Dear reviewer, 

Thank you for drawing our attention on the questions you raised. Our answer focuses mainly on the issue related to the binding between digital identities and physical entities. 

We updated the revised version accordingly to all the questions you raised.  

Target of the POC and digitale identities

POC as a response to FDA raised issues

Thank you for your constructive remarks. In fact, there are two main issues regarding the consent process. The first one is related to the quality of the process itself and the second one is related to the identity of the individual consenting. Monitoring of trials by the FDA has identified serious issues in about 10% of trials, major concerns being failure to obtain written informed consent, consent document not signed or not dated, missing pages in consent document provided to subjects,failure to re-consent when new information becomes available, use of expired, non-validated or unapproved forms (reference [3,4] in the manuscript and this link). In this POC study, we aimed at fighting these issues, where existing patients were included in a study in the presence of their physician or staff. In our implementation, we ensured that all the consent process was tracked in time all along the inclusion period, that the documents made available to the subjects were not corrupted, that they were in conformity with the current version of the protocol, and that (re-)consent was asked as many time as required. We however did not address the cases where consents were falsified by the investigating teams or where fake patients were invented for instance, which are more related to the second (identity) issue. This should be more explicit in the text, and has been emphasized in the revised manuscript.  

Linking digital identities and physical entities

We then agree with the reviewer that the second issue is important in the context of a real clinical trial. This relates to the question of pairing digital identification with physical persons. In our implementation of the POC study, the link between a participant and his/her digital identity is done through his/her email address. A participant cannot simply generate any Bitcoin address and use it to sign, because the private key is created on the server by the agent (but not saved on the server), then is sent to the email address. So the only guarantee is that the participant had access to that email address. This is pretty light, but seemed to be satisfactory given the scope and focus of the POC. Moreover, in the setting of a real online consent process, there is no chance that a patient who would not effectively consent—for instance if there were some fraudulous operation registering him/her as a consenting subject—would actually participate to the study.

However, in a production application we must implement a more secure mechanism, and we thank the reviewer again for outlining the possibilities. There are indeed several solution to secure the digital identity of participants.

First, we can mention that KYC processes are now quite widespread and there are plenty of examples where digital identities are linked to physical entities or human beings in the context of sensitive data: in most western countries the fiscal administration allows online service for taxpayers to declare their income and proceed to related operations, banking services also provides their services online such as bank transfer, account consultation. All these examples have in common that users (taxpayers, bank clients) are given a physical material, often by sending a document by regular postal service, or by giving a first card or document by hand. These documents carry an identification number. This approach could be implemented in production.

Second, even in regular off-line consent process, ensuring that the patient really signed the document is not without carrying problems. We have in mind that the patient must meet the medical doctor and receive by hand their consent document. So that, when they go back to the medical doctor with the signed document, there is no way to prove that it was signed by the patients himself or that the patient was not influenced at the time of signing the consent form.

Regarding a possible implementation of our blockchained consent process in a real clinical trial, we can provide, at the moment the patient meets the doctor, authentication cards with an identification number and so strengthen the binding between the electronic signature id and the physical one. Let’s mention that some bitcoin companies also provide material keys, such as USB keys, that hold the cryptographic signature, which can be unlocked by an easy-to-remember code. This can be an excellent candidate to get stronger digital-physical binding. These issues are now covered in the revised discussion.

Besides, we think that full online consent collection process raises more the issue to reach subjects that the one related to ensuring the targeted patient is really the one consenting.

Patients invention

Going further, we can summarily refer to the extreme case of patients invention. Unfortunately, there is almost no way to prevent data invention. And there are some documented case in the medical literature, fortunately very rare, where clinical trial patients and all related clinical data were invented from end to end. Let’s notice here that, in the first implementation of our POC, we timestamped an extensive part of interactions between the subjects and the online email and web platform : time of the email sending, reception, time email was opened, the links being clicked on. We then validated the transactions into the blockchain, this way we could at least detect anomalies if such data appear grouped in time, so that it does not prevent from invention but higher the barrier to fraud.  

Further technical improvements

On a more technical side, Stratumn’s technology, via proof-of-process, provide an implementation that would allow one to create an audit trail of the the different steps that happened until the participant provided enough evidence to convince the verifier of his/her identity, which is quite an upgrade to current KYC processes, because there would be a permanent record of what happened, and the process would impose rules that must be respected to the letter (by computer code) before moving to the next step. In short, this is not a complete out-of-the-box solution to linking digital identities, but Stratumn has the tools to build one. While implementing such a verification process with the technology is possible, this was beyond the scope of the POC.

Smart Contracts

Indeed, we did not implement it in our setting, we meant to mention that Smart Contract can bind the modifications occurred in the protocol and some to be defined events on which parties can agree.  

Besides, we did not detail or implement in the article all the advantages that can be derived from the algorithmic nature of the Smart Contracts: the way consent process is monitored, the way the related informations are shared between the stakeholders, the investigators and the IRB or building Smart contracts with the condition patients will only be included when the enrolment is complete or building one checking the whole consistency between the data and the blockchained proof of data, preventing from the whole hassle of gathering the documents and checking them by hand

Figures

Indeed, some figures are in french and we complied to the F1000 policy that invited us to proceed so.

Bibliography

We thank the reviewer for the precious remarks about bibliography and to have brought to the knowledge of the authors two of them, namely the one referred as `OriginStamp` and the Carlisle blogpost. We add and referenced them in the revised document.

Best regards,

Proof of concept, blockchain and the study generally

Dear reviewer, 

Here are some responses to the questions that were raised. Besides, thank you for your remark related to the bibliography and the reference duplicate. 

1. Is the reported study a "proof of concept" for the use in a real trial, or simply a demonstration that blockchain can be used for a series of sequential "signings"? If the latter, had that not been shown previously?

In the idea of establishing all the consent process in real conditions, we claim it is a proof of concept. We developed a complete and realistic set of interactions between fake patients and stakeholders, and we paired consent status and protocol revision through blockchain held by a single master document accounting for the whole process.

2. Are there any plans to test this in a real trial, perhaps as a SWAT[1] and to include it in Trial Forge[2]?

For the moment, we have no specific plan to implement in a real trial but our POC is precisely a preparation to go further to a real setting.

We have no expertise in SWAT or in using Trail Forge platform, but it should comply with no difficulty with our implementation.

3. How would this system be used if patients cannot get online personally?

This is more a problem related to online consent than a blockchain related question. In situations where patients cannot get online personally, then the medical doctor should provide the consent form to the subjects by hand. Besides, let's indicate that in most countries, the written consent is legally mandatory.

There are other situations where the online access is not possible, related for example to disabilities, then either the legal representative should be given access to the online consent form, or written consent should be sought.

4. How would the system cope if someone's email addresses changes? (I raise this because I am currently locked out of my Twitter account because the email I used to set it up is no longer active following my move away from that institution.)

In a real clinical trial, we would set multiple ways to reach a patient : digitally, phone number, postal mail. For sure, email is not sufficient, and we would use a stronger identifying system than email, i.e. material objects storing cryptographic keys, such as a USB key. We could also build a Smart Contract triggered by a destination email error callback. Then, when this condition is met, Smart Contract would cause the other reaching methods to be proceeded. Since Smart Contract are pieces of code, this automatized processed can be customized at will.

However, although this is not the situation you are pointing to, this procedure may find a limit: there is no way to distinguish between the situation where an email has been sent without response, and the one where the email is still maintained by the institution with no access anymore for the previous account holder. But, we think this very case looks quite exceptional.

5. Can you reflect more on the challenges of doing online trials?

There are some challenges regarding online trials:

- people that are not in a condition to access an online platform: severe conditions, lack of consciousness, learning disability, no access to internet or people not friendly to online tools

- the current state of technologies do not allow interventional trials. However, the explosion of IoT, miniaturization could lead to imagine some specific interventional trials to be conducted online. In this respect, we mention the existence of blockchain systems specifically dedicated to connected objects.

- ensuring that the person consenting is effectively the one pretending to be: this should lead to use a strong identifier, and at minimum use KYC process (Know Your Customer) implemented to bind digital identities to physical entities in the case of sensitive data. Fiscal administration, Banks makes use of that.

It is worth noting that from a blockchain point of view, the email is by no mean a method to identify. In our settings, we generate identifiers for each patient which consists in complex cryptographic strings. It would be possible in addition of these informations stored in the local machine of the subject, to duplicate this information on a USB key or identifier cards on the model of KYC procedure. Let's state that there are some companies providing material supports to keep the blockchain id's.

6. Do you believe that this system will be applicable to all trials, a majority or a minority? You seem very enthusiastic about the use of this system and the article might benefit from the addition of more caution about its general applicability. For example, you write "we evoked a possible improvement in the enrolment rate, by empowering patients and granting them information and control over the enrolment phase." but say little of the possible negatives (such as concerns about security of the data (see below); fear or discomfort with technology; and whether empowerment might come more from the ability to talk to a human being about the trial and the consent process).

Indeed, blockchain is not without carrying some issues. Our point was to put in a perspective a trend. Every new technological gap raises some fears, as the internet at its very beginning, but the overall trend is that usages have imposed. It is worth noting that users shape also technologies and their fear pushes the improvement of technologies conducting these to take more account of their needs and apprehensions.

Besides, our idea is not to rely on a technology by itself but to complete the blockchain network ability to ensure data consistency by a strong human support at any step of the clinical trial, first and foremost the consent process.

Besides, from the data security point of view, we positively think that it is much better ensured by blockchain-like technologies than the one currently used : first, because of the strong crypto-oriented transaction validation, second the distributed nature of the network prevent from the "single point of failure" problem related to centralized data collection. By the way, we can take the Bitcoin network as an example, which carries sensitive money data and which is proving to be resistant for almost ten years.

7. Who will ensure that blockchain is future proof? Might people need to print or export a copy of the electronic record for long-term storage?

Blockchain consist of a network of peers, anybody involved in the network storing in his computer the archive of all the history of transactions, i.e. the public ledger. So that, even if the network had to fail for one or other reason, any single node can restore the last state of the network. Moreover, if necessary, depending on the design of the blockchain implementation, we might enable the only stakeholders or if we want any participant, to export and print the copy of electronic transactions.

We may have in mind that data stored are "proof of data" that can be checked to match the true data on any dedicated public website.    

8. Does blockchain allow for "workarounds" (e.g. to move to the next step without completing the previous one if for some reason this is necessary)?

Yes, one core functionality of blockchain technologies, is Smart Contract. They allow to write algorithmically any set of conditions that modules the execution of some instructions.

But, we stress the fact the system can be "fault-tolerant" but there are no "roll-back" possibility. So, suppose that someone stores some informations but has mistaken, then he'll be able to add the new corrected information (that's what we can call a "fork"), but the first errored information is still accessible in the blockchain.

9. What do you mean by "transparency" in relation to the new system? If a potential participant thinks this means that others can see that they gave their consent, might this discourage them from joining the study?

We mean by transparency that the rules are clear for anybody taking part in the process. This is the very role of the Smart Contract we already mentioned.

Besides, the perimeter of the people sharing the data can be controlled : we can decide that data can be shared by the only stakeholders, or decide that participants will be able to share access to their data with persons of trust. All this fine-grained control can be powered on the top of blockchain.

Consent in general

10. How would this system cope with differences between the process for obtaining consent to take part in prospective research in different countries and cultures? For example, what if someone other than the patient might need to give consent?

Differences between cultures, countries need to be tackled one by one. So that we need true implementation of clinical trials to face with those kinds of issues. I don’t think there is a one general answer.

Online tools can help orienting the participant regarding to their specific situation. Moreover, we believe chat support should be provided in order to take account of specific situations  

11. Would patients be able to request that their ongoing consent is presumed without needing to be contacted again when there is a change in the trial? It might discourage patients from joining a trial if they are told that they will have to be contacted each time there is a change (especially if that change does not affect them personally).

Indeed, there is no need to overwhelm patients with a flood of informations. However, from a general point of view, patients association often complain about lack of informations regarding the clinical trial progress, so that some calibrated informations can be delivered conveniently to the patients.  

Moreover, in case of a major change in the protocol, they should be specifically targeted to get an email asking to consent again.  

12. What protocol changes should lead to new consent (e.g. should it only be those that directly affect the patient, or should it be those that might have influenced their decision to join?)

There is heavy litterature about this. We refer it in the article: [10,11,12] in our bibliograhy  and we mentionned these links detailing the protocol changes that should lead to renew the consent: http://www.irb.pitt.edu/sites/default/files/reconsent guidance.pdf; http://www.mayo.edu/research/documents/29-re-consent-or-notification-of-significant-new-findingspdf/doc-10027714; http://www.yale.edu/hrpp/policies/documents/Reconsentingguidance.pdf)

13. Would a patient need to be asked for their renewed consent if the change can no longer affect them? For example, if they have already completed treatment and are now on follow-up, do they need to be informed about changes in the evidence base about a side effect if they can no longer suffer that side effect?

Yes, these kind of new informations should be given to patients and require to ask for a renewed consent again, even if they are not supposed to suffer this side effect thereafter.   

14. Should patients be asked to consent again, or be asked if they want to withdraw? What assumption would be made if they do not reply?

If patients want to withdraw, they should not be asked again.

When patients do not reply, and after ensuring by other means (emails, mail, phone call if available) that they do not provide an answer, then they should be considered has consenting because they already gave their consent.

Besides, this kind of situation can be advantageously scheduled in a Blockchain Smart Contract, that can be adapted to local legal contexts.

15. Might it be worth discussing this new system in the context of other research into recruitment and retention (for example, as brought together in Cochrane Reviews [3,4,5,6]).

Indeed, we might implement some Smart Contracts, checking the recruitment and retention process. So Cochrane reviewers could have an insight about whether this process was done conformally to standard procedures. However, we notice that the code of the Smart Contract should also be reviewed, so that an experienced developer should be required.

16. Is a lack of informed consent a source of bias (or might it be closer to the "truth" if patients don't realise that they are being studied) or bad ethical practice?

Lack of informed consent is for sure a bad ethical practice, in a strict contradiction to Helsinki declaration, Nuremberg declaration and good clinical practices.

Regarding the matter of generalisability bias, the latter is more related to the setting of inclusive criteriae than related to consent.

17. Might it be worth discussing the double standards of needing written consent for someone to receive a treatment in a trial but not needing it if they are given the treatment as part of "routine practice"?

In any case, the participant to a clinical trial must to sign the consent form, even he is already taking the medication for which the consent form is seeking his/her consent. At this occasion, the patients may be informed of actual informations related to the treatment, for example new side effects of a drug.

18. How important is "written consent"? Is this unfair on difficult to reach populations who struggle to read or write?

The written status of the consent by opposition of the electronic has not by itself more credit. However, depending on the local legal context, “written consent” is mandatory.

Besides, collecting consent of people with reading, writing or learning disabilities needs care. The person collecting the consent must assess the ability of the person to understand correctly the informations and to make a decision. The information must be given orally and to the legal representative if any. Some ethics committees allow the mediation of families or other supports at this stage.

Electronic consent

19. How would you ensure that the appropriate person "signed" the consent form if you do not see them do so? Is it easier to submit someone's electronic key, than to forge their signature?

In this POC, we generated cryptographic keys for each patient. So, in this design indeed, we can't ensure that the person consenting is the person he or she pretends to be. This can be improved in different manner.

At least, using KYC standard procedures, i.e. doubling the electronic identification by one related to a physical object holding some number code. One step further would be to provide patients with an objects storing USB key storing the cryptographic signature and unlocked by a easy-to-remember id.

Security

20. Might patients' concerns over the security of their data and the importance of confidentiality make them cautious about joining a trial if they had to use this system? How worried might they be because of news stories about data from banks and other supposedly secure systems being hacked and leaked?

We refer to the question 6 on the notion of “single point of failure”, which answers at some level the raised issue.

In any case, patients are very sensitive to the security and the privacy of their data and this system addresses precisely this issue. Indeed, the decentralized structure of the blockchain, the involvement of anyone as a peer on the network, the ability to finegrain the data sharing perimeter, allows more control of the patients over the data workflow.

However, we are conscious that this system is very new and needs some pedagogical support. Anyway, Bitcoin is now a widespread, trusted electronic currency, available on payment platform of a wide range of websites such as Amazon, Apple’s App Store. An implementation of such processes in a real clinical trial should be the occasion to add different media support : documents, videos in order to inform patient of the benefit of using such technologies .

For the second part of the question, see the response to question 6. of the present reviewing question list.     

21. Might it be worth writing something about how patients may think that paper consent forms locked in a filing cabinet are more difficult to access and make available to everyone online, than documents that are already available to the research team from anywhere on the internet.

Absolutely it might be very interesting.

Language

22. The words "subject" and "participant" are used to refer to people who take part in trials. I prefer to avoid "subject".

We substituted the usage of "subjects" by "participants" in the revised document.

Best regards,