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HomeWomen HealthToward a greater framework for postmarketing reproductive safety surveillance of medicines

Toward a greater framework for postmarketing reproductive safety surveillance of medicines

Dr. Lee S. Cohen, Director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital, recently shared his insights on zuranolone for postpartum depression with Ob.Gyn News on December 14th.




For the last 30 years, the Center for Women’s Mental Health at Massachusetts General Hospital (MGH) has had as a part of its mission, the conveying of accurate information in regards to the reproductive safety of psychiatric medications. There was a spectrum of medicines developed across psychiatric indications over the past several many years, and plenty of studies over those many years have attempted to delineate the reproductive safety of those agents.

With the event of latest antidepressants and second-generation antipsychotics has come an appreciation of the utility of those agents across a wide selection of psychiatric disease states and psychiatric symptoms. Increasingly more data display the efficacy of those 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 latest antidepressants like selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors, and second-generation atypical antipsychotics, there was a greater interest and appreciation of the necessity to supply women with the very best details about reproductive safety of those medicines as well.

Once I began working in reproductive psychiatry, the FDA was using the pregnancy labeling categories introduced in 1979. The categories were easy, but in addition oversimplified by way of incompletely conveying details about reproductive safety. For example, category labels of B and C under the old labeling system may very well be nebulous, containing sparse information (within the case of category B) or animal data and a few conflicting human data (within the case of category C) that won’t have translated into relevant or easily interpretable safety information for patients and clinicians.

It was on that basis the present 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 sector 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 usage of postapproval pregnancy safety studies sought to debate the numerous questions that also surround this issue. Based on presentations at this workshop, a framework emerged for the long run of assessing the reproductive safety of medicines, which included an effort to develop essentially the most effective model using tools resembling pregnancy registries and harnessing “big data,” whether through electronic health records or large administrative databases from private and non-private insurers. Together, these various sources of knowledge can provide signals of potential concern, prompting the necessity for a more rigorous take a look at the reproductive safety of a medicine, or provide reassurance if data fail to point the absence of a signal of risk.

FDA’s latest commitments under the newest reauthorization of the Prescription Drug User Fee Act (PDUFA VII) include pregnancy-specific postmarketing safety requirements in addition to the creation of a framework for the way data from pregnancy-specific postmarketing studies will be used. The agency can be 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 assist accomplish these goals, and is implementing an Energetic Risk Identification and Evaluation (ARIA) system to conduct lively safety surveillance of medicines used while pregnant.

Pregnancy registries have now been available for many years, and a few have been more successful than others across different classes of medicines, with essentially the most rigorous registries including prospective follow-up of ladies 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 discussed in my testimony through 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 standard of those data must be adequate to establish a signal of risk in the event that they are for use as a basis for reproductive safety determination.

The flip side of using data from large administrative databases is using fastidiously collected data from pregnancy registries. With a pregnancy registry, accrual of a considerable variety of participants can even take a substantial time frame, and initial risk estimates of outcomes can have typically large confidence intervals, which may make it difficult to discern whether a drug is protected for ladies of reproductive age.

One other key issue is a scarcity 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 a part of a postmarketing requirement or commitment, will invest sparse resources to trace data on safety of fetal drug exposure. Participation is usually voluntary and varies from company to company unless, as noted previously, there may be a postmarketing requirement or commitment tied to the approval of a medicine. Just as a recent concrete example, the manufacturer of a brand new medication recently approved by the FDA for the treatment of postpartum depression (which is able to include presumably sexually lively women well into the primary postpartum yr) has no plan to support the gathering of reproductive safety data on this latest medication since it shouldn’t be required to, based on current FDA guidelines and the absence of a postmarketing requirement to achieve this.

Looking Ahead

While the PLLR was an enormous step forward in the sector from the old pregnancy category system that might misinform women contemplating pregnancy, it also sets the stage for the following iteration of a system that permits us to generate information more quickly in regards to the reproductive safety of medicines. In psychiatry, as many as 10% of ladies use SSRIs while pregnant. With drugs like atypical antipsychotics getting used across disease states — in schizophrenia, bipolar disorder, depression, anxiety, insomnia, and PTSD — and where latest classes of medication have gotten available, like with ketamine or steroids, we’d like to have a system by which we are able to more quickly ascertain reproductive safety information. This information informs treatment decisions during a critical life event of deciding to attempt to turn into pregnant or during an actual pregnancy.

In my mind, it’s reassuring when a registry has whilst few as 50-60 cases of fetal exposure without a rise in the chance for malformation, because it could mean we usually are not seeing a repeat of the past with medications like thalidomide and sodium valproate. Nevertheless, patients and clinicians are starved for higher data. Risk assessment can be different from clinician to clinician and patient to patient. We would like to empower patients to make decisions that work for them based on more rapidly accumulating information and help inform their decisions.

To return out on the “other side” of the PLLR, we’ll need to search out a option to speed up our ability to discover signals of risk or information that’s reassuring (or not reassuring) in order that clinicians and patients usually are not left waiting for the following paper to come back out, which will be confusing when study results continuously conflict. I consider now we have an obligation today to do that higher, since the areas of reproductive toxicology and pharmacovigilance are growing incredibly quickly, and clinicians and patients are seeing these volumes of information being published without the power to integrate that information in a scientific way.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. The Center for Women’s Mental Health at MGH was a non-enrolling site for the pivotal phase 3 SKYLARK trial evaluating zuranolone. Full disclosure information for Dr. Cohen is offered at womensmentalhealth.org. Email Dr. Cohen at obnews@mdedge.com.

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