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Dr. David Maslove

Medical Grand Rounds – Dr. David Maslove: Pandemic Science: the good, the not-so-good, and the ugly

Dilakshan Srikanthan, MD/PhD Candidate (Translational Medicine)

 

For the last Medical Grand Rounds (MGR) for the month of February, we had the pleasure of hearing from Dr. David Maslove about the effects of the COVID-19 pandemic on current affairs in academic medicine. Dr. Maslove is an internist and intensivist at Kingston Health Sciences Center and an Associate Professor cross-appointed in the Departments of Medicine and Critical Care. Dr. Maslove’s presentation summarized the positive and negative impacts of the pandemic on academic medicine, and what we can learn from them.

 

Dr. Maslove opened on a positive note, discussing how the pandemic has improved academic medicine by 1) identifying new models of clinical trial design, 2) implementing new models of collaboration, and 3) employing new models of publishing. Notably, the significance of platform trials was thoroughly assessed throughout the pandemic. Platform trials focus on the disease rather than a treatment, in essence, allowing a single trial to assess various treatments (1). Not only is this a time-efficient way of conducting clinical trials, but it is also resource-efficient, as all participants can be recruited to one trial and assigned to different arms. The RECOVERY trial was a trial that unearthed the potential of platform trials during the pandemic. Within 1 year of declaring a worldwide pandemic, this trial had enrolled approximately 47 thousand patients and had produced conclusive results on the efficacy of 7 possible treatment types (2,3). Another noteworthy platform trial is the REMAP CAP trial which predates the pandemic, however, also enrolled COVID-19 patients (4). This trial made tremendous contributions to the standard of care for COVID-19, based on disease severity. Benefits of platform trials include the usage of multiple treatment arms and continuous testing; however, platform trials require the use of Bayesian statistics rather than the traditional frequentist approach, which is often more complex and difficult to grasp. Furthermore, platform trials are relatively new, and their true potential remains to be seen.

 

While the concept of international collaboration is not new, it was paramount in the response to the COVID-19 pandemic. International collaborations have always existed in critical care, for example, in developing the guidelines for septic shock care (5). As previously mentioned, the REMAP CAP trial contributed tremendously to the COVID-19 standard of care, however, it would not have been possible without international collaborators (4). Dr. Maslove highlighted other successful trials that have emerged in the pandemic that owe their success to international collaboration, including the SPRINT- SARI trial and the GenOMICC trial (6,7). Notably, the genetic mechanisms of critical illness in COVID-19 were published within 1 year of the start of the pandemic, attesting to the impact of global collaborations in genetics research. While international collaborations allow improvements in sample size, representation, and inclusivity, they are also difficult to coordinate and maintain.

 

Dr. Maslove emphasized that the pandemic has resulted in the biological homogeneity of certain diseases. Traditionally, identifying biologically homogeneous populations is very difficult, and recruiting a sufficient sample size when you do identify homogeneous populations presents challenges. While conditions like sepsis tend to be heterogeneous, COVID-19-induced sepsis allowed patients to be viewed as homogeneous due to the shared underlying etiology. As such, scientists reaped the benefits of studying biologically homogeneous states, whereby patients are more likely to respond in the same way.  

 

One of the most prominent platforms that came to light in academic medicine during the pandemic is the use of preprint servers, permitting the distribution of manuscripts that are not yet peer reviewed. While preprint servers enable the rapid dissemination of research findings, they also present challenges in publication ethics and integrity. Dr. Maslove highlighted how preprint findings often make their way into the media and thus are prone to the rapid spread of disinformation in the public. While there are benefits associated with preprint servers such as accelerated discovery and knowledge translation, they should be approached with caution as they can lead to false starts and unsupported claims.

 

Following Dr. Maslove’s presentation, the graduate students of the Translational Medicine (TMED) program had the privilege of continuing the discussion with him. The discussion delved into the implications of the pandemic on patients, as well as relevant equity, diversity and inclusivity (EDI) initiatives, and representation in the lay press. The COVID-19 pandemic has revealed urgent needs, truths, and challenges in academic medicine, requiring deep reflection for moving forwards in the post-pandemic era (8). On behalf of the TMED class, I would like to thank Dr. Maslove for sharing his time and valuable insights.

 

References

1) Berry, Scott M., et al. “The Platform Trial.” JAMA, vol. 313, no. 16, 2015, p. 1619., https://doi.org/10.1001/jama.2015.2316

2) “Dexamethasone in Hospitalized Patients with Covid-19.” New England Journal of Medicine, vol. 384, no. 8, 2021, pp. 693–704., https://doi.org/10.1056/nejmoa2021436.

3) “Colchicine in Patients Admitted to Hospital with Covid-19 (Recovery): A Randomised, Controlled, Open-Label, Platform Trial.” The Lancet Respiratory Medicine, vol. 9, no. 12, 2021, pp. 1419–1426., https://doi.org/10.1016/s2213-2600(21)00435-5.

4) “Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19.” New England Journal of Medicine, vol. 385, no. 12, 2021, pp. 1147–1149., https://doi.org/10.1056/nejmc2108482.

5) “A Randomized Trial of Protocol-Based Care for Early Septic Shock.” New England Journal of Medicine, vol. 370, no. 18, 2014, pp. 1683–1693., https://doi.org/10.1056/nejmoa1401602.

6) Murthy, Srinivas, et al. “Characteristics and Outcomes of Patients with Covid-19 Admitted to Hospital and Intensive Care in the First Phase of the Pandemic in Canada: A National Cohort Study.” CMAJ Open, vol. 9, no. 1, 2021, https://doi.org/10.9778/cmajo.20200250.

7) Pairo-Castineira, Erola, et al. “Genetic Mechanisms of Critical Illness in Covid-19.” Nature, vol. 591, no. 7848, 2020, pp. 92–98., https://doi.org/10.1038/s41586-020-03065-y.

8) Maslove, David M., and J. Kenneth Baillie. “Two Key Takeaways from a Year of Pandemic Research.” Critical Care Medicine, Publish Ahead of Print, 2021, https://doi.org/10.1097/ccm.0000000000005078.

Comments

Name
Trinity Vey

Tue, 03/01/2022 - 17:27

Hi Dilakshan,

I think you did a great job facilitating last week – our discussion with Dr. Maslove was very engaging! I also want to thank you for a very well-written summary.

A common theme in our last few MGR discussions has been the contribution of preprints to the spread of COVID-19 misinformation in the general public. While there is certainly a case to be made for the rapid dissemination of scientific information during infectious disease emergencies, it’s worth noting that the amount of COVID-19 related preprint research vastly outnumbers that of other global RNA viral outbreaks. Notably, the publication of COVID-19 preprints was 100 times higher than for the Ebola or Zika virus outbreaks of 2014 and 2015, respectively (1). The first COVID-19 preprint appeared on bioRxiv only 22 days after the initial notification of cases in Wuhan, with over 6700 preprints by April 2020 (1). Some preprint claims include that the genome of SARS-CoV-2 contained HIV genetic material and that the many-banded krait snake was a SARS-CoV-2 host (1). Despite the validity of such claims being questioned by the scientific community, they were quickly spread by the lay press. Furthermore, a 2021 study by Frampton et al., found that more than half of retracted COVID-19 articles remained available online following their retraction (2). Based on this, I’m curious to hear your thoughts about how we can better regulate the interpretation and dissemination of information from preprints and retracted studies. Do you think that the greatest responsibility lies on the paper authors or the preprint servers? How much should a retraction or questionable preprint impact an author’s reputation?

Best,

Trinity

1. Brierley L. Lessons from the influx of preprints during the early COVID-19 pandemic. Lancet Planet Health. 2021;5(3):e115-e117. doi:10.1016/S2542-5196(21)00011-5
2. Frampton G, Woods L, Scott DA. Inconsistent and incomplete retraction of published research: A cross-sectional study on Covid-19 retractions and recommendations to mitigate risks for research, policy and practice. PLoS One. 2021;16(10):e0258935. Published 2021 Oct 27. doi:10.1371/journal.pone.0258935

Name
Trinity Vey

Hi Dilakshan,

Great job leading our discussion this week and providing an excellent summary of our time with Dr. Maslove! Along the lines of Trinity's comment, I too am very curious about the effects that retractions have, specifically on the public and their perception of information. While retractions may be better perceived and acknowledged by the scientific community, I am wondering firstly how the general public can be made aware of retractions if they are not habitually keeping up with scientific publications. The website Retraction Watch (1) seems to do a good job of allowing people to easily view recent paper retractions, however, I am curious as to the likelihood that the general public would actively look for retractions.

Secondly, I am wondering how "to get the cat back in the bag" once unreliable information is out there, and perhaps how to convince individuals that information is not being hidden from them. Similar to Trinity's point about papers still being available online after retraction, I found it really interesting when I came across an article stating that numerous papers continue to cite retracted papers despite their status (2). Personally, I think that especially with a global health problem like COVID, containing unreliable/retracted data once it is out there is a really challenging but important issue, and I would love to hear others thoughts on how this might be facilitated.

Best,
Cassie

(1) https://retractionwatch.com/
(2) https://www.science.org/content/article/many-scientists-citing-two-scan…

Name
Cassie Brand

Dear Trinity and Cassie,

Thank you so much for your kind words and insightful comments. Both of you have raised some great points regarding the increased utilization of preprints. It is a double-edged sword – while it serves as a platform for rapid dissemination of research and discovery, it can also be platform for misinformation to be spread. While I do not think it would be possible to ‘regulate’ what is posted on these open platforms, we can provide tools and skills for the public to assess the credibility of the source. This not only is vital for the public but also news media platforms. This will allow for a medium where scientists and researchers are not censored, however the public and media outlets are aware of what is credible research and what is not yet credible. I think educating the public on what preprint servers are and their function would allow them to gauge the credibility of the source. Furthermore, understanding the meaning of a retraction and peer-reviewed resources would also be helpful and may prevent misinformation from rapidly spreading.

Name
Dilakshan Srikanthan

Hi Cassie and Trinity,
I was also interested in the issues with pre-prints, news, and corrections/ retractions. I wanted to offer some of my thoughts on responsibility and solutions. I think responsibility in the scientific community and with preprints lies at many different levels. First, there is the responsibility of the authors to publish accurate information that meets high standards of scientific rigor. Authors that breach basic principles of scientific ethics, including publishing fabricated or falsified information, should experience career, employment, and potentially legal consequences. A similar responsibility exists for the journal publishing the preprint. One step a journal could take may include having a disclaimer statement that indicates that pre-prints have not gone through the same peer-review process as other publications. Journals should act quickly to retract and remove false information and misleading publications. Furthermore, journals that fail to do so should suffer consequences to their reputation. There is also a responsibility of journalists and news corporations that publish information from pre-prints. One step that could be taken here is to have writers with a background in science involved in the writing process. Writers should use good judgement and critical thinking when evaluating claims made by pre-prints, should specify that the work has not gone through the full peer-review process, and avoid publishing salacious headlines from information that has not been fully vetted. Finally, there is also the responsibility of the reader, who should critically evaluate information to the best of their abilities and before they make an informed decision about what they are reading. Ultimately, if authors, journals, and news outlets can improve scientific integrity and communication, the trust of the public can hopefully be regained.
I am wondering if anyone else had any thoughts to add (I'm happy to discuss disagreements as well).
Best,
James

Name
James King

Name
Alyssa Burrows

Tue, 03/01/2022 - 17:37

Hi Dilakshan,

Phenomenal post and great job last week! You have summarised really nicely that the pandemic helped improve academic medicine through platform trials, invigorating collaborations and pre-prints to distribute information faster. Without many of these innovations, the morbidity and mortality from COVID-19 would be undeniably higher as we likely wouldn’t have safe and efficacious vaccines and effective treatments (the fact that I can add pluralize those words is astounding!)

One sector that I would like to highlight is regulatory affairs which regulates everything from PPE, tests, clinical trials, to drugs and vaccines (1). The public health emergency posed challenges on regulators worldwide as they had to ensure the safety and efficacy of COVID-19 treatments and vaccines while expediting approval (2). Legislative amendments by 2019 Omnibus Bill C-97 created a new "agile" licensing framework known as the "Advanced Therapeutic Pathway" (ATPathway) and modernized the regulation of clinical trials of drugs, vaccines, and medical devices (2). Several aspects of this bill allowed for the expedited review of clinical trials, vaccines and therapeutics (2). All in all, without the advancements that we had in many sectors throughout the pandemic we wouldn’t be in the place we are now in this battle against COVID-19.

I would be excited to hear about other advancements that you and my peers are aware of that are tangential to academic medicine.

-Alyssa

Ref:
1) https://www.canada.ca/en/health-canada/services/drugs-health-products/c…
2) Eren Vural I, Herder M, Graham JE. From sandbox to pandemic: Agile reform of Canadian drug regulation. Health Policy. 2021 Sep;125(9):1115-1120. doi: 10.1016/j.healthpol.2021.04.018. Epub 2021 May 15. PMID: 34090723; PMCID: PMC8123380.

Name
Alyssa Burrows

Dear Alyssa,

Thank you so much for your kind words and insightful comments. Thank you for highlighting the improvements that are tangential to academic medicine. I have also noticed other domains related to academic medicine that have progressed over the course of the pandemic such as virtual learning and virtual clinical learning. With the rise of restrictions to prevent the spread of COVID19, education was severely disrupted. As a result, the roles of medical students and residents have been altered. However, similar to telemedicine, the potential of web-based education was realized in the pandemic. Web-based educational programs and tools were used to disseminate information and continue lectures. Furthermore, these innovations allowed medical educators to reflect on teaching practices and presented an opportunity to develop courseware that incorporates derived insights into how adults learn. Methods such as frequent testing with feedback, spaced learning and interleaving, a focus on threshold concepts, scaffolding, minimization of cognitive overload, and self-paced learning are all among the potential advantages presented by electronic educational materials and virtual courses. Albeit, it is important to note that this technology-mediated teaching is very time and labor intensive and requires learning additional skills and perhaps institutional infrastructure.

Name
Dilakshan Srikanthan

Dilakshan, great summary of the MGR and our discussion!

Alyssa, thanks for bringing up this really interesting point. It reminds me of our discussion with Dr. Nicole Mittmann from the Canadian Agency for Drugs and Technologies in Health (CADTH) from a few weeks ago. We had talked about how CADTH is working in parallel with Health Canada during the review process of therapeutic drugs/devices to improve access of these therapies.

I think the COVID-19 pandemic may have shed light on regulatory challenges or roadblocks that existed and provided an opportunity to consider more streamlined solutions, with tangible benefits. In addition to being tangential, I would argue that the advances in the regulatory affairs sector supported the advances of academic medicine, and vice versa.

Lubnaa

Name
Lubnaa Hossenbaccus

Name
Kiera Liblik

Wed, 03/02/2022 - 11:00

Hello Dilakshan,

Wonderful summary of last week's MGR. It was very informative and comprehensive. Ideally, all clinical studies strive to have a large sample size representative of their general patient population. Unfortunately, there are many resource and administrative barriers to this such as heterogeneity across ethics applications and electronic medical record systems (EMRs). In fact, many centers are still in the process of fully moving to EMR and some more rural and remote locations are fully paper-based.(1)

In Ontario, the Institute for Clinical Evaluative Sciences (ICES) has been working since 1992 to bridge this gap in data by linking large sets of data to healthcard numbers (with patient consent).(2) Do you foresee that in the future we'll move toward linked Canada-wide systems for ethics and EMR? I know some province-wide initiatives with a similar idea to ICES are being implemented.

Kiera

1) Callan, L., & Chen, N. (2014). Electronic Medical Records: Current status of implementation across Ontario. University of Western Ontario Medical Journal, 82(2), 31-32.
2) Schull, M. J., Azimaee, M., Marra, M., Cartagena, R. G., Vermeulen, M. J., Ho, M., & Guttmann, A. (2019). ICES: data, discovery, better health. International Journal of Population Data Science, 4(2).

Name
Kiera Liblik

Hello Dilakshan,

Outstanding work facilitating last week’s MGR and crafting this summary.

I wanted to add to Kiera’s question as to whether we will move toward a linked Canada-wide system for EMR. With the Canada Health Act stating that health care should be portable, I feel that it is only a matter of time before a centralized system is adopted allowing efficient transfer and access of health information across the country. However, if it was simple, this would likely have been done already. I can imagine that this can be a complex process due to the familiarity of the multitude of many systems already in place around the country as well as the discomfort that comes with change. I was wondering, what other factors prevent or slow down the progress to a single cohesive EMR system? If applicable, is there any solution that can be put in place to overcome the agents that seem to be blocking the country's progress toward this goal? Is there a way to approach this goal without hindering the commendable progress of province-wide initiatives like that of the Northwest Territories (1)?

References
1. Webster P. Northwest Territories leads Canada in electronic medical record coverage. Canadian Medical Association Journal. 2017;189:E1469-E1469. doi: 10.1503/cmaj.109-5511

Name
Emmanuel Fagbola

Dear Kiera and Emmanuel,

Thank you for your thoughts and insightful contributions to this discussion. As you both stated a cohesive Canada-wide EMR would come with tremendous benefits. Certainly, the benefits would include easier transfer of care across provinces, increased accessibility for telemedicine, and increased communication between physician regarding treatments. Of course, I believe strong security measures must be in place in order to avoid possible breaches, and would involve consistent maintenance. Furthermore, this system would require personnel support in order to ensure that these systems are functional, and would require continual improvements dictated by the needs of the medical system and physicians. This would be a large undertaking that would require multiple stakeholders to be involved, which would also take quite a bit of time.

Name
Dilakshan Srikanthan

Hi all,

Great post and thought-provoking commentary! Connecting the intriguing idea of a Canada-wide EMR system and the topic of platform trials that Dr. Maslove discussed last week, I'm wondering how the large, standardized multitude of data of a province- or country-wide EMR might revolutionize research and in turn patient care. Adaptive platform trials are an exciting and complex innovation in study design that enable a more real-world, dynamic approach to studying disease, treatment and outcome timelines (1). With the high volumes of standardized data characteristic of large EMR systems, movement towards a centralized data management program would unlock the potential of tackling our most important challenges in medical knowledge synthesis. One main unknown that we discussed with Dr. Maslove was the issue of research endpoints in a platform trial, and how we might use findings that come from dynamic, longitudinal data to change clinical practice. I'm curious to know what the class thinks of how this potential access to such a high volume of health data might change the landscape of medical research in Canada, and if that could involve a change in the structure of clinical trial systems as well.

(1) Angus DC, Alexander BM, Berry S, Buxton M, Lewis R, Paoloni M, Webb SA, Arnold S, Barker A, Berry DA, Bonten MJ. Adaptive platform trials: definition, design, conduct and reporting considerations. Nature Reviews Drug Discovery. 2019 Oct 1;18(10):797-808.

Name
Katie Lindale

Hi all,

Thank you for the summary of last week’s MGR and such interesting discussion!

I think accessing EMR for medical research would come with many benefits. Utilizing EMRs for randomized controlled trials may allow researchers to create larger pragmatic RCTs in clinical settings, with wider inclusion criteria, thus generating more generalizable findings. 1 EMR can also be used to recruit for clinical trials, by generating lists of patients that may be eligible. Additionally, if RCTs are conducted in routine care settings using EMR, some outcomes could be assessed through the EMR, instead of doing extra tests or using a system solely for data collection. One limitation of using EMR data for clinical trials is that the data collection isn’t primary for research, and thus may not be standardized. 1 Even with potential limitations, using EMR could make conducting clinical trials easier and provide unique benefits, such as including patients that wouldn’t meet the criteria for traditional RCTs. I look forward to hearing others’ thoughts on this!

References
1. McCord, K. A., & Hemkens, L. G. Using electronic health records for clinical trials: where do we stand and where can we go? Canadian medical association journal. 2019. https://www.cmaj.ca/content/191/5/E128

Samantha Ables

Name
Samantha Ables

Name
Pierce Colpman

Wed, 03/02/2022 - 13:10

Hi Dilakshan! Thank you so much for such a great summary of last weeks MGR! I think you did a great job of summarizing Dr. Maslove's key take home messages as well as evaluating the pros and cons of pre-print publications, Great job! My comment for you furthers the topic of how the COVID-19 pandemic has revealed urgent needs and challenges in academic medicine which as you mentioned will require deep reflection moving forwards throughout the post-pandemic era.
The clinical learning environment (CLE) encompasses the learner’s personal characteristics, experiences and social relationships, as well as the institutions physical and virtual infrastructure (1). Throughout the COVID-19 pandemic all aspects of the clinical learning environment have been massively disrupted which has led to many challenges. Physicians and learners in the CLE had to undergo quick adjustments in their personal and professional lives as they rose to meet the clinical and educational challenges they faced due to COVID-19. These difficult times have been cumbersome but through this we have also spurred exciting innovations. Social networks and collaborations have been expanded beyond traditional institutional and international boundaries in many different specialties, opening the door for new collaborations and discoveries. Specifically, epidemiology, public health, and medical ethics, were brought to the forefront in health professions education, while the physical learning environment underwent a rapid transition to a virtual learning space (1). As health professional education continues into the post COVID-19 era, educators must take advantage of these dynamic systems and what we have learned throughout the pandemic to identify additional gaps and implement meaningful change in the clinical learning environment. With this in mind, I was wondering if you had a specific example of something that you have noticed has changed throughout the COVID-19 pandemic for the better within the CLE that has either affected your life of the life of someone you know in the field? Do you think that more positives came out of the pandemic in terms of learning how to more effectively manage the CLE? Or do you think we were better off before?

1) Triemstra, J. D., Haas, M. R. C., Bhavsar-Burke, I., Gottlieb-Smith, R., Wolff, M., Shelgikar, A. V., Samala, R. V., Ruff, A. L., Kuo, K., Tam, M., Gupta, A., Stojan, J., Gruppen, L., & Ellinas, H. (2021). Impact of the COVID-19 pandemic on the Clinical Learning Environment: Addressing identified gaps and seizing opportunities. Academic Medicine, 96(9), 1276–1281. https://doi.org/10.1097/acm.0000000000004013

Name
Pierce Colpman

Hi Pierce,

Thank you for bringing up this topic! And thank you, Dilakshan, for expertly leading the discussion and sharing your summary! COVID-19 certainly spurred huge changes in virtually every curriculum in the country, including medicine. While virtual learning has been in the works for decades, the past 2 years have seen it develop and grow exponentially. I think that the pandemic made people in many fields recognize the need and feasibility of accessible learning and working opportunities. A report from the Eastern Kentucky University School of Nursing found that when patient simulations were shifted from in-person to online amid COVID-19 precautions, the student response was overwhelmingly positive (1). Their "flipped classroom" strategy saw students complete a lecture and assignment on their own time and then participate in semi-facilitated discussions about case studies. 98% of students felt that this style met all learning objectives (1). Clearly, there is an effective way to teach and learn from a distance. However, this has not been every student's experience. Another study of speech-pathology students found that virtual clinical experiences were more challenging. While they still gained confidence and knowledge, their empathy for patients did not improve to the same extent that it did for their counterparts who spoke with standardized patients or nursing home residents in-person (2). I would be curious to hear from someone with clinical experience as a medical student to see if their own experiences are in line with the findings of either study!

References
1. New, K., Edwards, C., & Norris, H. (2022). Meeting our students’ educational needs during a global pandemic: Creating online clinical learning experiences. Teaching And Learning In Nursing, 17(1), 126-129. https://doi.org/10.1016/j.teln.2021.07.006
2. Quail, M., Brundage, S., Spitalnick, J., Allen, P., & Beilby, J. (2016). Student self-reported communication skills, knowledge and confidence across standardised patient, virtual and traditional clinical learning environments. BMC Medical Education, 16(1). https://doi.org/10.1186/s12909-016-0577-5

Name
Georgia Kersche

Dear Pierce,

Thank you so much for your comments and insights. The clinical learning environment is constantly improving and meeting the changing needs of trainees. In the pandemic, we have seen drastic changes in the learning environment in general and especially the clinical learning environment. I have noticed that remote learning has allowed for increased accessibility for learners. While some of the curriculum requires physical presence for learning to occur, it became apparent that virtual learning environments come with their own benefit. Furthermore, virtual learning environments allow for increased flexibility, an inclusive environment, and is cost-effective. In addition to this, the use of engaging modern learning platforms allows educators and trainees to familiarize themselves with technology, which can be a valuable resource in the future.

Name
Dilakshan Srikanthan

Name
Nolan Breault

Thu, 03/03/2022 - 14:50

Hi Dilakshan & all,

Nice work on hosting our discussion last week & the blog post, Dilakshan! Even though we're not fully out of the woods regarding Covid, it's nice to see these presentations, at minimum, as stories that say "things aren't all bad", or potentially even as the beginning of retrospectives on the pandemic. Hopefully the situation continues to improve, especially within hospitals.

Regarding the MGR topic, it was really neat to be introduced to the platform trial as a new iteration in clinical study design. This segment was especially nice to see after the discussion of non-inferiority trials in the week prior, and got me interested in the diversity of ways in which the efficacy of therapies can be tested. A recent development is the popularization of "master protocols", which bear multiple concurrent hypotheses that are investigated through different studies in parallel (1). The earliest example of this comes from work revolving around imatinib, completed in 2008, where the compound received FDA approval as a treatment for 5 distinct presentations of cancer at the conclusion of a single trial (2). Platform trials exist as one manifestation of master protocol, with others consisting of umbrella and basket trials. The differences between each of these lie in the number of therapies involved, the flexibility of the study as it's ongoing, and the number of diseases being examined. Umbrella trials have multiple therapies concurrently tested in a single disease, platform trials do the same with the caveat that therapies may be added or dropped throughout the study, and basket trials revolve around one therapy tested in multiple diseases (3).

While over half of all master protocol studies conducted to date have been within the field of oncology, they clearly have potential in other branches of healthcare. I think their usage in Covid research will be a real boon to having them implemented in the investigation of other diseases, and perhaps we might see a bit of a revolution with respect to how quickly new drugs can come to market/how fast we can respond to future pandemics & the costs associated with developing such drugs (hopefully with savings passed on to the consumer!).

Wondering how everyone else thinks these studies might be of use in clinical research going forward!

Best,

Nolan

References
1. Bogin, V. (2020). Master protocols: New directions in drug discovery. Contemporary Clinical Trials Communications, 18, 100568. https://doi.org/10.1016/j.conctc.2020.100568
2. Heinrich, M. C., Joensuu, H., Demetri, G. D., Corless, C. L., Apperley, J., Fletcher, J. A., Soulieres, D., Dirnhofer, S., Harlow, A., Town, A., McKinley, A., Supple, S. G., Seymour, J., di Scala, L., van Oosterom, A., Herrmann, R., Nikolova, Z., McArthur, and G. (2008). Phase II, Open-Label Study Evaluating the Activity of Imatinib in Treating Life-Threatening Malignancies Known to Be Associated with Imatinib-Sensitive Tyrosine Kinases. Clinical Cancer Research, 14(9), 2717–2725. https://doi.org/10.1158/1078-0432.CCR-07-4575
3. Hirakawa, A., Asano, J., Sato, H., Teramukai, S. (2018). Master protocol trials in oncology: Review and new trial designs. Contemporary Clinical Trials Communications, 12, 1–8. https://doi.org/10.1016/j.conctc.2018.08.009

Name
Nolan Breault

Thank you for your comments and thoughts. Similar to platform trials, master trials can be very useful and efficient. With that being said, its implementation in COVID19 or any other diseases would also be paramount. There are numerous large scales trials that utilize master protocol principles and novel trial design approaches in diseases such as influenza (1), pneumonia (2), and Alzheimer’s disease (3). Similar to platform trials, master protocol trials also provide an opportunity to expedite the development of treatments. In addition, they are also time and cost efficient, allow for personalized treatment, allow for increased collaboration, and enable patient advocacy groups to accelerate preclinical research into novel treatment for patients. However, while they come with benefits, it is equally crucial to recognize the difficulties of implementing master trials, which may limit its applicability in some diseases. For example, the complexity may require a third party for management, as design, preparation and execution may be time consuming. Furthermore, they require larger patient cohorts for multiple interim analyses that can increase the study duration. Funding and competition among pharmaceutical companies can also be a barrier for master trials. Despite these barriers, the benefits certainly can outweigh the costs and contribute immensely to translation medicine.
1) C.C. Butler, S. Coenen, B.R. Saville, J. Cook, A. van der Velden, J. Homes, et al. A trial like ALIC4E: why design a platform, response-adaptive, open, randomised controlled trial of antivirals for influenza-like illness? ERJ Open Res., 4 (2018)
2) Randomized, embedded, multifactorial adaptive platform trial for community- acquired pneumonia (REMAP-CAP), https://clinicaltrials.gov/ct2/show/NCT02735707
3) R.J. Bateman, T.L. Benzinger, S. Berry, D.B. Clifford, C. Duggan, A.M. Fagan, et al. The DIAN-TU Next Generation Alzheimer's prevention trial: adaptive design and disease progression model, Alzheim Dement., 13 (2017), pp. 8-19

Name
Dilakshan Srikanthan

Name
Bethany Wilken

Mon, 03/07/2022 - 16:31

Hi Dilakshan,

Great job summarizing Dr. Maslove’s presentation and follow-up discussion. I am always impressed by the questions our classmates formulate and the direction of our discussions. I thoroughly enjoyed learning more about the academic/research endeavours that have been taking place during the pandemic. I think it really highlights the resilience of science!

I wanted to touch on one of the good parts of pandemic science; international collaboration. We have seen the far-reaching benefits of enhanced collaboration with COVID-19 research. Although I believe many scientists would agree on the importance of collaboration, their actual participation in international projects would be much lower. Thereby, I wanted to discuss some of the barriers that impede such collaboration. A study evaluating 9000 scientists from eight societies found the key barriers to collaboration included lack of funding for international work, restrictions on material and data sharing, and differences in academic standards (1). There was also bias discovered against scholars from emerging or developing countries (1). To address lack of funding for international work, I suggest implementing international grants instead of limiting grant money to only one country. Working together on one large grant would be favourable over each collaborator finding funding independently. I would love to hear if anyone has ideas on how to address the other barriers and how to make international collaboration the most equitable for all countries.

Best,
Bethany

1. Matthews, K. R., Yang, E., Lewis, S. W., Vaidyanathan, B. R., & Gorman, M. (2020). International scientific collaborative activities and barriers to them in eight societies. Accountability in Research, 27(8), 477-495.

Name
Bethany Wilken

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