Medtech Veteran Robert Ford Will Take Over As Abbott CEO ... THE LATEST INSIGHT ON THE MEDTECH...

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November 25, 2019 Issue 171

POLICY & REGULATION

FDA advisory panel debates science on human adverse biological reactions to metal-containing devices, p. 15

R&D

Medtronic’s Micra Transcatheter pacemaker improves cardiac function in MARVEL 2, p. 7

COMMERCIAL

How IBM Watson Health’s CTO uses blockchain to eliminate “friction points” in health care, p. 12

Medtech Veteran Robert Ford Will Take Over As Abbott CEO From Miles WhiteREED MILLER [email protected]

M iles White will step down as Abbott Labo-ratories Inc.’s CEO at

the end of March 2020 after 21 years on the job. Abbott COO Robert Ford, who has been with the company for 23 years, will be the new CEO and has been elected to the board, the company announced on 13 November.

Ford will be the 13th CEO in the 131-year history of Abbott. He originally joined Abbott in 1996, working in the company’s dia-betes business, and has served in various leadership roles in the company’s nutrition and medical devices businesses.

“I thank Miles for his mentorship, and I look forward to working with my colleagues to do what Abbott people do best – antici-pate where science, medicine and technology are going and in-novate to best serve our customers, shareholders and communi-ties,” Ford said.

Ford led Abbott’s $25bn acquisition of St. Jude Medical Inc. in 2017, which instantly turned Abbott into the second-biggest car-diovascular device company in the world behind Medtronic. (Also see “MTI 100: Major M&A Bookends Year Of Mainly Steady Growth For Leading Medtech Groups “ - Medtech Insight, 6 Dec, 2018.)

He led Abbott’s diabetes-care business when it launched the Free-Style Libre continuous glucose monitor in 2017. Sales of FreeStyle Libre, the first continuous glucose monitor that does not require patients to draw blood from their finger, reached almost $500m in the third quarter of 2018. (Also see “Diabetes, Mitral Repair And Diag-nostics Drive Big Quarter For Abbott” - Medtech Insight, 21 Oct, 2019.)

Ford was named president and COO in October 2018. At that time, White indicated that Ford would most likely become Ab-

bott’s next CEO, calling Ford’s appointment as COO “obvious-ly a succession step.”

White has overseen a gradual transformation of Abbott since he became CEO in 1998 to fo-cus the company on the areas where it expects to be a leader, especially in fast-growing med-ical device markets.

In addition to major acquisi-tions like St. Jude in 2017 and Alere Inc. in 2018, White also led some major divestitures in recent years. Abbott spun off most of its brand-ed pharmaceuticals business as AbbVie Inc. in 2013 and then sold its specialty and branded generics drug business to Mylan NV in 2014. Abbott sold its Abbott Medical Optics Inc. business to Johnson & Johnson in 2016.

William Osborn, the chair of Abbott’s board of directors’ nomi-nations and governance committee, said White “has positioned Abbott well for continued top-tier growth and innovation, and we thank him for his countless contributions.”

Osborn called Ford “a proven Abbott leader with significant ex-perience running Abbott’s global businesses,” and expects “he will continue Abbott’s outstanding legacy of success.”

In a 13 November note, Wells Fargo analyst Larry Biegelsen predicted that Ford will be “up to the task given his strong track record leading Abbott’s nutrition, diabetes and medical device businesses.” Biegelsen added that he expects Ford “to be more visible with investors before he officially assumes the CEO role next year and [is] confident investors will become comfortable with the transition as they get to know him better.”

Published online 13 November 2019

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medtech.pharmaintelligence.informa.com November 25, 2019 | Medtech Insight | 3

inside: Cover / Medtech Veteran Robert Ford Will Take Over As

Abbott CEO From Miles White – Miles White will step down in 2020 after 21 years leading the diversified health-care products company.

EDITORS’ PICKS 5 VIVA 2019: New Paclitaxel Data Shows Consistent

Mortality Signal, No Clear Cause – Clinical trials show paclitaxel-coated devices are associated with slightly greater mortality than bare-metal stents. But this signal does not appear in real-world data.

6 Senators Question FDA’s Proposed Progressive Approval Pathway For Devices – Democrats in the Senate want the FDA to explain how it will maintain device safety and efficacy with the proposed progressive regulatory pathway.

R&D 7 Medtronic’s Micra Transcatheter Pacemaker Improves

Cardiac Function In MARVEL 2 – New trial data show the leadless ventricular pacemaker can significantly improve atrioventricular synchrony in patients with sinus rhythm and atrioventricular block.

8 AHA 2019: Cardiawave Sees Positive Early Results For Non-Invasive Valve Disease Treatment – The French start-up claims first-in-man success for heart valve “softening” treatment and plans further trials for an EU launch.

9 FDA Expands Indication For Axonics’ Incontinence System; Medtronic Claims Patent Infringement – Axonics expects its r-SNM neuromodulation system to treat incontinence will rival Medtronic’s InterStim II. Medtronic claims the Axonics’ technology infringes its intellectual property.

COMMERCIAL 10 Roundup: XMed2019: 7 Innovators To Watch – The

shortlist of top innovators who showcased their products at the recent Exponential Medicine conference in San Diego.

explore more:exclusive online contentEU’s global impacthttp://bit.ly/2CUTNiT

Medtech consultant Arthur Brandwood explains why the EU’s medtech regulations are sending shock waves through so many other countries.

Pediatric contact lenshttp://bit.ly/2D0JKZr

The newly approved MiSight contact lens from CooperVision promises to slow the progression of nearsightedness when prescribed to children aged 8 to 12.

Cleaner duodenoscopehttp://bit.ly/2KzU9j0

The US FDA cleared Pentax Medical’s new duodenoscope as the first in the US with a disposable elevator part that reduces the number of parts needed to be disinfected compared to earlier designs.

Warning lettershttp://bit.ly/2Onmpqg

A manufacturer of in vitro diagnostic reagents was cited for premarket violations in the only device-related warning letter released by the US FDA on 19 November.

Importance of adaptability http://bit.ly/2OvoEYr

Consultants from Nypro explain how the medical device industry has been relatively slow to adopt connected technologies and must be ready to adapt more quickly in the future.

Execs on the Movehttps://bit.ly/2QMFWn1

J&J chooses a former Bayer exec as chief information officer; C-RAD brings aboard as COO a GE Healthcare software director; and more.

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12 Exec Chat: XMed2019: How IBM Watson Health’s CTO Uses Blockchain To Eliminate ‘Friction Points’ In Health Care – Ted Tanner, the new chief technology officer and chief architect of IBM Watson Health, recently sat down with Medtech Insight to discuss his plans for the company.

POLICY & REGULATION 15 FDA Advisory Panel Debates Science On Human

Adverse Biological Reactions To Metal-Containing Devices – Experts discussed the latest science on patients’ biological reactions to metal implants and mercury in dental amalgam at a recent meeting.

18 A Softer, Gentler FDA Inspectorate? It’s Possible With QSR/ISO 13485 Harmonization, Auditing Expert Says – The agency’s ongoing rewrite of its Quality System Regulation to harmonize it with international standard ISO 13485 could “soften FDA’s inspectorate,” NSF International’s Brian Ludovico says.

19 FDA Issues Final Export Certificate Guidance, Explains What To Do If Your Firm Is Turned Down For One – The guidance lays bare reasons why the FDA would deny an export certificate to a company and how a firm can appeal if it is turned down for a certificate.

20 Process Validation Can Be Problematic For Device-Makers. Here’s Why, And What Companies Can Do About It – Former US FDA investigations branch director Ricki Chase explains what those process validation hurdles are and offers tips to firms to make sure they’re on the road to compliance.

22 Will UK’s Own Registration Plans Be Affected By Two-Year Delay To Eudamed Database? – If the UK exits the EU on 31 January, the two-year delay in Eudamed may of less significance to the country. Or is it more complicated than that?

23 FDA Will Have To Scrape By On Continuing Resolution Funding Through December, Legislative Experts Predict – The agency may have to carry out its 2020 mission in the short term on the 2019 continuing resolution funding – probably through December.


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VIVA 2019: New Paclitaxel Data Shows Consistent Mortality Signal, No Clear CauseELIZABETH ORR [email protected]

O ngoing scrutiny has not ex-plained an apparent link between paclitaxel-coated cardiac devices

and an increased mortality rate, speakers said at the Vascular Interventional Advanc-es (VIVA) 2019 conference in Las Vegas the week of 4 November.

The issue has created major concerns in the sector since a December 2018 meta-analysis suggested patients who received balloons and stents coated in the drug had a five-year mortality rate almost twice that of patients who received bare-metal devices. Subsequent research by trade groups and the US Food and Drug Administration has cut the apparent increase significantly, but has not disproved the link. Scientists have also been unable to establish a specific mecha-nism of death. (Also see “German Patient Data Shows No Paclitaxel Mortality Risk” - Medtech Insight, 16 Oct, 2019.)

At the VIVA conference, several stakeholders presented addi-tional information on the possible risks of the drug but found few clear conclusions.

VIVA board member Krishna Rocha-Singh of St. John’s Hospital in Springfield, IL, said that ongoing review has found an increased mortality risk of about 27% in patients treated with paclitaxel-coat-ed devices, down significantly from the 93% increase found in the original study. The numbers dropped as the percentage of patients lost to follow up went from more than 20% to about 10%, he said.

“The most comprehensive analysis to date demonstrates a modest yet consistent mortality signal in patients exposed to pa-clitaxel,” Rocha-Singh said. “However, it did not identify an expla-nation and I would suggest to you today that it is time to turn the page. We have to consider complimentary real-world datasets that assist us in answering this question.”

Real-world evidence compiled from Medicare, private payers and the Vascular Quality Initiative has not shown an increased risk to patients associated with the use of paclitaxel, said Eric Secem-sky from Beth Israel Deaconess Medical Center in Boston.

“In six real-world population studies that I’ve now presented here today, we’ve seen no difference in survival for patients treat-ed with drug-coated devices compared with non-drug, coated devices,” he said. “We’ve seen no difference in survival within im-portant subgroups,” such as older patients.

The FDA’s ongoing analysis has also failed to turn up specific factors behind the mortality risk, FDA medical officer and in-terventional cardiologist Donna Buckley said. “We’re still in the stage of discerning where the meta-analysis data came from and

how we can add to the understanding,” she said, adding that the agency also continues to work with manufacturers to track down data from patients lost to follow-up.

The FDA has instructed physicians to discuss the paclitaxel mor-tality risk with patients and to consider alternative treatments. The agency is also considering labeling changes but has stopped well short of ordering a recall. (Also see “FDA Announces More Actions On Drug-Coated Devices” - Medtech Insight, 7 Aug, 2019.)

“There are still limitations with the datasets as we all recognize in moving forward to develop a public-health strategy that tries to have a measured approach,” she said. “There are lots of regulatory options available to us – everything from potentially pulling a device off the market to doing nothing. And those options need to be really approached with a lot of consideration and candid discussion.”

RESEARCHER POINTS TO STUDY BIAS Some researchers suggested that the apparent mortality link may stem from a problem with the studies included in the meta-analysis, rather than paclitaxel. Ramon Varcoe, from Prince of Wales Hospital in Sydney, Australia, speculated that the mortality signal could be explained by faulty trial designs and follow-up, as opposed to the toxicity of the devices.

For example, he said, none of the 28 studies included in the meta-analysis were thoroughly blinded. “Randomization doesn’t prevent bias in outcome assessment,” he said. “It’s blinding.”

And, Varcoe speculated, the lack of researcher blinding could have led to an affect known as ascertainment bias, which is when patients in a treatment group are more thoroughly scrutinized and tracked than patients in the control group.

“It’s about the unblinded research team being more tenacious in how they follow up the patients in the experimental arm,” he said. “That’s human nature. We’ve got an experimental new treat-ment and we want to know if it’s having a good or bad impact

“The most comprehensive analysis to date demonstrates a modest yet consistent mortality signal in patients exposed to paclitaxel. However, it did not identify an explanation and I would suggest to you today that it is time to turn the page.”

– Krishna Rocha-Singh



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on our patients. This may lead to fewer subjects being labeled as missing, with an increased number of mortalities recorded in those experimental arms.”

To test this hypothesis, Varcoe and his colleagues conducted a meta-analysis of 22 trials of endovascular treatments that did not involve drug-coated devices. The review found a higher mortal-ity rate in the study population than in the controls going out to three years, he said.

“Those effects were independent of paclitaxel completely, which in my view casts considerable doubt to the causal link be-tween paclitaxel and mortality,” he said.

Varcoe pointed to the lack of a common cause of death as fur-ther reason to believe factors beyond paclitaxel may account for the apparent mortality increase. Some, including original meta-

analysis author Konstantinos Katsanos of Greece’s General Uni-versity Hospital of Patras, have speculated that the drug might somehow cause cell deaths.

Varcoe said he is skeptical of that hypothesis because it “doesn’t explain why paclitaxel use in high doses in oncology for 27 years actually reduces long-term mortality rather than the opposite, why there’s no dose-response relationship or biological gradient, and why, as more and more new data emerge, with subjects lost to follow-up being found, the effect size is being reduced.”

He suggested that further paclitaxel studies should include the blinding of patients, clinicians, the research team and all out-come adjudicators.


Senators Question FDA’s Proposed Progressive Approval Pathway For DevicesSUE DARCEY [email protected]

T wo US senators have sent a letter to US Food and Drug Administration officials that raises new concerns about the agency’s legislative plan for a conditional progressive

approval pathway for medical devices. Democrats Elizabeth Warren of Massachusetts and Patty Mur-

ray of Washington State – both members of the Senate Health, Education, Labor and Pensions Committee – said in their 4 No-vember letterthat they were worried about how the agency intends to maintain device safety and efficacy through use of a progressive regulatory pathway.

The FDA in April 2019 proposed the pathway’s creation, which appeared to be “strikingly similar” to a conditional approval pathway for certain animal drugs, the senators told acting FDA Commissioner Brett Giroir and FDA device center director Jeff Shuren in their letter.

The conditional approval pathway lets manufacturers make certain animal drugs available on the market after demonstrat-ing a “reasonable expectation of effectiveness,” rather than the stricter “substantial evidence of effectiveness” standard currently required for full human-drug approval, Warren and Murray said.

“Progressive approval would weaken initial approval standards and allow certain medical devices onto the market before … completely demonstrating the device’s safety,” Warren and Mur-ray wrote. The duo noted that the FDA had cited unmet needs for pediatric medical devices in justifying its proposal – but Warren and Murray raised questions about how the new pathway pro-posal would address those needs while maintaining safety and efficacy standards for medtech products.

LAWMAKERS PROD FDA ON POSTMARKET DATA COLLECTIONAmong the questions that Warren and Murray asked in their let-

ter was what type of oversight the FDA envisions conducting on a progressive approval pathway to ensure safety standards are met, and how the agency would make its postmarket surveillance of progressively approved devices effective. They noted that an in-dependent audit of the agency’s expedited approval pathways by the Department of Health and Human Services revealed challeng-es with the FDA implementing postmarket requirements.

The senators also asked what real-world evidence would be sufficient to demonstrate a reasonable assurance of safety and effectiveness for devices reviewed under the progressive ap-proval pathway, and if the FDA had ever relied exclusively on real-world evidence to support approval or clearance of a device.

Warren and Murray also wanted to know if device registries were sufficiently widespread and well developed so the agency could rely on them for data collection.

They also wrote that they were “disappointed by FDA’s clari-fication that the agency no longer fully stands by former com-missioner [Scott] Gottlieb’s commitment that the ‘FDA does not believe this … pathway would be suitable for human medical products,’” and added that they continued to have questions re-garding the eligibility criteria that the FDA has in mind to carry out the conditional approval pathway proposal.

Warren and Murray have sent several letters to the FDA re-garding its handling of devices and other medical products, in-cluding a letter in late October questioning the agency’s regu-lation of digital devices. (Also see “US Senators Lay Out Concerns On FDA Digital Health Device Precertification Program” - Medtech Insight, 31 Oct, 2019.)

The lawmakers asked the FDA to respond to its progressive ap-proval pathway letter by 13 November.



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Medtronic’s Micra Transcatheter Pacemaker Improves Cardiac Function In MARVEL 2REED MILLER [email protected]

M edtronic PLC has submitted new clinical data to the US Food and Drug Administration

to support approval of the Micra AV lead-less pacemaker for patients with atrioven-tricular block.

Micra AV is a dual-chamber version of Medtronic’s Micra TPS leadless transcath-eter pacemaker system, which Medtronic touts as the world’s smallest pacemaker. Micra TPS has been a commercial success for Medtronic since it was introduced in 2016. (Also see “Medtronic Expects EV ICD To Reduce ICD Complications, Costs” - Medtech Insight, 22 Oct, 2019.)

The submission to the FDA for Micra AV is based on results of the MARVEL and MARVEL 2 studies.

Results from 64 patients in the MARVEL study, announced in May 2018, showed Micra TPS could be programmed to moni-tor and detect contractions in the atrium while pacing the ventricle in sequence with the atrium to create atrioventricular syn-chrony. (Also see “HRS 2018 Wrap-Up: Tendril Lead Failures; Metaanalysis Of Contact-Force Catheter; LuxCath’s OmniView; More Micra Results“ - Medtech Insight, 22 May, 2018.)

Results from 75 patients in MARVEL 2 showed Micra TPS programmed to pace both the ventricle and atrium could signifi-cantly improve synchrony and cardiac func-tion in patients with atrioventricular block, which impairs electrical conduction be-tween the chambers of the heart. Primary investigator Larry Chinitz of New York Uni-versity presented results from MARVEL 2 at the American Heart Association Scientific Sessions in Philadelphia on 16 November. The results were published on 11 Novem-ber in JACC: Clinical Electrophysiology.

“While leadless pacing has many advan-tages compared to traditional pacemak-ers – including fewer infection-related complications – leadless pacemakers are currently only capable of single-chamber ventricular sensing and pacing,” Chinitz

said. “Our investigation shows that accel-erometer-based atrial-sensing algorithms can sense signals from the atrium in the heart and make calculated adjustments to when ventricular pacing occurs, thus im-proving coordination between the atrium and ventricle. These results provide fur-ther evidence that these novel investiga-tional algorithms, added to the Micra TPS, may allow more patients, including those with normal sinus rhythm and AV block, to benefit from a leadless pacemaker.”

MARVEL 2 evaluated 75 patients with a Micra TPS downloaded with acceler-ometer-based atrial sensing algorithm software. The 40 patients with complete heart block and normal sinus rhythm were included in the trial’s efficacy analy-sis while all 75 patients were included in the safety analysis. The investigators used continuous device telemetry and an elec-trocardiogram Holter monitor to measure the patients’ atrioventricular synchrony.

They took measurements for 20 minutes during atrioventricular synchronous pac-ing and then again for 20 minutes during single-chamber ventricular pacing. The study’s primary efficacy objective was met because the percentage of patients with at least 70% atrioventricular synchrony was significantly greater with atrioventricular synchronous pacing enabled than with single-chamber ventricular pacing only. While the Micra was delivering atrioven-tricular synchronous pacing, 38 of the 40 patients showed at least 70% atrioven-tricular synchrony. None of the patients showed at least 70% atrioventricular syn-chrony while the device was delivering only single-chamber ventricular pacing. The median percent of atrioventricular synchrony was 94.3% during synchronous pacing and only 26.9% during single-chamber ventricular pacing.

Blood flow from the left ventricle, mea-sured by echocardiography, increased by 8.8% during atrioventricular synchronous

pacing compared with single-chamber ventricular pacing.

The study’s primary safety objective was the number of participants free from inappropriate pacemaker function events measured over a day. MARVEL 2 met this objective because there were no pauses or episodes of pacing-induced tachycar-dia reported during atrioventricular syn-chronous pacing in any of the 75 patients.

Micra’s ability to provide atrioventricu-lar synchrony did not diminish over time, the MARVEL 2 authors pointed out.

BRINGING LEADLESS PACEMAKERS TO MORE PATIENTSMedtronic hopes to commercialize the Micra AV in the fourth quarter of fiscal 2020, which translates to late spring in 2020. The current single-chamber Micra addresses about 15% of the bradycardia market while the dual-chamber version will address an additional 45% of that market.

In a 12 November note, Wells Fargo analyst Larry Biegelsen wrote: “Based on the positive physician feedback we’ve received as well as the early experience with [the single-chamber Micra], we believe the launch of Micra AV will help Medtronic capture additional share in the pacemaker market.”

Medtronic already controls about half of the worldwide pacemaker market and Micra will add another 0.3% to its share, Biegelsen wrote.

Medtronic is also developing Micra AR, which can pace and sense the atrium with a rate-response feature and Micra DDD, which provides dual-chamber pac-ing plus the rate-response feature.

The company also recently announced it had started a pivotal trial of its EV ICD, an implantable cardioverter defibrillator without a transvenous lead.




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AHA 2019: Cardiawave Sees Positive Early Results For Non-Invasive Valve Disease TreatmentPHIL GREENFIELD [email protected]

C ardiawave’s non-invasive ultra-sound therapy is feasible and safe in patients with severe symptom-

atic aortic stenosis, according to early trial data presented on 16 November at the American Heart Association (AHA) meet-ing in Philadelphia.

The company hopes the new technique could be used in patients judged to have symptoms not severe enough for trans-catheter aortic valve replacement (TAVR), or when TAVR is not available or is consid-ered too costly.

The French start-up company’s tech-nology, called Valvosoft, uses so-called pulsed cavitational ultrasound therapy delivered through the chest to break down calcification of valve leaflets. The focused ultrasound creates microscopic bubbles and shock waves within the valve leaflets, and these shock waves make tiny cracks in the calcification that is embed-ded in the aortic valve leaflets.

The Valvosoft applicator houses both the echocardiography ultrasound trans-ducer for imaging guidance and monitor-ing, and the focused ultrasound thera-peutic transducer for applying ultrasonic cavitation in the form of shock waves.

The 10-patient study, presented at the AHA by co-founder Emmanuel Messas, a cardiologist at Hôpital Européen Georges-Pompidou in Paris, showed improvement in New York Heart Association class in sev-en of the 10 patients after 90 days. In ad-dition, after 30 days, the aortic valve area increased in eight out of the 10 patients, growing between 6% and 68%. Hemody-namic improvements were observed in six out of 10 patients after 30 days.

“The normal valve opening has an area of around 2.5cm2. When stenosis is severe, this can be as low as 0.5cm2. However, when you replace the valve, it will not go back to [opening to] 2.5cm2. Our goal is to soften the valve, enabling it to open from 0.8 cm2 to 1.2cm2,” Messas told Medtech Insight. “It’s

very difficult to soften, if there is very hard calcification. But there is no other option for these patients, so there is nothing to lose.” If the patient is less sick, this treatment could delay the need for future treatment, includ-ing TAVR or surgery, he added.

CE MARK STUDY PLANNEDCardiawave CEO Benjamin Bertrand told Medtech Insight before the AHA meet-ing that he hoped the trial data could be pooled together with data from upcom-ing additional European studies to en-able the company to apply for a CE mark in 2021. Data will be needed from 40 to 50 patients with six to 12-month follow-up, said Bertrand.

With the likely delays as notified bod-ies dealt with the backlog of CE marking applications brought about by the intro-duction of the new EU medical device regulations, it will take six to nine months to gain CE marking once it had been sub-mitted, he said. As a result, the company expects to have a CE mark in 2022.

The next step in Europe is to begin a 10-patient clinical trial in Serbia, where there are no TAVR programs. The study will include brain magnetic resonance imaging to hopefully demonstrate that breaking down calcifications in the valve does not increase the risk of stroke. It will

also study longer treatment times – up to one hour – and higher-energy (> 100mW/cm2) treatment regimens.

In the US, Cardiawave plans a pre-sub-mission to the US Food and Drug Admin-istration in early 2020 and an early US fea-sibility study in 2021.

LARGE UNMET NEEDDespite the TAVR revolution, aortic steno-sis is still a largely unmet medical need, with around 70% of patients untreated, according to Cardiawave. The unmet need represents around 3 million pa-tients in Europe, the company estimates.

International guidelines recommend treatment of severe symptomatic aortic stenosis, with the remainder often not treated due to poor diagnosis, lack of in-frastructure, restrictions from payers or costs of aortic valve replacement. In ad-dition, patients with less severe stenosis must wait until they are ill enough to re-ceive TAVR, often too late.

The Paris-based company, which was formed in 2014, wants to collaborate on the guidance and monitoring elements of the system, which will require 3D/4D ul-trasound technology of sufficiently high resolution to track the microscopic bub-bles and their effect on the calcifications, and will outsource production of the final

Valvosoft delivers ultrasound therapy through the chest to break down calcification of valve leaflets

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Valvosoft system after completing the clinical phase.

Discussions regarding reimbursement have already begun.

“We’re working early on to make sure clinical trial, endpoints, sample size and follow-up data requirements [are discussed with the reimbursement bodies] to help with reimbursement. As you know, reim-bursement in each EU country is different, so we’re having those conversations with

the relevant organizations early,” said Ber-trand. He added that there is a fast-track scheme in France for disruptive technology that benefits patients to be reimbursed us-ing existing reimbursement codes.

The technology behind Cardiawave was initially developed at Institut Langevin and PhysMed in collaboration with an ad-vanced cardiology laboratory at Hôpital Européen Georges-Pompidou. The scien-tific advisory board includes Alain Cribier,

one of the primary inventors of TAVR.Cardiawave raised €14m in 2015. A fur-

ther injection of capital between €10m and €15m is needed in 2020 to reach sev-eral milestones over the coming months, said Bertrand. The company has also re-ceived funding from the EU’s Horizon 2020 research and innovation program (grant agreement No. 829492).


FDA Expands Indication For Axonics’ Incontinence System; Medtronic Claims Patent InfringementREED MILLER [email protected]

A xonics Modulation Technologies Inc. is fighting Medtronic PLC in both the incontinence-treatment

device market and in the courtroom.Axonics’ rechargeable sacral neuro-

modulation (r-SNM) system competes with Medtronic’s InterStim and InterStim II sacral neurostimulation systems, which are indicated for treating urinary reten-tion, overactive bladder and chronic fecal incontinence in patients who have failed other treatments or are not good candi-dates for more conservative treatments.

On 4 November, Medtronic filed a pat-ent infringement suit against Axonics in the US District Court for the Central Dis-trict of California, alleging Axonics’ sacral neuromodulation technology infringes four of Medtronic’s patents for implant-able electrical stimulation lead fixation methods and transcutaneous inductive charging for implantable medical devices.

“We’ve developed various aspects of sacral neuromodulation and related technologies for decades, including per-cutaneous implantable delivery tech-niques, recharging technologies, as well as microstimulators,” said Brooke Story, general manager of Medtronic’s pelvic health and gastric therapies business. “Medtronic welcomes competitors and we believe competition drives innovation and broader market awareness, which is good for the industry and for patients.

However, Medtronic is also committed to protecting our proprietary technology and intellectual property, which drives our ability to continue to innovate.”

During Axonics’ third-quarter 2019 earnings call on 14 November, Axonics CEO Raymond Cohen said: “We believe [Medtronic’s] claims are without merit and an attempt to suppress competition by confusing physician implanters with scare tactics.”

Cohen believes physicians interested in offering r-SNM to their patients will not be deterred by Medtronic’s lawsuit. “Phy-sicians have openly expressed dismay that, instead of investing money to bring attention to the benefits of sacral neuro-modulation therapy, [Medtronic] would rather spend its money harassing a new and innovative entrant,” he said.

AXONICS TAKES ON MEDTRONIC IN US MARKETThe US Food and Drug Administration ap-proved r-SNM for the fecal incontinence indication on 9 September based on the results from five studies with a total of 430 subjects. The FDA approved the system for the overactive bladder and urinary inconti-nence indications on 14 November, based on results from the 129-patient ARTISAN SNM pivotal trial. (Also see “FDA Approves Axonics’ Neuromodulation Device For Incon-tinence” - Medtech Insight, 9 Sep, 2019.)

The company began the US commercial launch of r-SNM at the end of October. It earned a CE mark in 2016 and is already available in Europe, Canada and Australia.

Axonics touts r-SNM as the first recharge-able sacral neuromodulation system avail-able in those countries and the only sacral neuromodulation device compatible with magnetic resonance imaging (MRI). It is about the size and shape of a USB drive and slightly smaller than InterStim II.

Axonics says r-SNM can last up to 15 years while Medtronic’s InterStim devices must be replaced, on average, every four years. Axonics also says its wireless char-ger is user-friendly and optimized for in-frequent charging, with a small “key fob” remote control for patients and an intui-tive clinician programmer.

Medtronic refers to InterStim II as “re-charge-free,” which is the current stan-dard of care since more than 300,000 patients have been treated with re-charge-free devices, according to the company. Recharge-free devices require less of the patient’s time to manage than rechargeable devices and do not compel the patient to carry recharge accessories when traveling, which many patients see as an advantage over a rechargeable sys-tem, according to Medtronic.

Medtronic believes patients and their doctors want a choice of either recharge-able or non-rechargeable sacral neuro-

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modulation systems and it hopes to soon be the only company offering both op-tions. The company is currently seeking FDA approval for its rechargeable, MRI-compatible InterStim Micro system with MRI-compatible InterStim SureScan leads.

Medtronic has previously said it ex-pects to launch InterStim Micro in the spring or summer of 2020. The company also expects to begin offering an MRI-compatible version of InterStim II around the same time.

Axonics’ Cohen agrees that many physi-cians treating patients who need sacral neu-romodulation devices may want both re-chargeable and non-rechargeable options.

“If physicians who are working with us would like to give patients a choice, then we’re perfectly happy with that,” he said. “But it’s going to depend on each of these physicians and institutions on a kind of a practice-by-practice or hospital-by-hos-pital basis.”

However, Cohen also boasted: “We have some customers who already have decided that they have no interest in

working with [Medtronic] and are going to be working with us exclusively for all of their [new] patients.”

AXONICS REPORTS RAPID ADOPTION OF R-SNMOn 14 November, Axonics reported revenue from sales of r-SNM outside the US totaled $1.3m in the third quarter, up from $200,000 in the third quarter of 2018. Most of the sales have been in 32 hospitals in England, the Netherlands, Germany and Switzerland.

The first commercial r-SNM patient in the US received the device on 29 October in Irvine, CA. So far, 273 physicians in the US have attended three one-day semi-nars about r-SNM and 46 more doctors are signed up to attend a seminar in De-cember, according to Axonics.

“We now have the approvals we need to execute a full launch without limitations or any post-approval delays,” Cohen said. Axonics already has a US commercial team of 146 sales representatives, regional man-agers and clinical specialists. “Our com-mercial team now has the ability to detail

our clinical results from the pivotal clinical study, facts that we have been unable to share with physicians until [the FDA ap-proved r-SNM for both indications].”

In a 15 November note, SVB Leerink an-alyst Danielle Antalffy wrote that about a third of the physicians who have been invited to Axonics’ seminars have signed up for one. “This encouraging leading indicator not only bodes well for the Q4 sales ramp, but also speaks to the strong underlying demand of sacral neuromod-ulation therapy broadly and r-SNM’s at-tractiveness, specifically with smaller size, MRI-compatibility and rechargeability.”

Wells Fargo analyst Larry Biegelsen proj-ects Axonics’ full-year revenue will be about $8.2m in 2019 and more than $80m in 2020.

“We continue to believe Axonics’ r-SNM device has several important advantages over Medtronic’s InterStim II, which now with the overactive bladder indication, should allow the company to gain a ro-bust piece of market share in 2020.”


Roundup: XMed2019: 7 Innovators To WatchMARION WEBB [email protected]

T he Exponential Medicine (xMed2019) conference, which was held from November 4 to 7 drew researchers and innovators from all over the world to San Diego. Here are Medtech In-

sight’s top picks from this year’s show, based on our Tweets. (Also see “Device Week, 14 November 2019 – Medtech Leaders Look To The Future At XMed 2019; Abbott Names New CEO” - Medtech Insight, 14 Nov, 2019.)

VIOMENaveen Jain, founder and CEO of Viome, Inc., told the audience: “I promise you, that in the next decade, we will find a solution for chronic diseases.” Jain believes that looking at gut bacteria will pave the way. The Bellevue, WA-based start-up, which is backed by venture capitalist Vinod Kholsa and Salesforce.com co-found-er Marc Benioff, has developed a microbiome test that uses artifi-cial intelligence to identify markers for certain diseases and con-ditions. Viome’s Gut Intelligence Test is a stool test that analyzes whether the body is turning foods into good nutrients or harm-ful toxins, then offers clients personalized recommendations on foods and supplements. Some research suggests that gaining insights into gut bacteria can minimize inflammation, which is

linked to chronic conditions such as depression, anxiety and bi-polar disorder. The test can be ordered on Viome.com’s website for $149. On 14 November, UK pharma giant GlaxoSmithKline PLC and Viome announced a partnership that will develop vaccine-based therapies to help prevent and treat chronic disease.

LARK HEALTHJulia Hu, CEO and co-founder of Mountain View, CA-based Lark Technologies Inc., said her own patient experience led her to develop an AI-based text-messaging program to help patients manage their chronic conditions. “I had a misdiagnosed, undi-agnosed chronic disease for the first 25 years of my life,” Hu told the audience. After a pediatrician worked with Hu to change her diet, manage her pain, stress, medication and sleep, her chronic condition was 95% cured, she said. Now Hu wants to bring 24/7 conversational AI to others. Lark’s app was released in late 2015. After getting 1 million patients to train the “AI nurse” in research studies, Lark was able to show clinical outcomes equivalent to live nurses in their first disease state; pre-diabetes. Initial results from a pilot study using the Lark Diabetes Management Platform

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showed that after an average of four months, users had an A1c level reduction of 1.1 points, from 8.5% to 7.4%. Nearly 2 million patients use the Lark app to consult with an AI nurse via text mes-saging to manage their disease. “Because it’s conversational AI and not live nurses doing the care protocols, [it’s] much, much cheaper,” Hu said. The focus is on real-time interventions, but the app is designed to escalate to a live nurse, if triaging is needed. This year, Lark launched an AI-based program for hypertension and wellness and is working on a mental-health product. Lark partners with US health plans and employers. (Also see “Innova-tor Spotlight: Innovation Through Partnerships Is In Omron Health-care’s Blood” - Medtech Insight, 9 Jul, 2019.)

Marion Webb @medtechMarion

Lark founder said app works with AI-driven texts to coach people with chronic disease. Talks focus on what to do next, all about real-time intervention. 5 min conversations is goal. Outcomes 1.1% A1c re-duction. #xmed2019 #diabetes had 361 m texts a yr 14,833 nurse equivalent9:07 PM - Nov 2, 2019

ALIVECORIn October, Mountain View, CA-based AliveCor Inc. raised $6m in equity financing for its mobile electrocardiogram devices and announced a new partnership with Huami Corp., a provider of biometric, data-driven wearables, to develop new devices. Alive-Cor has US Food and Drug Administration clearance for its Kar-diaMobile 6L six-lead personal ECG device, an AI-enabled plat-form to detect atrial defibrillation, bradycardia, tachycardia and normal rhythm in an ECG. “It’s actual information at the point of care rather us than trying to do tens of thousands - to hundreds of thousands of dollars’ worth of tests, just searching for some-thing,” Suraj Kapa, a professor at the Mayo Clinic told the audi-ence. The device costs $150, versus $15,000 for a traditional ECG machine, and sells on Amazon.com. AliveCor performs 1.7 mil-lion ECGs a month. David Albert, founder of AliveCor, offers this advice to entrepreneurs: “Don’t lead with a press release – lead with a published study. Find a partner like the Mayo Clinic that can help you validate it.” Kardia aims to help patients and clini-cians in the early detection of atrial fibrillation, the most common arrythmia, associated with a five times greater risk of stroke.


AliveCor 6 lead ECG demo on stage #xmed2019 big-gest barrier to adoption is awareness; consumers can use this at home; Suraj Kapa Mayo Clinic12:56 PM - Nov 5, 2019

HEALTHY.IOYonatan Adiri, founder and CEO of the Israeli smartphone uri-nalysis start-up Healthy.io Ltd., told the audience Healthy.IO was built on riding the “selfie-economics” wave, leveraging built-in smartphone cameras and using AI to build the camera into a medical-grade scanner. Healthy.IO’s primary product is Dip.io, a smartphone-enabled testing kit consisting of a disposable test strip, testing cups and a colored panel to help detect infections, pregnancy-related complications and certain chronic diseases. In the UK, the company launched DIP UTI (urinary tract infection) in partnership with Walgreens Boots. “We believe in the strength of local pharmacists,” Adiri said. “They know the community.” This September, Healthy.IO received FDA clearance for its smart-phone-based test to diagnose kidney disease and plans a US launch in 2020. The company leveraged part of its $60m series C funding round (closed in September) to put in place its US lead-ership team: general manager, Paula Leclair, and Mark Becker, VP of chronic wound management, another area of interest for the company. (Also see “US FDA Clears Smartphone Urine Test For Kidney Disease” - Medtech Insight, 12 Sep, 2019.)


Healthy.io founder shows urine test at home FDA cleared; Yonatan Adiri #xMed2019 ... get list of people who have not done detection of CKD test; study showed 72% adherence when people do it at home; product available in UK1:10 PM - Nov 5, 2019

CIRCADIA HEALTHFarés Siddiqui, co-founder and CEO of Circadia Health, demoed the company’s contactless breathing monitor, which measures and analyzes a person’s respiratory rate and sleep data using ul-tra-wideband radar technology combined with AI. Circadia’s goal is to prevent hospitalizations and reduce hospital readmissions through early prediction and diagnosis of respiratory disease, in-cluding chronic obstructive pulmonary disease and neurological and sleep disorders. The company plans to submit an applica-tion to the FDA for 510(k) clearance of the device next month. If clearance is granted, it will market the device and a physician portal and patient app for home use and in health-care facilities. So far, Circadia has raised $1.1m in pre-seed funding from venture firms Village Global, SOSV, Centre Gold and Particular Ventures and five angel investors, and hopes to raise another $3m in seed funding in early 2020 to fund clinical trials, said David Maltz, man-aging partner at consultancy firm Intervalent and a member of Circadia’s board of directors.

BRAIN4CAREBrazilian health-care company Brain4Care received FDA clear-ance on 17 October for a non-invasive device to monitor varia-




Medtech Insight: What prompted you to join IBM Watson Health?

Ted Tanner: I’ve had a lot of exits, and I’ve also worked at Apple and Microsoft … [when people ask] What brought you to IBM? The Red Hat acquisition [IBM bought open- source software company Red Hat in July 2019], because mainly I be-lieve that the future is open-source distributed AI everywhere. They’re doing some amazing things long-term in the area of quantum computing, and they’re a big proponent of open-source software. They’re doing some great stuff with AI as well.

So, while I didn’t really intend to go back into health, the offer to be the global CTO and chief architect at Watson Health was, as I thought about it [highlighted by the fact that] we just came back from HLTH (digital health conference in Las Vegas) – Uber, Lyft, Facebook, Google, Amazon – all the technology compa-nies were there. I think with the advancement in genomics and molecular pharmacology and protein engineering, the health sector is where it’s at as far as science is concerned. I believe that IBM Watson Health has all the pieces and parts, with the Red Hat acquisition and quantum computing pushing behind that – for instance, Red Hat has 10 million developers support-

tion in intracranial pressure waveforms in patients with sus-pected alteration of intracranial pressure and brain compliance. Claudio Menegusso, Brain4Care’s US country manager, said that traditional access to the waveform requires drilling “a hole on your skull and putting a sensor inside your head.” Brain4Care of-fers “a headband [where] you position the sensor on your head to expose the waveform.” The company plans to conduct more clinical studies to further validate the device before launching it in the US in 2022. A wireless version of the device has been grant-ed approval by medical-device regulator Anvisa in 2018 in Brazil, where it is currently used in nine hospitals. Brain4Care’s business model in Brazil is a monthly subscription per center. In the US, the device will also be subscription-based, said Menegusso.

UNEEQDanny Tomsett, CEO of UneeQ, introduced the concept of a “digi-

tal human” to help improve health outcomes. “The digital hu-man is built with all the emotional intelligence, but it needs to be plugged into a knowledge domain; and that is where the opportu-nity lies for creators,” Tomsett said. The goal is not to “trick people into thinking this is human,” but to take out the judgment that often goes hand-in-hand with human interaction. UneeQ works with mental-health organizations, youth groups and in pre- and post-operation care. “What the digital human is all about is emu-lating body language, emotional understanding, speech and time and conversation,” he said. In a children’s hospital, for instance, a digital human may augment the medical staff by helping children with anxiety issues and create a fun and interactive experience. A digital human health coach can be used to ask patients questions about their health and well-being and provide feedback.


Exec Chat: XMed2019: How IBM Watson Health’s CTO Uses Blockchain To Eliminate ‘Friction Points’ In Health CareMARION WEBB [email protected]

T ed Tanner, who joined IBM Watson Health in February, doesn’t mince words about the dichotomy in

health care and its slow embrace of tech-nology. While hospitals deploy some of the most advanced technologies to di-agnose and treat patients, Tanner said as an industry, health care is due for a major “behavioral shift.”

“There’s been all of these intermediar-ies in the space of health tech and the way that we operate in a 90-to-180-day float system. When you go to the doc-tor and you have a claim filed, a piece of paper shows up 180 days later with how

much it costs. Is there any other indus-try where that happens?,” Tanner told Medtech Insight.

According to the 2017 report by the Health Information Management Society, 35% to 45% of all health-care data is un-encrypted; 80% of health-care errors are due to miscommunication; and in 2015, 15 billion faxes were sent.

These are among the many “friction points” that Tanner wants to address with small steps and by listening to the needs of health-care providers. He plans to continue expanding IBM’s Health Util-ity Network, a consortium of multiple

health-care organizations, including in-surers Anthem, Cigna and Aetna, Sentara Healthcare, PNC Bank and the Health Care Service Corp., dedicated to developing a blockchain-based network that allows for the seamless, yet highly secure, exchange of information to reduce administrative errors and friction.

Tanner, a proud “tech geek” and en-trepreneur, co-founded PokitDot, a plat-form-as-a-service company that focused on streamlining data operations in health care that was bought by Change Health-care in 2018. He also held architect posi-tions at Apple and Microsoft.



ing their platform. I believe gaining the developer mind share is totally where it’s at in technology. If you look at Google, Apple and Microsoft, they completely focus on developer-first, and I think IBM has the pieces of the parts and with the multiple acquisitions in the health-care space and the data, that’s what attracted me to Watson Health.

IBM Watson had some significant challenges, right?

Tanner: Like every other company. At Microsoft, this is their fourth time in the health-tech space. People tend to forget the train wreck that was HealthWallet. I was there. It’s a be-havioral issue. It’s not a technical issue.

A behavioral issue. Can you explain a little bit more what you mean by that?

Tanner: Absolutely. The methodologies associated with health are by definition distributed. It’s network, it’s by proxy – meaning that health affects people. Other technical indus-tries like aviation or ad tech or telecommunications – you can take the human out of that and optimize it, but the center of the universe in health is the person. So, we need to have a be-havioral shift, especially with the way that the United States health system is being run. We need to have a shift in con-necting the provider to the consumer in a frictionless fashion. There’s been all these intermediaries in the space of health-tech and the way that we operate in a 90-to-180-day float sys-tem. When you file a claim – when you go to the doctor and you have a claim filed – a piece of paper shows up 180 days later with how much it costs. Is there any other industry where that happens? There’s too many friction points for a health transaction, and that’s what I mean by behavioral versus tech-nology. Let me run down some statistics that I think are just astounding. They’re mind-blowing. Thirty-five to 45% of all data in health is unencrypted [according to a 2017 report by the Health Information Management Society]; Eighty percent of health-care errors are due to miscommunication – think about that – 90% of all data goes unused in health because of all these so-called checks and balances. We’ve complied our-selves to death in the health space, and so your data is locked up somewhere and can’t be used for you. You see the problem there? With HIPAA and all these other compliances, we’ve put ourselves in a cage. And here’s the most mind-blowing one: in 2015, there were 15 billion faxes.

So, what does this all mean to you, to your work at IBM Wat-son Health?

Tanner: Well, I kind of compare it to the autonomous car in-dustry. We have to do slightly better than humans. Humans really can’t drive cars that good. Everybody says, “Oh my god, that car’s driving itself. I hope it doesn’t wreck.” But they don’t show the footage where the autonomous car stopped and

predicted a wreck four cars up. They don’t show any of that footage, right? It’s a red herring. I’m over genomics, pharma-cology, payer-provider and imaging. We have offerings in all of these areas. The consumerism of health care is happen-ing right now. I want to start with just the pragmatic, small wins. I also get asked this for AI as well: “What do we do for AI?” Well, start very narrow. We’re using AI to augment the health-care provider, not predict world peace and mankind, prosperity and everything. We are using it to augment and scale the health-care provider. What I tell everybody is “pick a very tractable thing that you already know the performance of, and add AI and scale it. Make it happen faster. Make it read documents. Have it come up with recommendations for drug interactions. Help the physician make faster decisions in the moment.” So, what I plan to do is start very small and trac-table with very minor wins that seem minor but scale greatly. So, getting the right infrastructure in place, getting the right roads in place.

We literally have what I call a ‘roads-and-rails problem’ in health. We want to bring that experience to health care. Fric-tionless transactions. But you have to start somewhere. Every-body says, “Well, it’s too large. I can’t.” And one of the main things in software is execution. Get something running so ev-erybody can agree to it. This is also the promise of blockchain technologies because by the very nature, getting multiple parties to agree to the same rule sets is very important. The right type of claims, the right type of medical outcomes, the right type of rules, the right type of identity. Getting that con-sensus in the health industry is paramount for success.

It’s amazing – the amount of inertia in a 40-to-50-year-old industry – if you think about the banking industry. PayPal happened to the banking industry. We haven’t had a PayPal event yet in the health industry, but everybody sees that they don’t want a PayPal event happen to them. You see the di-chotomy there? [IBM created a blockchain-based utility net-work to join broad ecosystems of health-care organizations in a secure, shared environment]. The Health Utility Network is a consortium of like-minded companies, payers, providers, technology companies [such as Aetna, CVS, Cigna, Sentara Healthcare, Anthem, Health Care Service Corp. and PNC Bank] that are coming to consensus in a blockchain environment that are saying we want to change the paradigm. It’s the first time I’ve ever seen the health industry not give the industry lip service but actually put pen to paper and agree to certain metrics and execution of transactions.

Can you offer some examples?

Tanner: Bundled payments. Identity. Provider-search di-rectories. Finding where your general practitioner moved to, just fundamental things. We have to start somewhere with wins that we can all agree to and say this is reducing cost. Because it’s not about revenue generation; it’s about cost reduction.




Can you talk a little bit about the role of interoperability?

Tanner: I say, by definition, smart contracts are in place in interoperability. What I mean by that is if you have a distrib-uted network where you have devices connected that are secure – one of the things that blockchain does for security is with respect to the 35% to 45% I just talked about – you cannot do a transaction on blockchain unless it is com-pletely secure. This is not like bitcoin blockchain. This is en-terprise-level blockchain, which is called permission block-chain, meaning I know who’s on the network, I know who’s transacting, and you are encrypted. All the transactions are encrypted both on and off chain. So, when you connect a device, you know exactly how it’s connected. You know ex-actly how it’s authorized and even what it is authorized to transmit with an identity. It’s like having that device person-alized on steroids for you. The amount of security metrics in a permission chain are far beyond what’s available in a regular health IT network.

How do you expand this network?

Tanner: Well, right now the Health Utility Network supports about one-third of the United States from a numbered-lived standpoint. We’re starting small, and the goal is to have a borderless trust protocol worldwide, where you actually branch out worldwide. We’re going to bring in new mem-bers as we get things running, and we’re going to publish the protocol, so other people can support it. We’re planning on the use cases, some of the use cases I just mentioned, ac-tually being deployed next year in production. It’s augment-ing the current rails so we can fade over to a new paradigm. It’s not a rip-and-replace thing. It’s not like we’re going to rip everything out, because these companies have spent mil-lions and billions of dollars on their current infrastructure. We see a lot of the sunk-cost argument happening in health care, which is very different than the tech world that I’m used to. They’re still holding onto a traditional way of do-ing business, and you have to run these things in parallel to show improvement.

Can you talk a little bit about where you see the biggest us-ages of AI in the medical device industry as a whole?

Tanner: There’s a behavioral side in the industry and the behavioral side on the consumer. It is very difficult to change people’s behaviors. You can have the quantified-self indus-try started, what, 10 years ago? Everybody put on their Fit-Bit and Jawbone device, they used it for a week and said, “Okay, I still want to eat a donut.” This is a pragmatic prob-lem because there’s a saying in the tech world, “I have 101 problems and all of them are alerts,” so having a device alert you to something is nothing more than noise. We need to work closely with health-care providers to find the right fit

of AI and scale it accordingly. That’s why I use the word “aug-ment.” Augment the care provider because most of them are burned out. I’m more in a listen mode than I am a tell-ing mode now. I want to hear what the health-care provider has to say versus saying, “Here’s a new algorithm, here’s a new widget, to help you.” When in fact, it is my volition that they’re over that. They want to take care of that person, get them well and get them on their way.

Is there anything that you wanted to add? Are there any other projects that we haven’t discussed that pertain in particular to the medical device industry?

Tanner: I think we’re going to see in the future with re-spect to genomic editing and some of the pharmacological molecular derivatives, we’re going to have adaptive device structures personalized for the consumer. Basically compu-tational biology at the device level. But that’s a much longer interview.

Since we’re at a conference, have you heard anything in the last day and a half that struck a chord with you or were you thought, “Yeah, this could be a potential partner,” or an inter-esting new development or trend?

Tanner: You know, I find it interesting, having worked in the original wave of virtual reality in the early ‘90s, I’m interested to see how spatial computing is applied to the medical in-dustry. I’m deeply interested in the aspects of programmatic editing for the genome as well. I think between the genomic editing and the molecular derivatives at the pharma individ-ual level, we’re going to see some amazing strides, as well as where literally they’re asking “what is a device?” Basically what I’m saying is what a device looks like is going to be very differ-ent at the individual layer. It’s going to be very different in the future. It’s not going to be something we can look at, per se.

What could it look like?

Tanner: Your skin. A blood vessel. It could be injectable. It’s going to take many different deployment modes. Miniaturiza-tion is at scale is going to be the future of devices, as far as I’m concerned. The time to be in health tech is now. I hope people listening or reading your column just go create more amazing things. The information theorists have arrived now. The geeks won, which I’m happy about. Go push the envelope.


LET’S GET SOCIAL@Medtech_Insight


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FDA Advisory Panel Debates Science On Human Adverse Biological Reactions To Metal-Containing DevicesSUE DARCEY [email protected] ELIZABETH ORR [email protected]

A t a recent US Food and Drug Ad-ministration Immunological De-vices Advisory Panel meeting,

agency and outside scientists explored the risks of human sensitivities and immu-nological reactions to implanted metal de-vices in an effort to better protect patients from any harms caused by the devices.

“Recent issues with metal-on-metal hips and gynecological metal implants have heightened concerns about safety,” Stephen Weber, a medical officer in the FDA device center’s Office of Device Eval-uation (ODE), told advisory committee members in a 13 November presentation, held on day one of the two-day panel meeting in Gaithersburg, MD.

“Physicians who suspect adverse reac-tions to metal debris that are systemic should do a workup with history, a physi-cal, and readings of metal ion levels via MRI or ultrasound,” he said.

The FDA requires materials tests to check for sensitivities, including the guinea pig maximization test and the mouse local lymph node assay, but these diagnostics may only reveal der-matological allergic reactions, said Jen-nifer Goode, a biocompatibility program adviser with the FDA’s Office of Product Evaluation and Quality (OPEQ), within the agency’s Center for Devices and Ra-diological Health (CDRH).

The FDA’s immunotoxicity guidance recommends that manufacturers con-sider testing for hypersensitivity, auto-immune sensitivity, immunosuppression and autoimmunity when immunological effects are seen, she added.

SENSITIVITIES TO METAL HIPS, ESSURE COILS PROMPT CONCERNSReasons behind the meeting included the FDA’s response to widespread con-cerns from female patients about adverse systemic reactions many experienced

after being implanted with Bayer’s Es-sure sterilization device, which consists of metallic coils made of nitinol. Their concerns were amplified four years ago by individual women and patient groups at a heavily attended FDA public hear-ing in September 2017. (Also see “Essure Panel Stresses Need For Patient Follow-Up, But Stressed-Out Patients Say, ‘Recall It’” - Medtech Insight, 28 Sep, 2015.)

The device has since been withdrawn from the market by the manufacturer (ex-cept for existing Essure devices already purchased by surgeons), and the FDA sent a notice to orthopedic surgeons re-cently to remind them to return remain-ing stockpiles of the devices to Bayer by 31 December. (Also see “Clock’s Ticking: FDA Says It’s Almost Time For Health-Care Professionals To Return Essure Devices To Bayer” - Medtech Insight, 5 Nov, 2019.)

The agency also continues to deal with the fallout from patients experiencing an array of adverse systemic effects from be-ing implanted with metal-on-metal hips. Johnson & Johnson/DePuy recalled all of its metal-on-metal hips in August 2010

following scientific findings that the hip can corrode over time, leading to several systemic effects in patients. (Also see “J&J/DePuy Recalls ASR Hip Systems - Effort Could Cost $1.2 Bil.” - Medtech Insight, 30 Aug, 2010.)

While FDA stopped short of declaring a ban on metallic orthopedic devices, con-tinued adverse patient reactions to metal-on-metal (MoM) hips causing problems in patients implanted in the last 15 years prompted the agency to make manufac-turers submit stricter PMA applications to win approval for new MoM hips. That effort began in spring 2016. (Also see “ US PMAs Are The New Reality For Metal-On-Metal Hips “ - Medtech Insight, 18 Feb, 2016.)

CLINICAL RESPONSES TO METAL IMPLANTS CATALOGUEDFDA medical officer Weber and Ben Fisch-er, director of CDRH’s Office of Health Tech-nology 3, emphasized at the meeting that allergic contact dermatitis is the primary clinical manifestation of patient reactions to implants, including metallic hips, Essure coils, and some metallic cardiac devices. Nonetheless, systemic adverse reactions

Metal-on-metal hips have injured patients




to metal debris that can corrode from de-vices over time are also seen, they said.

“Gender appears to be associated with significant differences in the biological response to some implants,” Fischer said. “There is a higher susceptibility [to metal sensitivity] in women, and that may have influenced the failure of gynecological metal implants.”

Fischer catalogued some of the sys-temic effects of the Essure implants that FDA scientists have recorded, based on the reports of female patients implanted with the devices, in the following chart: *Raynaud syndrome occurs when spasms of arteries cause reduced blood flow in fingers, toes or other parts of the body

These and other adverse responses de-scribed by patients as reactions to implant-ed metals are more symptomatic of metal debris-systemic effects, which are not syn-onymous with true allergies, and have the following characteristics, the duo said:

1. Cardiac, neurological and thyroid effects;

2. Effects are not always reversible with implant removal, and symp-toms may not disappear; and

3. Cancer risks are not shown or proven by existing registry studies.

EFFECTS OF COBALTISM EXPLAINED BY HARVARD PROFESSOR Another effect, cobaltism, can sometimes be seen, and can lead to organ failures. Cobaltism, thought to be caused by met-al hip implants, was evaluated by exam-ining a series of case reports describing temporal association with multiple-or-gan metal toxicity, said Young-Min Kwon, associate professor of orthopedic surgery at Harvard Medical School in a 13 Novem-

ber presentation on biological reactions to orthopedic hip implants.

Neurologic, endocrine and cardiac tox-icity were seen in case reports of patients who underwent metal-on-metal total hip arthroplasty, according to Kwon. Some had cobalt serum levels of 15-112 mcg/L, and optic atrophy and cardiac dysfunc-tion. However, the studies are limited to case reports, and further studies are re-quired, he added.

Kwon also enumerated implant, sur-geon and patient factors as leading to adverse local tissue reactions (ALTR) in patients . An example of an implant fac-tor would be MoM hip designs, while surgeon factors could be exemplified by impact of the metal hip assembly, which can cause deformation of the taper on an artificial hip, or contamination.

Activity level of the patient – such as a higher-than-normal body mass index or high activity levels – could also influence ALTR effects, Kwon said.

MERCURY IN DENTAL AMALGAMS SUSPECTThe FDA has long been concerned about any impacts of mercury from dental amalgams, and conducted reviews and assessments of the literature on effects in 2009, 2010 and from 2012-2014. The agen-cy is currently working on a new review, said Michael Adjodha, acting assistant di-rector of CDRH’s restorative and surgical dental devices team.

Agency scientists on 13 November pro-vided presentations on potential biological adverse impacts of mercury, a heavy metal, in amalgam, but primarily said that despite a few studies suggesting adverse effects, there is no consistent evidence that dental

amalgam-attributed mercury causes clini-cally manifested adverse outcomes.

Yet there has been some suggestion that specific subpopulations may be par-ticularly susceptible, said Yelizaveta “Lisa” Torosyan, a health scientist in CDRH’s Of-fice of Surveillance and Biometrics. For example, she said, risk assessments of dental amalgam safety have been com-plicated by interindividual variability and enhanced susceptibilities in a few patients.

Torosyan also noted that unaccounted for exposures to mercury, such as those from people whose dietary and cultural traditions lead to eating a lot of fish con-taminated with mercury, or exposure from mercury pollutants near waste-burning plants, can make it difficult to tease out how much of an impact mercury vapors from dental amalgam may have.

In addition, within populations that consume fish, measurement of total mer-cury loads in urine may overestimate mercury exposures due to demethylation of the substance in human tissue, said Al-fred Franzblau, a physician and professor at the University of Michigan’s School of Public Health. Like Torosyan, he empha-sized that more in vivo study of the im-pacts of dental amalgam are needed.

PANEL SUPPORTS MOVE AWAY FROM MERCURY FILLINGSUltimately, during 14 November discus-sions, the immunology devices panel backed a transition away from mercury amalgam dental fillings and pushed for more research into risks associated with metal implants.

The recommendations came after an emotional open public hearing, during which a dozen speakers argued that mer-

GENERAL GYNECOLOGICAL MUSCULOSKELETAL IMMUNOLOGICAL NEUROLOGICAL OTHER

Fatigue Pelvic pain Joint pain Alopecia Headache Nausea/vomiting

Weight change Menstrual irregularities Lower-back pain Rash Migraine Chest pain

Mood swings Hot flashes Leg pain Hives “Brain fog” Diarrhea

Irritability Breast changes Muscle weakness Raynaud syndrome* Depression Palpitations

Sweating Menopause Memory loss Tooth loss

Fever Cysts Vertigo

*Raynaud syndrome occurs when spasms of arteries cause reduced blood flow in fingers, toes or other parts of the body



cury dental amalgams should be phased out immediately, especially when used in pregnant women, children and other vul-nerable populations who receive dental care via public health programs such as Medicaid. Several of the speakers argued that the risks were heightened because people who live in disadvantaged com-munities historically have more exposure to environmental toxins and pollutants, leading to chronic diseases. Mercury amal-gam fillings, they said, add to that burden.

“Mercury amalgam is an ethical prob-lem, particularly as it impacts children of color,” said Rueben Warren, a dentist and the director of the Tuskegee University National Center for Bioethics in Research and Health Care.

Further, public hearing presenters ar-gued that the FDA has failed to follow both international precedent and previ-ous advisory panel recommendations in allowing mercury amalgams to remain in use. The agency down-classified den-tal amalgams from high-risk class III to class II in 2009, and hasn’t taken further regulatory steps despite repeated safety reviews. (Also see “FDA Will Review Safety Of Dental Amalgams In Light Of New Data” - Medtech Insight, 20 Dec, 2010.)

In general, the lack of readily available in-formation on amalgam safety is a problem, the speakers said. For example, surveys have repeatedly found that most Ameri-cans with dental fillings do not know that mercury is the primary metallic component.

“Absent patient labeling or patient warn-ings, neither physicians nor their dentists are in any position to discuss the risks of mercu-ry fillings,” said Sylvia Dove of the Consum-ers for Dental Choice. The group advocates for a ban on mercury fillings in the US.

Brittany Seymour, an assistant professor at the Harvard School of Dental Medicine, argued that social media sites have spread a false narrative about the safety of dental amalgam. The mercury compound, she said, has been a leading material used to treat tooth decay for 150 years with a low rate of allergic reactions. International ex-pert groups have found no evidence show-ing dental amalgam is unsafe, she added.

“There’s no universal substitute for dental amalgams available, and the sub-

stitutes that do exist are more costly,” Seymour said. “Any change in the FDA’s recommendations would have harmful effects, including exacerbating differenc-es in access to care.”

FEW ANSWERS ON METAL IMPLANTSPanelists on 14 November also said the FDA needed to gather much more information on metal implant patient outcomes be-fore making any safety recommendations. Specifically, the panelists suggested that a large prospective cohort of joint replace-ment patients could help tease out any commonalities among patients who expe-rienced adverse events. Current registries and other patient datasets aren’t large or detailed enough, they said.

“To study such a rare occurrence, we would need a large cohort,” said Nicholas Giori, professor of orthopedic surgery at the Palo Alto (CA) Veterans Affairs Health Care System.

To narrow the amount of data required, some panelists suggested starting with patients with known risk factors. Oth-ers recommended further research into underlying genomic science around re-sponses to metals.

Panelists agreed that known risk factors in metal implant patients include female gender, osteoporosis, age and the use of certain drugs such as antidepressants. Additionally, panel chairman Raj Rao said more research is needed into systemic re-actions to metal implants.

“A local inflammatory response clearly occurs,” George Washington School of Medicine professor Rao said. “But we do not have a scientific weight of evidence behind any systemic response. But given clinical and anecdotal evidence, that may be an area for further study.”

Additionally, panelists noted that devic-es that shed more debris inside the body, especially cobalt chrome debris, are more likely to cause adverse reactions. Other device-related factors identified by the group include the specific alloy composi-tion and the presence or absence of any coatings. Making information on what in-gredients a device contains more readily available to patients and physicians could

help avoid sensitivities, they said.Michael Pollard, an associate profes-

sor at Scripps Research Institute, drew an analogy to his own allergy to mushrooms.

“I know to ask whether sauces and things have mushrooms, but even if a patient knows they have a metal allergy and asks to look at the [implant] label, the doctor might not even be able to help them,” he said. “I can ask the chef, but does the patient even know who to ask?”

DENTAL AMALGAM PHASE-OUT RECOMMENDEDThe panel was more solid in its recom-mendations on dental amalgams, saying the country should shift away from their use when alternatives are available. But the FDA’s role in that shift may take fur-ther discussion to determine, they said.

“What is really compelling is that there is a disproportionate accumulation of mer-cury in the bodies of the disadvantaged, and there continue to be problems with health disparities,” said Michael Weisman, chair in rheumatology, Cedars-Sinai Medi-cal Center, Los Angeles. “Mercury amalgam should probably be on its way out. How to deal with that as far as the FDA is concerned should be a matter of discussion.”

Panelists were particularly concerned about the use of amalgams in children and pregnant women, suggesting those vulnerable groups could be told of poten-tial risks as soon as possible. For example, Melissa McDiarmid, professor of medicine at the University of Maryland School of Medicine, suggested the agency might want to issue a warning even if there wasn’t a scientific basis for taking dental amalgams off the market.

“Surely there could be a risk message that the FDA could say that we aren’t talking about taking amalgams out of people’s mouths, but we need to stop planting them in particularly vulnerable populations,” she said.

But other panelists urged caution, not-ing that overreaction to an FDA warning could also be harmful. For example, the risks of dental amalgam removal also are unknown.





A Softer, Gentler FDA Inspectorate? It’s Possible With QSR/ISO 13485 Harmonization, Auditing Expert SaysSHAWN M. SCHMITT [email protected]

L et’s be blunt: Device-makers aren’t particularly happy when the US Food and Drug Administration knocks on their door to conduct a facility inspection.

From audits that can sometimes drag on for weeks – with agency investigators traipsing in and out of plants – to nightmar-ish inspectionswell-documented by industry experts, there’s no shortage of tales of investigators that were difficult to handle.

But now, with the FDA in the middle of a harmonization effort to merge its 23-year-old Quality System Regulation (QSR) with international standard ISO 13485, one industry expert says that work will likely make the agency take a more wide-eyed look at how it operates its inspections and oversees its inspectorate.

The FDA’s QSR has been the bedrock rule for manufacturing safe and effective medical devices to be sold in the US since 1996. Meanwhile, ISO 13485:2016 is used by device firms to en-sure quality systems compliance with regulators in a variety of countries, including Canada, Japan, Australia and the 28 member states of the EU. Much of the QSR already aligns with ISO 13485.

“With the advent of MDSAP … and FDA’s ISO 13485 harmoni-zation work, I have to believe that internally at the agency there must be some discussion of, ‘Hey, do you know how we look to the public when we inspect?’” said Brian Ludovico, executive di-rector of MDSAP regulatory certification for NSF International.

MDSAP, created by the International Medical Device Regulators Forum (IMDRF), allows firms to undergo one audit by an accred-ited third party to satisfy quality regulations for the US, Canada, Brazil, Japan and Australia. MDSAP maps to ISO 13485. (Also see “MDSAP Is A Snap If Your Firm Follows Quality Systems Standard ISO 13485, Auditor Says” - Medtech Insight, 31 Jan, 2019.)

Auditing organizations like NSF are used to conduct MDSAP audits, and auditors traditionally tend to be more collaborative than FDA investigators. But that’s because the FDA is ultimately an enforcement agency, Ludovico said on Oct. 24 at FDAnews’ 14th Annual FDA inspections Summit in Bethesda, MD.

“If you let companies run wild, they’ll run wild, so there has to be that enforcement hammer in the form of the FDA,” he said. “But with this upcoming harmonization of the QSR with ISO 13485, you’re probably going to see within the agency some sort of understanding of, ‘Look, this is how they do [audits] through-out the rest of the world.’”

Ludovico went on: “MDSAP is a compliance-based, proactive, innocent-until-proven-guilty system – not a seemingly guilty-until-proven-innocent system” like the FDA has.

For example, when an agency investigator collects data during an inspection, “the attitude is, ‘I’m going to dig and dig and dig and dig, and when I feel like I finally can’t find something, then I’ll release you from questioning’ – versus an MDSAP audit, where the auditor will

say, ‘I’ve checked a sample size and it doesn’t fit within that popula-tion. Mathematically and statistically, we’re OK here. The onus is back on you that you don’t do something nefarious, so to speak,’” he said.

“So, I think the harmonization efforts will soften FDA’s inspec-torate – but there isn’t something yet that’s outward that we can see,” Ludovico said.

To its credit, the agency has been more open lately to learning from other regulators.

More notably, Jeff Shuren, director of the FDA’s Center for De-vices and Radiological Health (CDRH), said in September that he wants the agency to move away from using the phrase “gold standard” when referring to their device regulations.

“I would not view us as the gold standard; we’re merely a stan-dard out there,” Shuren said at the 2019 MedTech Conference in Boston, MA. (Also see “US FDA Toying With Idea Of ‘Regulatory Legos’ In MDUFA V” - Medtech Insight, 1 Oct, 2019.)

But when it comes to inspections, there may be some resis-tance by investigators to change in the wake of a retooled QSR.

That’s according to Kristen Grumet, a former FDA investigator who is now senior VP of regulatory compliance with consulting firm Greenleaf Health.

“It’s hard to change the mentality,” she said at the Inspections Summit. “If the agency brings in new people to be investigators and trains them with that new QSR/ISO 13485 mentality, then maybe it can happen. But it’s more difficult for an investigator who’s been doing the job for 20 years to change how they do things. So, it might take a while.”

A CHANGE FOR QSIT POST-HARMONIZATION? Both Grumet and Ludovico say that after the new Quality System Regulation – or whatever it is ultimately named – goes into ef-fect, agency investigators may operate under a hybrid FDA/au-diting organization approach.

That would call for an update to the FDA’s Quality System In-spection Technique, Grumet said. QSIT is designed currently to make sure that investigators look at the most important com-



FDA Issues Final Export Certificate Guidance, Explains What To Do If Your Firm Is Turned Down For OneSHAWN M. SCHMITT [email protected]

A final guidance from the US Food and Drug Administra-tion lays bare reasons why the agency would deny an ex-port certificate to a company. It also explains how a firm

can appeal if it is turned down for a certificate.The eight-page guidance, “Process to Request a Review of

FDA’s Decision Not to Issue Certain Export Certificates for Devic-es,” was released by the FDA on 13 November but carries a date of 14 November. It is nearly identical to the draft version of the document, released in August 2018.

The guidance was developed because the FDA Reauthoriza-tion Act of 2017 – FDARA – required the agency to provide a ra-tionale when it turns down a request for a Certificate to Foreign Government (CFG), including listing any specific grounds for a finding of noncompliance.

A CFG grants a company permission to export its product. The final guidance says the agency can deny an export certificate if:• There is an injunction or seizure action against the firm;• The device is the subject of a class I or class II recall; and/or• The company is out of compliance with the FDA’s Quality

System Regulation.When the FDA denies a CFG, it will provide the requesting com-

pany with a written explanation of the reasoning; if the reasoning involves good manufacturing practice (GMP) issues, the agency will provide a “substantive summary” of the grounds for noncompliance.

“Within the summary, FDA will describe the major noncompli-ance issues that are the basis for the denial and associated refer-ence to the Quality System Regulation,” the guidance says. “FDA does not intend to deny a CFG for an establishment with a No Action Indicated or Voluntary Action Indicated classification for the most recent quality system inspection.”

The guidance further says the agency won’t deny CFGs just because a particular device was manufactured in a facility that received an FDA-483 inspectional observation form – as long as the FDA and the company agree on a so-called “plan of correc-tion” – aka, an FDA-483 response.

A plan of correction should “include documentation demon-strating the corrective/preventive actions that have been taken and/or will be taken,” the guidance says.

The agency goes on to say in its document that it will respond

to a firm’s plan within 90 days. “If the plan is determined to be sufficient … FDA will issue a CFG,” the document notes.

HOW TO APPEAL There are two ways for companies to appeal when a decision from the FDA doesn’t go their way.

One way is for a firm to appeal within 60 days. It must send an email to the agency that includes:

• A subject line that states: “Request for Review of FDA’s Decision to Deny a CFG,” and includes the CFG application number;

• The name, title, firm, address, phone number and email ad-dress of the person submitting the request;

• The name, address and FEI number of the establishment for which the CFG was denied;

• A clear reference to the inspectional observation(s) as noted in the substantive summary of the denial; and

• Information demonstrating why the request for CFG should not have been denied, referencing previously submitted documentation.

Or, the company can appeal by presenting new information to the FDA that could sway its decision.

“A request for review of new information pertaining to a CFG denial should include the same information” that is listed above, the guid-ance says. However, the email subject line should read: “New Informa-tion – Denial of a CFG,” and include the CFG application number.


pliance issues and ask pertinent questions linked to four major quality system subsystems: management controls, corrective and preventive action (CAPA), design controls, and production and process controls.

“For QSIT post-harmonization, the language may change, the terminology may change, the flow may change,” she said. The

agency “will probably add additional questions and other things [to QSIT] to make sure that things are looked at appropriately.

“But I don’t think it will have to change much. It just needs to be massaged.”





A COMPLIANCE 360° Q&A

Process Validation Can Be Problematic For Device-Makers. Here’s Why – And What Companies Can Do About ItSHAWN M. SCHMITT [email protected]

D evice-makers often fall down when conducting process valida-tion activities because they fail to

continually monitor their processes, an industry expert says.

“One of the main reasons why FDA continues to cite process validation on FDA-483 [inspection observation forms] is due to a lack of continuous verifica-tion of a validated process,” said Ricki Chase, compliance practice director for Lachman Consultant Services and a for-mer FDA investigations branch direc-tor. “People tend to set it and forget it,

not understanding that a process must be monitored to ensure that it remains within a validated state.”

Chase also links poor process validation to product recalls.

“Most often, when you see a recall has been issued for a device, it’s because the process either wasn’t validated, wasn’t validated correctly, or was allowed to drift from the original validation param-eters,” she told Medtech Insight. “Process validation is critical to the quality – and therefore potentially the safety – of those devices you manufacture.”

Medtech Insight: Process validation expectations have been known to industry at least since the FDA’s Quality System Reg-ulation was enacted more than two decades ago. So why does this topic continue to perplex some manufacturers and need to be revisited?

Ricki Chase: You know, the change in technology is a lead-ing reason why process validation topics need to be revisited. With the changing technology and changing design comes more advanced processing activities. And these activities need to be evaluated to determine the best and the most ef-fective means of the process validation. This may mean think-ing outside of the normal expectations. For example, three process qualification [PQ] runs are no longer an acceptable standard to demonstrate that a process has been validated.

Instead, the expectation is that the number of PQ runs to demonstrate process validation should be based on statistical evidence and scientific rationale. A highly complex and/or a difficult to control or monitor process may require more than three runs to consider it validated.

So what does the FDA say about process validation that indus-try should know?

Chase: Well, I think that there’s been some change in the thought process behind process validation. For instance, the concepts of design of experiments (which should be used in operational qualification), risk assessment as a basis for vali-dation decisions, and sampling criteria are all concepts that

FDA expects to see when reviewing your process capabilities. Random selection of your sample size, or a random se-

lection of the number of process qualification runs, quan-titative acceptance criteria, and review and revalidation timeframes is just not acceptable. FDA will be looking to determine how familiar you are with your processes and how you know that they’re remaining in control. A solid risk assessment in scientific rationale should be the basis for all decisions being made in the quality system, including those surrounding process validation.

Is the expectation for software validation and the role it plays in processes new?

Chase: No. The expectation for software validation is not a new concept. The review of software validation by FDA investigators has become more robust as the investigators have become more familiar with software, with software val-idation, and potential weaknesses that software can present in a quality system. But data integrity is nothing new. The expectation has always been that demonstrable evidence is required to prove that data are accurate and maintained as part of the device history record. It has also been a require-ment that software, used for instance in PLCs – or Program Logical Controllers – on manufacturing equipment, and software used to maintain quality systems data is validated for its intended use and purpose.

The difference here is that now the FDA investigators are savvy, and they’re well trained, and they know how to chal-

“Process validation

is critical to the

quality – and therefore

potentially the safety –

of those devices

you manufacture.”

– Ricki Chase



lenge your systems, and they know how to determine if you have adequately validated the software you’re using. And with that said, the validation parameters have changed with changing technology. Specifically, the amount of digi-tal data and the housing of that data has really changed. Now terabytes of data can be stored on local hard drives and servers, and we have cloud computing, which has opened the door for new and serious concerns regarding cybersecurity. Validation, particularly of software control-ling and housing quality data, must demonstrate that the data is safe from manipulation, theft, destruction, data malware or security breaches.

More and more device firms are operating in a virtual universe. That is, they’re employing multiple contract manufacturing or-ganizations that play a role in the total product life cycle man-agement. How does this relationship affect process validation?

Chase: Well, the contract manufacturing organizations [CMOs] are an extension of the manufacturing process. Now, however, with that said, the ultimate responsibility for the design to meet specifications for safety and efficacy always remains with the device owner. Now, the owner and the CMO must work together to ensure that the process and the meth-ods are validated in such a way to support the device design. This could mean that the CMO is responsible for the process validation, and the owner is responsible for ensuring it has been done but leaves actual details to the CMO. You frequent-ly see this in laboratory contracts.

Most device owners do not possess the expertise to deter-mine if an analytical method has been adequately validated. In-stead, the agreement is such that the CMO must certify that they use validated and GMP-compliant test methods. The owner’s verification would be to ensure that the CMO maintains a qual-ity system requiring and supporting this validation element.

In situations where the CMO is physically manufacturing the finished device, the device owner should be integrally involved in ensuring their device design has been properly transferred into the production through solid process valida-tion principles. Protocols, reports, and deviations all need to be reviewed and approved before releasing the device for commercial production and distribution.

What are some tips that you can give to industry when it comes to process validation?

Chase: Well, I like to tell people to start early, as early as the design of the device. When you’re designing that device, you should be considering very far downstream what those pro-cesses and process controls will be in order to ensure that the device, when it’s completed, meets those acceptance criteria.

When you are qualifying your suppliers, you really need to make sure you understand how the materials and the ser-vices impact your validated processes, and you need to use risk-ranking to ensure that your suppliers are evaluated to a level commensurate with the risk. Most importantly, you need to monitor their performance, you need to communicate ex-pectations and concerns, and you need to ensure that you reevaluate on a frequent basis and change suppliers if neces-sary, to ensure compliance.

Now, when you’re using a CMO, you must ensure that you have a strong quality agreement that clearly delineates the responsibilities of both parties – and in particular, the respon-sibilities of the quality-control unit.

There are a lot of resources out there to help you along the way. You should reference Global Harmonization Task Force [GHTF] documents, the ISO guidances, as well as the FDA guidances for instructions and for inspection cover-age, because these are the documents that the FDA will be using. If you want to get an idea of what FDA is really concerned about, look at the 483s and the warning letters being issued, but don’t isolate those just to medical devices. Look across the industries. The FDA’s findings will give you an idea of what failures or shortcomings are rising to the level of 483 observations. Then you should step back and ask yourself if you’re making the same mistakes, and if so, address those before the FDA shows up.

You also should think about the most common areas of dis-crepancy. These include trying to take shortcuts, such as say-ing equipment is like-for-like, failing to consider the impact of changes to the process validation, failing to provide continuous verification of essential parameters to ensure that the process is not drifting out of control, and having poor supplier or CMO quality management practices. In the end, no medical device owner provides 100% of their raw materials or their services. Therefore, it’s important to understand the relationships that go into finished device manufacturing and distribution pro-cesses, and to ensure that each step along the way is quality-added, because ultimately, the device-owner is responsible.


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Will UK’s Own Registration Plans Be Affected By Two-Year Delay To Eudamed Database?AMANDA MAXWELL [email protected]

I f the UK exits the EU on 31 January 2020 and manages to roll out a work-able UK-only registration system

for medical devices ahead of the EU’s updated Eudamed medical devices da-tabase, this could increase confidence in the UK health-technology industry in the same way that the updated Eu-damed is supposed to do throughout Europe.

That is the view of Phil Brown, regula-tory and compliance director at the UK Association of British HealthTech Indus-tries (ABHI), in a recent statement on the Eudamed delay and consequences.

But that does not mean that the fate of Eudamed is less important to the UK, since its continued post-Brexit involve-ment with the EU database may yet be approved as a result of a “deal,” he explains.

Brown acknowledges, however, that as the precise nature of Brexit is yet to be determined, there have been no dis-cussions on the UK’s input into the data-base so far.

The ABHI is arguing for continued in-volvement in Eudamed, particularly in the vigilance modules, believing that the UK’s participation will protect the integrity of European-wide vigilance systems.

THE UK REGISTRATION DATABASEIn anticipation of a no-deal Brexit, the UK has already been upgrading its na-tional registration database.

But some ABHI members have ex-pressed difficulties in interacting with it, Brown says, and the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) has admitted having “teething problems.”

The public accessibility and function-ality of the UK national database have yet to be determined, he added, al-though it is unlikely to be as complete

as those anticipated in Eudamed. The UK database, he explains, will re-

quire all products to be registered with the MHRA prior to being placed on the market, and is coming at a price: each submission will cost around £100 (€117). Individual submissions can be for mul-tiple products of the same “code,” ie, a number of disposables used for the same product, or implants of the same design but different sizes.

WILL THE UK BE ALONE IN SETTING UP A NATIONAL DATABASE?The two-year delay to the start date of Eudamed may mean that it is not just the UK that bolsters its own existing na-tional database.

Brown speculates that there could be a proliferation of other national da-tabases across Europe in light of the Eudamed delay. The development of

these national databases needs to be monitored, he advises, as there may be additional charges for companies.

UDI QUESTIONBrown notes that the use of Unique De-vice Identification (UDI) as part of prod-uct labeling and traceability is largely unaffected by the Eudamed delay.

UDI is to be an important part of the data entered into Eudamed, for trace-ability and identification purposes, he notes, but “will be used irrespective of the Eudamed application date.”

Brown says that manufacturers are recommended to continue in their ef-forts to incorporate the requirements for UDI as part of the MDR transition and that the UK is still as committed to UDI implementation as the EU27 is.




FDA Will Have To Scrape By On Continuing Resolution Funding Through December, Legislative Experts PredictSUE DARCEY [email protected]

T he US Food and Drug Administra-tion will likely have to operate on continuing resolution dollars from

now until about the middle of December, government appropriations experts and analysts say.

“I think the 2020 budget situation is likely to go into next year,” predicted Jes-sica Schulken, a former Senate Appropria-tions Committee staffer, now a consultant with the Russell Group. “The US FDA has a broad mandate for a mid-sized agency, and it needs full funding to continue its transformation into becoming a 21st cen-tury regulatory agency.”

But she added that the budget for the FDA “has been abysmal this year,” so in order for the agency to move forward, funding levels need a boost.

Schulken’s comments came during an Alliance for a Stronger FDA webinar on 7 November. The Alliance is a government agency support group that lobbies Con-gress on behalf of FDA.

Steven Grossman, deputy direc-tor for the Alliance, agreed, noting that “for FDA, a continuing resolution comes with restrictions on initiations of new programs.”

POTENTIAL FOR A GOVERNMENT SHUTDOWN LESS LIKELYAlso, unlike the government shutdown that happened in late December 2018 through mid-February 2019, “I don’t think there will be a shutdown this year. I think that’s highly unlikely, because it would be a losing situation for everyone,” Schul-ken remarked. (Also see “Trump Signs 2019 US Federal Funding Bill, Stopping Another FDA Shutdown; CDRH Sees $69M Boost” - Medtech Insight, 15 Feb, 2019.)

Grossman also believes no shutdown will happen this budget cycle and said last year’s impasse could be dismissed as “very classic White House saber-rattling” that will not reoccur in January 2020.

Both noted that if a shutdown does happen in early 2020, FDA work on de-vice and drug applications could still be carried out, with the agency relying on user-fee dollars to keep the lights on and pay reviewers to scrutinize medical prod-uct marketing applications, as the agency did in early 2019. (Also see “About Three Months’ Worth Of Carryover Device Fees Remaining, FDA’s Gottlieb Says” - Medtech Insight, 14 Jan, 2019.)

US HOUSE BUDGET LINE FOR FDA WILL SHRINK TO MEET SENATE NUMBERSThe House earlier this year approved a much higher spending level for both the FDA and its device center than did

the Senate, with the House voting for the Center for Devices and Radiological Health to receive $420m in budget ap-propriations, while the Senate agreed to $394m. (Also see “Senate Wants To Keep FDA Device Center At Near-Current Levels In 2020 In ‘Minibus’ Funding Bill” - Medtech Insight, 30 Oct, 2019.)

“The Senate budget is lower because they had to respond to lower budget al-locations this year,” Schulken said. And “while it’s really hard to tell what will hap-pen, and what the final budget for FDA in 2020 will be, the House numbers will have to come down, and will look much closer to the Senate’s numbers.”


“For FDA, a continuing resolution comes with

restrictions on initiations of new programs.”

– Steven Grossman


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