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Having studied the conduct of a cross-European Phase III Clinical Trial in an acute setting under strict Advanced Therapy Investigational Medicinal Products (ATIMP) conditions we observe with great interest how the paradigm of the three phases of clinical trials, with particular emphasis on phase III, is being re-evaluated under present pandemic conditions. Although in order to advance in medicine it is indeed high time for reconsidering the when and how of the phase III trial, for reasons of good science as well as patient safety, new vaccines and drug treatments to stop a pandemic are not the place.
Long before the arrival of Sars-Covid-2 the phase III clinical trial had become contentious as the pinnacle of scientific medicine. New approaches in research and the technologies that underpin them juxtapose the premise on which the format of the three phases of clinical trials is built. One changing epistemic condition is the fine-tuning of diagnostic markers and categories, noticeable for example in cancer diagnosis and treatment. A second are tailored treatments, personalized medicine, such as therapeutics and procedures using tissues from the patient. There is an epistemic contradiction between the routes toward personalized medicine and the ideals of mass application that a phase III trial is designed to evidence. The lack of agreeing new evidential standards has contributed to a growing private market where desperate patients buy treatments in the growing category of treatments that have not been approved as therapies because of lacking evidence, but not proven ineffective either. Thirdly, rare diseases are inevitably marginalized if medical research is geared toward mass markets. There is rising pressure from within the medical professions as well as from patient groups. It appears unjust and in conflict with medical ethics if research is conducted in ways that delegitimize seeking cures for illnesses that affect very few patients. Furthermore, we must ask who should determine research pathways and the future of cures that become available. Big Pharma domineer medical science as long as phase III trial evidence is required for the approval of new treatments and there is no international public institutions with the means to fund big clinical trials for the public good.
The above failings in the present system are key reasons to question the primacy and universal adequacy of the phase III trial for medical science. The regenerative medicine clinical trial we bore witness to failed to produce a conclusive result concerning the stem cell procedure in question. Arguably, current regulations that require autologous cell-based treatments to be evidenced via phase III trials in the heavily controlled ATIMP format are not appropriate for this type of treatment approach.
The pressure produced by the mass of Covid-19 infections creates a situation where many urge reconsideration of the evidentiary standards applied in the approval of clinical treatments. The reasons for shaking up the phase III rule book are not sound in terms of medical epistemology, clinical practice or medical ethics and the desire to avoid as many infections as possible; we also frequently hear about the need to save the economy or be first among competing countries to rake in the revenue form scientific success in the global Covid-19 marketplace. Drugs and vaccines against the effects of Sars-Covid-2 are being considered for fast track rollout. The safety and global efficacy of drugs and vaccines is, however, the very type of medical treatments for which the clinical trial pyramid was designed. Is it right to give up epistemic standards not for treatments of a different nature but for drugs and vaccines designed for global use?
The COVID-19 situation has highlighted that there are circumstances when the esteemed one-size fits all phase III trial does not meet diverse societal needs for new and advanced treatment options. In an essay on the Ebola epidemic in West Africa, Philippe Calain recalls that the epidemic showed the ‘limits of a dogmatic understanding of clinical research’. He calls for an evolution in the current paradigms of therapeutic research with an increased flexibility in the choice of trial designs or emergency use but with reinforced safeguards including attention to ethics oversight. The pandemic is not the occasion to rashly loosen rigour, transparency and meticulous controls and monitoring. But it could start a thorough critical discussion about the methodologies of medical research and the strengths and weaknesses of clinical trial structures. What is needed is a multidisciplinary, collaborative and methodical analysis of different medical needs and treatment pathways and the evidence that is deemed epistemologically and ethically sound and sufficient for approval. This discussion can start with the reasons and circumstances that justify deviation from the established ideal mode of evidencing efficacy and benefit.
1 See recently Tanne Janice Hopkins. Covid-19: US will not join WHO in developing vaccine BMJ 2020; 370 :m3396. https://www.bmj.com/content/370/bmj.m3396.
2 Lin JA, He P. Reinventing clinical trials: a review of innovative biomarker trial designs in cancer therapies. British Medical Bulletin 2015, 114 17-27. https://doi.org/10.1093/bmb/ldv011.
3 Keating P, Ambrosio A. Clinical trials in the age of personalized medicine. J Med Pers. 2011. 9:91-98. https://link.springer.com/10.1007/s12682-011-0094-6.
4 Liska M, Crowley M, Borlongan V. Regulated and Unregulated clinical Trials of Stem Cell Therapies for Stroke. Transl Stroke Res. 2017 April; 8(2): 93-103. https://link.springer.com/article/10.1007/s12975-017-0522-x.
5 Hollak C, Biegstraaten M, Baumgartner M, et al. Position statement on the role of healthcare professionals, patient organizations and industry in European Reference Networks. Orphanet Journal of Rare Diseases. 2016. 11:7. https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1152-z.
6 Mathur A, Fernandez-Aviles F, Bartunek J, et al. The effect of intracoronary infusion of bone marrow-derived mononuclear cells on all-cause mortality in acute myocardial infarction: the BAMI trial. European Heart Journal. 2020 00. 1-9. https://onlinelibrary.wiley.com/doi/full/10.1002/ejhf.829
7 Hauskeller C, Baur N, Harrington J. Standards, Harmonization and Cultural Differences: Examining the Implementation of a European Stem Cell Clinical Trial. Science as Culture 28(2) 174-199. https://www.tandfonline.com/doi/full/10.1080/09505431.2017.1347613.
8 Hauskeller C. Between the Local and the Global: Evaluating European regulation of stem cell regenerative medicine. Perspect Biol Med. 2018. 61(1) 42-58. https://muse.jhu.edu/article/694819.
9 Calain, P. The Ebola clinical trials: a precedent for research ethics in disasters. J Med Ethics 2018;44:3–8. http://dx.doi.org/10.1136/medethics-2016-103474.
Conditions for when phase III trials should happen and when they are an obstacle to medical progress
Dear Editor
Having studied the conduct of a cross-European Phase III Clinical Trial in an acute setting under strict Advanced Therapy Investigational Medicinal Products (ATIMP) conditions we observe with great interest how the paradigm of the three phases of clinical trials, with particular emphasis on phase III, is being re-evaluated under present pandemic conditions. Although in order to advance in medicine it is indeed high time for reconsidering the when and how of the phase III trial, for reasons of good science as well as patient safety, new vaccines and drug treatments to stop a pandemic are not the place.
Long before the arrival of Sars-Covid-2 the phase III clinical trial had become contentious as the pinnacle of scientific medicine. New approaches in research and the technologies that underpin them juxtapose the premise on which the format of the three phases of clinical trials is built. One changing epistemic condition is the fine-tuning of diagnostic markers and categories, noticeable for example in cancer diagnosis and treatment. A second are tailored treatments, personalized medicine, such as therapeutics and procedures using tissues from the patient. There is an epistemic contradiction between the routes toward personalized medicine and the ideals of mass application that a phase III trial is designed to evidence. The lack of agreeing new evidential standards has contributed to a growing private market where desperate patients buy treatments in the growing category of treatments that have not been approved as therapies because of lacking evidence, but not proven ineffective either. Thirdly, rare diseases are inevitably marginalized if medical research is geared toward mass markets. There is rising pressure from within the medical professions as well as from patient groups. It appears unjust and in conflict with medical ethics if research is conducted in ways that delegitimize seeking cures for illnesses that affect very few patients. Furthermore, we must ask who should determine research pathways and the future of cures that become available. Big Pharma domineer medical science as long as phase III trial evidence is required for the approval of new treatments and there is no international public institutions with the means to fund big clinical trials for the public good.
The above failings in the present system are key reasons to question the primacy and universal adequacy of the phase III trial for medical science. The regenerative medicine clinical trial we bore witness to failed to produce a conclusive result concerning the stem cell procedure in question. Arguably, current regulations that require autologous cell-based treatments to be evidenced via phase III trials in the heavily controlled ATIMP format are not appropriate for this type of treatment approach.
The pressure produced by the mass of Covid-19 infections creates a situation where many urge reconsideration of the evidentiary standards applied in the approval of clinical treatments. The reasons for shaking up the phase III rule book are not sound in terms of medical epistemology, clinical practice or medical ethics and the desire to avoid as many infections as possible; we also frequently hear about the need to save the economy or be first among competing countries to rake in the revenue form scientific success in the global Covid-19 marketplace. Drugs and vaccines against the effects of Sars-Covid-2 are being considered for fast track rollout. The safety and global efficacy of drugs and vaccines is, however, the very type of medical treatments for which the clinical trial pyramid was designed. Is it right to give up epistemic standards not for treatments of a different nature but for drugs and vaccines designed for global use?
The COVID-19 situation has highlighted that there are circumstances when the esteemed one-size fits all phase III trial does not meet diverse societal needs for new and advanced treatment options. In an essay on the Ebola epidemic in West Africa, Philippe Calain recalls that the epidemic showed the ‘limits of a dogmatic understanding of clinical research’. He calls for an evolution in the current paradigms of therapeutic research with an increased flexibility in the choice of trial designs or emergency use but with reinforced safeguards including attention to ethics oversight. The pandemic is not the occasion to rashly loosen rigour, transparency and meticulous controls and monitoring. But it could start a thorough critical discussion about the methodologies of medical research and the strengths and weaknesses of clinical trial structures. What is needed is a multidisciplinary, collaborative and methodical analysis of different medical needs and treatment pathways and the evidence that is deemed epistemologically and ethically sound and sufficient for approval. This discussion can start with the reasons and circumstances that justify deviation from the established ideal mode of evidencing efficacy and benefit.
1 See recently Tanne Janice Hopkins. Covid-19: US will not join WHO in developing vaccine BMJ 2020; 370 :m3396. https://www.bmj.com/content/370/bmj.m3396.
2 Lin JA, He P. Reinventing clinical trials: a review of innovative biomarker trial designs in cancer therapies. British Medical Bulletin 2015, 114 17-27. https://doi.org/10.1093/bmb/ldv011.
3 Keating P, Ambrosio A. Clinical trials in the age of personalized medicine. J Med Pers. 2011. 9:91-98. https://link.springer.com/10.1007/s12682-011-0094-6.
4 Liska M, Crowley M, Borlongan V. Regulated and Unregulated clinical Trials of Stem Cell Therapies for Stroke. Transl Stroke Res. 2017 April; 8(2): 93-103. https://link.springer.com/article/10.1007/s12975-017-0522-x.
5 Hollak C, Biegstraaten M, Baumgartner M, et al. Position statement on the role of healthcare professionals, patient organizations and industry in European Reference Networks. Orphanet Journal of Rare Diseases. 2016. 11:7. https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1152-z.
6 Mathur A, Fernandez-Aviles F, Bartunek J, et al. The effect of intracoronary infusion of bone marrow-derived mononuclear cells on all-cause mortality in acute myocardial infarction: the BAMI trial. European Heart Journal. 2020 00. 1-9. https://onlinelibrary.wiley.com/doi/full/10.1002/ejhf.829
7 Hauskeller C, Baur N, Harrington J. Standards, Harmonization and Cultural Differences: Examining the Implementation of a European Stem Cell Clinical Trial. Science as Culture 28(2) 174-199. https://www.tandfonline.com/doi/full/10.1080/09505431.2017.1347613.
8 Hauskeller C. Between the Local and the Global: Evaluating European regulation of stem cell regenerative medicine. Perspect Biol Med. 2018. 61(1) 42-58. https://muse.jhu.edu/article/694819.
9 Calain, P. The Ebola clinical trials: a precedent for research ethics in disasters. J Med Ethics 2018;44:3–8. http://dx.doi.org/10.1136/medethics-2016-103474.
Competing interests: No competing interests