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Posts Tagged ‘Pharmacovigilance’


Twitter is Becoming a Powerful Tool in Science and Medicine

 Curator: Stephen J. Williams, Ph.D.

Updated 4/2016

Life-cycle of Science 2

A recent Science article (Who are the science stars of Twitter?; Sept. 19, 2014) reported the top 50 scientists followed on Twitter. However, the article tended to focus on the use of Twitter as a means to develop popularity, a sort of “Science Kardashian” as they coined it. So the writers at Science developed a “Kardashian Index (K-Index) to determine scientists following and popularity on Twitter.

Now as much buzz Kim Kardashian or a Perez Hilton get on social media, their purpose is solely for entertainment and publicity purposes, the Science sort of fell flat in that it focused mainly on the use of Twitter as a metric for either promotional or public outreach purposes. A notable scientist was mentioned in the article, using Twitter feed to gauge the receptiveness of his presentation. In addition, relying on Twitter for effective public discourse of science is problematic as:

  • Twitter feeds are rapidly updated and older feeds quickly get buried within the “Twittersphere” = LIMITED EXPOSURE TIMEFRAME
  • Short feeds may not provide the access to appropriate and understandable scientific information (The Science Communication Trap) which is explained in The Art of Communicating Science: traps, tips and tasks for the modern-day scientist. “The challenge of clearly communicating the intended scientific message to the public is not insurmountable but requires an understanding of what works and what does not work.” – from Heidi Roop, G.-Martinez-Mendez and K. Mills

However, as highlighted below, Twitter, and other social media platforms are being used in creative ways to enhance the research, medical, and bio investment collaborative, beyond a simple news-feed.  And the power of Twitter can be attributed to two simple features

  1. Ability to organize – through use of the hashtag (#) and handle (@), Twitter assists in the very important task of organizing, indexing, and ANNOTATING content and conversations. A very great article on Why the Hashtag in Probably the Most Powerful Tool on Twitter by Vanessa Doctor explains how hashtags and # search may be as popular as standard web-based browser search. Thorough annotation is crucial for any curation process, which are usually in the form of database tags or keywords. The use of # and @ allows curators to quickly find, index and relate disparate databases to link annotated information together. The discipline of scientific curation requires annotation to assist in the digital preservation, organization, indexing, and access of data and scientific & medical literature. For a description of scientific curation methodologies please see the following links:

Please read the following articles on CURATION

The Methodology of Curation for Scientific Research Findings

Power of Analogy: Curation in Music, Music Critique as a Curation and Curation of Medical Research Findings – A Comparison

Science and Curation: The New Practice of Web 2.0

  1. Information Analytics

Multiple analytic software packages have been made available to analyze information surrounding Twitter feeds, including Twitter feeds from #chat channels one can set up to cover a meeting, product launch etc.. Some of these tools include:

Twitter Analytics – measures metrics surrounding Tweets including retweets, impressions, engagement, follow rate, …

Twitter Analytics – Hashtags.org – determine most impactful # for your Tweets For example, meeting coverage of bioinvestment conferences or startup presentations using #startup generates automatic retweeting by Startup tweetbot @StartupTweetSF.

 

  1. Tweet Sentiment Analytics

Examples of Twitter Use

A. Scientific Meeting Coverage

In a paper entitled Twitter Use at a Family Medicine Conference: Analyzing #STFM13 authors Ranit Mishori, MD, Frendan Levy, MD, and Benjamin Donvan analyzed the public tweets from the 2013 Society of Teachers of Family Medicine (STFM) conference bearing the meeting-specific hashtag #STFM13. Thirteen percent of conference attendees (181 users) used the #STFM13 to share their thoughts on the meeting (1,818 total tweets) showing a desire for social media interaction at conferences but suggesting growth potential in this area. As we have also seen, the heaviest volume of conference-tweets originated from a small number of Twitter users however most tweets were related to session content.

However, as the authors note, although it is easy to measure common metrics such as number of tweets and retweets, determining quality of engagement from tweets would be important for gauging the value of Twitter-based social-media coverage of medical conferences.

Thea authors compared their results with similar analytics generated by the HealthCare Hashtag Project, a project and database of medically-related hashtag use, coordinated and maintained by the company Symplur.  Symplur’s database includes medical and scientific conference Twitter coverage but also Twitter usuage related to patient care. In this case the database was used to compare meeting tweets and hashtag use with the 2012 STFM conference.

These are some of the published journal articles that have employed Symplur (www.symplur.com) data in their research of Twitter usage in medical conferences.

B. Twitter Usage for Patient Care and Engagement

Although the desire of patients to use and interact with their physicians over social media is increasing, along with increasing health-related social media platforms and applications, there are certain obstacles to patient-health provider social media interaction, including lack of regulatory framework as well as database and security issues. Some of the successes and issues of social media and healthcare are discussed in the post Can Mobile Health Apps Improve Oral-Chemotherapy Adherence? The Benefit of Gamification.

However there is also a concern if social media truly engages the patient and improves patient education. In a study of Twitter communications by breast cancer patients Tweeting about breast cancer, authors noticed Tweeting was a singular event. The majority of tweets did not promote any specific preventive behavior. The authors concluded “Twitter is being used mostly as a one-way communication tool.” (Using Twitter for breast cancer prevention: an analysis of breast cancer awareness month. Thackeray R1, Burton SH, Giraud-Carrier C, Rollins S, Draper CR. BMC Cancer. 2013;13:508).

In addition a new poll by Harris Interactive and HealthDay shows one third of patients want some mobile interaction with their physicians.

Some papers cited in Symplur’s HealthCare Hashtag Project database on patient use of Twitter include:

C. Twitter Use in Pharmacovigilance to Monitor Adverse Events

Pharmacovigilance is the systematic detection, reporting, collecting, and monitoring of adverse events pre- and post-market of a therapeutic intervention (drug, device, modality e.g.). In a Cutting Edge Information Study, 56% of pharma companies databases are an adverse event channel and more companies are turning to social media to track adverse events (in Pharmacovigilance Teams Turn to Technology for Adverse Event Reporting Needs). In addition there have been many reports (see Digital Drug Safety Surveillance: Monitoring Pharmaceutical Products in Twitter) that show patients are frequently tweeting about their adverse events.

There have been concerns with using Twitter and social media to monitor for adverse events. For example FDA funded a study where a team of researchers from Harvard Medical School and other academic centers examined more than 60,000 tweets, of which 4,401 were manually categorized as resembling adverse events and compared with the FDA pharmacovigilance databases. Problems associated with such social media strategy were inability to obtain extra, needed information from patients and difficulty in separating the relevant Tweets from irrelevant chatter.  The UK has launched a similar program called WEB-RADR to determine if monitoring #drug_reaction could be useful for monitoring adverse events. Many researchers have found the adverse-event related tweets “noisy” due to varied language but had noticed many people do understand some principles of causation including when adverse event subsides after discontinuing the drug.

However Dr. Clark Freifeld, Ph.D., from Boston University and founder of the startup Epidemico, feels his company has the algorithms that can separate out the true adverse events from the junk. According to their web site, their algorithm has high accuracy when compared to the FDA database. Dr. Freifeld admits that Twitter use for pharmacovigilance purposes is probably a starting point for further follow-up, as each patient needs to fill out the four-page forms required for data entry into the FDA database.

D. Use of Twitter in Big Data Analytics

Published on Aug 28, 2012

http://blogs.ischool.berkeley.edu/i29…

Course: Information 290. Analyzing Big Data with Twitter
School of Information
UC Berkeley

Lecture 1: August 23, 2012

Course description:
How to store, process, analyze and make sense of Big Data is of increasing interest and importance to technology companies, a wide range of industries, and academic institutions. In this course, UC Berkeley professors and Twitter engineers will lecture on the most cutting-edge algorithms and software tools for data analytics as applied to Twitter microblog data. Topics will include applied natural language processing algorithms such as sentiment analysis, large scale anomaly detection, real-time search, information diffusion and outbreak detection, trend detection in social streams, recommendation algorithms, and advanced frameworks for distributed computing. Social science perspectives on analyzing social media will also be covered.

This is a hands-on project course in which students are expected to form teams to complete intensive programming and analytics projects using the real-world example of Twitter data and code bases. Engineers from Twitter will help advise student projects, and students will have the option of presenting their final project presentations to an audience of engineers at the headquarters of Twitter in San Francisco (in addition to on campus). Project topics include building on existing infrastructure tools, building Twitter apps, and analyzing Twitter data. Access to data will be provided.

Other posts on this site on USE OF SOCIAL MEDIA AND TWITTER IN HEALTHCARE and Conference Coverage include:

Methodology for Conference Coverage using Social Media: 2014 MassBio Annual Meeting 4/3 – 4/4 2014, Royal Sonesta Hotel, Cambridge, MA

Strategy for Event Joint Promotion: 14th ANNUAL BIOTECH IN EUROPE FORUM For Global Partnering & Investment 9/30 – 10/1/2014 • Congress Center Basel – SACHS Associates, London

REAL TIME Cancer Conference Coverage: A Novel Methodology for Authentic Reporting on Presentations and Discussions launched via Twitter.com @ The 2nd ANNUAL Sachs Cancer Bio Partnering & Investment Forum in Drug Development, 19th March 2014 • New York Academy of Sciences • USA

PCCI’s 7th Annual Roundtable “Crowdfunding for Life Sciences: A Bridge Over Troubled Waters?” May 12 2014 Embassy Suites Hotel, Chesterbrook PA 6:00-9:30 PM

CRISPR-Cas9 Discovery and Development of Programmable Genome Engineering – Gabbay Award Lectures in Biotechnology and Medicine – Hosted by Rosenstiel Basic Medical Sciences Research Center, 10/27/14 3:30PM Brandeis University, Gerstenzang 121

Tweeting on 14th ANNUAL BIOTECH IN EUROPE FORUM For Global Partnering & Investment 9/30 – 10/1/2014 • Congress Center Basel – SACHS Associates, London

https://pharmaceuticalintelligence.com/press-coverage/

Statistical Analysis of Tweet Feeds from the 14th ANNUAL BIOTECH IN EUROPE FORUM For Global Partnering & Investment 9/30 – 10/1/2014 • Congress Center Basel – SACHS Associates, London

1st Pitch Life Science- Philadelphia- What VCs Really Think of your Pitch

What VCs Think about Your Pitch? Panel Summary of 1st Pitch Life Science Philly

How Social Media, Mobile Are Playing a Bigger Part in Healthcare

Can Mobile Health Apps Improve Oral-Chemotherapy Adherence? The Benefit of Gamification.

Medical Applications and FDA regulation of Sensor-enabled Mobile Devices: Apple and the Digital Health Devices Market

E-Medical Records Get A Mobile, Open-Sourced Overhaul By White House Health Design Challenge Winners

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NIH Considers Guidelines for CAR-T therapy: Report from Recombinant DNA Advisory Committee

Reporter: Stephen J. Williams, Ph.D.

In the mid to late 1970’s a public debate (and related hysteria) had emerged surrounding two emerging advances in recombinant DNA technology;

  1. the development of vectors useful for cloning pieces of DNA (the first vector named pBR322) and
  2. the discovery of bacterial strains useful in propagating such vectors

As discussed by D. S, Fredrickson of NIH’s Dept. of Education and Welfare in his historical review” A HISTORY OF THE RECOMBINANT DNA GUIDELINES IN THE UNITED STATES” this international concern of the biological safety issues of this new molecular biology tool led the National Institute of Health to coordinate a committee (the NIH Recombinant DNA Advisory Committee) to develop guidelines for the ethical use, safe development, and safe handling of such vectors and host bacterium. The first conversations started in 1974 and, by 1978, initial guidelines had been developed. In fact, as Dr. Fredrickson notes, public relief was voiced even by religious organizations (who had the greatest ethical concerns)

On December 16, 1978, a telegram purporting to be from the Vatican was hand delivered to the office of Joseph A. Califano, Jr., Secretary of Health, Education,

and Welfare. “Habemus regimen recombinatum,” it proclaimed, in celebration of the

end of a long struggle to revise the NIH Guidelines for Research Involving

Recombinant DNA Molecules

The overall Committee resulted in guidelines (2013 version) which assured the worldwide community that

  • organisms used in such procedures would have limited pathogenicity in humans
  • vectors would be developed in a manner which would eliminate their ability to replicate in humans and have defined antibiotic sensitivity

So great was the success and acceptance of this committee and guidelines, the NIH felt the Recombinant DNA Advisory Committee should meet regularly to discuss and develop ethical guidelines and clinical regulations concerning DNA-based therapeutics and technologies.

A PowerPoint Slideshow: Introduction to NIH OBA and the History of Recombinant DNA Oversight can be viewed at the following link:

http://www.powershow.com/view1/e1703-ZDc1Z/Introduction_to_NIH_OBA_and_the_History_of_Recombinant_DNA_Oversight_powerpoint_ppt_presentation

Please see the following link for a video discussion between Dr. Paul Berg, who pioneered DNA recombinant technology, and Dr. James Watson (Commemorating 50 Years of DNA Science):

http://media.hhmi.org/interviews/berg_watson.html

The Recombinant DNA Advisory Committee has met numerous times to discuss new DNA-based technologies and their biosafety and clinical implication including:

A recent Symposium was held in the summer of 2010 to discuss ethical and safety concerns and discuss potential clinical guidelines for use of an emerging immunotherapy technology, the Chimeric Antigen Receptor T-Cells (CART), which at that time had just been started to be used in clinical trials.

Considerations for the Clinical Application of Chimeric Antigen Receptor T Cells: Observations from a Recombinant DNA Advisory Committee Symposium Held June 15, 2010[1]

Contributors to the Symposium discussing opinions regarding CAR-T protocol design included some of the prominent members in the field including:

Drs. Hildegund C.J. Ertl, John Zaia, Steven A. Rosenberg, Carl H. June, Gianpietro Dotti, Jeffrey Kahn, Laurence J. N. Cooper, Jacqueline Corrigan-Curay, And Scott E. Strome.

The discussions from the Symposium, reported in Cancer Research[1]. were presented in three parts:

  1. Summary of the Evolution of the CAR therapy
  2. Points for Future Consideration including adverse event reporting
  3. Considerations for Design and Implementation of Trials including mitigating toxicities and risks

1. Evolution of Chimeric Antigen Receptors

Early evidence had suggested that adoptive transfer of tumor-infiltrating lymphocytes, after depletion of circulating lymphocytes, could result in a clinical response in some tumor patients however developments showed autologous T-cells (obtained from same patient) could be engineered to express tumor-associated antigens (TAA) and replace the TILS in the clinical setting.

However there were some problems noticed.

  • Problem: HLA restriction of T-cells. Solution: genetically engineer T-cells to redirect T-cell specificity to surface TAAs
  • Problem: 1st generation vectors designed to engineer T-cells to recognize surface epitopes but engineered cells had limited survival in patients.   Solution: development of 2nd generation vectors with co-stimulatory molecules such as CD28, CD19 to improve survival and proliferation in patients

A summary table of limitations of the two types of genetically-modified T-cell therapies were given and given (in modified form) below

                                                                                                Type of Gene-modified T-Cell

Limitations aβ TCR CAR
Affected by loss or decrease of HLA on tumor cells yes no
Affected by altered tumor cell antigen processing? yes no
Need to have defined tumor target antigen? no yes
Vector recombination with endogenous TCR yes no

A brief history of construction of 2nd and 3rd generation CAR-T cells given by cancer.gov:

http://www.cancer.gov/cancertopics/research-updates/2013/CAR-T-Cells

cartdiagrampic

Differences between  second- and third-generation chimeric antigen receptor T cells. (Adapted by permission from the American Association for Cancer Research: Lee, DW et al. The Future Is Now: Chimeric Antigen Receptors as New Targeted Therapies for Childhood Cancer. Clin Cancer Res; 2012;18(10); 2780–90. doi:10.1158/1078-0432.CCR-11-1920)

Constructing a CAR T Cell (from cancer.gov)

The first efforts to engineer T cells to be used as a cancer treatment began in the early 1990s. Since then, researchers have learned how to produce T cells that express chimeric antigen receptors (CARs) that recognize specific targets on cancer cells.

The T cells are genetically modified to produce these receptors. To do this, researchers use viral vectors that are stripped of their ability to cause illness but that retain the capacity to integrate into cells’ DNA to deliver the genetic material needed to produce the T-cell receptors.

The second- and third-generation CARs typically consist of a piece of monoclonal antibody, called a single-chain variable fragment (scFv), that resides on the outside of the T-cell membrane and is linked to stimulatory molecules (Co-stim 1 and Co-stim 2) inside the T cell. The scFv portion guides the cell to its target antigen. Once the T cell binds to its target antigen, the stimulatory molecules provide the necessary signals for the T cell to become fully active. In this fully active state, the T cells can more effectively proliferate and attack cancer cells.

2. Adverse Event Reporting and Protocol Considerations

The symposium had been organized mainly in response to two reported deaths of patients enrolled in a CART trial, so that clinical investigators could discuss and formulate best practices for the proper conduct and analysis of such trials. One issue raised was lack of pharmacovigilence procedures (adverse event reporting). Although no pharmacovigilence procedures (either intra or inter-institutional) were devised from meeting proceedings, it was stressed that each institution should address this issue as well as better clinical outcome reporting.

Case Report of a Serious Adverse Event Following the Administration of T Cells Transduced With a Chimeric Antigen Receptor Recognizing ERBB2[2] had reported the death of a patient on trial.

In A phase I clinical trial of adoptive transfer of folate receptor-alpha redirected autologous T cells for recurrent ovarian cancer[3] authors: Lana E Kandalaft*, Daniel J Powell and George Coukos from University of Pennsylvania recorded adverse events in pilot studies using a CART modified to recognize the folate receptor, so it appears any adverse event reporting system is at the discretion of the primary investigator.

Other protocol considerations suggested by the symposium attendants included:

  • Plan for translational clinical lab for routine blood analysis
  • Subject screening for pulmonary and cardiac events
  • Determine possibility of insertional mutagenesis
  • Informed consent
  • Analysis of non T and T-cell subsets, e.g. natural killer cells and CD*8 cells

3. Consideration for Design of Trials and Mitigating Toxicities

  • Early Toxic effectsCytokine Release Syndrome– The effectiveness of CART therapy has been manifested by release of high levels of cytokines resulting in fever and inflammatory sequelae. One such cytokine, interleukin 6, has been attributed to this side effect and investigators have successfully used an IL6 receptor antagonist, tocilizumab (Acterma™), to alleviate symptoms of cytokine release syndrome (see review Adoptive T-cell therapy: adverse events and safety switches by Siok-Keen Tey).

 

Below is a video form Dr. Renier Brentjens, M.D., Ph.D. for Memorial Sloan Kettering concerning the finding he made that the adverse event from cytokine release syndrome may be a function of the tumor cell load, and if they treat the patient with CAR-T right after salvage chemotherapy the adverse events are alleviated..

Please see video below:

http link: https://www.youtube.com/watch?v=4Gg6elUMIVE

  • Early Toxic effects – Over-activation of CAR T-cells; mitigation by dose escalation strategy (as authors in reference [3] proposed). Most trials give billions of genetically modified cells to a patient.
  • Late Toxic Effectslong-term depletion of B-cells . For example CART directing against CD19 or CD20 on B cells may deplete the normal population of CD19 or CD20 B-cells over time; possibly managed by IgG supplementation

 Please look for a Followup Post concerning “Developing a Pharmacovigilence Framework for Engineered T-Cell Therapies”

References

  1. Ertl HC, Zaia J, Rosenberg SA, June CH, Dotti G, Kahn J, Cooper LJ, Corrigan-Curay J, Strome SE: Considerations for the clinical application of chimeric antigen receptor T cells: observations from a recombinant DNA Advisory Committee Symposium held June 15, 2010. Cancer research 2011, 71(9):3175-3181.
  2. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA: Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Molecular therapy : the journal of the American Society of Gene Therapy 2010, 18(4):843-851.
  3. Kandalaft LE, Powell DJ, Jr., Coukos G: A phase I clinical trial of adoptive transfer of folate receptor-alpha redirected autologous T cells for recurrent ovarian cancer. Journal of translational medicine 2012, 10:157.

Other posts on this site on Immunotherapy and Cancer include

Report on Cancer Immunotherapy Market & Clinical Pipeline Insight

New Immunotherapy Could Fight a Range of Cancers

Combined anti-CTLA4 and anti-PD1 immunotherapy shows promising results against advanced melanoma

Molecular Profiling in Cancer Immunotherapy: Debraj GuhaThakurta, PhD

Pancreatic Cancer: Genetics, Genomics and Immunotherapy

$20 million Novartis deal with ‘University of Pennsylvania’ to develop Ultra-Personalized Cancer Immunotherapy

Upcoming Meetings on Cancer Immunogenetics

Tang Prize for 2014: Immunity and Cancer

ipilimumab, a Drug that blocks CTLA-4 Freeing T cells to Attack Tumors @DM Anderson Cancer Center

Juno’s approach eradicated cancer cells in 10 of 12 leukemia patients, indicating potential to transform the standard of care in oncology

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The red tape challenge

reporter and curator: Dror Nir, PhD

Large part of the time and cost for developing a new medical device or a new drug is allocated for achieving regulatory compliance. While quality and safety are desired, having to continually spend additional time and  money throughout the product’s life cycle just on the proof of its quality and safety is painful to all, especially for the health systems which eventually have to pay for it.
On this issue, I bring you the following post:
It has almost become routine: under narratives of increased patient safety and improved efficiency new regulatory requirements are developed, resulting in increased requirements on the industry. The new European pharmacovigilance legislation and the upcoming European medical device regulatory updates are only two examples. Being part of the industry you have very limited impact on the regulations but have to comply with them anyway. That is – if you were to continue marketing your device or drug. Under certain circumstances the cost of meeting legal requirements is so great it may bring into question the viability of continuing certain business activities. This is especially the case for smaller companies or niche products.
R1
It is clear, thus, that you have a huge incentive to try to achieve compliance with minimal effort. If we take a bird’s eye view on the challenge of reaching compliance, two major elements become evident:
  1. The quality system is, in itself, a high maintenance object which consumes ongoing resources:
    • It needs to be revisited often due to changes in the regulatory system or in the business environment.
    • Each change may affect many components of the system and a quick modification may cause inconsistency.
    • Each modification needs to be accepted, signed-off formally by several people and be disseminated via formally recorded training.
    • The organization should withstand audits and inspections in regards to the quality system.
  2. Living with the quality system: Each SOP and work instruction has to be followed, and typically forms need to be filled, signed and filed.
Information Overload

Young companies which are just embarking on the regulatory path often do not realize these two characteristics of the quality system. Quick fixes in the form of SOP texts copied from other organizations or generic templates are being used to get the initial certification. However, as the organization evolves it realizes that a quality system is not a one-time effort and cannot be glued on from external sources.  It has to be streamlined and become part of the way that the organization lives and does business. Companies are enjoying the benefits of improved process design and automation on a large scale every day, in many areas. When recently did you see a delivery person arriving to a pickup without a Barcode reader, so that he does not need to fill any form manually? When was the last time that a software package was released without an automatic consistency check? So too your quality system and related processes may be dramatically engineered to serve you better.

Better efficiency in quality compliance should thus be achieved through careful analysis and optimization of two types of processes:
How do we better maintain the quality system? How do we make it easier to change the system, keep it consistent, train in it, etc.
The SOPs and work instructions: SOPs cannot be just imported from outside or suggested by a QA/RA consultant who does not know the organization very well. SOPs should be a true marriage between the legal and business requirements and should be the result of a careful consideration by all stakeholders. From my experience, the best SOPs are written by the process owner, with the guidance of the regulatory expert. For example: the R&D manager should be the one drafting the design control SOP, with input of the regulatory expert. Such a SOP is much more likely to fit the business needs, and also more likely to be followed by the process owner.
Yes, I realize that thinking this way is very often not what companies do when they rush compliance. I insist that this is what has to be done to achieve sustainable compliance. The good news is that, when companies do look at their quality system in this way, they see many opportunities for significant improvement. Some of those improvements are achieved through use of better IT tools. These tools would typically be in the area of document management and versioning, workflow automation, improved collaboration and electronic signatures. Like any other change, this also requires a vision and a certain effort. However, the long term business impact may be as significant as the difference between business success or failure.

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