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The Regulatory challenge in adopting AI

Author and Curator: Dror Nir, PhD

In the last couple of years we are witnessing a surge of AI applications in healthcare. It is clear now, that AI and its wide range of health-applications are about to revolutionize diseases’ pathways and the way the variety of stakeholders in this market interact.

Not surprisingly, the developing surge has waken the regulatory watchdogs who are now debating ways to manage the introduction of such applications to healthcare. Attributing measures to known regulatory checkboxes like safety, and efficacy is proving to be a complex exercise. How to align claims made by manufacturers, use cases, users’ expectations and public expectations is unclear. A recent demonstration of that is the so called “failure” of AI in social-network applications like FaceBook and Twitter in handling harmful materials.

‘Advancing AI in the NHS’ – is a report covering the challenges and opportunities of AI in the NHS. It is a modest contribution to the debate in such a timely and fast-moving field!  I bring here the report’s preface and executive summary hoping that whoever is interested in reading the whole 50 pages of it will follow this link: f53ce9_e4e9c4de7f3c446fb1a089615492ba8c

Screenshot 2019-04-07 at 17.18.18

 

Acknowledgements

We and Polygeia as a whole are grateful to Dr Dror Nir, Director, RadBee, whose insights

were valuable throughout the research, conceptualisation, and writing phases of this work; and to Dr Giorgio Quer, Senior Research Scientist, Scripps Research Institute; Dr Matt Willis, Oxford Internet Institute, University of Oxford; Professor Eric T. Meyer, Oxford Internet Institute, University of Oxford; Alexander Hitchcock, Senior Researcher, Reform; Windi Hari, Vice President Clinical, Quality & Regulatory, HeartFlow; Jon Holmes, co-founder and Chief Technology Officer, Vivosight; and Claudia Hartman, School of Anthropology & Museum Ethnography, University of Oxford for their advice and support.

Author affiliations

Lev Tankelevitch, University of Oxford

Alice Ahn, University of Oxford

Rachel Paterson, University of Oxford

Matthew Reid, University of Oxford

Emily Hilbourne, University of Oxford

Bryan Adriaanse, University of Oxford

Giorgio Quer, Scripps Research Institute

Dror Nir, RadBee

Parth Patel, University of Cambridge

All affiliations are at the time of writing.

Polygeia

Polygeia is an independent, non-party, and non-profit think-tank focusing on health and its intersection with technology, politics, and economics. Our aim is to produce high-quality research on global health issues and policies. With branches in Oxford, Cambridge, London and New York, our work has led to policy reports, peer-reviewed publications, and presentations at the House of Commons and the European Parliament. http://www.polygeia.com @Polygeia © Polygeia 2018. All rights reserved.

Foreword

Almost every day, as MP for Cambridge, I am told of new innovations and developments that show that we are on the cusp of a technological revolution across the sectors. This technology is capable of revolutionising the way we work; incredible innovations which could increase our accuracy, productivity and efficiency and improve our capacity for creativity and innovation.

But huge change, particularly through adoption of new technology, can be difficult to  communicate to the public, and if we do not make sure that we explain carefully the real benefits of such technologies we easily risk a backlash. Despite good intentions, the care.data programme failed to win public trust, with widespread worries that the appropriate safeguards weren’t in place, and a failure to properly explain potential benefits to patients. It is vital that the checks and balances we put in place are robust enough to sooth public anxiety, and prevent problems which could lead to steps back, rather than forwards.

Previous attempts to introduce digital innovation into the NHS also teach us that cross-disciplinary and cross-sector collaboration is essential. Realising this technological revolution in healthcare will require industry, academia and the NHS to work together and share their expertise to ensure that technical innovations are developed and adopted in ways that prioritise patient health, rather than innovation for its own sake. Alongside this, we must make sure that the NHS workforce whose practice will be altered by AI are on side. Consultation and education are key, and this report details well the skills that will be vital to NHS adoption of AI. Technology is only as good as those who use it, and for this, we must listen to the medical and healthcare professionals who will rightly know best the concerns both of patients and their colleagues. The new Centre for Data Ethics and Innovation, the ICO and the National Data Guardian will be key in working alongside the NHS to create both a regulatory framework and the communications which win society’s trust. With this, and with real leadership from the sector and from politicians, focused on the rights and concerns of individuals, AI can be advanced in the NHS to help keep us all healthy.

Daniel Zeichner

MP for Cambridge

Chair, All-Party Parliamentary Group on Data Analytics

 

Executive summary

Artificial intelligence (AI) has the potential to transform how the NHS delivers care. From enabling patients to self-care and manage long-term conditions, to advancing triage, diagnostics, treatment, research, and resource management, AI can improve patient outcomes and increase efficiency. Achieving this potential, however, requires addressing a number of ethical, social, legal, and technical challenges. This report describes these challenges within the context of healthcare and offers directions forward.

Data governance

AI-assisted healthcare will demand better collection and sharing of health data between NHS, industry and academic stakeholders. This requires a data governance system that ensures ethical management of health data and enables its use for the improvement of healthcare delivery. Data sharing must be supported by patients. The recently launched NHS data opt-out programme is an important starting point, and will require monitoring to ensure that it has the transparency and clarity to avoid exploiting the public’s lack of awareness and understanding. Data sharing must also be streamlined and mutually beneficial. Current NHS data sharing practices are disjointed and difficult to negotiate from both industry and NHS perspectives. This issue is complicated by the increasing integration of ’traditional’ health data with that from commercial apps and wearables. Finding approaches to valuate data, and considering how patients, the NHS and its partners can benefit from data sharing is key to developing a data sharing framework. Finally, data sharing should be underpinned by digital infrastructure that enables cybersecurity and accountability.

Digital infrastructure

Developing and deploying AI-assisted healthcare requires high quantity and quality digital data. This demands effective digitisation of the NHS, especially within secondary care, involving not only the transformation of paper-based records into digital data, but also improvement of quality assurance practices and increased data linkage. Beyond data digitisation, broader IT infrastructure also needs upgrading, including the use of innovations such as wearable technology and interoperability between NHS sectors and institutions. This would not only increase data availability for AI development, but also provide patients with seamless healthcare delivery, putting the NHS at the vanguard of healthcare innovation.

Standards

The recent advances in AI and the surrounding hype has meant that the development of AI-assisted healthcare remains haphazard across the industry, with quality being difficult to determine or varying widely. Without adequate product validation, including in

real-world settings, there is a risk of unexpected or unintended performance, such as sociodemographic biases or errors arising from inappropriate human-AI interaction. There is a need to develop standardised ways to probe training data, to agree upon clinically-relevant performance benchmarks, and to design approaches to enable and evaluate algorithm interpretability for productive human-AI interaction. In all of these areas, standardised does not necessarily mean one-size-fits-all. These issues require addressing the specifics of AI within a healthcare context, with consideration of users’ expertise, their environment, and products’ intended use. This calls for a fundamentally interdisciplinary approach, including experts in AI, medicine, ethics, cognitive science, usability design, and ethnography.

Regulations

Despite the recognition of AI-assisted healthcare products as medical devices, current regulatory efforts by the UK Medicines and Healthcare Products Regulatory Agency and the European Commission have yet to be accompanied by detailed guidelines which address questions concerning AI product classification, validation, and monitoring. This is compounded by the uncertainty surrounding Brexit and the UK’s future relationship with the European Medicines Agency. The absence of regulatory clarity risks compromising patient safety and stalling the development of AI-assisted healthcare. Close working partnerships involving regulators, industry members, healthcare institutions, and independent AI-related bodies (for example, as part of regulatory sandboxes) will be needed to enable innovation while ensuring patient safety.

The workforce

AI will be a tool for the healthcare workforce. Harnessing its utility to improve care requires an expanded workforce with the digital skills necessary for both developing AI capability and for working productively with the technology as it becomes commonplace.

Developing capability for AI will involve finding ways to increase the number of clinician-informaticians who can lead the development, procurement and adoption of AI technology while ensuring that innovation remains tied to the human aspect of healthcare delivery. More broadly, healthcare professionals will need to complement their socio-emotional and cognitive skills with training to appropriately interpret information provided by AI products and communicate it effectively to co-workers and patients.

Although much effort has gone into predicting how many jobs will be affected by AI-driven automation, understanding the impact on the healthcare workforce will require examining how jobs will change, not simply how many will change.

Legal liability

AI-assisted healthcare has implications for the legal liability framework: who should be held responsible in the case of a medical error involving AI? Addressing the question of liability will involve understanding how healthcare professionals’ duty of care will be impacted by use of the technology. This is tied to the lack of training standards for healthcare professionals to safely and effectively work with AI, and to the challenges of algorithm interpretability, with ”black-box” systems forcing healthcare professionals to blindly trust or distrust their output. More broadly, it will be important to examine the legal liability of healthcare professionals, NHS trusts and industry partners, raising questions

Recommendations

  1. The NHS, the Centre for Data Ethics and Innovation, and industry and academic partners should conduct a review to understand the obstacles that the NHS and external organisations face around data sharing. They should also develop health data valuation protocols which consider the perspectives of patients, the NHS, commercial organisations, and academia. This work should inform the development of a data sharing framework.
  2. The National Data Guardian and the Department of Health should monitor the NHS data opt-out programme and its approach to transparency and communication, evaluating how the public understands commercial and non-commercial data use and the handling of data at different levels of anonymisation.
  3. The NHS, patient advocacy groups, and commercial organisations should expand public engagement strategies around data governance, including discussions about the value of health data for improving healthcare; public and private sector interactions in the development of AI-assisted healthcare; and the NHS’s strategies around data anonymisation, accountability, and commercial partnerships. Findings from this work should inform the development of a data sharing framework.
  4. The NHS Digital Security Operations Centre should ensure that all NHS organisations comply with cybersecurity standards, including having up-to-date technology.
  5. NHS Digital, the Centre for Data Ethics and Innovation, and the Alan Turing Institute should develop technological approaches to data privacy, auditing, and accountability that could be implemented in the NHS. This should include learning from Global Digital Exemplar trusts in the UK and from international examples such as Estonia.
  6. The NHS should continue to increase the quantity, quality, and diversity of digital health data across trusts. It should consider targeted projects, in partnership with professional medical bodies, that quality-assure and curate datasets for more deployment-ready AI technology. It should also continue to develop its broader IT infrastructure, focusing on interoperability between sectors, institutions, and technologies, and including the end users as central stakeholders.
  7. The Alan Turing Institute, the Ada Lovelace Institute, and academic and industry partners in medicine and AI should develop ethical frameworks and technological approaches for the validation of training data in the healthcare sector, including methods to minimise performance biases and validate continuously-learning algorithms.
  8. The Alan Turing Institute, the Ada Lovelace Institute, and academic and industry partners in medicine and AI should develop standardised approaches for evaluating product performance in the healthcare sector, with consideration for existing human performance standards and products’ intended use.
  9. The Alan Turing Institute, the Ada Lovelace Institute, and academic and industry partners in medicine and AI should develop methods of enabling and evaluating algorithm interpretability in the healthcare sector. This work should involve experts in AI, medicine, ethics, usability design, cognitive science, and ethnography, among others.
  10. Developers of AI products and NHS Commissioners should ensure that usability design remains a top priority in their respective development and procurement of AI-assisted healthcare products.
  11. The Medicines and Healthcare Products Regulatory Agency should establish a digital health unit with expertise in AI and digital products that will work together with manufacturers, healthcare bodies, notified bodies, AI-related organisations, and international forums to advance clear regulatory approaches and guidelines around AI product classification, validation, and monitoring. This should address issues including training data and biases, performance evaluation, algorithm interpretability, and usability.
  12. The Medicines and Healthcare Products Regulatory Agency, the Centre for Data Ethics and Innovation, and industry partners should evaluate regulatory approaches, such as regulatory sandboxing, that can foster innovation in AI-assisted healthcare, ensure patient safety, and inform on-going regulatory development.
  13. The NHS should expand innovation acceleration programmes that bridge healthcare and industry partners, with a focus on increasing validation of AI products in real-world contexts and informing the development of a regulatory framework.
  14. The Medicines and Healthcare Products Regulatory Agency and other Government bodies should arrange a post-Brexit agreement ensuring that UK regulations of medical devices, including AI-assisted healthcare, are aligned as closely as possible to the European framework and that the UK can continue to help shape Europe-wide regulations around this technology.
  15. The General Medical Council, the Medical Royal Colleges, Health Education England, and AI-related bodies should partner with industry and academia on comprehensive examinations of the healthcare sector to assess which, when, and how jobs will be impacted by AI, including analyses of the current strengths, limitations, and workflows of healthcare professionals and broader NHS staff. They should also examine how AI-driven workforce changes will impact patient outcomes.
  16. The Federation of Informatics Professionals and the Faculty of Clinical Informatics should continue to lead and expand standards for health informatics competencies, integrating the relevant aspects of AI into their training, accreditation, and professional development programmes for clinician-informaticians and related professions.
  17. Health Education England should expand training programmes to advance digital and AI-related skills among healthcare professionals. Competency standards for working with AI should be identified for each role and established in accordance with professional registration bodies such as the General Medical Council. Training programmes should ensure that ”un-automatable” socio-emotional and cognitive skills remain an important focus.
  18. The NHS Digital Academy should expand recruitment and training efforts to increase the number of Chief Clinical Information Officers across the NHS, and ensure that the latest AI ethics, standards, and innovations are embedded in their training programme.
  19. Legal experts, ethicists, AI-related bodies, professional medical bodies, and industry should review the implications of AI-assisted healthcare for legal liability. This includes understanding how healthcare professionals’ duty of care will be affected, the role of workforce training and product validation standards, and the potential role of NHS Indemnity and no-fault compensation systems.
  20. AI-related bodies such as the Ada Lovelace Institute, patient advocacy groups and other healthcare stakeholders should lead a public engagement and dialogue strategy to understand the public’s views on liability for AI-assisted healthcare.

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That is the question…

Anyone who follows healthcare news, as I do , cannot help being impressed with the number of scientific and non-scientific items that mention the applicability of Magnetic Resonance Imaging (‘MRI’) to medical procedures.

A very important aspect that is worthwhile noting is that the promise MRI bears to improve patients’ screening – pre-clinical diagnosis, better treatment choice, treatment guidance and outcome follow-up – is based on new techniques that enables MRI-based tissue characterisation.

Magnetic resonance imaging (MRI) is an imaging device that relies on the well-known physical phenomena named “Nuclear Magnetic Resonance”. It so happens that, due to its short relaxation time, the 1H isotope (spin ½ nucleus) has a very distinctive response to changes in the surrounding magnetic field. This serves MRI imaging of the human body well as, basically, we are 90% water. The MRI device makes use of strong magnetic fields changing at radio frequency to produce cross-sectional images of organs and internal structures in the body. Because the signal detected by an MRI machine varies depending on the water content and local magnetic properties of a particular area of the body, different tissues or substances can be distinguished from one another in the scan’s resulting image.

The main advantages of MRI in comparison to X-ray-based devices such as CT scanners and mammography systems are that the energy it uses is non-ionizing and it can differentiate soft tissues very well based on differences in their water content.

In the last decade, the basic imaging capabilities of MRI have been augmented for the purpose of cancer patient management, by using magnetically active materials (called contrast agents) and adding functional measurements such as tissue temperature to show internal structures or abnormalities more clearly.

 

In order to increase the specificity and sensitivity of MRI imaging in cancer detection, various imaging strategies have been developed. The most discussed in MRI related literature are:

  • T2 weighted imaging: The measured response of the 1H isotope in a resolution cell of a T2-weighted image is related to the extent of random tumbling and the rotational motion of the water molecules within that resolution cell. The faster the rotation of the water molecule, the higher the measured value of the T2 weighted response in that resolution cell. For example, prostate cancer is characterized by a low T2 response relative to the values typical to normal prostatic tissue [5].

T2 MRI pelvis with Endo Rectal Coil ( DATA of Dr. Lance Mynders, MAYO Clinic)

  • Dynamic Contrast Enhanced (DCE) MRI involves a series of rapid MRI scans in the presence of a contrast agent. In the case of scanning the prostate, the most commonly used material is gadolinium [4].

Axial MRI  Lava DCE with Endo Rectal ( DATA of Dr. Lance Mynders, MAYO Clinic)

  • Diffusion weighted (DW) imaging: Provides an image intensity that is related to the microscopic motion of water molecules [5].

DW image of the left parietal glioblastoma multiforme (WHO grade IV) in a 59-year-old woman, Al-Okaili R N et al. Radiographics 2006;26:S173-S189

  • Multifunctional MRI: MRI image overlaid with combined information from T2-weighted scans, dynamic contrast-enhancement (DCE), and diffusion weighting (DW) [5].

Source AJR: http://www.ajronline.org/content/196/6/W715/F3

  • Blood oxygen level-dependent (BOLD) MRI: Assessing tissue oxygenation. Tumors are characterized by a higher density of micro blood vessels. The images that are acquired follow changes in the concentration of paramagnetic deoxyhaemoglobin [5].

In the last couple of years, medical opinion leaders are offering to use MRI to solve almost every weakness of the cancer patients’ pathway. Such proposals are not always supported by any evidence of feasibility. For example, a couple of weeks ago, the British Medical Journal published a study [1] concluding that women carrying a mutation in the BRCA1 or BRCA2 genes who have undergone a mammogram or chest x-ray before the age of 30 are more likely to develop breast cancer than those who carry the gene mutation but who have not been exposed to mammography. What is published over the internet and media to patients and lay medical practitioners is: “The results of this study support the use of non-ionising radiation imaging techniques (such as magnetic resonance imaging) as the main tool for surveillance in young women with BRCA1/2 mutations.”.

Why is ultrasound not mentioned as a potential “non-ionising radiation imaging technique”?

Another illustration is the following advert:

An MRI scan takes between 30 to 45 minutes to perform (not including the time of waiting for the interpretation by the radiologist). It requires the support of around 4 well-trained team members. It costs between $400 and $3500 (depending on the scan).

The important question, therefore, is: Are there, in the USA, enough MRI  systems to meet the demand of 40 million scans a year addressing women with radiographically dense  breasts? Toda there are approximately 10,000 MRI systems in the USA. Only a small percentage (~2%) of the examinations are related to breast cancer. A

A rough calculation reveals that around 10000 additional MRI centers would need to be financed and operated to meet that demand alone.

References

  1. Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: retrospective cohort study (GENE-RAD-RISK), BMJ 2012; 345 doi: 10.1136/bmj.e5660 (Published 6 September 2012), Cite this as: BMJ 2012;345:e5660 – http://www.bmj.com/content/345/bmj.e5660
  1. http://www.auntminnieeurope.com/index.aspx?sec=sup&sub=wom&pag=dis&itemId=607075
  1. Ahmed HU, Kirkham A, Arya M, Illing R, Freeman A, Allen C, Emberton M. Is it time to consider a role for MRI before prostate biopsy? Nat Rev Clin Oncol. 2009;6(4):197-206.
  1. Puech P, Potiron E, Lemaitre L, Leroy X, Haber GP, Crouzet S, Kamoi K, Villers A. Dynamic contrast-enhanced-magnetic resonance imaging evaluation of intraprostatic prostate cancer: correlation with radical prostatectomy specimens. Urology. 2009;74(5):1094-9.
  1. Advanced MR Imaging Techniques in the Diagnosis of Intraaxial Brain Tumors in Adults, Al-Okaili R N et al. Radiographics 2006;26:S173-S189 ,

http://radiographics.rsna.org/content/26/suppl_1/S173.full

  1. Ahmed HU. The Index Lesion and the Origin of Prostate Cancer. N Engl J Med. 2009 Oct; 361(17): 1704-6

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Reporter: Gail S. Thornton

This article appeared on the website of Cardiovascular Business

‘Patient No. 1’ from a Hep C heart transplant study shares his story

By the time three transplant physicians approached Tom Giangiulio Jr. about being the first patient in a new clinical trial to accept a heart from a Hepatitis C-positive donor, Giangiulio didn’t have much of a choice.

He had already been on the heart transplant waitlist for more than two years, he was a live-in at the Hospital of the University of Pennsylvania and he had a body size (6-foot-2, 220 pounds) and blood type (O-positive) that was difficult to match to a donor.

It took Giangiulio less than 24 hours to speak to his previous cardiologist and his family and decide to enroll in the program. The doctors at Penn explained to him that because of new medications that can cure Hepatitis C, they were confident the virus could be eradicated post-transplant.

“There was no hesitation at all, not with me,” said Carin Giangiulio, Tom’s wife of 33 years. “Because I knew what the alternative was and we didn’t have too much choice except for going on a VAD (ventricular assist device) … and he didn’t want to do that. I said, ‘If they have a cure, then it’s a no-brainer. Let’s just do it.’ And I’m glad we did because I don’t think he would’ve been here today.”

Tom, 59, is set to celebrate his second anniversary with his new heart in June. He received the heart the day after Father’s Day in 2017 and subsequently contracted Hepatitis C, which was promptly wiped out with a 12-week regimen of elbasvir/grazoprevir (Zepatier).

Some of Giangiulio’s doctors at Penn published in February their experience with the first 10 patients in the clinical trial, called USHER, in the American Journal of Transplantation. All nine patients who survived were cured of Hepatitis C thanks to the antiviral therapy.

The implications of the research are massive, said Rhondalyn McLean, MD, MHS, the medical director of Penn’s heart transplant program and lead author of the recently published study. For the past two decades, the U.S. has struggled to increase the number of heart transplants above about 3,000 per year. And every year, patients die waiting for a heart transplant or become too sick to handle a transplant surgery.

McLean estimated 700 hearts from donors with Hepatitis C are discarded each year in the U.S. If even half of those are suitable for transplant, it would increase by 10 percent the number of organs that are available for implantation.

“There are so many people who have end-stage heart failure who die waiting for transplant, so anytime that we can increase our access to organs then I think we’re all going to be happy about that,” McLean said. “I think the people believe in the medicine, they believe that Hepatitis C is curable, so the risk to these folks is low. With the results of the study, I think we’ve proven that we can do this safely and the medications have great efficacy.”

Transplanting Hepatitis C-positive hearts isn’t a new idea, McLean explained.

“We used to do this all the time (with) the thinking that Hepatitis C usually doesn’t cause a problem for many, many years, so if hearts are only going to last 13 years or so and Hepatitis C doesn’t usually cause a problem for 30 years in someone, it should be an OK thing to do,” she said.

But then a study published in the 1990s found Hepatitis C-negative patients who accepted a heart from a donor with Hepatitis C actually had an increased risk of death compared to those who received normal hearts, and the practice of using these organs ceased.

However, with the new medications—the first commercially available treatment for Hepatitis C was approved by the FDA in 2014—McLean and her team are systematically studying the safety of implanting these hearts and then wiping out the virus once it’s contracted. And they’re optimistic about the program, which showed the first 10 patients had no evidence of the virus after their 12-week medication regimens.

“That met the criteria for sustained virologic response and those patients are deemed to be cured,” she said. “There’s no reason to think that this population would be any different than your normal, nontransplant population (in terms of Hepatitis C reappearing) so I think it was a pretty successful study.”

Penn researchers are also studying a similar approach in kidney and lung transplant candidates, which could help patients stuck on waitlists for those organs as well.

McLean described the increasing availability of these organs as an “unfortunate benefit” of the opioid epidemic. Through sharing needles, many opioid users are contracting Hepatitis C and dying young. Organs from young donors tend to perform better and often have no other problems, so solving the Hep C issue through medication could have a huge impact if this strategy is eventually rolled out on a broader scale.

“It’s hard when you have single-center studies,” McLean said. “They’re always promising, but in order to get a better assessment of what we’re doing and how the drug is doing I think you need to combine numbers so there has to be a registry that looks at all of the patients who have received these drugs and then using numbers to determine whether this is a successful strategy for us. And I believe that it will be.”

Those are the large-scale implications of this research. Tom Giangiulio can share the personal side.

Patient No. 1

Giangiulio said he feels “extremely gifted” to be Patient No. 1 in the USHER program. He knows he may not be alive if he wasn’t.

He recalls going into ventricular tachycardia about a week before his transplant and said it “scared the daylights” out of him.

“The amount of red tape, meetings and research, technology, and things that had to happen at a very precise moment in time for me to be the first … it’s mind-boggling to think about it,” he said. “But for all that to happen and for it to happen when it happened—and for me to get the heart when I got it—there was a lot of divine intervention along with a lot of people that were involved.”

Giangiulio has also experienced some powerful moments since receiving the transplant. After a bit of written correspondence with his donor’s family, he met the young man’s family one weekend in December of 2018.

He said riding over to the meeting was probably the most tense he’s ever been, but once he arrived the experience far exceeded his expectations.

“We were there for 2 ½ hours and nobody wanted to leave,” Giangiulio said.

The donor’s mother got Giangiulio a gift, a ceramic heart with a photograph of her son. A fellow transplant patient had told Giangiulio about a product called Enso, a kidney-shaped object you can hold in your hand which plays a recording of a user’s heartbeat.

Giangiulio decided to give it to her.

“I was very cautious at the advice of the people here at Penn,” he said. “Nobody knew how she would react to it. It might bother her, she could be thrilled to death. And she was, she was thrilled to death with it and she sleeps with it every night. She boots up the app and she listens to my heartbeat on that app every night.”

Another moment that sticks out to Giangiulio is meeting Patient No. 7 in the USHER program, who he remains in touch with. They ran into each other while waiting to get blood work done, and began talking about their shared experience as transplant recipients.

The clinical trial came up and Giangiulio slow-played his involvement, asking Patient No. 7 about the trial and not letting on that he was ultra-familiar with the program.

When Giangiulio finally told him he was Patient No. 1, Patient No. 7 “came launching out of his chair” to hug him.

“He said, ‘I owe you my life,’” Giangiulio recalled.

After Giangiulio responded that it was the doctors he really owed, Patient No. 7 said he had specifically asked how Patient No. 1 was doing when McLean first offered the program to him.

“She explained that I was going to be No. 7. … I didn’t care about 6, 5, 4, 3 or 2. I wanted to know how No. 1 was doing,” Giangiulio recalled of the conversation. “He said, ‘That was you. … They told me how well you were doing and that if I wanted you’d come here and talk to me, so I owe you.’”

Giangiulio feels strongly about giving back and reciprocating the good fortune he’s had. That’s why he talks to fellow patients and the media to share his story—because it could save other people’s lives, too.

He can’t do as much physical labor as he used to, but he remains involved in the excavating company he owns with his brothers and is the Emergency Management Coordinator for Waterford Township, New Jersey. He also serves on the township’s planning board and was previously Director of Public Safety.

“To me, he’s Superman,” Carin Giangiulio said. “It was insane, completely insane what the human body can endure and still survive.”

That now includes being given a heart with Hepatitis C and then wiping out the virus with the help of modern medicine.

“I would tell (other transplant candidates) to not fear it, especially if you’re here at Penn,” Giangiulio said. “I know there’s a lot of good hospitals across the country, but my loyalty kind of lies here for understandable reasons.”

Other related articles were published in this Open Access Online Scientific Journal include the following:

2016

People with blood type O have been reported to be protected from coronary heart disease, cancer, and have lower cholesterol levels.

https://pharmaceuticalintelligence.com/2016/01/11/people-with-blood-type-o-have-been-reported-to-be-protected-from-coronary-heart-disease-cancer-and-have-lower-cholesterol-levels/

2015

A Patient’s Perspective: On Open Heart Surgery from Diagnosis and Intervention to Recovery

https://pharmaceuticalintelligence.com/2015/05/10/a-patients-perspective-on-open-heart-surgery-from-diagnosis-and-intervention-to-recovery/

No evidence to change current transfusion practices for adults undergoing complex cardiac surgery: RECESS evaluated 1,098 cardiac surgery patients received red blood cell units stored for short or long periods

https://pharmaceuticalintelligence.com/2015/04/08/no-evidence-to-change-current-transfusion-practices-for-adults-undergoing-complex-cardiac-surgery-recess-evaluated-1098-cardiac-surgery-patients-received-red-blood-cell-units-stored-for-short-or-lon/

2013

ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery

https://pharmaceuticalintelligence.com/2013/11/05/accaha-guidelines-for-coronary-artery-bypass-graft-surgery/

On Devices and On Algorithms: Arrhythmia after Cardiac SurgeryPrediction and ECG Prediction of Paroxysmal Atrial Fibrillation Onset

https://pharmaceuticalintelligence.com/2013/05/07/on-devices-and-on-algorithms-arrhythmia-after-cardiac-surgery-prediction-and-ecg-prediction-of-paroxysmal-atrial-fibrillation-onset/

 

Editor’s note:

I wish to encourage the e-Reader of this Interview to consider reading and comparing the experiences of other Open Heart Surgery Patients, voicing their private-life episodes in the ER that are included in this recently published volume, The VOICES of Patients, Hospital CEOs, Health Care Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures.

https://pharmaceuticalintelligence.com/2017/11/21/the-voices-of-patients-hospital-ceos-health-care-providers-caregivers-and-families-personal-experience-with-critical-care-and-invasive-medical-procedures/

 

I also wish to encourage the e-Reader to consider, if interested, reviewing additional e-Books on Cardiovascular Diseases from the same Publisher, Leaders in Pharmaceutical Business Intelligence (LPBI) Group, on Amazon.com.

  • Perspectives on Nitric Oxide in Disease Mechanisms, on Amazon since 6/2/12013

http://www.amazon.com/dp/B00DINFFYC

  • Cardiovascular, Volume Two: Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation, on Amazon since 11/30/2015

http://www.amazon.com/dp/B018Q5MCN8

  • Cardiovascular Diseases, Volume Three: Etiologies of Cardiovascular Diseases: Epigenetics, Genetics and Genomics, on Amazon since 11/29/2015

http://www.amazon.com/dp/B018PNHJ84

  • Cardiovascular Diseases, Volume Four: Regenerative and Translational Medicine: The Therapeutics Promise for Cardiovascular Diseases, on Amazon since 12/26/2015

http://www.amazon.com/dp/B019UM909A

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A Realistic 3D Model of a Human Heart Ventricle

Reported: Irina Robu, PhD

Scientists from Harvard University designed a working 3D model of a human heart’s left ventricle whose objective is to replace animal models with human models and patient-specific human models. The discovery could improve how diseases are studied, drugs are tested and lead to patient-specific treatments for various heart ailments, including arrhythmia.

The researchers reinvented the tissue’s unique structure, where parallel myocardial fibers act as a scaffold to direct brick-shaped heart cells to align and accumulate end-to-end and form a hollow, cone-shaped structure. When the heart beats, the cells expand and contract. The new tissue is engineered using a nanofiber scaffold that is seeded with human heart cells and acts like a 3D template to guide the cells and their assembly into ventricle chambers that beat in vitro.

In this research, they used a nanofiber production platform called pull spinning, which uses a high-speed rotating bristle that slopes into a polymer reservoir and pulls a droplet from the solution into a jet, to recreate the scaffold. The fiber travels in a spiral trajectory and solidifies before detaching from the bristle and moving toward a collector.

The team made the ventricle using a combination of biodegradable polyester and gelatin fibers collected on a rotating collector in which all of the fibers align in the same direction. The scientists then cultured the ventricle with rat myocytes or human cardiomyocytes from induced stem cells and found that within three to five days, a thin wall of tissue covered the scaffold and the cells were beating in synch. The procedure allowed control and monitor of the calcium and insert a catheter to study the pressure and volume of the beating ventricle.

The tissue is then exposed to a drug similar to adrenaline called isoproterenol and measured as the beat-rate increased.  They also poked holes in the ventricle to mimic a myocardial infarction and studied the effect of the heart attack in a petri dish. The ventricle is then conditioned in a self-contained bioreactor with separate chambers for optional valve inserts, extra access ports for catheters and ventricular assist capabilities. The cultures were run for six months and stable pressure-volume loops were measured.

With this new model, scientists might study the heart’s function by many of the same tools now being used in the clinic, including pressure-volume loops and ultrasound. They hope to use patient-derived, pre-differentiated stem cells to seed the ventricles, letting for more high-throughput production of the tissue.

SOURCE

https://www.rdmag.com/article/2018/07/tissue-engineered-heart-model-gives-researchers-realistic-testing-platform?et_cid=6407213

 

 

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From Thalidomide to Revlimid: Celgene to Bristol Myers to possibly Pfizer; A Curation of Deals, Discovery and the State of Pharma

 

Curator: Stephen J. Williams, Ph.D.

Updated 6/24/2019

Updated 4/12/2019

Updated 2/28/2019

Lenalidomide (brand name Revlimid) is an approved chemotherapeutic used to treat multiple myeloma, mantle cell lymphoma, and certain myedysplastic syndromes.  It is chemically related to thalidomide analog with potential antineoplastic activity. Lenalidomide inhibits TNF-alpha production, stimulates T cells, reduces serum levels of the cytokines vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), and inhibits angiogenesis. This agent also promotes G1 cell cycle arrest and apoptosis of malignant cells.  It is usually given with dexamethasone for multiple myeloma. Revlimid was developed and sold by Celgene Corp.  However, recent news of deals with Bristol Myers Squib

 

Revlimid Approval History

FDA Approved: Yes (First approved December 27, 2005)
Brand name: Revlimid
Generic name: lenalidomide
Dosage form: Capsules
Company: Celgene Corporation
Treatment for: Myelodysplastic SyndromeMultiple MyelomaLymphoma

Revlimid (lenalidomide) is an immunomodulatory drug indicated for the treatment of patients with multiple myeloma, transfusion-dependent anemia due myelodysplastic syndromes (MDS), and mantle cell lymphoma.

Development History and FDA Approval Process for Revlimid

Date Article
Feb 22, 2017  FDA Expands Indication for Revlimid (lenalidomide) as a Maintenance Treatment for Patients with Multiple Myeloma Following Autologous Hematopoietic Stem Cell Transplant (auto-HSCT)
Feb 18, 2015  FDA Expands Indication for Revlimid (lenalidomide) in Combination with Dexamethasone to Include Patients Newly Diagnosed with Multiple Myeloma
Jun  5, 2013  FDA Approves Revlimid (lenalidomide) for the Treatment of Patients with Relapsed or Refractory Mantle Cell Lymphoma
Oct  3, 2005 Revlimid PDUFA Date Extended Three Months By FDA
Sep 14, 2005 FDA Oncologic Drugs Advisory Committee Recommends Revlimid for Full Approval
Sep 13, 2005 FDA and Celgene Revlimid Briefing Documents for Advisory Committee Meeting Available Online
Jun 21, 2005 FDA Grants Priority Review for Revlimid NDA for Treatment of Low- and Intermediate- Risk MDS With Deletion 5q Chromosomal Abnormality
Jun  7, 2005 Revlimid (lenalidomide) New Drug Application Accepted for Review by FDA
Apr  8, 2005 Revlimid New Drug Application Submitted to FDA for Review

 

 

 

 

M&A Deals Now and On The Horizon

  1. Right before the 2019 JP Morgan Healthcare Conference and a month before Bristol Myers quarterly earings reports, Bristol Myers Squib (BMY) announes a $74 Billion offer for Celgene Corp.  From the Bristol Myers website press realease:

Bristol-Myers Squibb to Acquire Celgene to Create a Premier Innovative Biopharma Company

  • Highly Complementary Portfolios with Leading Franchises in Oncology, Immunology and Inflammation and Cardiovascular Disease
  • Significantly Expands Phase III Assets with Six Expected Near-Term Product Launches, Representing Greater Than $15 Billion in Revenue Potential
  • Registrational Trial Opportunities and Early-Stage Pipeline Position Combined Company for Sustained Leadership Underpinned by Cutting-Edge Technologies and Discovery Platforms
  • Strong Combined Cash Flows, Enhanced Margins and EPS Accretion of Greater Than 40% in First Full Year
  • Approximately $2.5 Billion of Expected Run-Rate Cost Synergies to Be Achieved by 2022
THURSDAY, JANUARY 3, 2019 6:58 AM EST

NEW YORK & SUMMIT, N.J.,–(BUSINESS WIRE)–Bristol-Myers Squibb Company (NYSE:BMY) and Celgene Corporation (NASDAQ:CELG) today announced that they have entered into a definitive merger agreement under which Bristol-Myers Squibb will acquire Celgene in a cash and stock transaction with an equity value of approximately $74 billion. Under the terms of the agreement, Celgene shareholders will receive 1.0 Bristol-Myers Squibb share and $50.00 in cash for each share of Celgene. Celgene shareholders will also receive one tradeable Contingent Value Right (CVR) for each share of Celgene, which will entitle the holder to receive a payment for the achievement of future regulatory milestones. The Boards of Directors of both companies have approved the combination.

The transaction will create a leading focused specialty biopharma company well positioned to address the needs of patients with cancer, inflammatory and immunologic disease and cardiovascular disease through high-value innovative medicines and leading scientific capabilities. With complementary areas of focus, the combined company will operate with global reach and scale, maintaining the speed and agility that is core to each company’s strategic approach.

Based on the closing price of Bristol-Myers Squibb stock of $52.43 on January 2, 2019, the cash and stock consideration to be received by Celgene shareholders at closing is valued at $102.43 per Celgene share and one CVR (as described below). When completed, Bristol-Myers Squibb shareholders are expected to own approximately 69 percent of the company, and Celgene shareholders are expected to own approximately 31 percent.

“Together with Celgene, we are creating an innovative biopharma leader, with leading franchises and a deep and broad pipeline that will drive sustainable growth and deliver new options for patients across a range of serious diseases,” said Giovanni Caforio, M.D., Chairman and Chief Executive Officer of Bristol-Myers Squibb. “As a combined entity, we will enhance our leadership positions across our portfolio, including in cancer and immunology and inflammation. We will also benefit from an expanded early- and late-stage pipeline that includes six expected near-term product launches. Together, our pipeline holds significant promise for patients, allowing us to accelerate new options through a broader range of cutting-edge technologies and discovery platforms.”

Dr. Caforio continued, “We are impressed by what Celgene has accomplished for patients, and we look forward to welcoming Celgene employees to Bristol-Myers Squibb. Our new company will continue the strong patient focus that is core to both companies’ missions, creating a shared organization with a goal of discovering, developing and delivering innovative medicines for patients with serious diseases. We are confident we will drive value for shareholders and create opportunities for employees.”

“For more than 30 years, Celgene’s commitment to leading innovation has allowed us to deliver life-changing treatments to patients in areas of high unmet need. Combining with Bristol-Myers Squibb, we are delivering immediate and substantial value to Celgene shareholders and providing them meaningful participation in the long-term growth opportunities created by the combined company,” said Mark Alles, Chairman and Chief Executive Officer of Celgene. “Our employees should be incredibly proud of what we have accomplished together and excited for the opportunities ahead of us as we join with Bristol-Myers Squibb, where we can further advance our mission for patients. We look forward to working with the Bristol-Myers Squibb team as we bring our two companies together.”

Compelling Strategic Benefits

  • Leading franchises with complementary product portfolios provide enhanced scale and balance. The combination creates:
    • Leading oncology franchises in both solid tumors and hematologic malignancies led by Opdivo and Yervoy as well as Revlimid and Pomalyst;
    • A top five immunology and inflammation franchise led by Orencia and Otezla; and
    • The #1 cardiovascular franchise led by Eliquis.

The combined company will have nine products with more than $1 billion in annual sales and significant potential for growth in the core disease areas of oncology, immunology and inflammation and cardiovascular disease.

  • Near-term launch opportunities representing greater than $15 billion in revenue potential. The combined company will have six expected near-term product launches:
    • Two in immunology and inflammation, TYK2 and ozanimod; and
    • Four in hematology, luspatercept, liso-cel (JCAR017), bb2121 and fedratinib.

These launches leverage the combined commercial capabilities of the two companies and will broaden and enhance Bristol-Myers Squibb’s market position with innovative and differentiated products. This is in addition to a significant number of lifecycle management registrational readouts expected in Immuno-Oncology (IO).

  • Early-stage pipeline builds sustainable platform for growth. The combined company will have a deep and diverse early-stage pipeline across solid tumors and hematologic malignancies, immunology and inflammation, cardiovascular disease and fibrotic disease leveraging combined strengths in innovation. The early-stage pipeline includes 50 high potential assets, many with important data readouts in the near-term. With a significantly enhanced early-stage pipeline, Bristol-Myers Squibb will be well positioned for long-term growth and significant value creation.
  • Powerful combined discovery capabilities with world-class expertise in a broad range of modalities. Together, the Company will have expanded innovation capabilities in small molecule design, biologics/synthetic biologics, protein homeostasis, antibody engineering and cell therapy. Furthermore, strong external partnerships provide access to additional modalities.

Compelling Financial Benefits

  • Strong returns and significant immediate EPS accretion. The transaction’s internal rate of return is expected to be well in excess of Celgene’s and Bristol-Myers Squibb’s cost of capital. The combination is expected to be more than 40 percent accretive to Bristol-Myers Squibb’s EPS on a standalone basis in the first full year following close of the transaction.
  • Strong balance sheet and cash flow generation to enable significant investment in innovation. With more than $45 billion of expected free cash flow generation over the first three full years post-closing, the Company is committed to maintaining strong investment grade credit ratings while continuing its dividend policy for the benefit of Bristol-Myers Squibb and Celgene shareholders. Bristol-Myers Squibb will also have significant financial flexibility to realize the full potential of the enhanced late- and early-stage pipeline.
  • Meaningful cost synergies. Bristol-Myers Squibb expects to realize run-rate cost synergies of approximately $2.5 billion by 2022. Bristol-Myers Squibb is confident it will achieve efficiencies across the organization while maintaining a strong, core commitment to innovation and delivering the value of the portfolio.

Terms and Financing

Based on the closing price of Bristol-Myers Squibb stock on January 2, 2019, the cash and stock consideration to be received by Celgene shareholders is valued at $102.43 per share. The cash and stock consideration represents an approximately 51 percent premium to Celgene shareholders based on the 30-day volume weighted average closing stock price of Celgene prior to signing and an approximately 54 percent premium to Celgene shareholders based on the closing stock price of Celgene on January 2, 2019. Each share also will receive one tradeable CVR, which will entitle its holder to receive a one-time potential payment of $9.00 in cash upon FDA approval of all three of ozanimod (by December 31, 2020), liso-cel (JCAR017) (by December 31, 2020) and bb2121 (by March 31, 2021), in each case for a specified indication.

The transaction is not subject to a financing condition. The cash portion will be funded through a combination of cash on hand and debt financing. Bristol-Myers Squibb has obtained fully committed debt financing from Morgan Stanley Senior Funding, Inc. and MUFG Bank, Ltd. Following the close of the transaction, Bristol-Myers Squibb expects that substantially all of the debt of the combined company will be pari passu.

Accelerated Share Repurchase Program

Bristol-Myers Squibb expects to execute an accelerated share repurchase program of up to approximately $5 billion, subject to the closing of the transaction, market conditions and Board approval.

Corporate Governance

Following the close of the transaction, Dr. Caforio will continue to serve as Chairman of the Board and Chief Executive Officer of the company. Two members from Celgene’s Board will be added to the Board of Directors of Bristol-Myers Squibb. The combined company will continue to have a strong presence throughout New Jersey.

Approvals and Timing to Close

The transaction is subject to approval by Bristol-Myers Squibb and Celgene shareholders and the satisfaction of customary closing conditions and regulatory approvals. Bristol-Myers Squibb and Celgene expect to complete the transaction in the third quarter of 2019.

Advisors

Morgan Stanley & Co. LLC is serving as lead financial advisor to Bristol-Myers Squibb, and Evercore and Dyal Co. LLC are serving as financial advisors to Bristol-Myers Squibb. Kirkland & Ellis LLP is serving as Bristol-Myers Squibb’s legal counsel. J.P. Morgan Securities LLC is serving as lead financial advisor and Citi is acting as financial advisor to Celgene. Wachtell, Lipton, Rosen & Katz is serving as legal counsel to Celgene.

Bristol-Myers Squibb 2019 EPS Guidance

In a separate press release issued today, Bristol-Myers Squibb announced its 2019 EPS guidance for full-year 2019, which is available on the “Investor Relations” section of the Bristol-Myers Squibb website at https://www.bms.com/investors.html.

Conference Call

Bristol-Myers Squibb and Celgene will host a conference call today, at 8:00 a.m. ET to discuss the transaction. The conference call can be accessed by dialing (800) 347-6311 (U.S. / Canada) or (786) 460-7199 (International) and giving the passcode 4935567. A replay of the call will be available from January 3, 2019 until January 17, 2019 by dialing (888) 203-1112 (U.S. / Canada) or (719) 457-0820 (International) and giving the passcode 4935567.

A live webcast of the conference call will be available on the investor relations section of each company’s website at Bristol-Myers Squibb https://www.bms.com/investors.html and Celgene https://ir.celgene.com/investors/default.aspx.

Presentation and Infographic

Associated presentation materials and an infographic regarding the transaction will be available on the investor relations section of each company’s website at Bristol-Myers Squibb https://www.bms.com/investors.html and Celgene https://ir.celgene.com/investors/default.aspx as well as a joint transaction website at www.bestofbiopharma.com.

2.  Then through news on Bloomberg and some other financial sites on a possible interest of a merged Celgene-Bristol Myers from Pfizer as well as other pharma groups

Here’s How John Paulson Is Positioning His Celgene/Bristol Trade

Billionaire John Paulson sees a 10 percent to 20 percent chance that Bristol-Myers Squibb Co. receives a takeover bid and he’s positioning his Celgene Corp. trade based on that risk, he said in an interview on Mike Samuels’ “According to Sources” podcast.

Bristol-Myers “is vulnerable and it has an attractive pipeline to several potential acquirers,” Paulson said in the podcast released Monday. “It’s a reasonable probability,” he said. “You have to be prepared someone may show up. It’s an attractive spread, but you can’t take that big a position.”

John Paulson

Photographer: Jin Lee/Bloomberg

Paulson has the Celgene/Bristol-Myers trade as a 3 percent portfolio position, though his firm is short a pharma index rather than Bristol-Myers for about half of the position. If an activist did show up, it would likely blow out the spread from its current $13.85 to probably $20 and, if an actual bid arrived, he said the spread could move out to $40.

“I just don’t feel comfortable being short Bristol in this environment,” Paulson said. “You can sort of get the same economics by shorting an index, maybe even do better because, since Bristol came down, if the pharma sector goes up, Bristol may go up more than the pharma sector, which would increase the profitability on the Celgene. ”

Celgene fell as much as 2.2 percent on Tuesday, its biggest intraday drop since Dec. 27. Bristol-Myers also sank as much as 2.2 percent, the most since Jan. 9.

The question of whether Bristol-Myers receives a hostile takeover offerhas been the top issue for investors since the Celgene deal was announced. The drugmaker was pressured in February 2017 to add three new directors after holding talks with activist hedge fund Jana Partners LLC. The same month, the Wall Street Journal reported that Carl Icahn had taken a stake and saw Bristol-Myers as a takeover target.

Pfizer Inc., AbbVie Inc. or Amgen Inc. “make varying amounts of sense as suitors, though we see many barriers to someone making an offer,” Credit Suisse analyst Vamil Divan wrote in a note earlier this month. AbbVie and Amgen “have the balance sheet strength and could look to beef up their oncology presence.”

CNBC’s David Faber said Jan. 3 — the day the Celgene deal was announced — that there had been “absolutely” no talks between Bristol-Myers and potential acquirers.

Jefferies analyst Michael Yee wrote in note Tuesday that he doesn’t expect an unsolicited offer for Bristol-Myers to “thwart” its Celgene purchase. He sees the deal spread as “quite attractive” again at the current range of 18 percent to 20 percent after it had earlier narrowed to 11 percent to 12 percent.

Paulson managed about $8.7 billion at the the beginning of November.

From StatNews.com at https://www.statnews.com/2019/01/22/celgene-legacy-chutzpah-science-drug-pricing/

 

Nina Kjellson was just two years out of college, working as a research associate at Oracle Partners, a hedge fund in New York, when a cabbie gave her a stock tip. There was a company in New Jersey, he told her, trying to resurrect thalidomide, a drug that was infamous for causing severe birth defects, as a treatment for cancer.

Kjellson was born in Finland, where the memory of thalidomide, which was given to mothers to treat morning sickness but led to babies born without arms or legs, was particularly raw because the drug hit Northern Europe hard. But she was on the hunt for new cancer drugs, and her interest was piqued. She ended up investing a small amount of her own money in Celgene. That was 1999.

Since then, Celgene shares have risen more than 100-fold; the company became one of the largest biotechnology firms in the world. Earlier this month, rival Bristol-Myers Squibb announced plans to purchase Celgene for $74 billion in cash and stock.

Reflecting on a company she watched for two decades, Kjellson, now a venture capitalist at Canaan Partners in San Francisco, marveled at the “grit and chutzpah” that it took to push thalidomide back onto the market. “The company started taking off,” she remembered, “but not without an incredible reversal.” Celgene faced resistance from some thalidomide victims, and the Food and Drug Administration was lobbied not to revive the drug. In the end, she said, it built a golden egg and became a favorite partner of smaller biotech companies like the ones she funds. And it populated the rest of the pharmaceutical industry with its alumni. “If I had a nickel for every company that says we want to do Celgene-like deals,” she said, “I’d have better returns than from my venture career.”

But there’s another side to Celgene. When the company launched thalidomide as a treatment for leprosy in 1998, it cost $6 a pill. As it became clear that it was also an effective cancer drug, Celgene slowly raised the price, quadrupling it by the time it received approval for an improved molecule, Revlimid. Then, it slowly increased the price of Revlimid by a total of 145 percent, according to Sector & Sovereign LLC, a pharmaceutical consultancy.

Revlimid now costs $693 a pill. In 2017, Revlimid and another thalidomide-derived cancer drug represented 76 percent of Celgene’s $12.9 billion in annual sales. Kjellson gives the company credit for guts in science, for taking a terrible drug and resurrecting it. But it also had chutzpah when it came to what it charged.

A pioneer in ‘modern pricing’

How did the price of thalidomide, and then Revlimid, increase so much? Celgene explained it in a 2004 front-page story in the Wall Street Journal. “When we launched it, it was going to be an AIDS-wasting drug,” Celgene’s chief executive at the time, John Jackson, said. “We couldn’t charge more or there would have been demonstrations outside the company.” But once Celgene realized that the drug was a cancer treatment, the company decided to slowly bring thalidomide’s price more in line with other cancer medicines, such as Velcade, a rival medicine now sold by the Japanese drug giant Takeda. In 2003, it cost more than twice as much as thalidomide. “By bringing [the price] up every year, it was heading toward where it should be as a cancer drug,” Jackson told the Journal.

Thalidomide was not actually approved as a myeloma treatment until 2006. That same year, Revlimid, which causes less sleepiness and nerve pain than thalidomide, was approved, and Barer, the chemist behind Celgene’s thalidomide strategy, took over as chief executive. He made good on thalidomide’s promise, churning out one blockbuster after another. In 2017 Revlimid generated $8.2 billion. Another cancer drug derived from thalidomide, Pomalyst, generated $1.6 billion. Otezla, a very different drug also based on thalidomide’s chemistry, treats psoriasis and psoriatic arthritis. Its 2017 sales: $1.3 billion.

With persistent price increases, quarter after quarter, Celgene pioneered something else: what Wall Street calls “modern pricing.” Cancer drug prices have risen inexorably.

 

Updated 2/28/2019

From FiercePharma.com

BMS’ largest investor condemns Celgene deal—and it’s music to activists’ ears

Activist investor Starboard Value is officially rallying the troops against Bristol-Myers Squibb’s $74 billion Celgene deal, and thanks to a big investor’s thumbs-down, it’ll have more support than some expected. But the question is whether it’ll be enough to scuttle the merger.

Starboard CEO Jeffrey Smith penned a letter (PDF) to Bristol-Myers’ shareholders on Thursday labeling the transaction “poorly conceived and ill-advised.” It intends to vote its shares—which number 1.63 million, though the hedge fund is seeking more—against the deal, and it wants to see other shareholders do the same. It’ll be filing proxy materials “in the coming days” to solicit “no” votes from BMS investors, Smith said.

Starboard picked up its stake early this year after the deal was announced, BMS confirmed last week, but until now, the activist fund hasn’t been forthcoming about its intentions. But the timing of its reveal is likely no coincidence; just Wednesday, Wellington Management—which owns about 8% of Bristol-Myers’ shares and ranked as its largest institutional shareholder as of earlier this week—came out publicly against the “risky” buyout.

But while “we believe it is possible at least one other long-term top-five [shareholder] may disagree with the transaction, too,” RBC Capital Markets’ Michael Yee wrote in his own investor note, he—as many of his fellow analysts do—still expects to see the deal go through. “We think the vast majority of the acquirer holder base that would not like the deal already voted by selling their shares earlier, leaving investors who are mostly supportive of the deal,” he wrote.

Meanwhile, Starboard has been clear about one other thing: It wants board seats. It’s nominated five new directors, including CEO Smith, and investors will vote on that group at an as-yet-unscheduled meeting. Thing is, that meeting will take place after BMS investors vote on the Celgene deal in April, so Starboard will have to rally sufficient support against the deal if it wants to see them installed.

The “probability of a third-party buyer for Bristol-Myers Squibb” before the April vote is “very low,” BMO Capital Markets analysts wrote recently, adding that “we do not believe a potential activist can change that.” Barclays analysts agreed Wednesday, pointing to a “lack of realistic, potential alternatives that could collectively provide a similar level of upside.”

Updated 4/12/2019

Bristol-Myers Squibb Shareholders Approve Celgene Tie-Up

Three quarters of Bristol-Myers Squibb shareholders vote to approve the deal with Celgene, paving the way for the largest pharmaceutical takeover in history.

Bristol-Myers Squibb (BMY – Get Report) on Friday announced that it had secured enough shareholder votes to approve its roughly $74 billion takeover of Celgene (CELG – Get Report) , putting the company closer to finalizing the largest pharmaceutical merger in history.

More than 75% of Bristol-Myers shareholders voted to approve the deal, according to a preliminary tally announced by Bristol-Myers on Friday.

Bristol-Myers’ position took a positive turn in late March after an influential shareholder advisory group recommended investors vote in favor of the cancer drug specialist’s takeover,  and a key activist dropped its opposition to the deal.

Institutional Shareholder Services recommended the deal, which had been challenged by key Bristol-Myers shareholders Starboard Value and Wellington Management, ahead of Friday’s vote.

 

Updated 6/24/2019

Bristol Myers agrees to sell off Celgene blockbuster psoriasis and arthritis drug Otezla to satisfy FTC in hopes to speed up merger

By SY MUKHERJEE

June 24, 2019

Happy Monday, readers!

Bristol-Myers Squibb hasn’t exactly had a pristine path to its proposed acquisition of Celgene. Sure, the legacy pharma giant racked up more than 75% of shareholder votes to approve the $74 billion acquisition following a quickly-quashed rebellion from some activist naysayers. But the company hit another hurdle in its Celgene acquisition quest that sent Bristol Myers stock tumbling nearly 7.5%, a $6 billion erasure in market value.

The reason(s)? For one, Bristol-Myers Squibb reported an unfortunate clinical trial result from a late-stage study of its cancer immunotherapy superstar Opdivo in liver cancer. For another—BMS made a somewhat surprising announcement that it would spin off Celgene’s blockbuster psoriasis and arthritis drug Otezla, slated to rake in nearly $2 billion in sales this year alone, in order to address Federal Trade Commission (FTC) antitrust concerns over the M&A.

That means the Bristol-Myers Celgene deal may not close until early 2020, rather than the originally expected timeline by the end of this year.

“Bristol-Myers Squibb reaffirms the significant value creation opportunity of the acquisition of Celgene,” the firm said in a statement. “Together with $2.5 billion of cost synergies, a compelling pipeline and a strong portfolio of marketed products, the company continues to expect growth in sales and earnings through 2025.”

Investors can be a fickle bunch. For now, though, they don’t seem particularly pleased at the decision to lop off one of Celgene’s tried and true cash cows.

 

Additional posts on Pharma Mergers and Deals on this Open Access Journal include:

Live Conference Coverage Medcity Converge 2018 Philadelphia: Clinical Trials and Mega Health Mergers

First Annual FierceBiotech Drug Development Forum (DDF). Event covers the drug development process from basic research through clinical trials. InterContinental Hotel, Boston, September 19-21, 2016.

Pfizer Near Allergan Buyout Deal But Will Fed Allow It?

New Values for Capital Investment in Technology Disruption: Life Sciences Group @Google and the Future of the Rest of the Biotech Industry

Mapping the Universe of Pharmaceutical Business Intelligence: The Model developed by LPBI and the Model of Best Practices LLC

 

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Reporter: Gail S. Thornton

 

From The Wall Street Journal (www.wsj.com)

Published January 9, 2019

Health-Care CEOs Outline Strategies at J.P. Morgan Conference

Chiefs at Johnson & Johnson, CVS discuss what’s next on a range of industry issues

One of the biggest health conferences of the year for investors, the J.P. Morgan Health-Care Conference, is taking place this week in San Francisco. Here are some of the hot topics covered at the four-day event, which wraps up Thursday.

BioMarin Mulls Payment Plans

BioMarin Pharmaceutical Inc. CEO Jean-Jacques Bienaimé said he would consider pursuing installment payment arrangements for the biotech’s experimental gene therapy for hemophilia. At the conference, Mr. Bienaimé told the Wall Street Journal that the one-time infusion, Valrox, is likely to cost in the millions because studies have shown it can eliminate bleeding episodes in patients, and current hemophilia treatments taken chronically can cost millions over several years. “We’re not trying to charge more than existing therapies,” he said. “We want to offer a better treatment at the same or lower cost.”

Johnson & Johnson Warns on Pricing

As politicians hammer drug prices, Johnson & Johnson CEO Alex Gorsky suggested companies need to police themselves. At the conference, Mr. Gorsky told investors that drug companies should price drugs reasonably and be transparent. “If we don’t do this as an industry, I think there will be other alternatives that will be more onerous for us,” Mr. Gorsky says. Some drugmakers pulled back from price increases in mid-2018 amid heightened political scrutiny, but prices went up for many drugs at the start of 2019.

Marijuana-Derived Drugs Show Promise

 

CVS Discusses New Stores

CVS Health Corp. Chief Executive Larry Merlo began showing initial concepts the company will be testing as it begins piloting new models of its drugstores that incorporate its Aetna combination. The first new test store will open next month in Houston, he told investors, and it will include expanded health-care services including a new concierge who will help patients with questions. 

Aetna Savings On the Way

Mr. Merlo also spelled out when the company will achieve the initial $750 million in synergies it has promised from the CVS-Aetna deal. In the first quarter, he said the company will see benefits from consolidating corporate functions. Savings from procurement and aligning lists of covered drugs should be seen in the first half, he says. Medical-cost savings will start affecting results toward the end of the year, he noted. 

Lilly Cuts Price

Drugmaker Eli Lilly & Co. expects average net US pricing for its drugs–after rebates and discounts–to decline in the low- to mid-single digits on a percentage basis this year, Chief Financial Officer Josh Smiley told the Journal. Lilly’s net prices had risen during the first half of 2018, but dropped in the third quarter as the company took a “restrained approach,” Mr. Smiley said. Lilly, which hasn’t yet reported fourth-quarter results, took some list price increases for cancer drugs in late December but hasn’t raised prices in the new year, he said.

Peter Loftus at peter.loftus@wsj.com and Anna Wilde Mathews at anna.mathews@wsj.com

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Reporter: Gail S. Thornton

This article appeared on the web site of Harley Street Concierge, one of the U.K.’s leading independent providers of clinical, practical and emotion support for cancer patients. 

Cancer at Work: An Interview With Barbara Wilson

Whether you’re supporting an employee through cancer at work. Or you’re a cancer patient struggling to get the support you need. Either way, this Q and A with Barbara Wilson will help you out. Read on for a glimpse into Barbara’s personal experience with breast cancer. Find out where companies are falling short of supporting employees. Discover what you need to do if you’re feeling unsupported at work. And learn what’s unacceptable for Barbara in a modern and civilised society.

In a 2013 interview about cancer at work, you expressed amazement at “the lack of understanding there is about cancer. And what the impact is on individuals”. How would you say this has improved in the last 4 years? And what do you feel still needs to change?

There’s greater awareness and understanding about cancer at work. More organisations are aware of the difficulties people face. But many organisations don’t appreciate that recovery isn’t straightforward or quick. They also tend to rely on generic return to work policies. And these are inappropriate when it comes to supporting people recovering from cancer. A lot still depends on how far the local line manager is prepared to support an employee. And whether they’ll bend rules if need be about leave or sick pay.

You were diagnosed with breast cancer in 2005 and given the all clear in 2010. What did you learn about yourself through treatment and recovery?

 

I learned that I wasn’t immortal or superhuman! And also that life is precious and so it’s important to make the best of it. That doesn’t actually mean counting off things on your bucket list. Or living each day as if it’s your last. It’s about appreciating what you have, family, friends and the sheer joy of being alive.

“Life is precious. It’s about appreciating what you have, family, friends and the sheer joy of being alive.”

It’s a common misperception that people in remission want more family time or to travel the world. What reasons do your clients share with you for wanting to get back to work?

Yes. Before I had cancer, I remember asking a terminally ill employee why she still wanted to work. And she worked until a fortnight before her death. The simple answer is that it’s about feeling normal. Using your brain. Being with friends and colleagues rather than on your own. And losing yourself in your work. There are also financial reasons. But typically – and I can say this based on my own experience – it’s about being ‘you’ again rather than a cancer patient.

“I remember asking a terminally ill employee why she still wanted to work. And she worked until a fortnight before her death. Typically – and I can say this based on my own experience – it’s about being ‘you’ again rather than a cancer patient.”

You share tips for employers and HR professionals in this article for Macmillan. And you set out how to support a colleague during and after cancer treatment. What would you say to an employee who isn’t feeling supported by their employer or colleagues in this way?

In my experience there are two main reasons why people often aren’t supported.

1. Bosses and colleagues don’t understand the full impact of cancer treatment. They won’t understand what fatigue is or chemo brain or peripheral neuropathy. So they often expect people to get ‘back to normal’ work after 6 to 8 weeks. But recovery can take many months. This isn’t helped by the person often looking fit and well.

2. People don’t like talking about cancer at work. They feel awkward. And as a result often decide to say nothing. We advise people to be open from the outset. To understand their right to reasonable adjustments. And their responsibility to update their employer about their recovery and support needs. Employees recovering from cancer often have to take the lead. They have to guide their colleagues about the specific help they need. You can’t expect others to do it for you. It sounds wrong but that’s how it is.

“Bosses and colleagues often expect people to get ‘back to normal’ work after 6 to 8 weeks. But recovery can take many months. “

More than 100,000 people had to wait more than 2 weeks to see a cancer specialist in the UK last year. 25,153 had to wait more than 62 days to start treatment. What’s your reaction to these statistics?

It’s shocking. The worry for patients and their families during this period is totally debilitating. And on top of this it means that the cancer is growing unchecked. Where the cancer is aggressive, the delay may threaten lives. And it will certainly add to the overall costs of care. We really have to address this. It’s just not acceptable in a modern and civilised society.

“The worry for patients and their families during this period is totally debilitating. We really have to address this.”

Finally, can you tell us more about Working With Cancer?

Working With Cancer is a social enterprise and was established in June 2014. We support people affected by cancer to lead fulfilling and rewarding working lives. That means helping people to successfully return to work or remain in work. Or sometimes it’s about helping people to find work – depending on their personal needs. We work with corporate, charities and other third sector organisations to support people throughout the UK.

We coach people diagnosed with cancer to re-establish their working lives. And we train employers to understand how to manage work and cancer. We’ll advise teams about how to support a colleague affected by cancer. And we help carers juggle work whilst supporting their loved ones. Working With Cancer also helps organisations to update or improve their policies.

Barbara Wilson - Cancer at Work

About Barbara Wilson

Barbara Wilson is a senior HR professional with almost 40 years’ experience.  Roles include Group Head of Strategic HR at Catlin Group Ltd. Deputy Head of HR at Schroders Investment Management. And Chief of Staff to the Group HR Director at Barclays. After a breast cancer diagnosis, Barbara launched Working With Cancer. It’s a Social Enterprise providing coaching, training and consultancy to employers, employees, carers and health professionals.

 

For more information about Working With Cancer, click here to visit the websiteFollow this link to connect with Barbara on Twitter. Email admin@workingwithcancer.co.uk. Or call 07508 232257 or 07919 147784.

 

SOURCE

https://harleystreetconcierge.com/cancer-at-work/

Other posts on the JP Morgan 2019 Healthcare Conference on this Open Access Journal include:

2018

Top 10 Cancer Research Priorities

https://pharmaceuticalintelligence.com/2018/12/24/top-10-cancer-research-priorities/

Innovation + Technology = Good Patient Experience

https://pharmaceuticalintelligence.com/2018/12/24/innovation-technology-good-patient-experience/

2017

Inspiring Book for ALL Cancer Survivors, ALL Cancer Patients and ALL Cardiac Patients – The VOICES of Patients, Hospitals CEOs, Health Care Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures

https://pharmaceuticalintelligence.com/2017/10/24/inspiring-book-for-all-cancer-survivors-all-cancer-patients-and-all-cardiac-patients-the-voices-of-patients-hospitals-ceos-health-care-providers-caregivers-and-families-personal-experience-with/

2016

Funding Opportunities for Cancer Research

https://pharmaceuticalintelligence.com/2016/12/08/funding-opportunities-for-cancer-research/

2012

The Incentive for “Imaging based cancer patient’ management”

https://pharmaceuticalintelligence.com/2012/08/27/the-incentive-for-imaging-based-cancer-patient-management/

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