Are electronically enabled delivery devices (EEDDs) the future?

www.team-consulting.comConfidential © Team Consulting 2012: type your filename here, slide 1

Created by:Date:

Andy Fry22nd March 2012

Injectable Drug Delivery , Management Forum, London

Are EEDDs (Electronically Enabled Delivery Devices) the Future?


• 110 years of innovation and progress

• Adherence, Compliance and Usability

• EEDDs in diabetes management

• EEDDs in Parenteral delivery - the wider picture

• The world outside of EEDDs

• EEDDs and anti-counterfeiting

• Trajectories for the future

• Conclusion

Contents

www.team-consulting.comConfidential © Team Consulting 2012: Are EEDDs the Future? slide 3

110 years of ‘modern pharmacy’

2010

2020

2000

1910

1980

1970

1960

1940

1920

Avastin

Humira

?

1930

1950

Epoetin

1900

1990

Remicade

• 1900; Aspirin (Bayer) is 20th century’s 1st ‘wonder drug’

• 1922; Insulin first used to treat diabetes melitus

• 1928; Alexander Fleming discovers penicillin

• 1953; Watson & Crick discover structure of DNA

• 1978; First recombinant insulin, Genentech

• 2010; Annual Biologic drug sales of $140 bn (16.5 % of world pharmaceutical market)


110 years of the ‘electronic age’

2010

2020

2000

1910

1980

1970

1960

1940

1920

1930

1950

1900

1990

• 1904; John Ambrose Fleming patents thermionic valve; the birth of the electronic age

• 1936; First electronic public TV service (BBC, London)

• 1947; First transistor developed by William Shockley

• 1958; First integrated circuit developed by Jack Kilby

• 1971; Intel launch the 4004, the first single chip microprocessor

• 2010; Launch of the Apple iPad


• 1900

110 years of drug delivery devices

2010

2020

2000

1910

1980

1970

1960

1940

1920

Avastin

Humira

?

1930

1950

Epoetin

1900

1990

Remicade


• 1900

When all the planets start to line up…..

2010

2020

2000

1910

1980

1960

1940

1920

Avastin

Humira

?

1930

1950

Epoetin

1900

1990

Remicade

1970

• EEDDs were not possible until the microprocessor in 1971

• 8 years later Dean Kamen launches first commercial CSII insulin pump….

• …about the same time Genentech develops recombinant insulin

• Unparalleled development in 50 years of electronics, pharmacy….

• ……and drug delivery devices

• 1900; life expectancy 45 years (USA and western Europe)

• 2010; life expectancy 85 years (USA and western Europe)







• EEDDs and anti- counterfeiting


• Conclusion


• Poor adherence is a major problem for individuals, society and national economies

• Recent US surveys reveal the staggering human impact;– an average of only 50% adherence1 was found in patients with chronic conditions– non-adherence is estimated to result in 125,000 deaths/year2

– 10% of hospital admissions and 23% of nursing home admissions are attributable to non-adherence3

• The economic impact sharpens the focus of attention still further;– Direct cost to the healthcare system estimated at $100 bn/yr4

– Loss of patient earnings estimated at $1.5 bn/yr4

– Loss of productivity (i.e. direct GDP loss) estimated at $50bn/yr4

– Lost pharmaceutical industry revenues estimated at $30bn/yr5

• It’s reasonable to assume a similar impact in other developed economies

Why all the fuss about Adherence/Compliance?

1 Haynes RB. Interventions for helping patients to follow prescriptions for medications: Cochrane Database of Systematic Review, 2001 Issue 1.2 Burrell CD, Levy RA.Therapeutic consequences of noncompliance. Improving medication compliance. Proceedings of a symposium.Washington, DC: National Pharmaceutical Council; 1984:7-16.3 Noncompliance with medication regimens. An economic tragedy. Emerging issues in pharmaceutical cost containing.Washington, DC: National Pharmaceutical Council; 1992:1-16.4 Peterson AM,Takiya L, Finley R. Meta-analysis of trials of interventions to improve medication adherence: American Journal of Health System Pharmacists; 60(7):657-665, 20035 Cutting Edge Information. Pharmaceutical Patient Adherence and Disease Management: Program Development, Management and Improvement.


• Human Factors Engineering, Usability and Compliance of combination products/ drug delivery devices are no longer a ‘nice to have’ but a regulatory necessity;

– FDA guidance– ISO/IEC 62366 (incl. ANSI/AAMI HE74)– ANSI/AAMI HE75:2009

• A delivery device introduces a dimension beyond just popping a pill;– ‘nothing is simpler than swallowing a tablet’– however even compliance with oral medication is poor (< 50% typically)– introducing a delivery device can complicate things still further…– …but can also reveal opportunities if handled the right way

• Delivery devices are an unavoidable necessity for many important therapies

• Recognise and grasp the potential of the delivery device to radically improve compliance – an opportunity rather than a problem

How can device design influence this for the better?


Usability - get the delivery device basics right to start with

• Reduce demands on users - minimise physical and cognitive burden of delivering therapy

• Eliminate the negatives;– perfect device reliability / consistency of performance in hands of users– no significant use-related risks– accommodate full range of grip styles, operation styles– maximise ease of use– minimise delivery pain / anxiety

• However there are some conflicts;– clarity of feedback vs. discretion/privacy– some users want to be in ‘control’, others want ‘distance’

• Excellent usability = zero “delivery task” burden

• However usability alone cannot address the “self-management task” burden

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Additional Functionality - reducing the self management burden

• Reduce the cognitive and emotional burden of managing treatment– support the user – add functionality to deal with forgetfulness, incomprehension and/or fear

• Revised formulation enabled by new device– reduced dose size/dose discomfort – reduced dosing frequency *

• Wearable devices– ‘fit & forget’– ‘autonomy’ of device (NB; restrictions on closed-loop control at present*)

• On-board electronic features – ‘integrated EEDDs’ – reminders – prompts to take a regular dose– memory of when last dose was taken/logging and recall of device usage

• Links to electronic devices – ‘companion EEDDs’– dedicated companion unit to remind/alert user (incl. wireless )– smartphone self-management apps

(*though this may bring challenges as well as benefits - see later comments)11


Bridging the gap – (1)

• The reality is that compliance will never reach 100% no matter what we do

• Excellent usability must always be a key design objective– but on it’s own may not always be enough

• Additional functionality, designed to take away some of the cognitive and emotional burden associated with self injection, can provide real benefit to the user/patient









• Conclusion


• 90 years ago insulin transformed diabetes from a death sentence into a manageable condition

• Not surprisingly, insulin delivery has enjoyed a head start over every other chronic medication delivery technology

• The first purpose-designed self administration syringe kits appeared in 1923

• The first blood glucose meters were marketed in 1970

• The first attempted ‘portable’ insulin pump was developed by Arnold Kadisch in 1963

• The AutoSyringe AS6C was launched in the late 1970’s by Dean Kamen

• This was the first of many manufacturers, mechanisms and models

Diabetes management and EEDDsPhoto courtesy of Eli Lilly and

Company Archives


Continuous Subcutaneous Insulin Infusion pumps - EEDDs with a long pedigree

• Continuous Subcutaneous Insulin Infusion pumps (CSII pumps) have come a very long way in the last 30 years

– sophisticated control of basal level and bolus delivery– carb counting/’food libraries’, record keeping, low battery/ low

insulin warning – many manufacturers and models

• Cellnovo mobile diabetes management system

• Pulsatile patch pump with a disposable insulin cartridge

• Controlled by a mobile (GSM) handset incorporating;– touch-screen interface– Built-in blood glucose meter– Full record of use maintained

• All data moved to a secure site in real-time

• Communication in both in near-field and over mobile networks worldwide.

Image reproduced by kind permission of Cellnovo Ltd


• Electronic memory for insulin pens– ‘keeping track’ of the last dose taken – memory-enabled pens (2 currently on the market)– after-market memory devices (2 currently on the market)

• NovoPen Echo® from NovoNordisk– re-usable device aimed at paediatric use (0.5 IU resolution) – records dose and time since last injection

• HumaPen MEMOIR® from Eli Lilly– re-usable device – allow the patient to look up the last 16 doses of insulin

• The InsulCheck™ clip on recorder– displays time of last injection

• The Timesulin™ smart cap – displays time since last injection,

• Both available to fit range of common pen families

Insulin Pens with EEDDs features – “when did I last take a dose?”


• For frequent, regular, ‘set’ dosing, a simple, regular prompt/ alert;

– e.g. patients with Type 2 diabetes – 1 or 2 daily injections in many cases

• Prompt should be a clear, audible, visible (and/or vibrate?) signal

• One option is to build into the pen (an extension of built-in timers)

– but CoG a potential issue, especially for disposable pens

• alternatively a retained ‘durable’ companion unit, communicating with a low-cost tag in the pen

– lower CoG, potential for use in disposable pens? – alert via custom cellphone app?– to a dedicated companion ‘bleeper’ keyfob– wristband/anklet (ASBO tag for the well-behaved!)

What else could a pen do and how else could it do it?









• Conclusion


Important differences between use of insulin and other chronic therapies;

• People with diabetes do become familiar and reasonably adept at self-administration

– in many cases, patients may be injecting 4+ times a day– for most, it becomes part of the pattern of life (although not out of choice)– pen or pump is with the patient all the time (person, pocket, purse, pc case….)

• A growing population of patients are reliant on regular but infrequent injections of biopharmaceuticals for an expanding range of conditions

– products are often formulated for monthly (or longer) intervals between injections – this is intended to be more convenient and less fearful/painful– however infrequency of use introduces a different set of issues;

• patients/carers do not become familiar or adept with the device• doses are taken late or sometimes missed altogether

• Usability is even more crucial as the patient may never become fully adept

• Alerts and reminders are more important as dosing gets less frequent

• dosing frequency *

What about parenteral delivery outside of diabetes?


• easypod™ from Merck Serono S.A.

• Electronically controlled self-injection device

• First of its kind, launched for delivery of HGH in 2007

• Reduces demands on user associated with dose delivery;– simple; 3 steps to use

• attach needle, position against skin, press button

• Provides support to assist compliance with dosing regime– prescribing physician can pre-set doses– device maintains record of doses taken – assists verification of compliance

• Respond to the particular needs of the patient group concerned – ‘smartphone-like’ display sympathetic with typical patients

What examples of full-featured EEDDs are out there right now?

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easypod® image by kind permission of Merck Serono


• SwissMedDev re-usable autoinjector

• Accepts pre-filled syringes to ISO 11040-4

• Electro-mechanical, fully automatic operation; – place prefilled syringe in loading tray– hold device against injection site– press start button;

• device removes RNS, inserts needle, injects syringe contents

• device withdraws needle, replaces RNS• tray opens for re-loading

• Either user configured (e.g. insertion & injection speed) / or ‘place & press’ pre-programmed operation

• Gives warning/reminder for infrequent use

• Device cost amortised over multiple doses delivered

What could the Future include?


• Full-featured EEDDs products are not what every patient wants or what all providers are able to offer

• Operation and funtionality of existing autoinjector may be completely acceptable when used by patient

• However people still take doses late/miss doses out, so their health suffers and the prescriber/payer may not be aware

• Passive near-field communication is already well proven;– public transport paycards– cattle tags– ...even up-market trainers!

• Opportunity to put a low cost tag in an autoinjector;– companion device (e.g. keyfob or smartphone app)– checks authenticity of injector (correct or counterfeit/mis-prescribed )– alerts patient when dose is due (bleep, buzz, text message etc)– detects/records completion of dose (injector actuation alters tag)

EEDDs with a low cost of implementation


SmartDose ® image by kind permission of West Pharmaceutical Services

SteadyMed ® image by kind permission of SteadyMed Therapeutics, Inc

• Variety of names and variants – patch pumps, infusers, bolus delivery devices

• SQ delivery of high viscosity and/or high volume products where autoinjector delivery impractical

• Adhere to skin, then automated sequence;• attach/insert needle /deliver dose/disable/remove /dispose

• Mechanical (e.g. spring/elastomer) energised devices require no electronics to deliver payload

• Electromechanically energised devices all have some degree of electronic control;

• ‘simple’ controlled discharge/infusion over time possible• presence of battery and some silicon unlocks potential for more

sophisticated flow control/dose profiling• EEDDs don’t need to be esoteric or threatening

• EEDDs can be discreet & compact but still powerful

Wearable devices – EEDDs and ‘traditional’ technology alternatives

Image by kind permission of Valeritas, Inc


Where else in drug delivery are EEDDs opportunities being pursued?

Inhalers and nasal delivery devices

• Dose counters;

– a requirement for several years – electronics a practical option for over a decade– very cautious attitude (regulators and pharmacos)– dose counting alone is a small step…

• Crossing the electronics Rubicon enables;

– reminders for infrequent therapies– prompts to aid correct use– rewards e.g. for children– lockout features (to prevent overdosing)– usage trends / history– data logger (‘spy in the inhaler’)

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• Conclusion


Bridging the gap – (2)

• ‘Just adding electronics’ is not a universal panacea

• It may be exactly right for some patients in some situations

• However for many patients what is needed is a simple to use device, likely to be disposable (and presence or absence of electronics is not of interest)

• What the device must have is a robust, reliable and accurate mechanism, clear indication/display, modest operating force and good ergonomics

• (and unless the price per shot is right, the payer may not make the device available anyway)

• Actually, understanding the patient


• Convenience and ease of use

• Disposable devices – “one in the office, one in the kitchen, one in my pocket”

• Auto-dose delivery, side-action actuation– no problems with hand span on large doses

• Auto-needle insertion and dose delivery– minimises needle phobia issues

• A wide choice of devices viewed as ‘a good thing’ by many diabetes nurses

– “a crucial factor in supporting compliance”

Insulin delivery – non-EEDDs pens address a range of user needs

Haselmeier Diapen®


Autoinjectors – non- EEDDs products

• A new generation of autoinjectors is emerging

• Different manufacturers, different designs but some fundamental objectives in common;

– consistent and reliable

– designed for manufacture

– competitively priced

– compact in size

– wide applicability for a range of therapies

– simple and intuitive in use

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• Conclusion


• This is just one recent example. Drug counterfeiting is a major problem and too big to be covered in detail in a couple of slides

• However the technologies already applied to make e-banking secure could be applicable for EEDDs devices

• Authentication token systems used for internet banking generate a unique code for every transaction. These systems operate over ordinary mobile phone networks

• Traceability and verification can be placed right in the hands of the patient

• We know drug counterfeiting is a huge problem; huge potential profits without the severe penalties of ‘regular’ crime

• EEDDs has the potential to really strike a blow at counterfeiters

EEDDs and anti- counterfeiting“fake versions of Roche's multibillion-dollar cancer drug Avastin turned up at U.S. oncology practices late last year… The WHO estimates that worldwide (counterfeit penetration) is around 10 percent, while in some developing countries as much as a third of medicines are estimated to be bogus.” Bill Berkrot, Reuters, New York, Mar 12, 2012









• Conclusion


The following trajectories are suggested;

1. Insulin pens seem likely to dominate the diabetes market in developing as well as developed economies

2. Issues of ‘sustainability’, either imposed or driven by market concern, may lead to a resurgence of re-usable pens in some markets

3. Widespread use of mobile phone applications in managing a range of conditions (including diabetes) is likely to be part of a universal culture of health-consciousness.

If trajectories 1 & 2 are correct, then a majority will rely on pens, many of which will be re-usable. Adding low-cost electronics to support compliant use will have a minimal effect on cost per shot.If pens contain a compact but efficient chip and if smartphones become part of health-consciousness, then a ‘companion EEDDs’ pen to smartphone relationship appears likely

Where might EEDDs be in 10 years? – In diabetes management


The following trajectories are suggested;

1. Non- diabetes parenterals have historically been influenced by what has happened in diabetes management (whether this is acknowledged or not)

2. A modest cost to encourage compliance with infrequent therapies is a strong incentive when medication is costly (e.g. $10,000/year + for biologics)

3. If insulin delivery (which already includes EEDDs in pumps) pioneers low cost EEDDs in pens, then proven compliance improving technologies will migrate to products more sensitive to the $$ cost of non-compliance

4. If EEDDs can also play a credible role in defence against counterfeiting of very high value products, EEDDs adoption should be considered very seriously

Where might EEDDs be in 10 years? – In other parenteral products


• The fundamental objective remains to help patients comply with their therapy and so manage their condition the delivery device is the drug to patient interface

• Device features and attributes must contribute to an intuitive and reassuring device, designed for ease of use and minimal risk of error. (Equally true for conventional and electronically – enhanced devices)

• The ‘best technology’ for the ‘ideal injection device’ isn’t necessarily electronic or mechanical. It resides in a combination of technologies and skills;

– excellent human factors engineering and industrial design which address patient need– outstanding mechanism design and production engineering which deliver therapy

correctly, reliably and cost effectively

What about non-EEDDs devices now and in 10 years time?









• Conclusion


• Electronics is neither a fundamentally good nor bad thing from the patient’s POV

• Remember that the delivery device is the drug to patient interface

• Therefore it’s all about how that interface relates to the patient;

– does electronics help the patient to comply? (reduces burden / supports their adherence)

– association with familiar products /technologies can be a great help

• Some patients want to engage with technology….– Craig, 10 years old, hGH daily, into smartphone gaming and

skateboarding

• …others really do not– Mavis, 70 years old, type 2 diabetes, 2 insulin shots per day, into

gardening and cooking for her grandchildren

Conclusion

Image by kind permission of Merck Serono

Image by kind permission of NovoNordisk A/S


Acknowledgements

Many thanks for images and data kindly provided by;• Aptar Pharma• BD Medical – Pharmaceutical Systems • Merck Serono S.A.• Novo Nordisk A/S• Oval Medical Ltd• Owen Mumford Ltd• Timesulin Ltd• Sanofi• SHL Group AB• SteadyMed Therapeutics, Inc.• SwissMedDev Sàrl • Valeritas, Inc,• West Pharmaceutical Services, Inc.• Ypsomed AG

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Team Consulting Ltd.Abbey Barns, Duxford RoadIckleton, Cambridge, CB10 1SX, UK

For more information please contact:Andy FryTel: +44 1799 532739Mob: +44 7764 178439Email: [email protected]

Technology

Are electronically enabled delivery devices (EEDDs) the future?