Regulatory Rapporteur
February 2025 | Vol. 22 | No. 2
Regulation (EC) 1901/2006 is clear that paediatric investigation plans (PIPs) apply to children from birth to 18 years of age, which omits the unborn foetus. To understand whether any recommendations exist which would support seeking agreement on a PIP for this special population, a review of European legislation, guidelines and other application precedents was undertaken. This article summarises the review and provides insight into distinctions that may be made by the agency in this matter, as well as highlighting relevant precedents which were identified during the review.
While PIPs are not required for foetal medicines, the Paediatric Development Committee (PDCO) appears willing to consider them. Filing a PIP could help de-risk development and represents a valuable opportunity to gauge whether the proposed clinical development plan meets other established requirements.
Considering legislation and guidelines
Regulation (EC) 1901/2006, (the ‘Paediatric Regulation’) is quite unequivocal in its scope, with Article 2 specifically stating that the paediatric population ‘means that part of the population aged between birth and 18 years’.[1] This clearly excludes the foetus in utero. It also limits the scope of PIPs to ‘ensuring the necessary data are generated …to treat the paediatric population’. This was known at the start of the review and the question remained as to whether this was the end of the matter.
Directive 2001/83/EC, (the ‘Medicinal Products Directive’), includes expectations for data to be presented on the use of a medicinal product in special populations, which includes pregnant and breastfeeding women, but not specifically unborn children.[2] Regulation (EC) 726/2004, (‘the Medicines Regulation’) also does not tackle this issue.[3]
Regulation (EU) No 536/2014 (the ‘Clinical Trial Regulation’ (CTR)), does include additional expectations for the assessment of clinical trial (CT) applications on pregnant women (Article 33) and the intention is to ensure that, where a trial is conducted in a pregnant woman, there is an expectation of direct benefit to that woman or their embryo or foetus, or their infant after birth.[4] Where such a benefit is not expected, the trial must contribute to the attainment of results capable of benefiting these groups in future. This suggests that the matter is not alien to the legislature.
Given this consideration in the Clinical Trial Regulation, there was optimism that the European Commission’s (EC) proposal for a new regulation and directive to revise and replace the existing legislation for pharmaceuticals might make a clearer distinction in this area.[5] Unfortunately, this has not been the case. As of February 2025, the definition of ‘paediatric population’ within the new Directive has remained unchanged.[6] The proposed Directive also maintains the existing recommendations regarding pregnant and breastfeeding women as being one of several special categories of users. Neither piece of legislation addresses or presents additional expectations for the development of treatments for use on a foetus in utero.
Guidelines specifically relevant to paediatric drug development were also considered and these are conveniently collated on the European Medicines Agency (EMA) website.[7] Over the years, several of these have been revised, so only the most recent revision was considered. To investigate the industry attitudes and opinions on a revised guideline, the most recent public consultation document was also reviewed to understand if concerns around foetal exposure were ever discussed. No significant recommendations on foetal medicine development were identified in the listed guidelines. Through the later PIP review, the ‘Guideline on clinical evaluation of vaccines’ was also examined, although this guideline is not listed on the EMA’s ‘Scientific guidelines: paediatrics’ list. This guideline makes recommendations on developing vaccines during pregnancy to impart immunity upon the newborn child, a matter already filtering its way through to approvals, as discussed below. Despite the absence of clear guidance on foetal medicine development, comments were identified that offer valuable insights into the EMA’s opinion.[8] A recommendation from industry to address the topic of foetal exposure to medicines was positively acknowledged, but considered to fall outside the scope of the guideline update:
‘Recommendation to pay specific attention to perinatal and foetal medicine as a part of neonatal medicine is supported and will be further discussed as appropriate; however, in utero drug exposure due to treatment of the mother is outside the scope of the guideline.’
While one comment is unlikely to be considered established opinion, two inferences were made:
- That the agency does recognise the need to clarify expectations when developing medicines for the unborn foetus
- That there is a distinction in the EMA’s thinking between in utero drug exposure from the treatment of the mother and in utero exposure with the intention to treat, diagnose or prevent disease in the foetus, which is a helpful distinction to be aware of
Tangentially, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is preparing a guideline on the inclusion of pregnant and breastfeeding women in CTs. While this is still only at the stage of being a concept paper (ICH E21), this suggests that a future guideline may address expectations for foetal exposure during pregnancy and provide recommendations on the need for studies in pregnant women and the effects of drugs on the unborn foetus, as well as how to assess the uncertainties from such exposures.
Paediatric investigation plans and Paediatric Development Committee (PDCO) discussion
Having identified a lack of legal framework, it was assumed that, if the PDCO had been asked to assess a plan for a medicine for use in unborn children, it was unlikely to refuse without at least acknowledging the reason why in its meeting minutes. A review of both the list of decisions and the PDCO minutes showed that the following drugs included conditions or populations of interest:
- RSVpreF3 and RSVpreF
- Retosiban
- Human Immunoglobulin G1 constant region and
- Anti-neonatal Fc receptor human monoclonal antibody
RSVpreF3 and RSVpreF
RSVpreF3 and RSVpreF are both respiratory syncytial virus (RSV) vaccines found to be for ‘maternal immunisation’. The paediatric study population covered in each of these PIPs related to the age of the mothers and not to the gestational age of the foetus during the period of vaccination. However, the indication targeted by both PIPs relates to the active immunisation of pregnant women to prevent RSV-associated lower respiratory tract illness in infants. This is consistent with the identified guideline recommendations discussed earlier. In both cases, PDCO minutes do appear to indicate that questions were asked,[9][10] but it is not possible to clarify the scope of the questions. Both of these PIPs arose from, and addressed, the needs of females of childbearing potential from an appropriate pubertal age and included waivers for all male and other female subsets.
RSVpreF was licensed as Abrysvo in September 2023. The European public assessment report (EPAR) was reviewed (EMA/351226/2023).[11] The clinical programme included a Phase IIb and a Phase III study in women exposed to the vaccine during pregnancy, which followed earlier development in other populations. The main inclusion criteria for the trial during pregnancy included an uncomplicated singleton (single foetus) pregnancy without assisted reproduction, no significant foetal abnormalities on ultrasound, mothers undergoing prenatal standard of care with a negative urinalysis for protein and glucose at screening (allowance for trace proteinuria if there was normal blood pressure) and a BMI of <40kg/m2 at screening.
Treatment was a result of indirect exposure and injections were into the mother’s deltoid. Maternal objectives included safety and tolerability as well as immune response. Infant objectives included the safety of maternal immunisation, the RSV antibody levels in the infant, and exploratory efficacy objectives relating to RSV positive lower respiratory tract illness (LRTI) and, in Phase III, reducing the severity of LRTI due to RSV. Follow-ups lasted for six months after delivery and monitoring included the duration of the pregnancy. Rates of foetal loss, congenital abnormalities, developmental delays and preterm delivery were compared between vaccinated and unvaccinated groups.
Both of these drugs are considered to be examples of indirect foetal exposure rather than direct treatment of the foetus.
Retosiban
Another result was for retosiban for the ‘treatment of spontaneous preterm labour’ with the indication ‘Treatment of spontaneous preterm labour to improve neonatal outcomes by prolonging pregnancy in women with an uncomplicated singleton pregnancy between 24 and less than 34 weeks gestation’. Retosiban has not undergone a compliance check as of January 2025 and therefore no EPAR is available for review. This PIP also includes an agreed waiver for males and pre-pubescent girls. This is likely to be an example of indirect foetal exposure rather than direct treatment of the foetus.
Human Immunoglobulin G1 constant region
Human Immunoglobulin G1 constant region, a human ectodyslasin-A1 receptor binding domain fusion protein (ER004), was the anticipated example of a PIP specifically for a treatment targeted at the developing foetus in utero rather than the mother. This product is for intra-amniotic use for the treatment of X-linked hypohidrotic ectodermal dysplasia (XLHED), also known as Christ-Siemens-Touraine Syndrome. XLHED is a disorder characterised by hyotrichosis (absence of hair growth on the head), adnodontia (complete absence of teeth) or hypodontia (absence of some teeth), and anhidrosis (absence of sweating) or hypohidrosis (inability to sweat efficiently).[12] Efforts were made to understand more about the drug and its development to date. ER004 is expected to replace the missing EDA1 protein in unborn patients with XLHED. ER004 holds an orphan drug designation and the Committee of Orphan Medicinal Products (COMP) opinion was reviewed and confirmed that XLHED is an orphan condition considered to affect <0.1 in 10,000 people in the EU at the time the designation was granted.[13]
The application for the PIP was originally filed in April 2021 and received a positive D60 opinion with no questions or comments from the PDCO.[14][15] No press release from the developer, EspeRare, could be identified to describe why a PIP had been sought, or to describe what benefit or benefits were anticipated. It did not appear that the drug was presently in the priority medicines (PRIME) scheme at the time of the review.[16] It is possible that agreement on a PIP was sought as a risk mitigation measure to demonstrate engagement with the PDCO or in response to a request to seek a PIP following an earlier agency engagement.
Anti-neonatal Fc receptor human monoclonal antibody
The final result was an anti-neonatal Fc receptor human monoclonal antibody for the ‘prevention of haemolytic disease of the foetus and newborn’ (HDFN). Similarly to ER004, efforts were made to understand more about the drug and its development to date. The drug was considered likely to be nipocalimab, a high profile product which holds orphan drug designation (ODD) in both the EU and the US, as well as US Fast Track and Breakthrough Designations, and which recent press releases show has completed phase II development.[17]
Agreed PIPs/waivers for the drug were present in the PDCO list for other conditions (autoimmune haemolytic anaemia, chronic inflammatory demyelinating polyradiculoneuropathy and warm autoimmune haemolytic anaemia). HDFN is another example of a condition that occurs during pregnancy where the blood types of the pregnant mother and the foetus are incompatible, potentially resulting in anaemia in the foetus or the newborn.[18] The mechanism of action is described by the developer as follows: ‘nipocalimab…is believed to selectively block the FcRn to reduce levels of circulating IgG antibodies…FcRn blockade is also believed to prevent placental transfer of maternal alloantibodies to the fetus’.[19] Unlike ER004 described above, here the sponsor had sought and successfully obtained a waiver on the grounds that the disease does not occur in subsets of the paediatric population (in relation to treatment of males) and that it does not represent a significant therapeutic benefit over existing treatments (in relation to females of childbearing potential) (Articles 11(1)(b) and 11(1)(c) of Regulation (EC) No. 1901/2006 respectively). Based on the described mechanism of action, it is considered likely that any PIP would relate to the treatment of women of childbearing potential rather than addressing indirect foetal exposure.
These products were considered to support the inference that the EMA makes a distinction between exposure due to treatment of the mother and in utero drug exposure where the intention is to treat the foetus given the stated paediatric populations concerned by each.
A similar strategy was also applied to drugs with orphan designations which resulted in two further results, both of which are for the ‘prevention of fetal and neonatal alloimmune thrombocytopenia (FNAIT)’. FNAIT is a condition where maternal alloantibodies are directed against antigens present on the foetal and neonatal platelets with diagnosis depending on demonstrating maternal/neonatal or maternal/paternal platelet antigen incompatibility.[20] These drugs, and the condition, were both searched for in the list of agreed PIPs but neither was located. It was considered likely that both ‘human platelet antigen-1a immunoglobulin’ and ‘anti-(integrin beta-3) human monoclonal antibody’ may either be separate assets or the same asset under development by Rallybio. Prophylix, the original sponsor of ‘human platelet antigen-1a immunoglobulin’ was acquired by Rallybio in August 2019.[21] Both orphans are presently held by the same EU agent. Rallybio’s pipeline describes RLYB212 as an ‘anti-HPA-1a monoclonal antibody’;[22] however, on National Library of Medicine, RLYB212 is described as an ‘anti-(integrin beta-3) human monoclonal antibody’[23] and the mechanism of action is described by Rallybio as ‘RLYB212 is designed to rapidly eliminate HPA-1a positive fetal platelets from an expectant mother’s circulation, thereby preventing HPA-1a alloimmunization and eliminating risk of FNAIT’,[24] which would suggest that any PIP for the drug may ultimately only include women of childbearing potential rather than addressing indirect foetal exposure.
Finally, the strategy was repeated with EPARs but none of the results were deemed to be of more significant interest than what has been described above.
Conclusion
Existing and planned EU pharma legislation and guidelines confirm ICON’s initial opinion that PIPs are not technically necessary where a medicine is developed for treatment of the foetus in utero. This appears unlikely to change in the foreseeable future.
Despite this, based on limited precedent, ICON has been able to determine that, as expected, the PDCO will consider a PIP for the treatment of the foetus in utero. There may be strategic grounds for filing such a PIP: such products appear to be rare and the PIP may help to derisk development. Prior to undertaking such a filing, initial approaches such as seeking advice or a designation to support development (for example, PRIME) would be an advisable first step, particularly as members of the PDCO, particularly the neonatal group, are likely to be involved and would contribute recommendations on evaluating potential outcomes in neonates.
A PIP is required for cases of in utero drug exposure from treatment of the mother but the population concerned by such a PIP will be women of childbearing potential.
Acknowledgements
The author would like to thank Jo Dewhurst, Director, Centre for Paediatric Clinical Development, and Karen Benson, Director, Global Regulatory Strategy, and Martine Dehlinger Kremer, Vice President Scientific Affairs and Paediatric Subject Matter Expert at ICON for constructive criticism of the initial manuscript.
References
[1] European Union (EU) (2006) ‘Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004’. (Accessed: 31 January 2025).
[2] European Union (EU) (2001) ‘Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use’. (Accessed: 29 January 2025).
[3] European Union (EU) (2004) ‘Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency’. (Accessed 31 January 2025).
[4] European Union (EU) (2012) ‘Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC’. (Accessed 31 January 2025).
[5] European Commission (EC) (2023) ‘Reform of the EU pharmaceutical legislation’. (Accessed: 29 January 2025).
[6] European Union (EU) (2023) ‘Proposal for a DIRECTIVE OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL on the Union code relating to medicinal products for human use, and repealing Directive 2001/83/EC and Directive 2009/35/EC’. (Accessed: 29 January 2025).
[7] European Medicines Agency (EMA) ‘Scientific guidelines: paediatrics’. (Accessed: 29 January 2025).
[8] European Medicines Agency (EMA) (2019) ‘Comments received during the Public Consultation on ‘Concept paper on the need for revision of the guideline on the investigation of medicinal products in the term and preterm neonate’ (EMA/PDCO/362462/2016)’. (Accessed: 31 January 2025)
[9] European Medicines Agency (EMA) (2021) ‘Paediatric Committee (PDCO) Minutes for the meeting on 23-26 March 2021’. (Accessed: 31 January 2025).
[10] European Medicines Agency (EMA) (2021) ‘Paediatric Committee (PDCO) Minutes for the meeting on 26-29 January 2021’. (Accessed: 31 January 2025).
[11] European Medicines Agency (EMA) (2023) ‘Assessment report – Abrysvo’. (Accessed: 31 January 2025).
[12] Schneider H, Hadj-Rabia S, Faschingbauer F, Bodemer C , Grange D, Norton M, Cavalli R, Tadini G, Stepan H, Clarke A, Guillén-Navarro E, Maier-Wohlfart S, Bouroubi A and Porte F (2023) ‘Protocol for the Phase 2 EDELIFE Trial Investigating the Efficacy and Safety of Intra-Amniotic ER004 Administration to Male Subjects with X-Linked Hypohidrotic Ectodermal Dysplasia’. Genes (Basel), Vol. 14(1):153. doi: 10.3390/genes14010153.
[13] European Medicines Agency (EMA) (2005) ‘EU/3/05/334 - orphan designation for treatment of X-linked hypohidrotic ectodermal dysplasia (Christ-Siemens-Touraine Syndrome)’. (Accessed: 31 January 2025).
[14] European Medicines Agency (EMA) (2021) ‘Paediatric Committee (PDCO) Minutes of meeting 18-21 May 2021’. (Accessed: 29 January 2025).
[15] European Medicines Agency (EMA) (2021) ‘Paediatric Committee (PDCO) Minutes for the meeting on 22-25 June 2021’. (Accessed: 31 January 2025).
[16] European Medicines Agency (EMA) (2024) ‘List of medicines currently in PRIME scheme’. (Accessed: 18 September 2024).
[17] Janssen Global Services (2024) ‘Groundbreaking nipocalimab study of pregnant individuals at high risk for early onset severe hemolytic disease of the fetus and newborn published in The New England Journal of Medicine’. (Accessed: 31 January 2025).
[18] Hall V, Vadakekut E, Avulakunta, ID (2024) ‘Hemolytic Disease of the Fetus and Newborn’. StatPearls Publishing LLC. (Accessed 31 January 2025).
[19] Johnson & Johnson (2023) ‘New Phase 2 Data Demonstrate Potential Benefit of Nipocalimab for Pregnant Individuals at High Risk of Early-Onset Severe Hemolytic Disease of the Fetus and Newborn (HDFN)’. (Accessed: 31 January 2025).
[20] Regan F, Lees CC, Jones B, Nicolaides KH, Wimalasundera RC and Mijovic A (2019) ‘Prenatal Management of Pregnancies at Risk of Fetal Neonatal Alloimmune Thrombocytopenia (FNAIT)’. British Journal of Obstetrics and Gynaecology. Vol. 126, pp. 173-185. doi: 10.1111/1471-0528.15642
[21] Prophylix AS (2019) ‘Prophylix AS Rare Disease Programs Acquired by Rallybio’. (Accessed: 31 January 2025).
[22] Rallybio ‘RLYB212’. (Accessed: 31 January 2025).
[23] National Library of Medicine (2024) ‘Phase 2 Study on the Pharmacokinetics and Safety of RLYB212 in Pregnant Women at Higher Risk for HPA-1a Alloimmunization’. ClinicalTrials.gov. (Accessed: 31 January 2025).
