For the last 30 years, the Center for Women’s Mental Health at Massachusetts General Hospital (MGH) has had as part of its mission, the conveying of accurate information about the reproductive safety of psychiatric medications. There has been a spectrum of medicines developed across psychiatric indications over the last several decades, and many studies over those decades have attempted to delineate the reproductive safety of these agents.
With the development of new antidepressants and second-generation antipsychotics has come an appreciation of the utility of these agents across a wide range of psychiatric disease states and psychiatric symptoms. More and more data demonstrate the efficacy of these medicines for mood and anxiety disorders; these agents are also used for a broad array of symptoms from insomnia, irritability, and symptoms of posttraumatic stress disorder (PTSD) just as examples — even absent formal approval by the US Food and Drug Administration (FDA) for these specific indications. With the growing use of medicines, including new antidepressants like selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors, and second-generation atypical antipsychotics, there has been a greater interest and appreciation of the need to provide women with the best information about reproductive safety of these medicines as well.
Dr. Lee S. Cohen
When I began working in reproductive psychiatry, the FDA was using the pregnancy labeling categories introduced in 1979. The categories were simple, but also oversimplified in terms of incompletely conveying information about reproductive safety. For instance, category labels of B and C under the old labeling system could be nebulous, containing sparse information (in the case of category B) or animal data and some conflicting human data (in the case of category C) that may not have translated into relevant or easily interpretable safety information for patients and clinicians.
It was on that basis the current Pregnancy and Lactation Labeling (PLLR) Final Rule was published in 2014, which was a shift from categorical labeling to more descriptive labeling, including updated actual information on the package insert about available reproductive safety data, animal data, and data on lactation.
Even following the publication of the PLLR, there has still been an acknowledgment in the field that our assessment tools for postmarketing reproductive safety surveillance are incomplete. A recent 2-day FDA workshop hosted by the Duke-Margolis Center for Health Policy on optimizing the use of postapproval pregnancy safety studies sought to discuss the many questions that still surround this issue. Based on presentations at this workshop, a framework emerged for the future of assessing the reproductive safety of medications, which included an effort to develop the most effective model using tools such as pregnancy registries and harnessing “big data,” whether through electronic health records or large administrative databases from public and private insurers. Together, these various sources of information can provide signals of potential concern, prompting the need for a more rigorous look at the reproductive safety of a medication, or provide reassurance if data fail to indicate the absence of a signal of risk.
FDA’s new commitments under the latest reauthorization of the Prescription Drug User Fee Act (PDUFA VII) include pregnancy-specific postmarketing safety requirements as well as the creation of a framework for how data from pregnancy-specific postmarketing studies can be used. The agency is also conducting demonstration projects, including one for assessing the performance of pregnancy registries for the potential to detect safety signals for medications early in pregnancy. FDA is expanding its Sentinel Initiative to help accomplish these aims, and is implementing an Active Risk Identification and Analysis (ARIA) system to conduct active safety surveillance of medications used during pregnancy.
Pregnancy registries have now been available for decades, and some have been more successful than others across different classes of medicines, with the most rigorous registries including prospective follow-up of women across pregnancies and careful documentation of malformations (at best with original source data and with a blinded dysmorphologist). Still, with all of its rigor, even the best-intentioned efforts with respect to pregnancy registries have limitations. As I mentioned in my testimony during the public comment portion of the workshop, the sheer volume of pregnancy data from administrative databases we now have access to is attractive, but the quality of these data needs to be good enough to ascertain a signal of risk if they are to be used as a basis for reproductive safety determination.
The flip side of using data from large administrative databases is using carefully collected data from pregnancy registries. With a pregnancy registry, accrual of a substantial number of participants can also take a considerable period of time, and initial risk estimates of outcomes can have typically large confidence intervals, which can make it difficult to discern whether a drug is safe for women of reproductive age.
Another key issue is a lack of participation from manufacturers with respect to commitment to collection of high-quality reproductive safety data. History has shown that many medication manufacturers, unless required to have a dedicated registry as part of a postmarketing requirement or commitment, will invest sparse resources to track data on safety of fetal drug exposure. Participation is typically voluntary and varies from company to company unless, as noted previously, there is a postmarketing requirement or commitment tied to the approval of a medication. Just as a recent concrete example, the manufacturer of a new medication recently approved by the FDA for the treatment of postpartum depression (which will include presumably sexually active women well into the first postpartum year) has no plan to support the collection of reproductive safety data on this new medication because it is not required to, based on current FDA guidelines and the absence of a postmarketing requirement to do so.