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There is growing pressure being placed on pharmaceutical companies to make their clinical trials more transparent. Despite this pressure, there remain privacy concerns about publicizing clinical research data. How can companies successfully balance privacy requirements with transparency? Join Darshan Kulkarni as he talks about the growing need for transparency in clinical research, and how to develop transparent clinical trials.

Darshan Kulkarni: Hey everyone. Welcome to another talk about transparency. My name's Darshan Kulkarni, and I will be talking to you about some of the changes that we have in the context of transparency. If you want to hear more about what I do and what kind of topics that may come up and that I might be able to help you with, just go to darshantalks.com and you can hear more about what I get into.

Darshan Kulkarni: What you want to look at is, when you look at global transparency in the context of clinical trials, you really want to start considering the type of information that is being requested. While there are numerous global authorities really talking about global transparency, you're really seeing the impetus coming from three major authorities of this moment, which is the US, so the USFDA, there's the EMA, and there's Health Canada. Just in January of 2019, there was a headline that, in the US, only 62% of clinical trials are being reported, and that the UK parliament was clamping down at universities because they were not disclosing the clinical trial results. So obviously this was hugely problematic.

Darshan Kulkarni: The US obviously, as many of us know, really use something like clinicaltrials.gov to help look at clinical trial transparency. There are some exclusions. For example, phase one studies do not get included. It must relate to FDA regulated drugs and biologics. So for example, if you're doing a study for China that's never going to enter the US, you don't have to register that in clinicaltrials.gov, and then a controlled clinical investigations may, in certain cases, not be reported. Must be reported. Then there is medical devices and small feasibility studies are excluded. Prototype testing is excluded and FDA required pediatric post-market surveillance, however, is included. So to be included in clinicaltrials.gov, the trial must have one or more sites in the US, the trial's conducted under an FDA investigational new drug application or investigational device exemption, and the trial involves a drug, biological, or other other device product that is manufactured in the US or it's territories and is exported for research.

Darshan Kulkarni: So in general, for a applicable clinical trial to be subject to the results, the requirements must be submitted by the responsible party no later than 12 months after the primary completion date. There are specific rules for studies that were terminated. Then Commissioner Scott Gottlieb, then FDA Commissioner Scott Gottlieb, in January, 2018, basically said that the FDA is taking on transparency measures to look to support the innovation and scientific inquiry related to drugs. Now that has gotten a little sidelined in recent times, not only because of COVID, but because of the FDA's own perspectives on what transparency should look like. In 2018, Commissioner Gottlieb came out and said, "Today, we're launching a new pilot program to evaluate whether disclosing certain information included within CSRs, which is clinical study reports, following approval of an NDA improves public access to drug approval information. In this pilot, we will select up to nine recently approved NDAs, who sponsors volunteered to participate and post portions of clinical trial related summaries from pivotal trials that were submitted to the FDA by the drug sponsor on drugs at FDA."

Darshan Kulkarni: Since then no additional CSRs were posted and professionals, including Peter Doshi, Jennifer Miller, and Matthew Herder, came out on January 23rd, 2019, and said no additional CSRs were posted. So there was this disappointment in the community.

Darshan Kulkarni: Then you also have to look at the Civil Monetary Penalties Act. In October, 2018, the FDA put out a guidance basically saying that if responsible parties and/or submitters of certain application submissions to the FDA basically don't submit the information for clinicaltrials.gov, some monetary penalties may be applicable, and that will come with a $10,000 per day per study fine. That can add up very quickly if you have multiple studies that are noncompliant. So what you really want to do is not only make sure that your studies are compliant, but make sure that you have a protocol to make sure that this doesn't happen again.

Darshan Kulkarni: Additionally, what you also want to look at is the recent guidance that came out in 2020. I want to say it was in June or July of 2020. Again, it reiterated this decision to start finding $10,000 per day. You have to balance this requirement for transparency against innovation, where you have, in many cases, got to consider the idea first file and about intellectual property disclosure. So if you're putting out all the information, you've got to make sure that you're balancing that against the need to control your innovation and make sure that you're still getting value and you're still being able to recoup your investment.

Darshan Kulkarni: For the most part, because of that, you're going to have an impact on at least six major places. You're going to have to make sure that you're registering your study. You're then going to have to make sure that you're disclosing the results from the study, both of which are typically done by our clinicaltrials.gov, though the EMA is looking at launching their own version. We're still sort of delayed between Brexit and COVID. You then have to look at CSR disclosures, and this is where it gets a little bit more complicated. The reason it gets complicated is because you've got to look at not just the transparency element, but you've got to balance that against privacy requirements. That may actually fall out in the context of GDPR, CCPA, HIPAA, and numerous other laws and considerations.

Darshan Kulkarni: Additionally, when you're talking about innovation, like we just spoke about, you have to consider whether certain information can be redacted. When you're redacting this information, you have to consider on what basis, because if you come out and say that everything is redactable, does that trigger the materiality provisions of a disclosure as may be required if you're a publicly traded company. Those considerations need to be, well, considered. You then have to also consider that raw data may need to be disclosed as well. That's number four, and you also have to consider lay summaries, which means that the studies that these individuals participated in are understandable and accessible. Most of these came from requirements from the EMA.

Darshan Kulkarni: Having said that, the key thing to also consider is that there's another element, which is publication. Unlike the regulatory requirements, which have caused these other five considerations, a lot of publishing companies are now saying that if you want to publish your results in our reputable journals, we want to actually have access to the data itself. So you need to have publishing guidelines that you're going to have as well. If you need some help, trying to figure out what that looks like and what considerations you need to have, feel free to reach out to me. You can reach me at darshantalks on Twitter, or you can reach out to me via my cell phone, or you can just find me by email, [email protected]

Darshan Kulkarni: The other thing to start considering is the European Union. As we mentioned in 2018, the new website that they were going to launch shows nearly half of EU clinical trial data isn't publicly disclosed. That's hugely problematic as well. Like I mentioned, in January, 2019, according to all trials, 46% of EU clinical trials have not been reported according to EU reporting rules and only 44% of the world's largest charity and government bodies required researchers to report clinical trial results. This was obviously problematic. This resulted in the UK universities potentially being brought in front of the House of Commons Science and Technology Committee if they failed to improve the reporting of these clinical trial results.

Darshan Kulkarni: So as you're looking at this, as you start considering transparency, what you need to start thinking about is why are you doing it? What is actually included? Now, one of the key pieces of why you're doing this, and this is where you have to be worried about looking at transparency in isolation, you really need to balance transparency against three other pillars, which is transparency, privacy, innovation, and what I would consider it to be the most important one, which is patient centricity. Because you're doing the rest of these with the goal that, in the end, patients benefit from it.

Darshan Kulkarni: In fact, you're running a business because patients should benefit from it and from the drugs. So how do you do that in a way that is patient centric? So you have to be careful about not letting the tail wag the dog. So clinical data for the purposes of transparency can mean a lot of different things. It could be the clinical overview providing critical analysis of the clinical data in the submission package, including the conclusions and implications of the clinical data, the clinical summary, the study reports and the appendices, namely the study protocol, the sample case report, and the documentation of the steps of the statistical methods used to analyze the data. The EMA has some timelines that go along with that as well. Again, if you need more details about what the timelines look like, feel free to reach out to me.

Darshan Kulkarni: The other thing to start thinking about is how does the EMA actually look at studies and look for redactions? So the company actually submits a redaction proposal, which the EMA reviews and provides recommendations. At that point, the company reviews it and then submits a revised redaction proposal, and then the EMA publishes that redacted version. If you have questions about how that works, feel free to reach out to me as well. There are, as we mentioned, certain things that are confidential and are being protected. Number one is the individual patient data. So individual patient data shall mean the individual data separately recorded for each participant in a clinical study. On the other hand, personal data shall mean any information relating to an individual or identifiable natural person. An identifiable person is one who can be identified directly or indirectly in particular by reference to an identification number or to one or more factors specific to the physical, psychological, mental, economic, cultural, social identity.

Darshan Kulkarni: The other piece that you can redact is the CCI, the commercial confidential information, which means that any information contained in the clinical reports submitted to the agency that is not in the public domain or publicly available, and that may undermine the legitimate economic interests of the applicant. Now, remember when you're doing this, this becomes really complicated because you have to be careful that it's not just you kept the information secret. So it's not just, is it a trade secret? It's got to go beyond it. It's got to have a financial interest, got to have a legitimate economic interest, and this can be complicated for individuals if they're going, I didn't submit this before. Why do I have to submit this now? That heightened standard becomes more complicated. The other thing to start considering is how much can you redact?

Darshan Kulkarni: Depending on the agency, you will get different levels of redactions that are allowed, and we can have a conversation about that as well. There are various reasons why company confidential information could be redacted. Because it's detailed information, analytical methods, because they're practical agreements, if it includes future development plans, if there is post-marketing exposure, and if there are some details on financial compensation. There are additional things such as acceptance criteria, certain manufacturing processes, and qualitative composition may all be potentially redacted depending on how you're doing it. On the other hand, CCI is often rejected on the following reasons. Number one, it's already in the public domain. Number two, there's no innovative portion of this anymore. Number three, it's in the public interest. Number four, there's insufficient justification provided, or number five, there's irrelevant justification provided. So what you need is someone who understands not just how to combat these concerns around clinical trials and around transparency, but how to actually propose the right answer.

Darshan Kulkarni: So if you need questions, feel free to reach out to me. Again, darshantalks on Twitter, or you can just go to my website, darshantalks.com. Similar to talking about the data itself, we also need to talk about lay summaries. Again, this standard, according to the EMA, requires sponsors to provide summary results of clinical trials in a format understandable to lay persons. So it must take into account the average literacy of the general population, provide simple explanations, and apply Other measures to support health literacy. You must focus on unambiguous factual information, and it must not contain promotional content. You should consider involving patients, patient representatives, advocates, or members of the public and the development.

Darshan Kulkarni: Now, this may not always be feasible, but it is possible that it likely will enhance the final version, and if you start thinking about that and you start considering how this should be done, what you really should start thinking about is what format should this take. Now, there are different schools of thoughts. Some will say that you actually want to go down a more visual format, others say it's a more written format. There've been several studies done in each of these. What is clear however, is that you don't want to give up.

Darshan Kulkarni: What you'll see often is companies mistaking this idea that if I bring it all down to one page, it automatically makes it more understandable to patients and that's completely untrue and that's hugely problematic. What you have to do, and you'll see examples of this floating around. You often see them on company websites because if the EMA actually reviewed those, they probably aren't going to go for it very easily. This is often coming from individuals who really do mean well, but they are thinking like scientists and not like patients. TransCelerate actually came out and said that some sponsors may choose to provide lay person summaries for studies not conducted in the EU. These additional summaries could include all clinical trials or a subset of trials about posting it on a public website or even a more direct, more personal way if the logistics can be worked on.

Darshan Kulkarni: There are several logistics that do need to be worked out. An example of that is if you have blinded patients, how do you get these studies back? Now, again, the key piece when you're talking about lay summaries is that the study documents must align with the participants expectations and the sponsor's plans. Beyond the inclusion of an end of study definition, other explicit plans are not recommended for inclusion in the protocol itself. So you have to consider who are the various stakeholders, and you might consider patients, IRBs, investigators that maybe use this, clinicians would all be interested in how the lay summary plays out. The impact of that can, again, come in a variety of different forms. When you're talking about Health Canada however, unlike the EMA, we start talking about some different considerations.

Darshan Kulkarni: So Health Canada has a clinical trial registry, but Health Canada does not consider the clinical trials database to be a registry, and therefore it does not contain comprehensive information about each trial. In fact, they come out and basically say that you should often consider looking at clinicaltrials.gov. The database authorizes clinical trials involving healthy volunteers, such as bioavailability or bioequivalents in bioeqivalents trials. Also, first in human studies and pharmacokinetic studies. However, information about these is not included in the database. It also authorizes trials involving natural health products and devices. But again, these trials is not contained within the database. Phase four studies carried out with a marketed drug under its approved conditions, you are again, not required to include that. Therefore, information about these studies is not reviewed by Health Canada prior to the start of the trial and is not contained within the database.

Darshan Kulkarni: Again, you can see a copy of that if you like, and we can talk about that as well. Additionally, that's something to consider in the context of Health Canada, which is Vanessa's Law. In the context of Vanessa's Law, a minister may disclose confidential business information about a therapeutic product without notifying the person whose business or affairs the information relates or obtaining their consent if the purpose of the disclosure is related to the protection of promotion of human health, or the safety of the public and the disclosure is to either a government, a person from whom the minister seeks advice, or a person who carries out functions related to the protection or promotion of human health or the safety of the public. Now, what this is, is a very wide opportunity that could come back to haunt pharmaceutical companies if they are not maintaining close scrutiny by what could be happening with their information.

Darshan Kulkarni: Again, there is guidance out there as we've talked about and we've worked on Health Canada type submission. So feel free to reach out if you have questions about that. There are several categories of confidential business information. Certain types of CMC could fit in, certain clinical information within drug submissions prior to issuance or notice of noncompliance, issuance of notice of non compliance withdrawal, or issuance of deficiency, or there's no medical device license, or there's notice of medical device license amendment, or prior to the issuance of a notice of a refusal letter. The clinical information is not used in the submission application or to supplement the proposed conditions for use or the clinical information that describes the test methods assays are used exclusively by the manufacturer or if it includes individual patient records.

Darshan Kulkarni: So each of those needs to be considered as well. Again, there's a whole category, if you will, of drugs and devices that would be considered reportable. Now, remember there are at least four different steps and Health Canada's primarily still in step one, which is drug submissions within new active substances, supplemental new drug submissions contain confirmatory trials, and submissions to switch to non-prescription status. So we haven't even reached the stage two, which is proactive publication of new drug substances and non new active substances. Then there's step three, like we talked about, which is proactive publications for clinical information within SMDS, which is the supplemental new drug commissions confirmatory trials. Then there's step four, which is for the abbreviated new drug submissions and class three medical devices. So we're still at this moment in step one. So keep that in mind as well.

Darshan Kulkarni: So how is information from past submissions considered? So there's the request for that information. Health Canada will prioritize that request depending on what else they're dealing with, they'll annotate it, and you get a chance to review it and finalize it, and then it gets published. So if you're requesting information through Health Canada's information portal, you have to identify at minimum the product name of the information requested, though you should ideally also be able to provide the submission or application number, the study name, the manufacturer name, and the date of regulatory decision.

Darshan Kulkarni: There is a certain type of prioritization of the Health Canada [inaudible 00:21:14] consider. So they're going to consider metrics. They're going to consider information with the highest health system impact. Drugs or devices subject to an ongoing query by health systems would also be considered. Then it's the studies that are abundantly used and products of high public interest. Each of those would be considered. Again, it must be annotated and submitted through the common electronic submissions gateway, and theoretically, you're able to submit final redacted documents previously accepted by the EMA. That may make sense in certain cases. However, it doesn't always make sense because EMA and Health Canada accept different levels of redactions. So it's something to consider as well.

Darshan Kulkarni: Proposed redactions may be rejected for a variety of reasons. Number one, if you don't include the fact that the proposed information is used exclusively by the manufacturer, whether it's a test, a method, or an assay. If the proposed redaction pertains to information already in the public domain, they aren't going to consider that. If the information was not used to support the conditions of use or purpose for the drug or device except in the submission application, that would not be considered as well. Again, the information must be in non readable text or not machine-readable or searchable, and it will be on Health Canada's information portal. There have been cases, for example, a reporter from CBC made an Access to Information Act request for the Canadian adverse drug reactions information system, which is CADRIS, which is maintained by Health Canada, and Health Canada disclosed most of the fields of CADRIS, but refused to disclose certain fields that directly identified individuals and also refused to disclose a province field on grounds that are maybe used to identify an individual.

Darshan Kulkarni: The position that was taken was that the information about an individual, an identifiable individual, where there's a serious possibility of an individual could be identified through the use of the information is problematic. The court was satisfied that there was substantial evidence that this disclosure of the province field would substantially increase the possibility that the individual could be identified. Therefore, if there is a serious possibility that an individual could be identified through the use of that information alone or in combination with other information, that would actually not be okay. So the court held, the federal court held that the province field in combination with other publicly available information was personal information under the Privacy Act and therefore should not be disclosed. So what does the Privacy Act define as personal information? Personal information is information about an identifiable individual that is recorded any form. It's not just the fact that it exists in its obvious form, but if it can be combined, that would also constitute personal information.

Darshan Kulkarni: The test to consider is use the serious possibility test to determine when information is about an identifiable individual. Now, we can get into the details on the principles of anonymization, but that may not be the goal here. You should consider the Peter Doshi versus Attorney General of Canada case, where he requested information about Gardasil 9 and Cervarix, Tamiflu and Relenza. The goal was to conduct a systematic review of regulatory data, which is basically a Cochran review, and to take a methodology project and focus on the methodology of evidence since there's an appraisal of regulatory documents. Health Canada took the position that they'll only disclose this information if Dr. Doshi signed a confidentiality agreement and the court basically considered a couple of different things. They said that Vanessa's Law is intended to afford a greater protection against risks related to drugs. It provides for strict regulation of pharmaceutical industry and makes allowance for trade secrets already. It's sites TRIPS, which are the trade related aspects of intellectual property.

Darshan Kulkarni: It says that membership protects such data against unfair commercial use. In addition, members shall protect such data against disclosure, except where necessary, to protect the public or unless steps are taken to ensure that the data is protected against unfair commercial use. Parliament intended to afford greater protection for what can properly be called trade secrets or, to use the language of Vanessa's Law, confidential business information in contrast to data submitted to government, which would include clinical trial reports. So the court in July, 2018 took the position that Health Canada's blanket confidentiality policy is unreasonable because it violates Vanessa's Law and violate the clinical trial disclosure policies. Therefore, it must adhere to confidentiality requirements as set forth in NAFTA and TRIPS. So the non-Canadian impact again, you should consider when you're looking at transparency at a variety of other factors.

Darshan Kulkarni: You could be looking at publication factors. You can be looking at patient centricity. You could be looking at privacy, which you could be talking about HIPAA. You could be talking about GDPR. You could be considering international treaties like TRIPS and NAFTA. You may have to consider the export control laws, each of which needs to be considered as you're making these decisions. Then we can talk a little bit about de-identification, the types of the either de-identification, whether it's redaction, offsetting, randomization, generalization, or something else. Then we really need to start considering what are the other impacts out there. One of the more significant impacts that most people don't consider is when you participate in a clinical trial, one of the things that everyone agrees to is that they will adhere to the Declaration of Helsinki.

Darshan Kulkarni: The Declaration of Helsinki actually comes out and says that every research study involving human subjects must be registered in a publicly accessible database before recruitment of the first subject, and that researchers, authors, sponsors, editors, and publishers all have ethical obligations with regard to the publication and dissemination of the results of the research. Researchers have a duty to make publicly available the results of their research on human subjects and are accountable for the completeness and accuracy of their reports. All parties must adhere to accepted guidelines for ethical reporting, such as negative and inconclusive as well as positive results must be published or otherwise made publicly available, and sources of funding, institutional affiliations, and conflicts of interest must be declared in the publication itself. Reports of research not in accordance with the principles of this declaration should not be acceptable for publication. Now, is that binding? No, but if you adhere to it as part of your contract, that may become binding to you.

Darshan Kulkarni: So again, we're just thinking about the WHO requirements. For example, there are certain registration expectations. Clinical trials must be registered before it is initiated any phase. The details must be publicly available, free to access, and searchable, and it must be updated as necessary to include enrollment numbers that are actually achieved. Then there are certain timelines and outcomes that are expected and each of those may be considered as well. Then there is the, ISRCTN, I-S-R-C-T-N registry, which is a clinical trial registry recognized by both the WHO and ICMJ that accepts all clinical studies. That's another one that you may consider as you continue.

Darshan Kulkarni: So as you continue, some of the other things you should be considering is the ICMJ data sharing plan, and there is information about what ICMJ will consider and accept. So when you are creating your policy, and again, if you need help creating a policy, feel free to reach out to me at darshantalks on Twitter, or you can just reach out to me via email at [email protected] or [email protected] Either one will work. You should be considering how do you disclose this information and what is deemed to be acceptable? ICMJ has certain standards in what would be deemed acceptable.

Darshan Kulkarni: Again, there are different levels of disclosure that are possible, and a lot of these companies have made their plans public. Now, when you start looking at what companies are doing and what you should expect, big companies will have very different requirements and different expectations from both patients and providers than, say, a orphan disease state company. When you're talking to orphan disease state companies, they have certain expectations and requirements that larger companies will not have. For example, they have to worry more about inadvertent disclosures. So keep that in mind as you continue.

Darshan Kulkarni: But there are, as you continue, more and more growth around both the types of data that's going to be required. For example, Ukraine has been talking about making preclinical data available, and India is saying that you can take the data outside India at all. So each of those needs to be considered as well. What is the impact going to be on your internal operations? One of the most common impacts we've seen is the fact that, as you continue and as you do this, companies are finding that they need to reach inwards and not just connect their clinical trial transparency people to the clinical trial department, or just the medical writing department, but also to legal, to regulatory, to clinical, to marketing, medical affairs, compliance, patient centricity, sales watchdog groups, healthcare practitioners, government agencies, patients, payers, publishers, and VCs, and many, many more.

Darshan Kulkarni: Again, these lay summary requirements coming out, not just from the EMA, but also under [inaudible 00:31:23], 21st Century Cures Act, and PDUFA VI, and how they're doing it is being done in a variety of different ways. There are different strategies as you continue. What you also want to start thinking about is how do you actually approach this plan? What you really want to start thinking about is what have you done so far? How does this fit into the larger picture? What gaps do you have? Then filling in those gaps. Again, we can talk about how you do that appropriately, because there are ways to do that wrong.

Darshan Kulkarni: Again, if you need to reach out to me, if you have questions, feel free to call. You can reach me directly at (302)252-6959, or you can reach me via Twitter at darshantalks, or you can email me [email protected] or [email protected] I look forward to hearing from you. If you have any questions, if you disagree, I'd love to hear from you.

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