Transparency too little, too late? Why and how Health Canada should make clinical data and regulatory decision-making open to scrutiny in the face of COVID-19

Hard-won gains in the transparency of therapeutic product data in recent years1 have occurred alongside growing reliance by regulators upon expedited review processes.2 The concurrence of these two trends raises fundamental questions for the future of pharmaceutical regulation about whether the institutionalization of transparency will foster improved oversight of drugs, biologics, vaccines, and other interventions, or else, provide cover for a relaxing of regulatory standards of safety, effectiveness, and quality.3 The urgency of the COVID-19 pandemic, however, has brought this tension into immediate and sharp relief. During the course of the global health crisis, regulatory bodies have markedly expanded the number and use of expedited review processes for COVID-19 therapies, and at the same time, the proliferation of misinformation about any potential SARS-CoV-2 intervention4 reveals the limitations of recently implemented transparency measures. Over the course of the pandemic, a range of candidate ‘therapeutic products’ (ie pharmaceuticals, biologics, vaccines, and medical devices)5 have rapidly entered clinical trials. In some cases, these products have already entered clinical use despite weak evidence of safety and effectiveness.6 Meanwhile, ‘preliminary findings,’ disclosed by companies, researchers, government officials, and the media have obscured the value of SARS-CoV-2 targeting products, fueling hype and precipitating misunderstanding about the merits of the product in question.7 With disclosure of the evidence behind these experimental products forestalled until formal market approval under existing transparency mechanisms, the limitations of a point-in-time approach to transparency have been revealed during the course of the pandemic.8 In this article, we explain why transparency must be radically expanded in several ways. We argue that meaningful transparency in the context of COVID-19 requires that the clinical data behind SARS-CoV-2 interventions and the regulatory decisions made based on that data must be open to scrutiny. We also argue that transparency should be expanded to occur upstream during therapeutic product development and continue in an expanded manner throughout its lifecycle, beyond the point of regulatory approval, as knowledge about the product’s safety and effectiveness continues to evolve. And, while the argument we develop applies in principle across jurisdictions, we zero in on Canada in particular where recently enacted transparency laws provide ample authority to implement our recommendations. Specifically, we detail how Canada’s existing transparency laws can be deployed to ensure that data, which only the sponsoring company may hold during the research process, are made available9 and facilitate independent scrutiny of information held by sponsors and the regulator alike in order to improve judgments about the safety and effectiveness of SARS-CoV-2 interventions. We begin by setting out the mechanisms by which COVID-19 therapeutic products are being authorized for clinical study and use, then develop arguments about why greater transparency is warranted before finally presenting how to do so precisely under current Canadian law. We close by considering how added transparency might better assure public trust in regulatory agencies, such as Health Canada. Regulators worldwide have mobilized existing and new temporary mechanisms to expedite clinical trial approval and facilitate access to therapeutic products with uncertain benefits and harms in order to combat COVID-19.10 In Canada, this involves three mechanisms (Table 1): two of which pre-date the COVID-19 pandemic, while the third has been developed as the global health crisis has unfolded. Regulatory mechanisms to expedite clinical trials and authorize clinical use of therapeutic products during the COVID-19 pandemic in Canada. Regulatory mechanisms to expedite clinical trials and authorize clinical use of therapeutic products during the COVID-19 pandemic in Canada. The pre-existing pathways by which unapproved interventions can enter clinical use in Canada are the Special Access Program (SAP)11 and the Access to Drugs in Exceptional Circumstances (ADEC) pathway.12 The SAP grants access for individual patients on a case-by-case basis upon physician request.13 Prior to its conditional approval by Health Canada in late July,14 the antiviral drug therapy remdesivir had been accessed by individual physicians under the SAP for the treatment of at least a dozen patients.15 In contrast to the case-by-case nature of the SAP, the ADEC (which has not yet been invoked during COVID-19) allows Health Canada to authorize the distribution and use of drugs at a population level, provided that they have been previously approved by a regulator in the USA, European Union, or Switzerland.16 The third mechanism known as Interim Orders, which authorize the federal Minister of Health to make temporary changes to the standard regulatory framework, has emerged as the option of choice for Health Canada, presumably because of the efficiency and flexibility that it provides.17 Several Interim Orders have been enacted during the pandemic to date, including one that streamlines clinical trial authorization for both drugs and medical devices,18 another that facilitates (or expedites) the clinical use of medical devices,19 and, in September 2020, an Interim Order that creates several new ways for drugs (defined to include pharmaceuticals, biologics, and vaccines) to enter the Canadian market.20 Pursuant to these Interim Orders, a number of clinical trials, testing hydroxychloroquine, remdesivir, and several vaccines, have been authorized in record time (Supplementary File),21 and one medical device has been authorized for clinical use (although it was subsequently recalled).22 No therapeutic products have been authorized under the most recent Interim Order to date, but a number of its features are worth noting. To begin, the Interim Order specifies three new pathways to authorization by Health Canada. One is an expedited authorization procedure that allows for a ‘rolling application’ in which the sponsor submits information to the regulator based upon an agreed-upon schedule.23 This mirrors rolling application processes elsewhere and, by reducing the amount of information required initially upon submission, is intended to trigger faster decision-making about whether the benefits of the therapeutic product outweigh its risks.24 Another pathway allows for authorization where the product has been previously approved by one or more trusted foreign regulators, opening up the list of such regulators from the three eligible regulators under ADEC to at least seven foreign regulatory authorities.25 Finally, the Interim Order also describes how Health Canada can, without waiting for an application from the sponsor, seek to expand the indication of a previously approved drug to encompass treatment for COVID-19.26 Secondly, the drug-focused Interim Order aims to prioritize the review of applications by a sponsor for a new or modified ‘establishment license’ in order to lawfully produce a COVID-19 drug.27 Granting the regulator the discretion to alter the requirements typically applied to establishment license applications, the Interim Order’s stated that aim is to equip Health Canada with the ‘agility to facilitate rapid access to COVID-19 drugs while mitigating risks’.28 The third notable change introduced by the Interim Order is the creation of a ‘pre-positioning’ option to allow a drug to be imported into Canada by an establishment license holder and be prepared for distribution prior to market authorization.29 To be pre-positioned, the Government of Canada must have a procurement contract in place with the sponsor in respect of the Covid-19 drug in question,30 and the Chief Public Health Official of the Public Health Agency of Canada must provide notice to the federal Minister of Health. While Health Canada has, with the enactment of several Interim Orders, demonstrated a responsiveness to the urgency of the pandemic, it is notable that these efforts to expedite access to experimental COVID-19 drugs, vaccines, and other interventions have not been accompanied by parallel increases in transparency.31 Health Canada has released little to no information underlying any of its therapeutic clinical trial authorizations,32 including relevant pre-clinical studies, clinical data from trials conducted abroad, and crucial details about the design of proposed clinical trials, such as clinical trial which for and that will be to the product’s safety and and to ensure the of the and a of other of Health Canada’s to remdesivir, raises more questions it that the sponsor has yet to provide that regulators upon to safety and any of the COVID-19 remdesivir clinical And, while several for any applications that the regulator has for authorization in with the September Interim no meaningful changes made to the approach to the Health Canada will only data to a therapeutic product’s safety and effectiveness at the point of that the regulator has, in one the of information required for authorization approval for remdesivir in the of and information is to the Interim Order a rolling application for is to that Health Canada may not data to how the regulator can a more and approach to transparency under Canadian we explain in why the of transparency during the research and development and beyond approval may a range of harms in the context of data in any to trial and clinical trial and has the potential to trust in health pharmaceutical and regulatory is also some evidence that a of transparency is one of the of have for greater transparency across the of pharmaceutical research and with some notable including the creation and of clinical trial such as the development of physicians and and the of a of laws and to with transparency a in but the to which the of previously data from clinical trials, which the and Health Canada upon product will be to independent scrutiny which is has the potential for by beyond the of regulator and sponsor in the of pharmaceutical in and relevant in the product’s the transparency that have been made in the pharmaceutical in the recent have value in the context of where experimental interventions are being rapidly clinical use expedited regulatory disclosure of the data underlying these regulatory decisions until the point of approval may be late to decision-making the misinformation about that are not the of a clinical trial and, at the same time, to a the merits are In this particular transparency to prior to the therapeutic product authorization or approval, and across the product lifecycle, in order to or several the potential harms to trial Several trials authorized under the Interim Order to clinical trials aim to or the of a This to trial the safety of the in a of as of a as the to in a of from a trial in of the COVID-19 known as by as the basis for a trial in as as a trial in the of public access to data from the or to the for the trial in Canada, it is not to whether patients will be of these or into the design of the the trial for with Health Canada on the prior approval of a as an in the whether to authorize a With a stated of trials under the Interim is upon research to the design as as the in which the research is being Canadian research have to and requirements in a by Public access to the trial upon the by trial while also that are as with a particular COVID-19 candidate are a in a trial of a under development by at and it is whether that potential was into processes trials of the the of in which a is to in an to more the effectiveness of the experimental the of has been growing in trials, by a to in such a trial one to be despite the of existing for the course of the To ensure that the public is that are of the in the course of the trial should be in of regulatory oversight of clinical trials of a of transparency to the of clinical the trials are not to the most public health trials are to the potential to the of COVID-19 and or without access to the trial which do not it is to whether the trial design can one of the COVID-19 trials, a to that is the trial may not be to whether the the of of the to the of COVID-19 in the Several trials have already as new of COVID-19 in the new trials must have a for without transparency of study such as trial or sponsors and regulators, the is for can in be design may be regulators have the authority to changes to study a public can be more about the potential of a some trial the disclosed during the course of the pandemic, including both and trials, which include and as as trial of its The details of these some in about whether the of in the design of the trials and trials include and may to the trials being or modified the experimental to the the of the in is in a how decisions will be made is not in the that have been made will to known as safety or which typically under of in order to both based on and to from the point trial a to scrutiny to only sponsors to as as other such as the by to decisions about or an trial because a safety has or the is therapeutic it is not to the of COVID-19 trial and the of trial And, in the of trial and before data from the trial is is a that decisions by physicians about whether to the in to patients will be made without the of the to has the potential to is the why data that are by during the course of a trial are Over the course of the pandemic, however, data has the not the while have an for rapidly they also have the potential to be or as before they have been to the of a access to the underlying data which provide a more record of a is a that the of a product will be by both and the for to No trial before before ‘preliminary in details of the benefits to in the which by government officials, remdesivir the of treatment for details only these and including the of data of as as design such as of and and which may have the government that it of fueling a global for the the evidence at the time only clinical reducing time from to which the Health trial not with and expedited regulatory of remdesivir for or the of other that more SARS-CoV-2 because of to the of a in a new trial is an drug already The and the drugs and is also In 2020, the for the two drugs to COVID-19 including to authorization as an which and of safety and trials of in COVID-19 patients no evidence of and the was subsequently by the in a of and of transparency the independent scrutiny of the that of made it to that may be in from the the is to its stated standard of not a on an at least two have trial have the in and its or a and an is it will be to ensure that the knowledge which continues to during the of the trial is and The that this for data transparency is a the may to allow it to be to in the of the the no changes to the trial design are will from the study the has been made to an In the of the will be that any changes made to trial and the trial are open to both as the trial and an is is a of the Interim Order in it that Health Canada can an by the the expanded foreign authorization mechanism that was the Canadian regulator or the expedited mechanism by which remdesivir was authorized in trial and more may be to public that COVID-19 interventions are as as they are Canada’s regulator has a of to data as a of The of in however, fundamental a of safety to Canada’s and Drugs including the to drugs from the market and to data with the federal one of the of was to greater in the oversight of therapeutic products by To that several new added to the Canada to a global in of these transparency has been but with the of Health Canada’s in has been To date, the Canadian regulator has safety and data to drugs and vaccines) and medical data are from including that for individual trial and in other a range of other data, including and and trial are the which not only to interventions that have been approved (or the but also previously to one Health Canada’s the and most access clinical data to the and the however, has revealed limitations to Health Canada’s The disclosure of trial design and safety and data during trials is by a and Health Canada or a a most data to an experimental are as (Table before a regulatory is To its the recent Interim Order this point of disclosure to include under the in the context of trials are being rapidly authorized and misinformation about merits of experimental interventions is disclosure of clinical trial regulators and sponsors about and the basis for crucial decisions to be made by about whether to or a trial at the point of until the to authorize or the the of potential in trial and the to public of the knowledge and behind a COVID-19 that is as until that is as until information to COVID-19 interventions to be to and public information to COVID-19 interventions to be to and public Secondly, disclosure is Health Canada may not the data to make it In Health Canada for sponsors to a has occurred in the course of a the regulator to such data, it is not for independent to out a of a of independent scrutiny that continues to be but has, at revealed and the trial In the context of the current pandemic, however, Health Canada has a to data on a basis and approved one drug without the of are to Health Canada, little to no information about safety and is to be the With the Interim Order’s of a new expedited ‘rolling application’ process, it is how data Health Canada will have to at the time of market Finally, the not product safety and data that Health Canada, the to provide little information about must be in or the of the product’s safety and in of is that of the trials COVID-19 drugs and will continue authorization an however, that evidence is into the the evidence that will be open to independent scrutiny may only a of is Canada’s and Drugs several to the in the transparency of the data and decision-making SARS-CoV-2 interventions. on the information at a particular mechanisms can be invoked (or modified by of an Interim to ensure that data disclosure one of the several existing transparency not disclosure to the public the approach to disclosure should be to the of information and by the (Table Canadian grants the federal Minister of Health the discretion to information that is to eligible that are in the or of health public provided they to use the for a or public a This authority be in the context of to a number of data with independent before a is made to authorize a COVID-19 for clinical from an eligible (or government for the Minister COVID-19 pre-clinical and trials conducted Canada that are to Health Canada as of an application to a new clinical With several candidate under study in clinical trials, this same authority also be invoked to the Interim conducted by and with the it is that such Interim will be to an expedited authorization of a While the trials will continue such an any by a to alter a trial should be open to scrutiny by independent and other Finally, at a point in time, the trials are Health Canada can make the individual data to eligible in order to the safety and that are by the In the that Health Canada not the from trials, an in the and Drugs can be invoked to sponsors to that by respect of products that have been imported into Canada for the of a clinical trial an authorization or approval from Health The regulator to how that occur a new Interim Order and, in with other government Canadian of Health the to the of and trial the that the of the the of trial of the already for the development of SARS-CoV-2 interventions for independent to be a of data disclosure to the In order for the public to that are being about the of in rapidly and authorized clinical trials, that to should be before trials begin and in the that the are in to an trials, must be accompanied by disclosure not only of the but also the underlying for a trial the of an treatment SARS-CoV-2 in order to public about this of the is to improve clinical trial and scrutiny of trial as as regulatory Health Canada should its existing and and Health to make these and other data The can to the pre-clinical and clinical evidence behind clinical trial and expedited to ADEC or the Interim The can provide a for in trials while also as a for the regulator to its for including trials, with sponsors about trial trial required to be out and any other that into the to authorize a both the and encompass information only to approved drugs and Health Canada has authority to alter information is and to it no to be in order to the to the or an Interim can be to expand the information to be disclosed to upstream in the research as as authorization as the evidence continues to The the clinical evidence to be on the is pre-clinical and other data that the regulator as of an application to a clinical the the safety and for trials (ie can or to The of remdesivir that Health Canada is prepared to and a drug without and more data in and the recent of a rolling application to that same approach for the of the to improve scrutiny of clinical trial and Health Canada should the information it has new trials, trial of trial authorization same time in which the regulator is trial applications during the The regulator should also its to expedite the and of of trials to Health The regulator can then these data to the public the a time trial as to the current Finally, the which only of and of Health Canada’s of the evidence requires to provide a record of regulatory No change in is for as the for Health Canada’s decisions have been to The should include the regulator and with respect to trial as as a about why a is being made authorized under the Interim Order’s or approved another The should also include any information to to an approval, to studies, with and as are and transparency in the the Health Canada can is known about a COVID-19 as the evidence at a With one already approved in Canada and one or more authorization the the federal government may to to knowledge in order to up of the most products as no one has the to produce to the This may a license in order to allow other to produce a as as to and which may be as The prior however, is to ensure that the knowledge about COVID-19 product is and to scrutiny. In clinical and decision-making data open to scrutiny but The with law. Canada, other to is required to data is an to the of and the as they for market In the context of however, this can and has already been in other ways. Specifically, the Interim Order in September that any product by its underlying that is authorized under the Order be as a product by a in an to regulatory sponsors that the market will not they are to market for in any allows data to be use in a of ways and, as the data are being made to its as to a such use should not be as disclosure of the data behind a COVID-19 as a to Canada’s Secondly, the of transparency will Health Canada has, however, already to the of the and are already in place and, of the information to be made Prior to the pandemic, Health Canada developed a of review to the of or information from being disclosed the In the this is to the urgency of COVID-19 and the potential harms that from a of an Interim Order to expand transparency might this review to and to sponsors that trial or product In the disclosure of data and will some in to review with a to that the intended have the to provide independent scrutiny of the data in to independent scrutiny will also be such are to be in time to of a drug or safety and and, its improve in the population as a With the that COVID-19 are being by sponsors and regulators and public on the for independent to the data behind one or more a In the is no transparency and information in of potential the other the current from the such as the one developed for the pandemic, the of which to to this COVID-19 that is to of the transparency about its safety and not only COVID-19 but also a range of other interventions with more safety and The to that is to ensure clinical trials, independent scrutiny of the and an of regulatory about experimental COVID-19 interventions in transparency should be a of the of the regulatory to is to open that knowledge and up to and to about whether a particular drug or will to from and of the the of the of the to the design of the it for approval of the to be and to be for of the This was by an from the Canadian of Health The had no in the design and of the and of the or approval of the and to the for for a in an for of a drug for and a on the of in for is a of the of Health from of and for has has from the European and grants from the and of of and for Health and is an at The and of the for the is research from the COVID-19 Health and the as as from the of and the of being a of the Canada’s drug and from the for No other

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