The cost of innovation in healthcare

Jo Chikwe MD, Professor & Chairman of Cardiac Surgery

Cedars-Sinai Medical Center, Los Angeles

#1 by US News & World Report for Cardiology & Cardiac Surgery in the West, #3 in US

Department of Cardiac Surgery

cedars-sinai.org
Smidt Heart Institute
Disclosures

Conflicts of interest:

• None

• Cedars-Sinai Medical Center receives honoraria from Edwards-Lifesciences and Medtronic for
speaker and consulting activities.

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Improving mortality from heart disease

Mensah GA et al Circ Res 2017; 160: 266. 5

Rising costs of treating heart disease

Benjamin EJ et al Circ 2019; 139:me56-528 6

Costs of treating heart disease vs. other illness

Benjamin EJ et al Circ 2019; 139:me56-528 7

Innovation is a huge cost driver

8
Comparing innovations with standard technology

vs

9
Disseminating successful innovations

10
What if your innovation is a medical device?

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The average cost to go from concept to first patient

$7 to $19m
Makower J D et al November 2010 12
Comparing innovations with standard technology

vs

13
1 randomized trial is required for medical device approval

vs

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The cost to go from concept to FDA approval

On average $31m to $95m

Makower J D et al November 2010 15

Quality of evidence comparing 2 treatments

Meta-
analysis

RCT
Propensity
matched study
Cohort
Case control / cross-
sectional study

16
Quality of evidence when comparing 2 treatments

Meta-
analysis

RCT
Propensity
matched study
Cohort
Case control / cross-
sectional study

17
Quality of evidence when comparing 2 treatments

Meta-
analysis

RCT Randomized control trials

Propensity
matched study
Cohort
Case control / cross-
sectional study

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What is randomized data and why do we use it?

• Randomized data comes from trials where choice between 2 treatments is

decided at random – so the treatment should be the only difference between
study groups

• Randomization eliminates selection bias i.e. the factors that can influence
treatment choice and outcome

• This is central to the ability of randomized trials to prove causality and

treatment safety and efficacy

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An example of a randomized trial

Taggart D et al NEJM 2018 20

Cross-over

Intention-to-treat analysis As-treated analysis

Taggart D et al NEJM 2018 21

Selection bias

As-treated
patients

Taggart D et al NEJM 2018 22

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Mitral regurgitation due to heart failure

Carpentier’s Reconstructive Valve Surgery,

Carpentier A, Adams D, Filsoufi F
Mitral regurgitation due to heart failure

Carpentier’s Reconstructive Valve Surgery,

Carpentier A, Adams D, Filsoufi F
MitraClip

www.Abbott.com 1/29/2020
The MitraClip website

LOW HOSPITAL IMPROVED 73% REDUCTION

LENGTH OF STAY QUALITY OF LIFE IN HOSPITAL VISITS

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MitraClip trials for mitral regurgitaion

Stone et al NEJM Dec 2018

Obadia et al NEJM Dec 2018 28
MitraClip trials for mitral regurgitaion

Stone et al NEJM Dec 2018

Obadia et al NEJM Dec 2018 29
MitraClip trials for mitral regurgitaion

Stone et al NEJM Dec 2018

Obadia et al NEJM Dec 2018 30
Why were the results of these trials so different?

COAPT MITRA-FR
Patients 614 300
Disease severity Moderate or moderate to Severe MR
severe MR:
Differences

Symptoms Symptomatic heart failure Symptomatic heart failure

More patients with moderate More patients with severe
symptoms symptoms

Device use 65% 2+ clips, 94% “success” 53% 2+clips, 80% “success”
Follow-up 24 months 12 months

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Which trial was funded and designed by the device manufacturer?

COAPT MITRA-FR

Stone et al NEJM Dec 2018

Obadia et al NEJM Dec 2018 32
Which trial was funded and designed by the device manufacturer?

COAPT

Funded & designed

by
Device manufacturer

Stone et al NEJM Dec 2018

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The German mitral experience

Mitral Repair Mitral Replacement

Deutscher Herzbericht 2016

The German mitral experience

Mitral Repair Mitral Replacement

Deutscher Herzbericht 2016

The German mitral experience

5600
Mitral Repair Mitral Replacement Mitraclip

Deutscher Herzbericht 2016

Strengths and challenges of randomized data

Advantages Disadvantages

• Best way to prove causality • Need equipoise

• Best way to show efficacy and safety • Unrepresentative patients

• Long lead time or short follow-up

• Surrogate endpoints

• Crossover

• Expensive

• Industry driven

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How robust are randomized cardiac device trials?

NNC= Number of patients needed to

change clinical outcome for a trial
result to change
NNC

RCTS in interventional cardiology and cardiac surgery 2008-2018

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How robust are randomized cardiac device trials?

NNC= Number of patients needed to

change clinical outcome for a trial
result to change

Median = 5 patients!
NNC

RCTS in interventional cardiology and cardiac surgery 2008-2018

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How reliable are cardiovascular randomized trials?

Compared with non-industry sponsored trials:

Industry sponsored trials have more favourable efficacy results:

RR 1.27 (95%CI:1.17-1.37) Moderate Quality Evidence

Industry sponsored trials have more favourable conclusions:

RR 1.37 (95%CI: 1.19-1.51) Low Quality Evidence

Slide courtesy of Domenico Pagano MD 40

How can randomized trials be biased?

Pre-study: During study: Post-study:

Conceptualisation & Execution & analysis Interpretation &
design dissemination

• Conflicts of interest • Breaking • Not reporting

• Selective reporting randomization conflicts of interest
literature to • Crossover • Selective reporting
formulate the • Biased assessment of outcomes
rationale of a study of outcomes • Under reporting of
• Choosing study • Under reporting negative results
design that favors statistical analyses • Premature reporting
one treatment • Not sharing analytic of results
• Not reporting the code • Spinning neutral or
planned methods, • Changing trial poor results into
analysis & design favourable
outcomes outcomes

Slide courtesy of Domenico Pagano MD Richards GR, et al In: Catalog Of Bias 2019
 How can randomized trials be biased?

Trials can be designed to showcase new device positively:

• Use of end-points
• Statistical design
• Large “ unacceptable” inferiority margins
• Short follow up
• Unblinded end-point committees
• Using “as treated” analysis

Slide courtesy of Domenico Pagano MD

Trends in registered clinical trials

Change 2006-2014
120%
97%
100%
80%
60%
43%
40%
20%
0%
-20%
-40% -24%

Trials NIH Funded Industry Funded

Slide courtesy of Domenico Pagano MD

 Why do our best journals publish flawed studies?

Trials are published in major impact journals despite significant methodological issues.

Potential advantages for Journals:

• Increase impact of the journal and its revenue

• Increase sale of reprints (via Industry)

• Large Institutional subscriptions

Slide courtesy of Domenico Pagano MD

Journal income from reprints – lack of transparency

Merck purchased $697,000 worth of reprints from NEJM in 2000

Slide courtesy of Domenico Pagano MD

An investigation of the medical device industry

Slide courtesy of Domenico Pagano MD

What did the ICIJ investigation find?

• Obtaining CE market approval “too easy” and not always transparent.

• Undeclared significant COI between industries and clinicians.

• Regulatory bodies not disseminating information on problems with devices.

• Lack of registries to follow up patients with implants.

Slide courtesy of Domenico Pagano MD

How does the FDA approve medical devices?

Post-
Pre-market
marketing
Approval
monitoring

Benefit
Early
Safety
Introduction

Slide courtesy of Domenico Pagano MD

FDA market approval for devices was introduced in 1976

Devices
Before 1976

Supplemental
501K
pathway

Slide courtesy of Domenico Pagano MD

FDA approval of new class 3 devices

• Standard for drug approval - 2 randomized controlled clinical trials.

• Approval of class 3 medical devices is a lower standard evidence.

• Manufacturers don’t have to prove improvement in clinical outcomes or life

expectancy.

• Clinical Trials use surrogate end points.

Slide courtesy of Domenico Pagano MD J. Lenzer; The Danger Within Us.

ISBN-10-03163437765
Monitoring safety: the MAUDE database

• Voluntary reporting

• Data incomplete, unverified and possibly biased.

• Off-label use: doctors afraid to report due to liability.

• FDA does not have total number of devices implanted (denominator).

• DEVICE EVENTS- a private company is more comprehensive.

Slide courtesy of Domenico Pagano MD J. Lenzer; The Danger Within Us.

ISBN-10-03163437765
Political environment

• 1988 President Reagan changed the the position of the FDA commissioner from
civil servant to political appointee.

• 2008: Riegel vs Medtronic Supreme Court ruling: individuals cannot sue

manufacturer if product is FDA approved.

• 21st Century Cure Act (Obama) to speed marketing:

• Real world data can be used

Slide courtesy of Domenico Pagano MD J. Lenzer; The Danger Within Us.

ISBN-10-03163437765
Problems at the FDA

“…Part of the problem is that the agency has too few

resources and too little power to fulfill its key
responsibilities. But it has also become profoundly
vulnerable to political interference and other special
interests. And a revolving door – FDA staffers frequently go
on the lucrative jobs at the very companies they were tasked
with policing – has hurt the agency’s credibility.”

Slide courtesy of Domenico Pagano MD Editorial, New York Times Jan 11 2020
Problems at the FDA

“…In the just the past few years the FDA has been
faulted for its roles in the opioid epidemic (regulators
allowed too many opioids on the market without
properly flagging them as addictive or deadly) and a
surge in youth vaping (the agency failed to keep
untested e-cigarettes off the market or to establish the
safety of these produces, as millions began using them).
Slide courtesy of Domenico Pagano MD Editorial, New York Times Jan 11 2020
 Problems in academic leadership

Top Cancer Doctor

Resigns as Editor of
Medical Journal “…Dr. Baselga resigned as chief medical officer of
Memorial Sloan Kettering in September after The
New York Times and ProPublica reported that he had
failed to disclose millions of dollars in payments from
health care companies in dozens of research
articles…”

Thomas & Ornstein, New York Times Dec 19 2018

What are conflicts of interest?

• Patients and the public benefit when physicians and researchers collaborate with
pharma, medical device companies….to develop products that benefit individuals and
public health.

• IOM defines COI: “circumstances that create a risk that professional judgement or
actions regarding a primary interest will be unduly influenced by a secondary interest:

• Primary Interests: conducting research, taking care of patients or medical education

• Secondary Interest: Individual's gain- financial, professional, political or interpersonal.

Slide courtesy of Domenico Pagano MD

Payments from drug and device companies to doctors in 2018

Slide courtesy of Domenico Pagano MD OpenPaymentsData.CMS.gov

Conflicts of interest statement longer than the abstract

Slide courtesy of Domenico Pagano MD Banning et al, JACC 2019; 73

Payments received by individual journal editors from industry

$100,000 per year

Slide courtesy of Domenico Pagano MD

https://doi.org/10.1371/journal.pone.0197141
 Self-disclosure versus full disclosure

Author reported
relationships
N=174= 16.1%
Company
reported
8.9 relationships
% N=584= 75%

Agreement= N=62

Slide courtesy of Domenico Pagano MD

Even small incentives can influence physician practice

Slide courtesy of Domenico Pagano MD JAMA Int Med 2016

Quality of evidence

Meta-
analysis

RCT Randomized control trials

Propensity
matched study
Cohort
Case control /
cross-sectional study

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Quality of evidence

Meta-analys
is

RCT
Propensity
matched study
Real world data
Cohort
Case control / cross-
sectional study

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What is real-world data?

Real-world data is information

gathered in the course of routine clinical practice

Clinical Administrative
Patient records, registries Billing, claims, social security

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What is real-world data?

Real-world data is information

gathered in the course of routine clinical practice

Clinical Administrative
Patient records, registries Billing, claims, social security

Example: Medical records Example: Medicare billing

Recorded by “clinicians” Recorded by “coders”
Rich clinical detail Limited content e.g. ICD-9, DRG
Thousands of patients Mandatory (state / national)
May be mandatory Millions of patients

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What is real-world data?

Real-world data is information

gathered in the course of routine clinical practice

Clinical Administrative
Patient records, registries Billing, claims, social security

Example: Medicare billing

Recorded by “coders”
Limited content e.g. ICD-9, DRG
Mandatory (state / national)
Millions of patients

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What is real-world data?

Real-world data is information

gathered in the course of routine clinical practice

Clinical Administrative
Patient records, registries Billing, claims, social security

Example: Medical records Example: Medicare billing

Recorded by “clinicians” Recorded by “coders”
Rich clinical detail Limited content e.g. ICD-9, DRG
Thousands of patients Mandatory (state / national)
May be mandatory Millions of patients

Linkage combines 2 or more databases at individual patient level

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Strengths and weakneses of real-world data

Advantages Disadvantages

• No need for equipoise • Limitations of dataset

• Representative patients • Cannot control for unknown bias

• Short lead time, long follow-up • Cannot “prove” casuality

• Meaningful endpoints

• Can look at practice variation

• Inexpensive

• Investigator driven

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Primary mitral regurgitation

Carpentier’s Reconstructive Valve Surgery,

Carpentier A, Adams D, Filsoufi

Smidt Heart Institute at Cedars-Sinai Medical Center

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Mitral prolapse

Smidt Heart Institute at Cedars-Sinai Medical Center

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Early surgery for primary mitral regurgitation

Successful mitral repair

surgery restores normal
life expectancy for patients
with degenerative mitral

Replacement doesn’t

Enriquez Sarano et al 71
Mitral repair rates for New York hospitals

Huge variability
in chances of successful
mitral repair depending on
which hospital does the
surgery

Chikwe J et al, JACC 2017; 69

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Mitral repair rates for New York surgeons

Huge variability
in chances of successful
mitral repair depending on
which surgeon does the
surgery

Chikwe J et al, JACC 2017; 69:

Chikwe J et al, JACC 2017; 69
73
What are the real-word outcomes with MitraClip?

MitraClip has inferior

outcomes
Up to 1/3rd of patients have
moderate or severe MR at
30 days, die or need
surgery

Chikwe J et al, JACC 2017; 69:

Chahartriwalla AK et al, JACC 2019 74

How to design a trial to support MitraClip in primary MR

• Choose your primary endpoint to suit the device – this defines how the results will be reported
◦ Avoid primary endpoints where the device is inferior e.g. residual mitral regurgitation
◦ Include hospitalization or transfusion which are more common after surgery
• Choose a non-inferiority design with a wide margin.
◦ The device can give much poorer results, but if within this margin it is “non-inferior” and approved
• Short follow-up
◦ You can publish the results earlier
◦ Early results almost never favor surgery because it takes many years for survival benefit
• Use strict device and operator criteria to ensure the device performs well in the trial
• But use broad patient inclusion criteria so the device is approved for the most possible patients

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The Abbott FDA-approved trial summary protocol

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Thank you

#1 by US News & World Report for Cardiology & Cardiac Surgery in the West, #3 in
US 77