Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Sex hormones and their antagonists: unmet medical needs in rare and paediatric diseases

Dr. Ilona Ahonen (Abschlußjahr: 2021)

Summary
Language: English
The sex hormones testosterone and estrogen and their antagonists are used in medicinal products for e.g. male hypogonadism, menopause symptoms and prostate and breast cancers. They are also used in treatment of rare diseases, such as gender dysphoria (GD), which is the major focus of this work, and disorders of sex development (DSDs), which partially overlap with GD. In masculinizing hormone therapy, testosterone is given to female-to-male transgender persons who have GD, to establish greater congruence of the patient’s body with their gender identity. In the same way, estrogen, and sometimes testosterone antagonists, are given to male-to-female transgender persons in feminizing hormone therapy. Not only adults but also paediatric population (under 18 years) may be treated. Additionally, puberty suppression treatment with GnRH agonists may be given to paediatric patients who have GD (and/or a DSD). Treatment of paediatric GD patients is a matter of controversy, and while proponents wish to increase the availability of the treatment, opposing voices claim that it should not be conducted at all. Reportedly, feminizing/masculinizing hormone therapy and puberty suppression treatment tend to fall under off-label use, meaning that there are no medicinal products that have marketing authorization for GD, and thus there is an unmet medical need for this condition.
Aims of this work were to confirm the reported lack of authorized products for hormonal treatment of GD in the EU, to characterize the products that are used for off-label treatment of GD patients, and to outline hypothetical development of a medicinal product for this indication, exploring what steps would be needed to obtain a marketing authorization. Motivation of pharmaceutical companies to obtain an authorization for hormonal treatment of GD is discussed in the work, as well as ethical controversialities regarding the treatment, especially the treatment of paediatric population.
Searches in European authorization databases confirmed the lack of authorizations for GD for testosterone, the estrogen estradiol, the testosterone antagonist cyproterone acetate and the testosterone/estrogen antagonist (GnRH agonist) goserelin. These substances were selected as representative substances for hormonal treatment of GD. There are no centrally authorized products (for any indication) available for these substances, but several MRP/DCP/nationally authorized products are available for each substance (for indications other than GD).
Searches in clinical trial databases showed that some clinical trials on hormonal treatment of GD are conducted by academic institutions, and some of the studies include paediatric population. However, no controlled Phase 3 trials to show a specific product’s efficacy and safety in GD patients have been conducted. Thus, hypothetically, if a company would develop a medicinal product for GD, they would need to conduct at least one Phase 3 clinical trial. Studies on paediatric population would also need to be conducted, according to a PIP agreed by EMA’s PDCO. Conducting such paediatric studies would be challenging due to practical and ethical concerns.
To obtain an authorization for GD, a company could submit an indication extension application (Type II variation) for an existing product, via MRP/DCP or national process. At least an updated SmPC and the clinical study report of a phase 3 clinical trial would need to be included in the submission.
Responses from two companies were received to an anonymous survey on potential authorizations of hormonal treatment products for GD. Interestingly, both companies stated that submitting such a MAA application in the future could be a possibility.
The confirmed lack of authorized products for hormonal treatment of GD means that there is an unmet medical need for this indication in the EU in both adult and paediatric populations. An authorization process, and especially the generation of data to support the GD indication, would be laborious and costly. As initial authorizations of the available products are usually from long ago, competitor products are already on the market, and return on investment might not justify the costs. In that case there would be no incentive for companies to proceed with indication extensions for GD. An orphan designation or a PUMA would bring a long market exclusivity and thus increase incentive. However, an orphan designation would not be certain due to GD’s ambiguous prevalence and classification, and a PUMA would require successful conduct of paediatric clinical trials. Initiatives to increase authorizations for rare and paediatric conditions, such as European Commission’s plan to revise the orphan and paediatric regulations, might increase incentive to obtain authorization for treatment of GD and DSDs with sex hormones and their antagonists.
Pages: 86
Annexes: 2, Pages: 21