SGLT2 Inhibitors are Blockbusters in Adults - But Not Studied in Children with Kidney Disease due to Industry Conflicts of Commercial Interest: A Call for Help To Regulators
Main Article Content
Abstract
This article reviews the circumstances why and how the pharmaceutical industry is avoiding the pediatric investigation plans for their block-buster drugs in chronic kidney diseases. The "why" is easy to answer because it is just about economic reasons. This is much to the disadvantage of sick children, who are thus deprived of the opportunity for evidence-based therapy. Just as in the time prior to the pediatric trial regulation, pediatricians remain in a legal gray zone of off-label use and expose themselves to the risk of lawsuits. The article is intended to start a discussion on how regulatory authorities could support the development of better treatment recommendations for children with kidney disease for drugs that are not promoted by the industry. This could be by working more closely with patient representatives and academia, by supporting the planning phase of investigator-initiated trials, or by scientific advice on cumulative real world and randomized controlled trial data on specific medications or substance groups.
Keywords:
Dapagliflozin, Empagliflozin, Ramipril, SGLT2-inhibitors, ACE-inhibitors, pediatric investigation plan, chronic kidney disease, children, pediatrics, Alport syndrome, off-label use in children
Article Details
How to Cite
GROSS, Oliver.
SGLT2 Inhibitors are Blockbusters in Adults - But Not Studied in Children with Kidney Disease due to Industry Conflicts of Commercial Interest: A Call for Help To Regulators.
Medical Research Archives, [S.l.], v. 11, n. 8, sep. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4383>. Date accessed: 04 dec. 2024.
doi: https://doi.org/10.18103/mra.v11i8.4383.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Press release University Medicine Goettingen, July 7, 2023. Accessed August 9, 2023. https://www.umg.eu/en/presse/news-detail/news-detail/detail/news/chronic-kidney-disease-in-children-new-drug-study/
2. Daga S, Ding J, Deltas C, et al. The 2019 and 2021 International Workshops on Alport Syndrome. Eur J Hum Genet. 2022;30(5):507-516.
3. Mabillard H, Sayer JA. SGLT2 inhibitors - a potential treatment for Alport syndrome. Clin Sci (Lond). 2020;134(4):379-388.
4. Zeng M, Di H, Liang J, Liu Z. Effectiveness of renin-angiotensin-aldosterone system blockers in patients with Alport syndrome: a systematic review and meta-analysis. Nephrol Dial Transplant. 2023;May 22:gfad105. doi: 10.1093/ndt/gfad105
5. Gross O, Tönshoff B, Weber LT, et al. A multicenter, randomized, placebo-controlled, double-blind phase 3 trial indicates safety and efficacy of nephroprotective therapy in children with Alport’s. Kidney Int. 2020;97(6):1275-1286.
6. Gross O, Licht C, Anders HJ, et al. Early angiotensin converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy. Kidney Int. 2012;81:494-50.
7. Weinstock BA, Feldman DL, Fornoni A, et al. Clinical trial recommendations for potential Alport syndrome therapies. Kidney Int. 2020;97(6):1109-1116.
8. Boeckhaus J, Gross O. Sodium-Glucose Cotransporter-2 Inhibitors in Patients with Hereditary Podocytopathies, Alport Syndrome, and FSGS: A Case Series to Better Plan a Large-Scale Study. Cells. 2021;10(7),1815.
9. Google platform for patents from around the world. Accessed July 23, 2023. https://patents.google.com/patent/WO2020020896A1/en
10. European Medicines Agency decision P/0373/2018 of 7 December 2018. PIP number EMEA-000694-PIP04-18. Accessed July 23, 2023. https://www.ema.europa.eu/en/documents/pip-decision/p/0373/2018-ema-decision-7-december-2018-granting-product-specific-waiver-dapagliflozin-forxiga-emea-000694_en.pdf
11. European Medicines Agency decision P/0082/2019 of 22 March 2019. PIP number EMEA-000828-PIP06-18. Accessed July 23, 2023. https://www.ema.europa.eu/en/documents/pip-decision/p/0082/2019-ema-decision-22-march-2019-granting-product-specific-waiver-empagliflozin-jardiance-emea-000828_en.pdf
12. Ge M, Molina J, Kim JJ, et al. Empagliflozin reduces podocyte lipotoxicity in experimental Alport syndrome. Elife. 2023;12:e83353. doi: 10.7554/eLife.83353.
13. Zhu Z, Rosenkranz KA, Kusunoki Y, et al. Finerenone Added to RAS/SGLT2 Blockade for Chronic Kidney Disease in Alport Syndrome. Results of a Randomized Controlled Trial with Col4a3-/- Mice. J Am Soc Nephrol. 2023;Jul 10. doi: 10.1681/ASN.0000000000000186.
14. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446.
15. Herrington WG, Staplin N, Wanner C, et al. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023;388(2):117-127.
16. THE VOICE OF THE PATIENT Externally Led Patient–Focused Drug Development Meeting on Alport Syndrome. Submitted as patient experience data for consideration Pursuant to section 569C of the Federal Food, Drug, and Cosmetic Act to: Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration (FDA). This report reflects the National Kidney Foundation’s and Alport Syndrome Foundation’s accounts of the perspectives of patients and caregivers who participated in an Externally Led Patient-Focused Drug Development Meeting, an effort to support the FDA’s Patient-Focused Drug Development Initiative. Public Meeting: August 3, 2018. Report Date: November 1, 2019. Accessed July 23, 2023. https://www.kidney.org/sites/default/files/vop_alport-syndrome_20191101.pdf
17. Help for children with kidney disease. Video portrait by the German Ministry of Education and Research, BMBF. Accessed July 23, 2023. https://www.gesundheitsforschung-bmbf.de/de/videoportrait-hilfe-fur-nierenkranke-kinder-14890.php
18. Röver C, Sturtz S, Lilienthal J, Bender R, Friede T. Summarizing empirical information on between-study heterogeneity for Bayesian random-effects meta-analysis. Stat Med. 2023;42(14):2439-2454.
19. Kasthan CE, Gross O. Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults-an update for 2020. Pediatr Nephrol 2021;36(3):711-719.
20. Proposal for a framework to support not-for-profit organisations and academia (institutions and individuals) in drug repurposing. Prepared by a working group of the Safe and Timely Access to Medicines for Patients (STAMP) expert group. June 2019. Accessed August 12, 2023. https://health.ec.europa.eu/system/files/2021-10/pharm773_repurposing_annex_en_0.pdf
21. Khurana M, Egger GF, Yao L, Thompson A, Pallidis C, Goldstein SL, Laskin BL, Tuchman S, Malley MA, Uhlig K. Overcoming Barriers to Drug Development in Children with CKD. Clin J Am Soc Nephrol. 2023;18(8):1101-110
2. Daga S, Ding J, Deltas C, et al. The 2019 and 2021 International Workshops on Alport Syndrome. Eur J Hum Genet. 2022;30(5):507-516.
3. Mabillard H, Sayer JA. SGLT2 inhibitors - a potential treatment for Alport syndrome. Clin Sci (Lond). 2020;134(4):379-388.
4. Zeng M, Di H, Liang J, Liu Z. Effectiveness of renin-angiotensin-aldosterone system blockers in patients with Alport syndrome: a systematic review and meta-analysis. Nephrol Dial Transplant. 2023;May 22:gfad105. doi: 10.1093/ndt/gfad105
5. Gross O, Tönshoff B, Weber LT, et al. A multicenter, randomized, placebo-controlled, double-blind phase 3 trial indicates safety and efficacy of nephroprotective therapy in children with Alport’s. Kidney Int. 2020;97(6):1275-1286.
6. Gross O, Licht C, Anders HJ, et al. Early angiotensin converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy. Kidney Int. 2012;81:494-50.
7. Weinstock BA, Feldman DL, Fornoni A, et al. Clinical trial recommendations for potential Alport syndrome therapies. Kidney Int. 2020;97(6):1109-1116.
8. Boeckhaus J, Gross O. Sodium-Glucose Cotransporter-2 Inhibitors in Patients with Hereditary Podocytopathies, Alport Syndrome, and FSGS: A Case Series to Better Plan a Large-Scale Study. Cells. 2021;10(7),1815.
9. Google platform for patents from around the world. Accessed July 23, 2023. https://patents.google.com/patent/WO2020020896A1/en
10. European Medicines Agency decision P/0373/2018 of 7 December 2018. PIP number EMEA-000694-PIP04-18. Accessed July 23, 2023. https://www.ema.europa.eu/en/documents/pip-decision/p/0373/2018-ema-decision-7-december-2018-granting-product-specific-waiver-dapagliflozin-forxiga-emea-000694_en.pdf
11. European Medicines Agency decision P/0082/2019 of 22 March 2019. PIP number EMEA-000828-PIP06-18. Accessed July 23, 2023. https://www.ema.europa.eu/en/documents/pip-decision/p/0082/2019-ema-decision-22-march-2019-granting-product-specific-waiver-empagliflozin-jardiance-emea-000828_en.pdf
12. Ge M, Molina J, Kim JJ, et al. Empagliflozin reduces podocyte lipotoxicity in experimental Alport syndrome. Elife. 2023;12:e83353. doi: 10.7554/eLife.83353.
13. Zhu Z, Rosenkranz KA, Kusunoki Y, et al. Finerenone Added to RAS/SGLT2 Blockade for Chronic Kidney Disease in Alport Syndrome. Results of a Randomized Controlled Trial with Col4a3-/- Mice. J Am Soc Nephrol. 2023;Jul 10. doi: 10.1681/ASN.0000000000000186.
14. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446.
15. Herrington WG, Staplin N, Wanner C, et al. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023;388(2):117-127.
16. THE VOICE OF THE PATIENT Externally Led Patient–Focused Drug Development Meeting on Alport Syndrome. Submitted as patient experience data for consideration Pursuant to section 569C of the Federal Food, Drug, and Cosmetic Act to: Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration (FDA). This report reflects the National Kidney Foundation’s and Alport Syndrome Foundation’s accounts of the perspectives of patients and caregivers who participated in an Externally Led Patient-Focused Drug Development Meeting, an effort to support the FDA’s Patient-Focused Drug Development Initiative. Public Meeting: August 3, 2018. Report Date: November 1, 2019. Accessed July 23, 2023. https://www.kidney.org/sites/default/files/vop_alport-syndrome_20191101.pdf
17. Help for children with kidney disease. Video portrait by the German Ministry of Education and Research, BMBF. Accessed July 23, 2023. https://www.gesundheitsforschung-bmbf.de/de/videoportrait-hilfe-fur-nierenkranke-kinder-14890.php
18. Röver C, Sturtz S, Lilienthal J, Bender R, Friede T. Summarizing empirical information on between-study heterogeneity for Bayesian random-effects meta-analysis. Stat Med. 2023;42(14):2439-2454.
19. Kasthan CE, Gross O. Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults-an update for 2020. Pediatr Nephrol 2021;36(3):711-719.
20. Proposal for a framework to support not-for-profit organisations and academia (institutions and individuals) in drug repurposing. Prepared by a working group of the Safe and Timely Access to Medicines for Patients (STAMP) expert group. June 2019. Accessed August 12, 2023. https://health.ec.europa.eu/system/files/2021-10/pharm773_repurposing_annex_en_0.pdf
21. Khurana M, Egger GF, Yao L, Thompson A, Pallidis C, Goldstein SL, Laskin BL, Tuchman S, Malley MA, Uhlig K. Overcoming Barriers to Drug Development in Children with CKD. Clin J Am Soc Nephrol. 2023;18(8):1101-110