Scientific considerations for global drug development

Wilson, Jennifer; Cheung, Kit Wun Kathy; Lin, Lawrence; Green, Elizabeth A.E.; Porrás, Analía; Zou, Ling; Mukanga, David; Akpa, Paul A.; Darko, Delese Mimi; Yuan, Rae; Ding, Sheng; Johnson, Wiltshire C. N.; Lee, Howard A.; Cooke, Emer; Peck, Carl C.; Kern, Steven E.; Hartman, Dan; Hayashi, Yoshikazu; Marks, Peter; Altman, Russ B.; Giacomini, Kathleen M.; Blaschke, Terrence F.

doi:10.1126/scitranslmed.aax2550

Cited by 8 publications

(10 citation statements)

References 30 publications

(35 reference statements)

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“…Worldwide experience with all LSD types has uncovered no known founder effect or specific geographic predilection [ 27 – 29 ]. It is important to consider the international translation of clinical trials for novel drug treatments in resource-poor countries along with the development of collaborative, international data sets [ 30 ]. Disparities within countries should also be considered.…”

Section: Discussionmentioning

confidence: 99%

Fetal therapies and trials for lysosomal storage diseases: a survey of attitudes of parents and patients

Schwab

Brown

Lianoglou

et al. 2022

Orphanet J Rare Dis

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Background Lysosomal storage diseases (LSDs) are inherited metabolic disorders that may lead to severe multi-organ disease. Current ERTs are limited by anti-drug antibodies, the blood–brain barrier, and early disease onset and progression before ERT is started. We have opened a phase I clinical trial of enzyme replacement therapy (ERT) for fetuses with LSDs (NCT04532047). We evaluated the attitudes of parents and patients with LSDs towards fetal clinical trials and therapies. Methods A multidisciplinary team designed a survey which was distributed by five international patient advocacy groups. We collected patients’ demographic, diagnostic, and treatment information. Associations between respondent characteristics and attitudes towards fetal therapies/trials were analyzed using multivariate ordinal logistic regression. Results The survey was completed by 181 adults from 19 countries. The majority of respondents were mothers from the United States. The most common diseases were MPS1 (26%), MPS3 (19%), and infantile-onset Pompe (14%). Most patients (88%) were diagnosed after birth, at a median of 21 months. Altogether, 65% of participating patients and children of participants had received ERT, 27% a stem cell transplant, and 4% gene therapy. We found that half (49%) of respondents were unlikely to terminate a future affected pregnancy, 55% would enroll in a phase I clinical trial for fetal ERT, and 46% would enroll in a fetal gene therapy trial. Respondents who received postnatal ERT were significantly more likely enroll in a trial for fetal ERT or gene therapy (ERT OR 4.48, 95% CI 2.13–9.44, p < 0.0001; gene therapy OR 3.03, 95% CI 1.43–6.43, p = 0.0038). Respondents who used clinicaltrials.gov as a main source of information were more likely to choose to participate in a fetal trial (ERT OR 2.43, 95% CI 1.18–5.01, p = 0.016; gene therapy OR 2.86, 95% CI 1.27–6.46, p = 0.011). Conclusions Familiarity with postnatal ERT increased respondents’ likelihood of pursuing fetal therapies. Families who use clinicaltrials.gov may be more receptive to innovative fetal treatments. The patient community has a favorable attitude towards fetal therapy; over half of respondents would enroll in a phase I clinical trial to assess the safety and efficacy of fetal ERT.

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Section: Discussionmentioning

confidence: 99%

Fetal therapies and trials for lysosomal storage diseases: a survey of attitudes of parents and patients

Schwab

Brown

Lianoglou

et al. 2022

Orphanet J Rare Dis

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“…3 Reliance: is employed for products already approved by other stringent regulatory agencies and involves either a verification review process to validate that the product conforms to the previously authorized specifications or an abridged evaluation that takes into consideration local factors and environment. 4 SAHPRA inherited medical products dossiers from its predecessor, the Medicines Control Council that dates back to 1992, which is being cleared via a detailed separate strategy from the business as usual (current) dossiers.…”

Section: The Regulatory Assessment Pathways Used In Africamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…There is a critical skills gap on the African continent in regulatory sciences, and an acknowledged need to develop a long‐term strategy for training and professional development of African regulatory personnel. 1 , 2 , 3 , 4 Due to multiple factors including the low presence of research‐based pharmaceutical industries on the African continent, the available clinical pharmacology and regulatory sciences skills and expertise are extremely underutilized, often resulting in the flight of this talent to other parts of the world. The increase in new biotechnological products and advances in medical device technology as well as the evolving digital health landscape have challenged regulators across the world to stay updated with the development, manufacture and the use of these products in clinical settings.…”

Section: Introductionmentioning

confidence: 99%

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Needs‐driven talent and competency development for the next generation of regulatory scientists in Africa

Semete-Makokotlela¹,

Mahlangu

Mukanga

et al. 2021

Brit J Clinical Pharma

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Funding informationBill & Melinda Gates Foundation Capacity building programmes for African regulators should link education, training and research with career development in an approach that combines an academic base and experiential learning aligned within a competency framework. A regulatory ecosystem that engages with a broad range of stakeholders will mean that expertise in the ever-expanding field of regulatory science filters into teaching and research in a symbiotic way. In this way capacity development interventions will be a collaborative approach between the learning context (academic and training institutions) and the performance context (regulatory agencies and industry), which will ultimately best serve the patients. Monitoring and evaluation of capacity development interventions will be essential to show value of investments and ultimately guide continued funding and sustainability. This paper reviews the skills and human capacity gaps, reports on regulatory assessment pathways used in Ghana, South Africa and Zimbabwe and outlines a staged tactical approach for Africa that builds on previous efforts to strengthen African regulatory ecosystems.

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“…A notably challenging issue is why many drugs that meet the requirements for successful indication of safety and efficacy in phase I and II clinical trials fail to show comparable activity in phase III trials [ 29 , 32 ] . New approaches in clinical study design, such as the use of phase 0 designs [ 33 ] , window of opportunity trials for biomarker discovery [ 34 ] , and/or a more effective use of data from regional/global populations [ 35 ] , continue to emerge. These and other advances may yet change the standard workflows for screening and developing some agents and eventually improve the success rate for new drugs completing phase III clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Experimental models of endocrine responsive breast cancer: strengths, limitations, and use

Clarke

Jones

Sevigny

et al. 2021

CDR

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Breast cancers characterized by expression of estrogen receptor-alpha (ER; ESR1) represent approximately 70% of all new cases and comprise the largest molecular subtype of this disease. Despite this high prevalence, the number of adequate experimental models of ER+ breast cancer is relatively limited. Nonetheless, these models have proved very useful in advancing understanding of how cells respond to and resist endocrine therapies, and how the ER acts as a transcription factor to regulate cell fate signaling. We discuss the primary experimental models of ER+ breast cancer including 2D and 3D cultures of established cell lines, cell line-and patient-derived xenografts, and chemically induced rodent models, with a consideration of their respective general strengths and limitations. What can and cannot be learned easily from these models is also discussed, and some observations on how these models may be used more effectively are provided. Overall, despite their limitations, the panel of models currently available has enabled major advances in the field, and these models remain central to the ability to study mechanisms of therapy action and resistance and for hypothesis testing that would otherwise be intractable or unethical in human subjects.

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Scientific considerations for global drug development

Cited by 8 publications

References 30 publications

Fetal therapies and trials for lysosomal storage diseases: a survey of attitudes of parents and patients

Fetal therapies and trials for lysosomal storage diseases: a survey of attitudes of parents and patients

Needs‐driven talent and competency development for the next generation of regulatory scientists in Africa

Experimental models of endocrine responsive breast cancer: strengths, limitations, and use

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