PMC:7195088 / 71559-74320 JSONTXT

{"project":"LitCovid-PubTator","denotations":[{"id":"1903","span":{"begin":49,"end":57},"obj":"Disease"},{"id":"2061","span":{"begin":2402,"end":2415},"obj":"Species"},{"id":"2062","span":{"begin":2421,"end":2429},"obj":"Species"},{"id":"2063","span":{"begin":2580,"end":2588},"obj":"Species"},{"id":"2064","span":{"begin":2752,"end":2760},"obj":"Species"},{"id":"2065","span":{"begin":2345,"end":2352},"obj":"Chemical"},{"id":"2066","span":{"begin":2732,"end":2739},"obj":"Chemical"},{"id":"2067","span":{"begin":2743,"end":2751},"obj":"Disease"}],"attributes":[{"id":"A1903","pred":"tao:has_database_id","subj":"1903","obj":"MESH:C000657245"},{"id":"A2061","pred":"tao:has_database_id","subj":"2061","obj":"Tax:11118"},{"id":"A2062","pred":"tao:has_database_id","subj":"2062","obj":"Tax:9606"},{"id":"A2063","pred":"tao:has_database_id","subj":"2063","obj":"Tax:9606"},{"id":"A2064","pred":"tao:has_database_id","subj":"2064","obj":"Tax:9606"},{"id":"A2065","pred":"tao:has_database_id","subj":"2065","obj":"MESH:C558899"},{"id":"A2066","pred":"tao:has_database_id","subj":"2066","obj":"MESH:C558899"},{"id":"A2067","pred":"tao:has_database_id","subj":"2067","obj":"MESH:C000657245"}],"namespaces":[{"prefix":"Tax","uri":"https://www.ncbi.nlm.nih.gov/taxonomy/"},{"prefix":"MESH","uri":"https://id.nlm.nih.gov/mesh/"},{"prefix":"Gene","uri":"https://www.ncbi.nlm.nih.gov/gene/"},{"prefix":"CVCL","uri":"https://web.expasy.org/cellosaurus/CVCL_"}],"text":"Future perspectives\nIn these first phases of the COVID-19 pandemic, where there are no clearly supported and approved treatments, there are two apparently mutually exclusive forces driving therapeutic choices supported only by preclinical and/or low-level clinical evidence: the willingness to administer potentially active therapies to COVID-19 patients; and the willingness not to harm by administering potentially inactive therapies that may unfavourably influence the outcome because of either expected or unexpected toxicity. Finding the right balance between these two forces is certainly not simple, but it remains more necessary than ever if we want to rapidly find effective and safe treatment. For this reason, RCT should always be the first option to be proposed to patients because RCT are the only way to provide high-level efficacy and safety information for optimizing the treatment of future patients. However, even when rapidly implemented during evolving pandemics, RCT are usually not immediately available (e.g. even if accelerated, local approval still and correctly requires time to guarantee ethical standards), and also many patients are usually excluded from RCT because of strict selection criteria [86,87]. For some of these patients, off-label uses (for drugs approved for other indications) and compassionate-use/expanded-access programmes (for investigational drugs) may represent an ethically justifiable option in the case of worsening conditions and unlikely survival with only supportive care.\nAgainst this background, the role of the attending physician is crucial, by favouring and not discouraging RCT participation (in favour of off-label administration) whenever the former is possible. Otherwise, scientific data will still be produced, but most information will be burdened by only partially adjustable selection biases and confounding factors, with consequent risks of inconclusive results and low-level supporting evidence for the various treatment options. If participation in RCT is maximized, high-level evidence will be available for guiding treatment, with lower-level evidence from off-label uses still remaining useful for hypothesis-generating purposes in order to better design further RCT (and not for directly guiding treatment choices). Notably, this is what, in our opinion, happened with LPV/RTV: (a) preclinical data supported activity against coronaviruses; (b) patients were enrolled onto RCT whenever possible, and otherwise they were offered off-label administration when not spontaneously improving; (c) because many patients were rapidly enrolled onto the first RCT, evidence rapidly become available that in our opinion discouraged a universal off-label provision of LPV/RTV in COVID-19 patients."}

{"project":"LitCovid-PD-MONDO","denotations":[{"id":"T395","span":{"begin":49,"end":57},"obj":"Disease"},{"id":"T396","span":{"begin":337,"end":345},"obj":"Disease"},{"id":"T397","span":{"begin":2743,"end":2751},"obj":"Disease"}],"attributes":[{"id":"A395","pred":"mondo_id","subj":"T395","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A396","pred":"mondo_id","subj":"T396","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A397","pred":"mondo_id","subj":"T397","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"}],"text":"Future perspectives\nIn these first phases of the COVID-19 pandemic, where there are no clearly supported and approved treatments, there are two apparently mutually exclusive forces driving therapeutic choices supported only by preclinical and/or low-level clinical evidence: the willingness to administer potentially active therapies to COVID-19 patients; and the willingness not to harm by administering potentially inactive therapies that may unfavourably influence the outcome because of either expected or unexpected toxicity. Finding the right balance between these two forces is certainly not simple, but it remains more necessary than ever if we want to rapidly find effective and safe treatment. For this reason, RCT should always be the first option to be proposed to patients because RCT are the only way to provide high-level efficacy and safety information for optimizing the treatment of future patients. However, even when rapidly implemented during evolving pandemics, RCT are usually not immediately available (e.g. even if accelerated, local approval still and correctly requires time to guarantee ethical standards), and also many patients are usually excluded from RCT because of strict selection criteria [86,87]. For some of these patients, off-label uses (for drugs approved for other indications) and compassionate-use/expanded-access programmes (for investigational drugs) may represent an ethically justifiable option in the case of worsening conditions and unlikely survival with only supportive care.\nAgainst this background, the role of the attending physician is crucial, by favouring and not discouraging RCT participation (in favour of off-label administration) whenever the former is possible. Otherwise, scientific data will still be produced, but most information will be burdened by only partially adjustable selection biases and confounding factors, with consequent risks of inconclusive results and low-level supporting evidence for the various treatment options. If participation in RCT is maximized, high-level evidence will be available for guiding treatment, with lower-level evidence from off-label uses still remaining useful for hypothesis-generating purposes in order to better design further RCT (and not for directly guiding treatment choices). Notably, this is what, in our opinion, happened with LPV/RTV: (a) preclinical data supported activity against coronaviruses; (b) patients were enrolled onto RCT whenever possible, and otherwise they were offered off-label administration when not spontaneously improving; (c) because many patients were rapidly enrolled onto the first RCT, evidence rapidly become available that in our opinion discouraged a universal off-label provision of LPV/RTV in COVID-19 patients."}

{"project":"LitCovid-PD-CLO","denotations":[{"id":"T386","span":{"begin":317,"end":323},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T387","span":{"begin":1266,"end":1271},"obj":"http://purl.obolibrary.org/obo/CLO_0007225"},{"id":"T388","span":{"begin":1671,"end":1676},"obj":"http://purl.obolibrary.org/obo/CLO_0007225"},{"id":"T389","span":{"begin":2135,"end":2140},"obj":"http://purl.obolibrary.org/obo/CLO_0007225"},{"id":"T390","span":{"begin":2355,"end":2356},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T391","span":{"begin":2385,"end":2393},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T392","span":{"begin":2418,"end":2419},"obj":"http://purl.obolibrary.org/obo/CLO_0001021"},{"id":"T393","span":{"begin":2508,"end":2513},"obj":"http://purl.obolibrary.org/obo/CLO_0007225"},{"id":"T394","span":{"begin":2697,"end":2698},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T395","span":{"begin":2713,"end":2718},"obj":"http://purl.obolibrary.org/obo/CLO_0007225"}],"text":"Future perspectives\nIn these first phases of the COVID-19 pandemic, where there are no clearly supported and approved treatments, there are two apparently mutually exclusive forces driving therapeutic choices supported only by preclinical and/or low-level clinical evidence: the willingness to administer potentially active therapies to COVID-19 patients; and the willingness not to harm by administering potentially inactive therapies that may unfavourably influence the outcome because of either expected or unexpected toxicity. Finding the right balance between these two forces is certainly not simple, but it remains more necessary than ever if we want to rapidly find effective and safe treatment. For this reason, RCT should always be the first option to be proposed to patients because RCT are the only way to provide high-level efficacy and safety information for optimizing the treatment of future patients. However, even when rapidly implemented during evolving pandemics, RCT are usually not immediately available (e.g. even if accelerated, local approval still and correctly requires time to guarantee ethical standards), and also many patients are usually excluded from RCT because of strict selection criteria [86,87]. For some of these patients, off-label uses (for drugs approved for other indications) and compassionate-use/expanded-access programmes (for investigational drugs) may represent an ethically justifiable option in the case of worsening conditions and unlikely survival with only supportive care.\nAgainst this background, the role of the attending physician is crucial, by favouring and not discouraging RCT participation (in favour of off-label administration) whenever the former is possible. Otherwise, scientific data will still be produced, but most information will be burdened by only partially adjustable selection biases and confounding factors, with consequent risks of inconclusive results and low-level supporting evidence for the various treatment options. If participation in RCT is maximized, high-level evidence will be available for guiding treatment, with lower-level evidence from off-label uses still remaining useful for hypothesis-generating purposes in order to better design further RCT (and not for directly guiding treatment choices). Notably, this is what, in our opinion, happened with LPV/RTV: (a) preclinical data supported activity against coronaviruses; (b) patients were enrolled onto RCT whenever possible, and otherwise they were offered off-label administration when not spontaneously improving; (c) because many patients were rapidly enrolled onto the first RCT, evidence rapidly become available that in our opinion discouraged a universal off-label provision of LPV/RTV in COVID-19 patients."}

{"project":"LitCovid-PD-CHEBI","denotations":[{"id":"T14062","span":{"begin":1266,"end":1271},"obj":"Chemical"},{"id":"T26421","span":{"begin":1282,"end":1287},"obj":"Chemical"},{"id":"T69721","span":{"begin":1390,"end":1395},"obj":"Chemical"},{"id":"T38758","span":{"begin":1671,"end":1676},"obj":"Chemical"},{"id":"T7632","span":{"begin":2135,"end":2140},"obj":"Chemical"},{"id":"T22983","span":{"begin":2508,"end":2513},"obj":"Chemical"},{"id":"T82876","span":{"begin":2713,"end":2718},"obj":"Chemical"}],"attributes":[{"id":"A13519","pred":"chebi_id","subj":"T14062","obj":"http://purl.obolibrary.org/obo/CHEBI_35209"},{"id":"A70757","pred":"chebi_id","subj":"T26421","obj":"http://purl.obolibrary.org/obo/CHEBI_23888"},{"id":"A76037","pred":"chebi_id","subj":"T69721","obj":"http://purl.obolibrary.org/obo/CHEBI_23888"},{"id":"A32182","pred":"chebi_id","subj":"T38758","obj":"http://purl.obolibrary.org/obo/CHEBI_35209"},{"id":"A14881","pred":"chebi_id","subj":"T7632","obj":"http://purl.obolibrary.org/obo/CHEBI_35209"},{"id":"A73415","pred":"chebi_id","subj":"T22983","obj":"http://purl.obolibrary.org/obo/CHEBI_35209"},{"id":"A59992","pred":"chebi_id","subj":"T82876","obj":"http://purl.obolibrary.org/obo/CHEBI_35209"}],"text":"Future perspectives\nIn these first phases of the COVID-19 pandemic, where there are no clearly supported and approved treatments, there are two apparently mutually exclusive forces driving therapeutic choices supported only by preclinical and/or low-level clinical evidence: the willingness to administer potentially active therapies to COVID-19 patients; and the willingness not to harm by administering potentially inactive therapies that may unfavourably influence the outcome because of either expected or unexpected toxicity. Finding the right balance between these two forces is certainly not simple, but it remains more necessary than ever if we want to rapidly find effective and safe treatment. For this reason, RCT should always be the first option to be proposed to patients because RCT are the only way to provide high-level efficacy and safety information for optimizing the treatment of future patients. However, even when rapidly implemented during evolving pandemics, RCT are usually not immediately available (e.g. even if accelerated, local approval still and correctly requires time to guarantee ethical standards), and also many patients are usually excluded from RCT because of strict selection criteria [86,87]. For some of these patients, off-label uses (for drugs approved for other indications) and compassionate-use/expanded-access programmes (for investigational drugs) may represent an ethically justifiable option in the case of worsening conditions and unlikely survival with only supportive care.\nAgainst this background, the role of the attending physician is crucial, by favouring and not discouraging RCT participation (in favour of off-label administration) whenever the former is possible. Otherwise, scientific data will still be produced, but most information will be burdened by only partially adjustable selection biases and confounding factors, with consequent risks of inconclusive results and low-level supporting evidence for the various treatment options. If participation in RCT is maximized, high-level evidence will be available for guiding treatment, with lower-level evidence from off-label uses still remaining useful for hypothesis-generating purposes in order to better design further RCT (and not for directly guiding treatment choices). Notably, this is what, in our opinion, happened with LPV/RTV: (a) preclinical data supported activity against coronaviruses; (b) patients were enrolled onto RCT whenever possible, and otherwise they were offered off-label administration when not spontaneously improving; (c) because many patients were rapidly enrolled onto the first RCT, evidence rapidly become available that in our opinion discouraged a universal off-label provision of LPV/RTV in COVID-19 patients."}

{"project":"LitCovid-sentences","denotations":[{"id":"T493","span":{"begin":0,"end":19},"obj":"Sentence"},{"id":"T494","span":{"begin":20,"end":530},"obj":"Sentence"},{"id":"T495","span":{"begin":531,"end":703},"obj":"Sentence"},{"id":"T496","span":{"begin":704,"end":917},"obj":"Sentence"},{"id":"T497","span":{"begin":918,"end":1233},"obj":"Sentence"},{"id":"T498","span":{"begin":1234,"end":1527},"obj":"Sentence"},{"id":"T499","span":{"begin":1528,"end":1725},"obj":"Sentence"},{"id":"T500","span":{"begin":1726,"end":2000},"obj":"Sentence"},{"id":"T501","span":{"begin":2001,"end":2291},"obj":"Sentence"},{"id":"T502","span":{"begin":2292,"end":2761},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"text":"Future perspectives\nIn these first phases of the COVID-19 pandemic, where there are no clearly supported and approved treatments, there are two apparently mutually exclusive forces driving therapeutic choices supported only by preclinical and/or low-level clinical evidence: the willingness to administer potentially active therapies to COVID-19 patients; and the willingness not to harm by administering potentially inactive therapies that may unfavourably influence the outcome because of either expected or unexpected toxicity. Finding the right balance between these two forces is certainly not simple, but it remains more necessary than ever if we want to rapidly find effective and safe treatment. For this reason, RCT should always be the first option to be proposed to patients because RCT are the only way to provide high-level efficacy and safety information for optimizing the treatment of future patients. However, even when rapidly implemented during evolving pandemics, RCT are usually not immediately available (e.g. even if accelerated, local approval still and correctly requires time to guarantee ethical standards), and also many patients are usually excluded from RCT because of strict selection criteria [86,87]. For some of these patients, off-label uses (for drugs approved for other indications) and compassionate-use/expanded-access programmes (for investigational drugs) may represent an ethically justifiable option in the case of worsening conditions and unlikely survival with only supportive care.\nAgainst this background, the role of the attending physician is crucial, by favouring and not discouraging RCT participation (in favour of off-label administration) whenever the former is possible. Otherwise, scientific data will still be produced, but most information will be burdened by only partially adjustable selection biases and confounding factors, with consequent risks of inconclusive results and low-level supporting evidence for the various treatment options. If participation in RCT is maximized, high-level evidence will be available for guiding treatment, with lower-level evidence from off-label uses still remaining useful for hypothesis-generating purposes in order to better design further RCT (and not for directly guiding treatment choices). Notably, this is what, in our opinion, happened with LPV/RTV: (a) preclinical data supported activity against coronaviruses; (b) patients were enrolled onto RCT whenever possible, and otherwise they were offered off-label administration when not spontaneously improving; (c) because many patients were rapidly enrolled onto the first RCT, evidence rapidly become available that in our opinion discouraged a universal off-label provision of LPV/RTV in COVID-19 patients."}

{"project":"2_test","denotations":[{"id":"32360444-29240890-22369826","span":{"begin":1226,"end":1228},"obj":"29240890"},{"id":"32360444-31607179-22369827","span":{"begin":1229,"end":1231},"obj":"31607179"}],"text":"Future perspectives\nIn these first phases of the COVID-19 pandemic, where there are no clearly supported and approved treatments, there are two apparently mutually exclusive forces driving therapeutic choices supported only by preclinical and/or low-level clinical evidence: the willingness to administer potentially active therapies to COVID-19 patients; and the willingness not to harm by administering potentially inactive therapies that may unfavourably influence the outcome because of either expected or unexpected toxicity. Finding the right balance between these two forces is certainly not simple, but it remains more necessary than ever if we want to rapidly find effective and safe treatment. For this reason, RCT should always be the first option to be proposed to patients because RCT are the only way to provide high-level efficacy and safety information for optimizing the treatment of future patients. However, even when rapidly implemented during evolving pandemics, RCT are usually not immediately available (e.g. even if accelerated, local approval still and correctly requires time to guarantee ethical standards), and also many patients are usually excluded from RCT because of strict selection criteria [86,87]. For some of these patients, off-label uses (for drugs approved for other indications) and compassionate-use/expanded-access programmes (for investigational drugs) may represent an ethically justifiable option in the case of worsening conditions and unlikely survival with only supportive care.\nAgainst this background, the role of the attending physician is crucial, by favouring and not discouraging RCT participation (in favour of off-label administration) whenever the former is possible. Otherwise, scientific data will still be produced, but most information will be burdened by only partially adjustable selection biases and confounding factors, with consequent risks of inconclusive results and low-level supporting evidence for the various treatment options. If participation in RCT is maximized, high-level evidence will be available for guiding treatment, with lower-level evidence from off-label uses still remaining useful for hypothesis-generating purposes in order to better design further RCT (and not for directly guiding treatment choices). Notably, this is what, in our opinion, happened with LPV/RTV: (a) preclinical data supported activity against coronaviruses; (b) patients were enrolled onto RCT whenever possible, and otherwise they were offered off-label administration when not spontaneously improving; (c) because many patients were rapidly enrolled onto the first RCT, evidence rapidly become available that in our opinion discouraged a universal off-label provision of LPV/RTV in COVID-19 patients."}