Medical Device Technology and Regenerative Medicine: The Infrastructure of the Industry

Professor David Williams

Adjunct Professor, University of Technology, Sydney Professor, Wake Forest Institute of Regenerative Medicine, USA

Chairman, Strait Access Technologies, South Africa Partner, Morgan & Masterson LLC, USA

Immediate Global Past-President, TERMIS Professor Emeritus, University of Liverpool, UK

Visiting Professor Universities in Cape Town, Shanghai, Beijing, Taipei,

Workshop at University of Technology, Sydney, Australia 20th April 2016

Disclaimer and Conflicts of Interest •  Discussions are based on personal experiences with

academic research, publishing, consulting and writing opinions, working in / with industry and regulators, and product liability / patent litigation.

•  No information given is proprietary •  Anything written in slides is non-confidential and in the

public domain •  Anything I say that is not reproduced in a slide, may not

necessarily be in the public domain and should not be quoted

•  Some matters are still in litigation and may be, or should be, sub judice

•  PLEASE; NO PHOTOGRAPHS OR RECORDING

Medical Device Technology and Regenerative Medicine: The Infrastructure of the Industry

q Globally the industry is massive and adds

significantly to quality and quantity of life

q The questions are whether it could do more and, if so, how?

Bouton C et al Nature April 13th 2016 doi:10.1038/nature17435

Restoring cortical control of functional movement

in a human with quadriplegia

This is the first demonstration to our knowledge of successful control of muscle activation using intracortically recorded signals in a paralysed human. These results have significant implications in advancing neuroprosthetic technology for people worldwide living with the effects of paralysis.

Robot-assisted Hysterectomy In 2013, the President of the American Congress of Obstetrics and Gynecologists was moved to issue a statement cautioning on the use of robotic techniques in hysterectomy procedures. He states that the number of robot-assisted hysterectomies in the USA had increased from 0.5% to 10% in three years, adding an average of $2,000 per procedure ($1.9 billion in total) without any demonstrable benefit. He adds “ aggressive direct-to-consumer marketing of the latest medical technology may mislead the public into believing they are the best choice…our patients deserve and need factual information about all their treatment options, including costs, so that can make truly informed health care decisions”.

Robotic surgery in urological oncology: patient care

or market share? Deborah R. Kaye, Jeffrey K. Mullins, H. Ballentine Carter & Trinity J.

Bivalacqua

Nature Reviews Urology 12, 55–60 (2015) doi:10.1038/nrurol.2014.339

Surgical robotic use has grown exponentially in spite of limited or uncertain benefits and large costs. In certain situations,

adoption of robotic technology provides value to patients and society. In other cases, however, the robot provides little or no

increase in surgical quality, with increased expense, and, therefore, does not add value to health care.

A systematic review of the cost and cost-effectiveness studies of proton radiotherapy

Verma V et al

Cancer March 2016; DOI: 10.1002/cncr.29882 The cost-effectiveness for prostate cancer—the single most common diagnosis

currently treated with PBT—was suboptimal. PBT was the most cost-effective option for several pediatric brain tumors. PBT costs for breast cancer were increased but

were favorable for appropriately selected patients with left-sided cancers at high risk of cardiac toxicity and compared with brachytherapy for accelerated partial breast irradiation. For non-small cell lung cancer, the greatest cost-effectiveness benefits

using PBT were observed for locoregionally advanced tumors. PBT offered superior cost-effectiveness in selected head/neck cancer patients at higher risk of acute

mucosal toxicities. Similar cost-effectiveness was observed for PBT, enucleation, and plaque brachytherapy in patients with uveal melanoma. Careful patient

selection is absolutely critical to assess cost-effectiveness. Clinical trial evidence, and ongoing major technological improvements, the cost-effectiveness data and

conclusions from this analysis could change rapidly

Just caring: Assessing the ethical and economic costs of personalized medicine

Fleck L M, Urologic Oncology: Seminars and Original Investigations

2014; 32(2) 202

Given the best information available regarding a large range of therapeutic options for a broad range of medical problems, and not knowing our future possible health needs, what health care priorities and limits would we choose for our future possible selves through this democratic deliberative process? The implication of this question is that if I believe it is waste of my tax dollars to provide an 80-year old with metastatic renal or prostate cancer a $100,000 targeted cancer therapy for 4 extra months of life, then I am morally bound to accept that same limitation for my future self if I were in comparable clinical circumstances.

Survival in advanced heart failure continues to improve.

Leslie W. Miller et al. Circulation. 2013;127:743-748

Copyright © American Heart Association, Inc. All rights reserved.

The USA

u Over 65% of the world’s top medical device companies are based in the USA

u Over 70 % of medical device related patents granted are filed by US organizations

u Over 50% of the world’s top ranking hospitals and medical schools are in the USA

Country comparisons Data for 2013, Source WHO

Healthcare expenditure as % of GDP

Australia 9.4 Brazil 9.7 China 5.6 DRCongo 3.5 France 11.7 India 4.0 Myanmar 1.8 UK 9.1 USA 17.1

Life expectancy at birth, both sexes

Australia 83 Brazil 75 China 75 DRCongo 52 France 82 India 66 Myanmar 66 UK 81 USA 79

The FDA Version of the Medical Device Product Life Cycle

Key Issues with Medical Technologies Device design and preclinical testing

Risk management and quality systems Regulatory policies and politics; Clinical trials

Regulatory submissions and post-market surveillance Clinical competence and patient selection

Clinical targets and disparities Health economics

Global markets and competition Balancing risk with innovation

Ethics

The Workshop is based on Case Histories (1)

Bjork-Shiley heart valves SJM Silzone heart valves

Breast implants: silicones, Trilucent, PIP DuPont and Vitek Hip replacements

Design History Files Occlutech – AGA patent litigation

The Workshop is based on Case Histories (2)

European Commission Scientific Opinions European Commission Regulations and

Directives ISO 10993 Testing

Commercialization of tissue engineering The Xi’an Papers

Strait Access Technologies

Bjork-Shiley Heart Valves Considerations

•  Performance of the device •  Design expectations and testing •  Quality control •  Skill of welders •  Rates of failure •  Risk factors •  Metallurgical assessment •  Bowling – Pfizer Settlement (bowling-pfizer.com) •  Position of Pfizer Inc

Silzone Heart Valves Scientific, clinical and regulatory issues

•  Performance of mechanical heart valves •  Incidence of bacterial endocarditis •  Anti-bacterial activity of silver •  Toxicity of silver to mammalian cells •  Robustness of silver coating technique •  Requirement of pre-clinical testing •  Adequacy of pre-clinical testing •  Regulators response to patient’s death •  Outcome of clinical observational study

Silzone Heart Valves Legal Action in Canada

On June 26, 2012, the Ontario Superior Court of Justice dismissed the action Andersen v. St. Jude Medical, Inc. bearing Court File No. 00-CV-195906CP , This decision meant that no Class Member was entitled to any recovery or compensation from this class action, On July 2, 2014, the Ontario Superior Court of Justice, approved the settlement of this action, This Notice summarizes the terms of the settlement. The essential terms of the settlement are:

(a) the appeal of the trial decision on the common issues will be dismissed on a without costs basis;

(b) the claims of the class members and relevant provincial health insurers in the action are released;

Silzone Heart Valves Considerations (1)

•  Patent on previous top SJM valve soon to

expire •  Impossible to confirm improved resistance to

infection; claim not allowed by FDA •  Scientific arguments about effects of silver on

bacteria and mammalian cells not unequivocal but balance of opinion rested with minimal toxicity to mammalian cells and not of any clinical consequence

Silzone Heart Valves Considerations (2)

•  FDA requirements for pre-clinical testing not very demanding

•  SJM failed to report one animal death (unrelated causes) to FDA

•  Rapid response to two deaths (Wales and Canada) by regulators

•  SJM forced into recall •  Clinical observational study showed superior

performance of Silzone valves after six months compared to controls

The Story of Silicone Breast Implants (1) •  Large market, after 1960, especially in the USA, both for

reconstruction and augmentation •  Silicone shell and silicone gel ideal combination •  Some ruptures occurred; massive media coverage,

especially after Connie Chung TV show Face-to-Face, 1990 •  Many lawsuits against Dow Corning, big settlements •  Jan 1992 Kessler of FDA demands ‘voluntary moratorium’ •  Class action settlement over $4 billion •  Dow Corning, Bristol Myers Squibb, Baxter, 3M all lose

heavily on grounds that silicones cause auto-immune disease

The Story of Silicone Breast Implants (2) •  Hundreds of thousands of women in USA have no access

to breast implants •  Opinions change in late 1990s •  Thirteen epidemiological studies published in early 2000s

that show no connection between silicone and autoimmune diseases. One study shows patients with breast implants have less chance of acquiring scleroderma and lupus

•  Companies start to win law suits •  Implants gradually placed back on market with much

stricter regulatory control •  But not before huge damage done elsewhere.

The Story of Other Breast Implants

•  Saline filled silicone shell implants remained on the market, but ruptured far more frequently

•  Several companies produced alternative gels, including polyacrylamide, but without success

•  Biggest problem was with Trilucent implants in which the filler was a triglyceride.

•  Manufacturers did not know, and regulators did not know, that triglycerides degrade the silicone shell and once released into the tissue undergo auto-oxidation where the by-products are mutagenic

•  One other company in France, Poly Implant Prothese (PIP) produced implants, mostly for South American market using cheap industrial rather than medical grade silicone gel. Owner now in jail.

Breast Implants Considerations

•  Too many pharmaceutical companies entered the device market through acquisitions without much due diligence

•  Poor, often dishonest science can win legal cases when the actual evidence is sparse

•  Politically inspired regulatory responses can result in products taken off the market to the disadvantage of patients

•  However, introduction of ‘innovative’ solutions without proper regulatory oversight is also harmful

Hip replacements; historical issues (1)

Charnley and PTFE / Cement Charnley and clinical training Early metal-on-metal hips Design failures; 3M Capital Hip, Christiansen prostheses, Boneloc bone cement Introduction of registries (Scandinavia) Effects of gamma irradiation sterilization on PE Cross-linked polyethylene

Hip replacements; historical issues (2) Increase in devices available (2003, 42,000 cases in Australia using 265 types of product) Increase in number of surgeons implanting hips (in Australia, many surgeons were performing less than 10 per year in 2005) Trend towards younger, more active patients Re-introduction of metal-on-metal Litigation and product re-calls

Hip replacements; observations Patient selection Clinical skill and the learning curve Pros and cons of implant registries Power of the media, internet and lawyers Biomaterial selection Need for clinical trials Do we need new innovation – is 95% success at 20 years good enough

Occlutech – AGA patent litigation

•  Septal defect occluder, market leader invented and patented in USA by AGA Medical

•  Small German company, Occlutech develops own device, patented and sold in Europe

•  AGA unsuccessfully tries to buy Occlutech •  AGA then sues Occlutech for patent infringement,

Occlutech counter-sues for invalidity •  Cases have to be dealt with country-by-country in

Europe •  Verdicts go both ways, usually go to appeal

Occlutech – AGA patent litigation

•  Occlutech wins case in Courts of Appeal in London and Stockholm and eventually in Germany

•  Occlutech, prevented from selling products in jurisdictions where AGA win first level, running out of money.

•  AGA tries to buy Occlutech at lower price •  AGA, now part of SJM, brings slightly different case

against Occlutech •  Loses case in London •  Waiting for next phase

EP(UK) 808138 Claims

1. A collapsible medical device comprising a metal fabric formed of braided metal strands, the device

having a collapsed configuration for delivery through a channel in a patient's, and has a generally

dumbbell-shaped expanded configuration with two expanded diameter portions separated by a reduced diameter portion formed between opposed ends of

the device, characterized in that clamps are adapted to clamp the strands at the opposed ends

of the device.

EP(UK) 808138 Claims 16. A method of forming a medical device according to any one of the

preceding claims, the method comprising the steps of: (a) providing a metal fabric formed of a plurality of braided strands, the

strands being formed of a metal which can be heat treated to substantially set a desired shape;

(b) deforming the metal fabric to generally conform to an internal wall surface of a moulding element:

(c) heat treating the metal fabric in contact with the surface of the moulding element at an elevated temperature, the temperature and the

duration of the heat treatment being sufficient to substantially set the shape of the fabric in its deformed state;

(d) removing the metal fabric from contact with the moulding element; and

(e) clamping the opposite ends of the strands of the device with clamps.

Concepts in Biocompatibility: New Biomaterials,

New Paradigms and New Testing Regimes

Professor David Williams Wake Forest Institute of Regenerative Medicine, USA

Editor-in-Chief, Biomaterials President, TERMIS

Professor Emeritus, University of Liverpool, UK

Visiting Professor Universities in Cape Town, Singapore, Shanghai, Beijing, Taipei, Sydney, Trivandrum

MINNEAPOLIS

May 2013

© D.F.Williams