Overall Results

Seventeen (17) of the TransCelerate member companies responded to the survey in whole or in part. Of the 17 survey participants, all reported at least 1 post-approval activity focused on data generation in pregnancy and/or lactation that was under protocol development, submitted, ongoing, or completed within the pre-specified 11 year period (January 1, 2013, to December 31, 2023). Overall, there was a greater number of post-approval activities on pregnancy than on lactation (Fig. 1).

Figure 1.

Number of survey participants reporting post-approval activities on pregnancy and/or lactation.

The therapeutic areas (more than one could be selected) with the highest proportion of companies reporting post-approval activities on pregnancy and lactation were neurology (59%; 10/17), infectious disease (53%; 9/17), and pulmonology and allergy (47%; 8/17). Figure 2 summarizes all the therapeutic areas with post-approval activities. The product types with regard to which survey respondents conducted the post-approval activities included, among others small molecules, monoclonal antibodies, and proteins and peptides. Additionally, nearly all (88%, 15/17) survey participants had post-approval activities on pregnancy and lactation that were registered in the Heads of Medicines Agencies (HMA)-EMA Catalogue of real-world data (RWD) studies [16] and/or the National Institutes of Health (NIH) National Library of Medicine [17].

Figure 2.

Therapeutic areas with post-approval activities on pregnancy and/or lactation.

As shown in Fig. 3, most survey participants noted that the E2B(R3).was used for pregnancy and lactation primary data collection; however, other data formats were also utilized. Where “other” was selected by survey participants, the following data formats were cited (responses in free text): E2B R2, Council for International Organizations of Medical Sciences (CIOMS), MedWatch, clinical registries, standard internal case report form (CRF), follow-up forms, modified ConcePTION core data fields [18], and custom standard per study.

Figure 3.

Data format for primary data collection on pregnancy and lactation.

Post-approval Activities Focused on Data Generation in Pregnancy

All 17 survey participants conducted post-approval activities on pregnancy. Seventy-six percent (13/17) conducted post-approval activities that were proactively proposed by the Sponsor/MAH to the HAs, whereas 94% (16/17) conducted post-approval activities that were requested by the HAs (Fig. 4; participants could select more than 1 type of initiator).

Figure 4.

Number of post-approval activities on pregnancy: proposed by Sponsor/MAH vs requested by HAs.

Post-approval Activities Proposed by Sponsor/MAH—Types and Reason

Among the 13 survey participants that reported post-approval activities on pregnancy that were proactively proposed by the Sponsor/MAH to the HAs, 62% (8/13) had at least 1 post-approval activity with the following types: pregnancy registry, database study, or enhanced PV. Thirty-eight percent (5/13) of these survey participants proposed an interventional study, while only 23% (3/13) proposed a drug utilization study (Fig. 5).

Figure 5.

Types of post-approval activities on pregnancy: proposed by Sponsor/MAH vs requested by HAs.

In regards to the reason for post-approval activities on pregnancy that were proposed by the Sponsor/MAH to the HAs, the majority of proposals occurred at the initial marketing authorization application (MAA) for a new molecular entity (NME), while 31% (4/13) of the survey participants reported the reason as an anticipated HA request due to being first-in-class/mechanism of action (MOA) and only 8% (1/13) reported the reason to be a post-approval safety signal. Figure 6 summarizes all reported reasons for proposed activities on pregnancy.

Figure 6.

Reason for the post-approval activities on pregnancy: proposed by Sponsor/MAH vs requested by HAs.

Post-approval Activities Requested by HAs—Types and Reason

Among the 16 survey participants that reported post-approval activities on pregnancy that were requested by HAs, 88% (14/16) indicated that a pregnancy registry was the most frequently requested type of post-approval activity, followed by a database study (56%; 9/16), enhanced PV (50%; 8/16), a drug utilization study (25%; 4/16), and an interventional study (19%; 3/16) (Fig. 5).

The reason for most of the HA-requested activities was to address “missing information” on the use of medicine during pregnancy per Good Pharmacovigilance Practice ( GVP) Module V (75%; 12/16) and potential risks (56%; 9/16) in the safety specification of an NME during the initial MAA, whereas 38% (6/16) of survey participants indicated that the HA request during the initial MAA was due to missing information for a non-NME. Additionally, 44% (7/16) of survey participants indicated that the HA request was at a subsequent regulatory procedure interaction, while only 6% (1/16) indicated that HAs requested the activities to evaluate a post-approval safety signal (Fig. 6). Lastly, 71% (12/17) of all survey participants reported that more than 1 post-approval activity on pregnancy or lactation for at least 1 product was initiated due to varying HA requests for the same product.

Impact of Post-approval Activities on Pregnancy

The impact of post-approval activities on pregnancy (proposed by Sponsor/MAH and requested by HAs) by type of impact and activity is summarized in Fig. 7. For 59% (10/17) of all survey participants, data generated by the post-approval activities led to the inclusion of data in the PI, wherein the main sources of pregnancy data were pregnancy registries and database studies. Twenty-nine percent (5/17) of the survey participants reported a modification of pregnancy recommendation in the PI, with 4 participants reporting a loosening of restriction on pregnancy recommendation and 1 reporting an increase in restriction of pregnancy recommendation. The time intervals between initial MA and PI modification (reported by 4 survey participants) were between 5 and 10 years for half of the responding participants and greater than 10 years for the other half of responding participants.

Figure 7.

Impact of post-approval activities on pregnancy (proposed by Sponsor/MAH and requested by HAs).

For 41% (7/17) of the survey participants, the post-approval activities on pregnancy led to the removal of missing information from the RMP as per GVP V, while 6% (1/17) reported the reclassification of safety concern to important risk; these outcomes were based on data generated mainly from database studies and pregnancy registries, followed by enhanced PV and drug utilization studies. Twenty-nine percent (5/17) of participants reported development or modification of risk minimization measures (resulting from data generated from pregnancy registries, database studies, and enhanced PV) and 35% (6/17) reported that post-approval activities (mostly pregnancy registries followed by database studies, enhanced PV, and drug utilization studies) led to the initiation of another post-approval activity to generate additional data.

For 47% (8/17) of the survey participants, the post-approval activities resulted in an evaluation of a new safety finding; the most frequent sources of new safety findings were registries followed by database studies and interventional studies. Lastly, 53% (9/17) of all survey participants reported that pregnancy data (from mainly pregnancy registries, followed by enhanced PV and database studies) were published in posters, abstracts, or publications.

To provide numerical context to these impact outcomes, Table 3 summarizes results from multiple survey questions that allowed calculation of the lowest possible minimum and highest possible maximum number of post-approval activities on pregnancy (by type) and of impact outcomes (per post-approval activity) reflected in the survey responses.

Post-approval Activities Focused on Data Generation in Lactation

Seventy-one percent (12/17) of all the survey participants conducted post-approval activities on lactation, of which 42% (5/12) conducted post-approval activities that were proactively proposed by the Sponsor/MAH to the HAs and 100% (12/12) conducted post-approval activities that were requested by HAs (Fig. 8, participants could select more than 1 type of initiator). All 12 survey participants that reported post-approval activities on lactation (encompassing both Sponsor-proposed and HA-requested activities) responded that they conducted somewhere within a range of between 1 and 4 activities.

Figure 8.

Number of post-approval activities on lactation: proposed by Sponsor/MAH vs requested by HAs.

Post-approval Activities Proposed by Sponsor/MAH—Types and Reason

Among the 5 survey participants that reported post-approval activities on lactation that were proactively proposed by the Sponsor/MAH to the HAs, at least 1 participant conducted 2 types of post-approval activities. Specifically, more survey participants proposed a mother-infant pair study on lactation and a lactation sub-study in pregnancy registries compared to a lactating women (milk-only) study or a lactating women (milk and plasma) study (Fig. 9). The post-approval activities on lactation that were proposed by the Sponsor/MAH were primarily conducted at the beginning of the product life cycle, with the reported reasons being MA submission and first-in-class MA submission.

Figure 9.

Types of post-approval activities on lactation: proposed by Sponsor/MAH vs requested by HAs.

Post-approval Activities Requested by HAs—Types and Reason

Among the 12 survey participants that reported post-approval activities on lactation that were requested by HAs, there was a more even spread on the types of activities requested (i.e., lactating women [milk-only] study, lactating women [milk and plasma] study, lactation sub-study in pregnancy registries), with slightly fewer participants reporting a mother-infant pair study on lactation (Fig. 9). The reason for most of the HA-requested activities was to address early-stage requirements of the product life cycle, such as MA submission.

Impact of Post-approval Activities on Lactation

The impact of post-approval activities on lactation (proposed by Sponsor/MAH and requested by HAs) were reported by 11 survey participants, with only a minority of participants reporting that activities resulted in an actual outcome (each respondent could select more than 1 answer). Most survey participants reported 0 impact outcomes resulting from the lactation activities, regardless of whether the activity was proactively proposed by the Sponsor/MAH to the HAs or requested by HAs (Fig. 10). Of the reported impact outcomes (e.g., update of PI), these changes were typically implemented within 5 to 10 years and sometimes greater than 10 years after completion of the studies.

Figure 10.

Impact of post-approval activities on lactation (proposed by Sponsor/MAH and requested by HAs).