. Further, the guidance recognizes that the DSM-5 revisions of female sexual disorders, in this case, Female Sexual Interest and/or Arousal Disorder (FSIAD) “have not been universally accepted the scientific community.”

With regard to clinical trial design, I commend the FDA for removing Satisfying Sexual Events (SSEs) as a “required” primary endpoint and for allowing sponsors more flexibility to choose primary endpoints that will better align regulatory standards with the definition and key symptoms of HSDD (as well as FSAD and FSIAD). These endpoints include validated patient-reported outcome instruments that assess the symptoms of low desire (or arousal) and sexually related distress.

On the negative side, the guidance also reflects some carryover myths that are not in keeping with evidence or expert opinion. Specifically, the FDA cautions against the use of the Female Sexual Function Index desire (FSFI-D) subdomain as a primary endpoint in its current form. The FSFI-D has excellent construct and content validity. Furthermore, the guidance cautions against using a long recall period – 28 days/4 weeks – reflecting the FDA’s concern that women’s recall over that period of time will be inaccurate. They strongly recommend a 24-hour recall period.

Although it is certainly appropriate to evaluate on-demand treatments using more immediate and specific time frames, longer recall of desire is still appropriate as well. Longer recall periods provide a more accurate assessment of desire, which is best understood as state as of mind. A 24-hour recall (e.g., daily log of desire) is more akin to assessing one’s current hunger, whereas a 28-day look-back reflects one’s overall appetite, a concept more similar to desire.

And finally, although the FDA supports inclusion of postmenopausal women as a target population, it would be best if they not divide women into “groups” based on menopausal status unless hormonal status is relevant. This could further marginalize postmenopausal women and delay access to treatments for this population.

Once finalized, this draft guidance should serve its stated purpose to enhance discussion among FDA, pharmaceutical companies, academics, and the public.
 

Dr. Kingsberg is chief of the division of behavioral medicine in the department of obstetrics and gynecology at MacDonald Women’s Hospital, part of the University Hospitals Cleveland Medical Center, Ohio. She is also a professor in the departments of reproductive biology and psychiatry at Case Western Reserve University, Cleveland. Dr. Kingsberg reported being a consultant or member of the scientific advisory board for Acerus, AMAG, Bayer, Emotional Brain, Endoceutics, NovoNordisk, Palatin, Pfizer, Shionogi, Sprout, TherapeuticsMD, Sermonix, Strategic Science & Technologies, and Valeant. Valeant is the manufacturer of the HSDD drug flibanserin.

On Oct. 25, 2016, the Food and Drug Administration issued a draft guidance document titled “Low Sexual Interest, Desire, and/or Arousal in Women: Developing Drugs for Treatment.” The document outlines FDA’s current thinking about how best to design phase III trials for drugs to treat these problems. The purpose of this guidance is to provide pharmaceutical companies with a road map of what the FDA recommends should be addressed in clinical trials designed for new drug approval.

The FDA makes it clear that this guidance is only a “recommendation,” reflecting the agency’s current thinking on this important issue, and is not a requirement (unless specific regulatory or statutory requirements are cited). That may well be, but this puts me in mind of my graduate school days when my advisor used to tell me that his suggestions for my dissertation were only “recommendations.” I knew, of course, that to ignore these recommendations was folly.

We need to acknowledge that this guidance reflects tremendous progress in the field of sexual medicine. We have come a long way since the first draft guidance was made available in May 2000. The guidance from 16 years ago was never finalized and was eventually withdrawn. So this is progress. We should applaud the FDA for using the most up-to-date, expert opinion and evidence-based recommendations in this 2016 guidance. Also of note is that these recommendations are likely informed by the agency’s 2-day “Patient-Focused Drug Development Public Meeting and Scientific workshop on Female Sexual Dysfunction” held in October 2014.

Specifically, I would like to highlight several remarkable advances in this document. First, the guidance document acknowledges that there is a medical need for drugs to treat women with sexual dysfunction. Second, the guidance supports retaining the disorders of Hypoactive Sexual Desire Disorder (HSDD) and Female Sexual Arousal Disorder (FSAD) from the DSM-IV as treatment indications. Further, the guidance recognizes that the DSM-5 revisions of female sexual disorders, in this case, Female Sexual Interest and/or Arousal Disorder (FSIAD) “have not been universally accepted the scientific community.”

With regard to clinical trial design, I commend the FDA for removing Satisfying Sexual Events (SSEs) as a “required” primary endpoint and for allowing sponsors more flexibility to choose primary endpoints that will better align regulatory standards with the definition and key symptoms of HSDD (as well as FSAD and FSIAD). These endpoints include validated patient-reported outcome instruments that assess the symptoms of low desire (or arousal) and sexually related distress.

On the negative side, the guidance also reflects some carryover myths that are not in keeping with evidence or expert opinion. Specifically, the FDA cautions against the use of the Female Sexual Function Index desire (FSFI-D) subdomain as a primary endpoint in its current form. The FSFI-D has excellent construct and content validity. Furthermore, the guidance cautions against using a long recall period – 28 days/4 weeks – reflecting the FDA’s concern that women’s recall over that period of time will be inaccurate. They strongly recommend a 24-hour recall period.

Although it is certainly appropriate to evaluate on-demand treatments using more immediate and specific time frames, longer recall of desire is still appropriate as well. Longer recall periods provide a more accurate assessment of desire, which is best understood as state as of mind. A 24-hour recall (e.g., daily log of desire) is more akin to assessing one’s current hunger, whereas a 28-day look-back reflects one’s overall appetite, a concept more similar to desire.

And finally, although the FDA supports inclusion of postmenopausal women as a target population, it would be best if they not divide women into “groups” based on menopausal status unless hormonal status is relevant. This could further marginalize postmenopausal women and delay access to treatments for this population.

Once finalized, this draft guidance should serve its stated purpose to enhance discussion among FDA, pharmaceutical companies, academics, and the public.
 

Dr. Kingsberg is chief of the division of behavioral medicine in the department of obstetrics and gynecology at MacDonald Women’s Hospital, part of the University Hospitals Cleveland Medical Center, Ohio. She is also a professor in the departments of reproductive biology and psychiatry at Case Western Reserve University, Cleveland. Dr. Kingsberg reported being a consultant or member of the scientific advisory board for Acerus, AMAG, Bayer, Emotional Brain, Endoceutics, NovoNordisk, Palatin, Pfizer, Shionogi, Sprout, TherapeuticsMD, Sermonix, Strategic Science & Technologies, and Valeant. Valeant is the manufacturer of the HSDD drug flibanserin.

On Oct. 25, 2016, the Food and Drug Administration issued a draft guidance document titled “Low Sexual Interest, Desire, and/or Arousal in Women: Developing Drugs for Treatment.” The document outlines FDA’s current thinking about how best to design phase III trials for drugs to treat these problems. The purpose of this guidance is to provide pharmaceutical companies with a road map of what the FDA recommends should be addressed in clinical trials designed for new drug approval.

The FDA makes it clear that this guidance is only a “recommendation,” reflecting the agency’s current thinking on this important issue, and is not a requirement (unless specific regulatory or statutory requirements are cited). That may well be, but this puts me in mind of my graduate school days when my advisor used to tell me that his suggestions for my dissertation were only “recommendations.” I knew, of course, that to ignore these recommendations was folly.

We need to acknowledge that this guidance reflects tremendous progress in the field of sexual medicine. We have come a long way since the first draft guidance was made available in May 2000. The guidance from 16 years ago was never finalized and was eventually withdrawn. So this is progress. We should applaud the FDA for using the most up-to-date, expert opinion and evidence-based recommendations in this 2016 guidance. Also of note is that these recommendations are likely informed by the agency’s 2-day “Patient-Focused Drug Development Public Meeting and Scientific workshop on Female Sexual Dysfunction” held in October 2014.

Specifically, I would like to highlight several remarkable advances in this document. First, the guidance document acknowledges that there is a medical need for drugs to treat women with sexual dysfunction. Second, the guidance supports retaining the disorders of Hypoactive Sexual Desire Disorder (HSDD) and Female Sexual Arousal Disorder (FSAD) from the DSM-IV as treatment indications. Further, the guidance recognizes that the DSM-5 revisions of female sexual disorders, in this case, Female Sexual Interest and/or Arousal Disorder (FSIAD) “have not been universally accepted the scientific community.”

With regard to clinical trial design, I commend the FDA for removing Satisfying Sexual Events (SSEs) as a “required” primary endpoint and for allowing sponsors more flexibility to choose primary endpoints that will better align regulatory standards with the definition and key symptoms of HSDD (as well as FSAD and FSIAD). These endpoints include validated patient-reported outcome instruments that assess the symptoms of low desire (or arousal) and sexually related distress.

On the negative side, the guidance also reflects some carryover myths that are not in keeping with evidence or expert opinion. Specifically, the FDA cautions against the use of the Female Sexual Function Index desire (FSFI-D) subdomain as a primary endpoint in its current form. The FSFI-D has excellent construct and content validity. Furthermore, the guidance cautions against using a long recall period – 28 days/4 weeks – reflecting the FDA’s concern that women’s recall over that period of time will be inaccurate. They strongly recommend a 24-hour recall period.

Although it is certainly appropriate to evaluate on-demand treatments using more immediate and specific time frames, longer recall of desire is still appropriate as well. Longer recall periods provide a more accurate assessment of desire, which is best understood as state as of mind. A 24-hour recall (e.g., daily log of desire) is more akin to assessing one’s current hunger, whereas a 28-day look-back reflects one’s overall appetite, a concept more similar to desire.

And finally, although the FDA supports inclusion of postmenopausal women as a target population, it would be best if they not divide women into “groups” based on menopausal status unless hormonal status is relevant. This could further marginalize postmenopausal women and delay access to treatments for this population.

Once finalized, this draft guidance should serve its stated purpose to enhance discussion among FDA, pharmaceutical companies, academics, and the public.
 

Dr. Kingsberg is chief of the division of behavioral medicine in the department of obstetrics and gynecology at MacDonald Women’s Hospital, part of the University Hospitals Cleveland Medical Center, Ohio. She is also a professor in the departments of reproductive biology and psychiatry at Case Western Reserve University, Cleveland. Dr. Kingsberg reported being a consultant or member of the scientific advisory board for Acerus, AMAG, Bayer, Emotional Brain, Endoceutics, NovoNordisk, Palatin, Pfizer, Shionogi, Sprout, TherapeuticsMD, Sermonix, Strategic Science & Technologies, and Valeant. Valeant is the manufacturer of the HSDD drug flibanserin.