Healthcare Buyer Beware

First screened at the Tribeca Film Festival in April 2018, and still available on Netflix, The Bleeding Edge is a documentary that could have easily been made about any sector of the health care industry.

No medical intervention is without risk, and although informed consent includes a discussion of potential negative outcomes, health consumers are invariably in no position to make an informed decision.

Firstly, they do not have the requisite medical knowledge, and no amount of internet searching can substitute for formal education and clinical experience in a field. Secondly, objectivity must be affected when a health issue is impacting an individual’s quality of life to the extent that he/she is considering something invasive, be it a medicine or procedure.

Consumers are encouraged to ask questions, and seek a second opinion. However, when you may have already waited months for an appointment, and then paid a substantial out of pocket for the consultation, it takes courage, as well as time and money, to seek the opinion of another medical specialist. This is a very real situation for patients, as confirmed by the Australian Government Department of Health’s newly launched Medical Costs Finder website, and as reported in the media last week.

ESSURE Medical Device Reports (MDR) to FDA during post-market surveillance^

For those who have missed seeing the documentary, it explores Bayer’s permanent birth control device Essure, Johnson & Johnson’s transvaginal mesh, the Da Vinci Surgical System, and chrome-cobalt hip-replacements. Patients who have experienced adverse effects are followed as they try to regain their health; search for answers; support others; and make efforts to raise the alarm. Unlike scientific data, the film personalises and, despite the MedTech industry viewpoint, it clearly shows what ill health, irrespective of the cause, can do to a person’s life.

The documentary also highlights how an intervention can be experienced very differently depending on your perspective. This issue is illustrated using PSA levels as the basis for prostate surgery in a 2018 video on value-based healthcare produced by the Metro North Hospital and Health Service in Queensland. Over diagnosis of prostate cancer and over servicing with prostatectomy are well documented. Urinary incontinence and erectile dysfunction are frequent side effects that are debilitating for patients, while from the health sector viewpoint, the treatment has been a success (see screen shots from the video).

This disconnect is behind increasing calls to integrate patient feedback into clinical practice by use of Patient-Reported Outcome Measures (PROMs) and Patient-Reported Experience Measures (PREMs) (see figure).

A concern focused on in the documentary is the lack of evidence required for medical devices to be approved for marketing in the US. The FDA’s 510(k) pathway enables medical devices to be approved if the manufacturer demonstrates equivalence to a device already on the market. This is considered less rigorous than the standards that apply to new medicines.

Patient Reported items (Source)

Parvizi and Woods (Clinical Medicine 2014;14(1):6-12 ) compare and contrast regulations for medicines and devices and explain that differences are a function of the nature of the challenges in defining and monitoring the safety and performance of devices under conditions of use. Namely, the large number of types of medical device in use; short timelines of innovation with a medical device typically changed by incremental steps every 1–2 years; and the main causes of adverse incidents being sporadic manufacturing faults, long-term wear (particularly in the case of implants) and operator factors.

The Therapeutic Goods Administration (TGA) is responsible for medical device approvals in Australia. Compliance with a set of Essential Principles (EP) for the quality, safety and performance of a medical device is required to be demonstrated by manufacturers to achieve marketing approval (ARTG listing). The rigorousness of requirements depends on classification of risk level for different classes of device. For example, for surgical retractors classified as low risk (Class I), a sponsor can self-certify that their product meets the EPs.  Active implantable medical devices (AIMD), such as pacemakers and those include medicines, tissues or cells, are the highest risk and must be assessed in full by the TGA.

EP#14 Clinical evidence states:“Every medical device requires clinical evidence, appropriate for the use and classification of the device, demonstrating that the device complies with the applicable provisions of the Essential Principles.” It is acknowledged that in some circumstances clinical investigation data are not available or are insufficient in quantity or quality (see Box 4 from Parvizi and Woods 2014). In this situation clinical investigation data from a ‘substantially equivalent’ device such as a predicate or similar marketed device may be used to support the safety and performance of the device under assessment.

In response to public concerns, the TGA published an overview of regulation of Medical Devices in late 2018. It includes that “The TGA has only recently started accepting US FDA 510k approvals to support applications for some implantable medical devices, and these applications are being subjected to further scrutiny by us to ensure that devices that use this pathway are meeting Australia’s requirements.”

Risk benefit evaluations are an ongoing conundrum for health consumers. Until the equation can be communicated with clarity, the same warning must apply as with any other purchase, caveat emptor.

Note: A week prior to the film release in 2018, Bayer removed the Essure birth control device from the U.S. market. The Essure contraceptive device was cancelled from the ARTG on 9 February 2018. Since the device began supply in Australia in 1999 until 6 August 2018 the TGA received 59 adverse event reports relating to women implanted with the Essure device. The reports included changes in menstrual bleeding, unintended pregnancy, chronic pain, perforation, migration of the device, and allergy/hypersensitivity or immune-type reactions. Surgery, including hysterectomy, was required in some instances to remove the device.


Advanced Therapy Medicinal Products (ATMPs)

Advanced Therapy Medicinal Products (ATMPs) encompass gene, somatic cell therapies and tissue-engineered products, as well as these in combination with a medical device. Refer to  classification decision tree of AMTPs for further detail.

In general, these products involve replacement or regeneration of human cells, tissues or organs in the ultimate personalised medicine. Many also have the potential for a one-time cure. For example, GSK’s Strimvelis for treatment of adenosine deaminase deficiency–severe combined immunodeficiency (ADA–SCID), referred to as ‘bubble boy’ syndrome (below).

Regulation of ATMPs

The legal and regulatory framework for ATMPs in the European Union was formalised under Regulation (EC) No 1394/2007 over a decade ago. Since June 2009, the primary responsibility of the Committee for Advanced Therapies (CAT) is to assess the quality, safety and efficacy of ATMPs, and to follow scientific developments in the field on behalf of the European Medicines Agency. A summary of work to date is available in this presentation by the CAT Secretariat (May 2018).  New guidelines on GMP and GCP  for ATMPs have also been developed.

Meanwhile, the US FDA Center for Biologics Evaluation and Research (CBER) Office of Tissue and Advanced Therapies (OTAT, formerly known as the Office of Cellular, Tissue and Gene Therapies, or OCTGT) was renamed out of a restructure in 2016. In August 2017, the FDA Commissioner Scott Gottlieb, M.D. issued a statement on the agency’s new policy steps and enforcement efforts to ensure proper oversight of stem cell therapies and regenerative medicine. This has been followed by a further statement in July 2018 focused on gene therapies and ongoing releases of guidelines for consultation.

The International Pharmaceutical Regulators Forum’s (IPRF) currently has working groups for Gene Therapy and Cell Therapy to foster broad consultation and harmonisation. Identified challenges include the small quantities generated, often autologously, and short shelf-lives which do not fit with GMP principles. Similarly, without suitable animal models how is non-clinical testing to be performed, and does it need to be? Additionally, clinical trial design and data collection will require flexibility due to the rarity of most of the conditions being treated.

Reimbursement of ATMPs

In 2017, NICE commissioned a mock appraisal of ATMPs which concluded: ‘(1) the existing appraisal methods and decision framework were applicable to regenerative medicines; (2) quantification of decision uncertainty was key in decision-making; (3) where uncertainty is substantial, innovative payment mechanisms may play an important role and facilitate timely patient access; and (4) choice of discount rate is extremely important and can have an impact on the incremental cost-effectiveness ratio (ICER).‘ GSKs Strimvelis® received a positive NICE recommendation in October 2017 as an option for treating ADA–SCID when no suitable human leukocyte antigen-matched related stem cell donor is available. The cost at the time was Euro 594,000 (approximately AU$ 1 million) for the one-off treatment.

In a recent open access article, Jonsson and colleagues describe the convening of an Expert Panel to identify and discuss potential issues for ATMPs when evaluated using Health Technology Assessment (HTA) frameworks.  Identified challenges included clinical evidence generation, safety concerns, assessing and paying for value, uncertainty, affordability, and the manufacturing and organisation of service delivery. They prioritised three topics similar to those considered important by the NICE appraisal described above:

  1. Uncertainty – due to the nature of evidence likely to be available for ATMPs. Potential solutions posed include measuring survival separately for cured and non-cured patients. They reference an article by Othus et al. 2017  which uses this approach for ipilimumab in melanoma and reduces the ICER by a third. Collection of real world evidence and outcome based agreements, or leasing schemes are also discussed.
  2. Discounting – cost-effectiveness estimates for one-off treatments are sensitive to distribution of costs and benefits. ATMPs are likely to involve high treatment costs occurring years before all health benefits accrue, and it is this time period that is sensitive to discount rates and thus estimates of cost-effectiveness. They consider if specific discounting rules should apply to ATMPs reflecting on the opportunity cost of capital, time preference of stakeholders, and decreasing marginal utility of income and conclude that a lower discount rate should be used to support technologies with costs now and outcomes in the long-term, as well as benefiting future generations.
  3. Health outcomes and value when considering potential curative treatment for a few versus smaller incremental benefits for a much larger population. They discuss ‘priority setting’, how current HTA frameworks do not fully capture stakeholder values, QALYs and thresholds for decision making and limitations on how to account for other factors. They point out that ‘guidelines for reimbursement are silent about the role of empirical studies for assessing the value of specific products or classes of products from patients or the general public.’ Those who work in the HTA space know that other factors may also be relevant for payers, patients, and society in addition to health gain and health system costs.

The article concludes with recommendations as a means to initiate and continue discussion. Interestingly, the first four, of eight ATMPs currently EC-approved (ChondroCelect®, Glybera®, MACI®, Provenge®) have all been withdrawn from market for commercial reasons. After 15 years of research and development involving 500 patients, ChondroCelect® received marketing approval in the EU in 2009. It was voluntarily withdrawn by the sponsor in 2016.

The challenges faced by ATMPs include complex and expensive regulatory and manufacturing processes, small patient populations with limited clinical data, and the need for high upfront investment for a course of therapy that may only be a single treatment. As with current therapies for rare and ultra-rare diseases, how society can provide equitable patient access at the same time as commercial returns will be an ongoing debate.

Sources: AT-MP; Flow diagram

Domo Arigato Dr. Roboto [originally published in PulseLine]

The word ‘robot’ was introduced into the English language by writer Karel Capek in his 1920’s play ‘R.U.R.’ (Rossum’s Universal Robots). ‘Robota’ means forced labour in his native Czech. Although entities with robot-like features have been depicted in tales since prehistoric times and modern pop culture is littered with them!

The first use of robots in medicine, however, came much later. Robotic surgery originated alongside minimally invasive surgical techniques in an effort to improve sight of the surgical field, as well as extend dexterity beyond that of a surgeon’s hands in the confined spaces of the body. Surgical robots helped provide the fine-motor control and magnified three-dimensional imaging and depth perception generally lost in keyhole surgery.

In 1985, a surgical robot was developed for neurosurgical biopsies, and this was quickly followed by specifically designed equipment to assist in prostate removal and total hip replacements. The da Vinci® robot evolved out of work with telemedicine, and enabled a surgeon to work remote from the patient while directing robotic arms via controls and a display. It was FDA approved for laparoscopic procedures in 2000.

While robotic surgery offers considerable technical advantages over traditional laparoscopy, the improvement in patient outcomes measured in trials ranges from significant to marginal at best. When looking at clinical studies, the appropriate comparison is laparoscopic versus robotic-assisted, not open technique, which generally has a higher complication rate. Disadvantages of robotic surgery, in addition to the up-front capital and maintenance costs, include increased set-up and operating times, and the requirement for additional training. Cost is the key factor in any debate regarding the place of robotic surgery in modern practice.

Handmer and colleagues conducted a randomised study to demonstrate this point. They showed that despite the wide-spread ‘hype’ and adoption of robotic-assisted laparoscopic radical prostatectomy (RALP), Australian Fellowship-trained laparoscopic radical prostatectomy (LRP) surgeons achieve comparable functional outcomes to their robotic-assisted peers. Their advice to patients is to select a surgeon based on experience and trust rather than the ‘tech’ they use.

Private health facilities were early adopters of robotic technology in Australia with a da Vinci system installed at Victoria’s Epworth Hospital in 2003 to perform robotic-assisted radical prostatectomies. In 2008, the Royal Brisbane and Women’s Hospital (RBWH) became the first public hospital in Australia to have a da Vinci Surgical Robot purchased by government funding ($AU 3.5 million, at the time) and thus making the technology available to public patients. Hall and colleagues conducted a cost analysis at the RBWH comparing open radical prostatectomy (RRP) and robotic-assisted radical prostatectomy (RALP) and found, due to the activity-based funding formulas in place, the average expense of a RALP admission was approximately $AU 12K while a RRP cost the hospital $AU 2K on average. As indicated above however, that the readmission rate and associated costs for the open group were significantly higher than that of the robotic group. Although not included in his analysis, Hall surmised that these readmissions would impact waiting lists and so ultimately cost the hospital.

To justify its cost, robotic surgery is more suitable for patient groups where there is clear evidence of greater benefit, such as obese patients and those with cancer of the lower rectum, where space is extremely limited. Total knee replacement surgeries, where alignment and positioning of the prosthetic is critical to long-term performance and quality of life. The most obvious use for and benefits of robotic surgery in a country as large as Australia is as a technological add-on for telemedicine in remote and rural areas. For public patients in NSW, the wait has been a long one with robotic assisted procedures only becoming available in 2017 with the opening of the Surgical & Robotics Training Institute at Sydney’s Royal Prince Alfred Hospital. For many patients, robots will continue to be in the realm of science fiction into the foreseeable future.

PulseLine is a digital-first publication dedicated to providing news, commentary and insights on the Australian health landscape.