3 sure steps to faster R&D

Are you an R&D manager who would like to get your products to market more quickly?

You may have suffered project delays such as: just can’t get it working; people seem to be busy on other things; you thought it was all fine but after it was all tooled problems started to occur.

Or the worst one of all: a product recall because of an adverse patient safety event.

Everyone wants to avoid problems like these, but the big question is how can you greatly increase the chances of success?

Here’s one good answer:

Many organisations go straight in to step 2. Design the product, do a few tests and then commission production tooling. But often, the production environment is slightly different from R&D. A few changes are made. Aspects that “just worked” before, now “don’t always work”. Problems grow and it is mighty painful to iterate your design within the constraints of already-made tooling. You can spend ages trying to get it to work with minor modifications, and eventually accept that you have to spend that $5m on tooling and automation again. Ouch.

Step 1 is the key to fast, low-cost R&D. If it costs, say $100k to properly understand the science, that is peanuts compared to spending the $5m twice for step 3. A good understanding comes not only from scientific insight, but rigorous and methodical testing of the failure modes, backed up by sufficient statistical evaluation to be sure you have confidence in the results.

Very many companies I work with don’t do step 1 to sufficient detail. As a result, they often suffer delays of, quite literally, many years. For a product worth $50m a year, it’s mad to suffer that loss for the sake of a few $100k up front for a few months. So my advice is to invest effort in step 1 to reduce risk as much as you can. Get the best people you can find to do so. And make sure that when you spend the big money in step 3, you are certain that you’re only going to do it once.

Nanopatterning for medical applications

Nanotechnology appears in popular culture as a cure for everything from cancer to balding. In science nanotechnology is an umbrella term for a variety of structures and molecules used in optics, MEMS, materials, chemicals and some biological systems.

In this new blog series, we shall explore nanopatterning (the engineering of nanoscale structures on surfaces), its prevalence in nature, manufacture and application to medical devices.

Drawing inspiration from nature

Figure 1 – Sunset moth scales macro by Johan J.Ingles-Le Nobel, Cropped, CC BY-NC-ND 2.0

Nanoscale structure plays a fundamental role in numerous biological systems, and in some cases has developed to aid an organism’s survival and proliferation. Nanostructures can impact on the wetting and optical properties of a surface as well as their molecular interactions. Adjusting the spacing and morphology of these structures can change how they behave in contact with solids, liquids, biomolecules and how they catalyse certain chemical reactions. Organisms rely on these structures to stay clean, aid communication, and promote or prevent adhesion. The presence of ordered micro- and nanoscale structure appears to the human eye as iridescence created by the selective scatter of certain wavelengths of light.

Dry adhesion

While the exact mechanisms of adhesion differ, the feet of various tree frogs, insects and lizards rely on nanoscale and microscale structure to cling to and climb vertical or inverted surfaces. Perhaps the most famous climbers that rely on adhesion are geckos. Gecko climbing ability comes from millions of hair or setae on their feet which experience Van der Waals interactions with the substrate [1]. Individually the interactions are weak but collectively give the gecko the adhesive force necessary to hold up to four times its own weight. These setae evolved from tiny hair-like growths present on the bodies of all geckos [2]. Generating setae involves lengthening these hairs and splitting the tips to produce micro- and nanoscale hierarchical structures. Curiously, researchers have found that several gecko species developed these adhesive abilities independently when faced with an environment where climbing aided survival, losing them again over time when the environment changed [2].

Figure 2 – Gecko’s secret power by Matteo Gabaglio, Annotation, Order, CC BY-SA 3.0

In the last 20 years, the adhesive strength, reusability and non-fouling properties have attracted increased interest in gecko-inspired adhesives. Manmade micro- and nanoscale hierarchical patterns produced by embossing, casting or roll-to-roll printing have resulted in several tape and patch analogues. As popular as this topic has been, it has not been without its challenges. In addition to difficulties in manufacturing, gecko mimetic adhesives experience poor adhesion to wet and contaminated surfaces [3]. Water disrupts the surface interactions which is also the reason why PTFE (which exhibits weak Van der Waals dispersion forces) is one of few materials that a gecko can’t climb on [4].

Wet adhesion

For wet adhesion it makes more sense to look to water dwelling organisms. Mussels create an adhesive containing a tyrosine residue called DOPA, which has seen increased attention. DOPA and similar coatings are key to allowing nanopattern based adhesives to work in wet conditions. The structure of DOPA allows mussels to form strong and reversible bonds with a variety of substrates [5]. Mussels use this to anchor their pads to rocks and withstand significant punishment from tides and currents. Researchers have so far used DOPA and analogues in an attempt to develop improved surgical adhesives, particularly for amniotic sac repair[6]. Some have combined this with the gecko adhesive above to produce all-purpose hybrids named “Geckel” [7]. These hybrid surfaces consist of a microstructure coated in mussel mimetic adhesive to achieve adhesion in wet or dry conditions. As with any novel technology, achieving a robust product and scalable process has likely limited its implementation. Alternative adhesive-free-adhesives for wet conditions look to the octopus for inspiration. Although an octopus sucker is far larger than the other features we have discussed, its design has been the inspiration for many micro- and nanoscale mimics. Octopodes use suckers as muscular-hydrostats where the internal volume is increased to generate low pressure (≤ 2.7 bar below ambient pressure when submerged) [8]. The octopus vulgaris differs from other species in that it utilises a ball in cup morphology to maintain adhesion and resist shear [9].  Its unique morphology creates two regions of low pressure with the ball protrusion sealing the two volumes and mechanically locking the sucker configuration.

Figure 3 A.) Suckers of octopus by Steve Lodefink, Suckers of octopus by Steve Lodefink, CC BY 2.0. B.) Illustration of sucker adhesion mechanism of Octopus vulgaris.

Octopus mimetic surfaces produced by vacuum casting use microscale suction cups (~ 100 μm) with a similar ball in cup morphology to generate suction [10]. This approach has seen some applications targeting skin but so far appears limited to working on flat surfaces and generating relatively weak vacuums. Some commercial materials such as REGABOND micro-suction foam are aimed for the general consumer market and work on a similar principle [11].

Repulsion

Some plants use micro- and nanoscale texture for an alternative purpose, the “lotus effect” being the most famous example. The lotus effect arises from the ability of micro- and nanostructures to amplify the natural tendency of a surface, making hydrophobic materials superhydrophobic. A lotus leaf has arrays of hydrophobic waxy hierarchical micropillars on its surface [12]. The high roughness and low contact area of these pillars forces water droplets to adopt a Cassie-Baxter state where air is trapped below the fluid meniscus. To reduce the Gibbs free energy of the system the water droplets adopt a highly rounded shape. This allows them to slide off and pick up dirt in the process, keeping the leaves free of debris. The springtail takes this effect further with a cuticle that has a re-entrant or overhanging surface structure [13]. These structures resemble nanoscale mushrooms which pin the fluid line to prevent even low surface tension fluids from fully wetting the surface in what is referred to as oleophobicity. The springtail uses this for survival creating an air trap around its body when submerged. Both superhydrophobicity and oleophobicity are found in industry, often finding use in semipermeable membranes and self-cleaning coatings. The surface energy and morphology of the of the coating material dictate the degree of nonwetting. These structures are still vulnerable in high pressure applications where the structures or the film of air can collapse.

Figure 4 – The springtail cuticle has been used as inspiration for manmade re-entrant omniphobic surfaces A.) Springtails. B.) Springtail submerged in water. C.) Springtail submerged in oil. Scale bars: 1 mm. Image from R. Hensel et al. [13], CC BY-NC 3.0.

A very different, and potentially more robust approach is used by the pitcher plant. In these plants a microporous surface is used to retain a lubricating fluid film. The films are created when water or nectar becomes locked into microscale textures in the surface of the plant creating a continuous layer of lubrication. The film is immiscible in the oil on the insect’s feet resulting in a surface that easily shears away on contact and very low friction. Unlucky insects which land on the plant’s lip end up sliding down into the plants digestive fluid to become a snack. The film is replenished by capillary effects which redistribute fluid across the film surface. The advantage of this arrangement is the immiscible fluid is incompressible unlike the air used by the lotus leaf and allowing it to serve in higher pressure applications.

Figure 5 A.) Sarracenia pitcher anatomy by Noah Elhardt, Sarracenia pitcher anatomy basic, marked as public domain. B-E.) Microstructure of N. gracilis waxy surfaces. Scale bars shown. Image from Bauer et al. [14], CC BY 4.0.

Pitcher plant mimetic surfaces have been named “slippery liquid-infused porous surface(s)” or SLIPS. These surfaces can be tailored and often use a lubricant which is immiscible in the target substance. The porous substrate consists of open interconnected pores to retain the lubricating fluid. While evidence of industrial application is limited, it is a promising route to stain-resistant coatings for optics.

Optical effects

Certain organisms use micro and nanostructures to produce iridescence that makes the rest of the animal kingdom pale by comparison. While many rely on chemicals for coloration, using microscale structures is called structural coloration or physical colour. Butterflies use this effect for visual communication to find mates or scare away would-be predators. The most famous example is the Morpho butterfly native to Latin America [15]. The Morpho is an underwhelming (but well hidden) shade of brown with its wings closed but a bright iridescent blue when they open. The blue iridescence comes from tiny chitin gratings on the surface of a butterfly’s wings [3]. The layering of these structures causes diffraction and constructive interference of visible light waves according to Bragg’s law, producing the visual perception of a very intense colour [17]. The angle at which the butterfly is observed changes the colour we perceive the wings to be, shifting from blue to copper when viewed at an angle. The papilionidae family of butterflies use similar architectures combined with fluorophores to harvest NIR light to create luminescence [18].

Figure 6 – A.) Blue morpho butterfly by Gregory Phillips, Blue morpho butterfly, CC BY-SA 3.0. B.) Nanoscale Structures on a Blue Morpho Butterfly Wing Image from Potyrailo et al. [19], CC BY 4.0.

The unique physical, chemical, and optical properties of these structures have led to interest in several industries. Extensive research and development efforts have gone into mimicking these effects for energy harvesting, sensing and photocatalysis [19]. For medical applications they have a role to play in optical biosensing. By coating a grating in environmentally responsive molecules or hydrogels an optical indicator can be constructed. Structures such as this have been coined hydrogel-actuated integrated responsive systems (HAIRS)[20].

We hope that this has been an interesting read. The next edition will discuss the practicality of fabricating these structures, and their suitability for parts used in medical devices.

If you have any questions about micro engineering and smart surfaces, please do not hesitate to get in touch or find me on LinkedIn.

Bibliography

[1]        K. Autumn and N. Gravish, “Gecko adhesion: evolutionary nanotechnology,” Philos. Trans. R. Soc. A Math. Phys. Eng. Sci., vol. 366, no. 1870, p. 1575 LP-1590, May 2008.

[2]        T. Gamble, E. Greenbaum, T. R. Jackman, A. P. Russell, and A. M. Bauer, “Repeated origin and loss of adhesive toepads in Geckos,” PLoS One, vol. 7, no. 6, 2012.

[3]        A. Y. Stark, T. W. Sullivan, and P. H. Niewiarowski, “The effect of surface water and wetting on gecko adhesion,” J. Exp. Biol., vol. 215, no. 17, p. 3080 LP-3086, Sep. 2012.

[4]        A. Y. Stark et al., “Adhesive interactions of geckos with wet and dry fluoropolymer substrates,” J. R. Soc. Interface, vol. 12, no. 108, p. 20150464, Jul. 2015.

[5]        J. H. Waite, “Mussel adhesion – essential footwork,” J. Exp. Biol., vol. 220, no. 4, p. 517 LP-530, Feb. 2017.

[6]        M. Perrini, D. Barrett, N. Ochsenbein-Koelble, R. Zimmermann, P. Messersmith, and M. Ehrbar, “A comparative investigation of mussel-mimetic sealants for fetal membrane repair,” J. Mech. Behav. Biomed. Mater., vol. 58, pp. 57–64, 2016.

[7]        H. Lee, B. P. Lee, and P. B. Messersmith, “A reversible wet/dry adhesive inspired by mussels and geckos,” Nature, vol. 448, p. 338, Jul. 2007.

[8]        J. J. Wilker, “How to suck like an octopus,” Nature, vol. 546, p. 358, Jun. 2017.

[9]        F. Tramacere, L. Beccai, M. Kuba, A. Gozzi, A. Bifone, and B. Mazzolai, “The Morphology and Adhesion Mechanism of Octopus vulgaris Suckers,” PLoS One, vol. 8, no. 6, p. e65074, Jun. 2013.

[10]      S. Baik, D. Wan Kim, Y. Park, T.-J. Lee, S. Ho Bhang, and C. Pang, “A wet-tolerant adhesive patch inspired by protuberances in suction cups of octopi,” Nature, vol. 546, pp. 396–400, 2017.

[11]      “materialdistrict.com.” [Online]. Available: https://materialdistrict.com/material/regabond-s. [Accessed: 05-Sep-2018].

[12]      T. Darmanin and F. Guittard, “Superhydrophobic and superoleophobic properties in nature,” Mater. Today, vol. 18, no. 5, pp. 273–285, 2015.

[13]      R. Hensel, C. Neinhuis, and C. Werner, “The springtail cuticle as a blueprint for omniphobic surfaces,” Chem. Soc. Rev., vol. 45, no. 2, pp. 323–341, 2016.

[14]      U. Bauer, B. Di Giusto, J. Skepper, T. U. Grafe, and W. Federle, “With a Flick of the Lid: A Novel Trapping Mechanism in Nepenthes gracilis Pitcher Plants,” PLoS One, vol. 7, no. 6, p. e38951, Jun. 2012.

[15]      Y. Ding, S. Xu, and Z. L. Wang, “Structural colors from Morpho peleides butterfly wing scales,” J. Appl. Phys., vol. 106, no. 7, pp. 1–6, 2009.

[16]      R. Yan et al., “Bio-inspired Plasmonic Nanoarchitectured Hybrid System Towards Enhanced Far Red-to-Near Infrared Solar Photocatalysis,” Sci. Rep., vol. 6, no. December 2015, pp. 1–11, 2016.

[17]      S. Zhang and Y. Chen, “Nanofabrication and coloration study of artificial Morpho butterfly wings with aligned lamellae layers,” Sci. Rep., vol. 5, pp. 1–10, 2015.

[18]      E. Van Hooijdonk, C. Vandenbem, S. Berthier, and J. P. Vigneron, “Bi-functional photonic structure in the Papilio nireus (Papilionidae): modeling by scattering-matrix optical simulations,” Opt. Express, vol. 20, no. 20, p. 22001, 2012.

[19]      R. A. Potyrailo et al., “Towards outperforming conventional sensor arrays with fabricated individual photonic vapour sensors inspired by Morpho butterflies,” Nat. Commun., vol. 6, p. 7959, Sep. 2015.

[20]      J. M. J. den. Toonder and P. R. Onck, “Artificial cilia.” Royal Society of Chemistry, Cambridge, 2013.

What does ‘rapid’ really mean?

One of the real strengths of working with a consultancy is the ability to increase the size of your team, bring in extra skills and get a project off the ground very quickly.  When you’re behind schedule on a market launch, regulatory submission, or faced with an unexpected verification test failure or recall, this speed can be the difference between successful and unsuccessful outcomes for your project.

So what does ‘rapid’ actually mean?  How fast is fast?  Let’s illustrate with an example of a project Springboard completed recently:

One Wednesday, we received a call from a client already known to us, asking us for help with an urgent problem.  This would require a mix of literature-based scientific research and practical testing in the lab.  Results were needed as quickly as possible, and certainly in time for a meeting three weeks later.

Springboard pulled out all the stops to plan the project and write a detailed proposal within two days, submitting this to the client on Friday morning.  The client was able to send written authorisation the same day, and put parts in the post for next day delivery.

The project leader briefed his team at 10 am on Monday morning.  The team – comprising two PhD-level scientists and a graduate engineer, with technical oversight from one of Springboard’s directors – hit the ground running.  Devices were disassembled and testing began before lunchtime.

The first update call to the client was delivered at lunchtime on Thursday.  This was a 30-slide PowerPoint presentation rich in technical detail, all of which was backed up with either laboratory experiments or cited academic papers.  In discussion with the client’s team members, we agreed the priorities for the next week of research.

Two more updates were delivered before the client’s original deadline, and the client went into their meeting briefed and confident.  A 42-page report, backing up all of the observations and conclusions drawn with full references, followed a week later.

Project timeline

Two days to plan and propose a project.  One week to deliver first results.  One month to deliver a complete project yielding real technical insight to drive policymaking.  No ongoing commitment.  A real illustration of how an agile consultancy can react much faster than a large corporation, and so add real value to urgent development and troubleshooting projects.

Connected drug delivery

The need for connected drug delivery devices

Most people would agree that drug delivery devices have improved in recent years, particularly with the increased focus on usability (or ‘human factors’).  However, adherence remains a challenge and payers are looking for ways to increase the cost-effectiveness of healthcare.  One strategy for managing both issues is connecting drug delivery devices to the internet.

The potential benefits of connected drug delivery devices have been much discussed and can be summarised for stakeholders as follows:

  • Patient
    • Reminders
    • Training
    • Evidence for incentives
    • Hawthorne effect
    • Peer support
  • Carer
    • Reminders
    • Training
  • Payer
    • (Non)adherence data
    • Reduced costs (50% of patients suffering chronic illness do not take their medication as prescribed, costing US $100 billion to $300 billion annually in avoidable direct healthcare costs in the US alone [1])
  • Healthcare professional
    • (Non)adherence data
    • Additional support for least adherent
    • Adverse events
  • Healthcare provider, or regulatory authority
    • (Non)adherence data
    • Adverse events
    • Clinical trial data (pre and post market)
    • Population trends
  • Pharma
    • Adverse events
    • (Non)adherence data
    • Clinical trial data (pre and post market)
    • Reimbursement evidence
    • Market understanding
    • Product and training improvements
    • Increased sales by increased adherence. (Non-adherence causes US $637 billion lost pharma revenue annually [2])

The disadvantages of connecting drug delivery devices to the internet are:

  • Increased cost of devices and infrastructure.
  • Potential increase in usability risks.
  • Reliability risks due to technical complexity.
  • Concerns over data privacy and robustness against hacking and malware.
  • Unclear regulatory landscape due to the unfamiliarity of the technologies in the regulatory context.
  • Environmental concerns for disposal of electronic waste.

Nevertheless, for some drugs and indications the advantages are compelling, so we should look at how connectivity might be implemented in a drug delivery device.

Device strategies

There are 3 main strategies for implementing connectivity in a drug delivery device:

  1. An add-on, typically to an existing design.
  2. An upgrade, which is integrated but does not change the core functionality or use case.
  3. Built-in, which can change the core functionality and use case.

Many pharmaceutical companies and drug delivery device manufacturers already have devices either on the market or in late stage development.

An industry survey of inhalers, for example, shows various companies using one or more of the three strategies.  Note that we see the same trends in the injector industry.

Add-ons

Add-ons have the advantages that:

  • They can be added to existing devices, in most cases without interfering with the existing device function.
  • They could be reusable even if the existing device is disposable.
  • Patients could pay for the add-on themselves, whereas the existing drug delivery device might be paid for by an insurer or national health service.
  • There is less development risk due to limited revalidation of the existing device.

Propeller and Adherium are notable because they support a wide range of existing inhalers.

Propeller Health

Propeller Health’s smart phone app, and inhaler add-on

Adherium

Adherium’s add-ons fitted to various commercial inhalers, and Adherium’s smart phone app

Cohero provides a spirometer so patients can measure their lung function.  This combination of drug delivery device and diagnostic device is powerful because it can provide direct disease management results to help patients and clinicians assess progress and can enable payment-by-results rather than pay-per-dose.  Linking delivery devices with diagnostics was pioneered by the insulin pens (and to a greater degree, insulin pumps) and blood glucose meters used for diabetes.  The obvious benefit is that the drug delivery device can respond to changes in the biomarker in real-time.  In addition, it gives much better insight than measuring only the quantity and time of dose taken because the patient and healthcare professional can see how the body responds to the drug. Perhaps the diagnostics could be used to identify more subtle problems.  For example, if outcomes were poor in a certain area, an investigation might reveal poor training by the local healthcare facility.

Cohero's add-on

Cohero Health’s BreatheSmart™ app, HeroTracker™ sensors, and spirometer.

Inspair measures inspiratory flowrate so can determine both if the patient’s breathing profile is correct, and if they actuated the inhaler at the right point in their inspiration. Devices which provide feedback like this can be used for ‘continuous improvement’ training, which is more interactive and personalised than a static training video or patient instruction leaflet.  It helps with the ‘learn-ability’ of the device, which was identified as a major challenge in recent industry-wide research performed by Springboard.

Biocorp Inspair

Biocorp Inspair

However, it is important to consider that add-ons have the obvious disadvantage that the existing geometry is not modified so:

  • Add-ons cannot be integrated into the existing device, and thus add bulk to the device, and there are additional use steps to attach them.
  • Technical possibilities are limited. For example, it is more difficult to sample the air flow.

Upgrades

A strategy to overcome the limitations of the add-ons is to upgrade an existing design.  Novartis is supporting the Propeller add-on [3], but is also upgrading the Breezhaler to the cloudhaler and adding built-in connectivity by working with Qualcomm Life. [4, 5]

Novartis Cloudhaler

Novartis Cloudhaler

H&T Presspart is working with Cohero to upgrade standard Metered Dose Inhaler actuators with connectivity. [6]  A notable feature of the Presspart strategy is that the connected functionality is optional.  That is, the drug delivery and dose counter functions are still entirely mechanical, so the patient can, in principle, use the device safely and effectively even if the electronic functions fail.

Presspart eMDI

H&T Presspart eMDI

An alert reader will notice that the upgraded devices do not change the use steps or core functionality of the devices.  If we want to use electronics and connectivity to change fundamentally the way the patients (and carers, trainers etc.) interact with their device, we need to build the electronics and connectivity into the device from the ground up.

Built-in connectivity

Devices which have connectivity built into them from the beginning can make significant changes in user interaction.  The design being built-in also allows more substantial changes to the device, such as advanced features and sensing options. For example, the 3M Intelligent Control Inhaler actively adapts the flowrate to suit the patient and delivers the dose automatically at the right point in the inspiration. A similar example is Opko’s Inspiromatic active dry powder inhaler, and Aptar is partnering with Propeller to develop a new connected metered dose inhaler. [7]

3M Intelligent Control Inhaler

3M Intelligent Control Inhaler

The disadvantages of built-in connectivity mirror substantially the advantages of add-ons.  For example, a device with built-in connectivity could be more difficult to make reusable, which adds built-in cost and environmental impact.

Uptake and retention of connected devices

Public interest in connected drug delivery devices has not been measured on a wide scale yet, but we can draw inferences from health-related smartphone apps.  More than 50% of US smartphone users downloaded a health-related app in 2015.  Individuals more likely to use health-related apps tended to:

  • Be younger,
  • Have higher incomes,
  • Be more educated,
  • Be Latino/Hispanic, and
  • Have a body mass index (BMI) in the obese range (all P<0.05). [8]

However, weekly retention of apps is poor, even for apps which tend to be associated with hardware such as Fitbit, Garmin and Nike+.

Market Share of the Top 5 Fitness Apps

Market Share of the Top 5 Fitness Apps

The reasons for people stopping the use of health apps were primarily:

  • High data entry burden 45%
  • Loss of interest 41%
  • Hidden costs 36%

Out of 1604 people, 662 (41%) said they would not pay anything for a health app. [8]

In November 2017, an analyst from Ernst & Young identified the following hurdles to the widespread adoption of connectivity in drug delivery devices: [9]

  1. Devices and services.
  2. Evidence.
  3. Data infrastructure.
  4. Business model.

Let us assess the progress and challenges in each area in turn.

Devices and services

Merck Group launched easypod for human growth hormone in 2006, which gained connectivity in 2012, [10] and RebiSmart for multiple sclerosis, which was launched in 2007 and gained connectivity in 2011.  They use the easypod Connect [11] and MSdialog [12] web platforms, respectively, for uploading patient data from the device and adding supporting information manually.

One of the challenges is gaining regulatory approval of medical devices that connect to smartphones, but AliveCor has pioneered the way here by being the first to gain FDA approval for smartphone-based medical device software with its atrial fibrillation diagnostic app.

In diabetes, Roche has bought the mySugr web platform, whose Bolus Calculator has Class IIb approval in the EU, and the logbook has Class I approval in both the EU and USA.

So, we can see that connected drug delivery devices are breaking through onto the market, and the regulatory approval and services around them are entirely feasible.

Evidence

Payers and regulators (not to mention patients and healthcare professionals) will want to see clinical evidence for the efficacy of connectivity.  Fortunately, the evidence is mounting.  Data from Propeller Health, for example, shows reduced short-acting beta agonist use, [13] reduced hospitalisations and reduced emergency room visits. [14]  Adherium claims similar clinical evidence. [15]

If efficacy is proven for certain indications, we would still need evidence for preference and adherence.  Fortunately, several studies have been done in these areas too.  For example:

  • An observational study on the RebiSmart device found that 91% liked using the device, and 96% found it ‘easy or very easy to use’. [16]
  • An autoinjector preference patient survey found that 82% of BetaConnect patients were ‘highly satisfied’ compared to 67% of RebiSmart and 60% of ExtaviPro patients. [17] The first two devices have connectivity, but the latter does not.
  • A retrospective adherence study on patients with multiple sclerosis using RebiSmart found ‘greater than 95% adherence’ over a 140-week duration (N = 110). [18]

Unfortunately, evidence of malware and hacking has also appeared.  For example, remote hacking exploits have been demonstrated on some Medtronic insulin pumps, [19] Hospira infusion pumps, [20] and Animas OneTouch Ping insulin pumps. [21]

Data infrastructure

It is logical for companies to roll out their connectivity infrastructure using the following building blocks:

  1. Adding connectivity to the drug delivery device.
  2. Optionally connecting the drug delivery device to a ‘mobile medical app’. This can be an app running on a smart phone (such as AliveCor’s KardiaMobile app), or on a dedicated device (such as Abbot’s FreeStyle Libre device).
  3. Cloud storage and web apps that can be accessed through a web browser.
  4. Electronic Health Records.

The main cloud computing providers (Amazon Web Services, Google Cloud Platform and Microsoft Azure) have various offering that are HIPAA compliant, so can be used for some medical data in the United States, but HIPAA compliance is not regarded as strong enough protection for the data of EU citizens.  The  General Data Protection Regulation (in force from 25 May 2018) places further requirements on the controllers and processors of personal data.

Several companies and collaborations are creating cloud technologies to handle data from connected medical devices. For example, Salesforce.com (in the form of its force.com platform), Qualcomm Life and Philips HealthSuite are working on patient data platforms.  Roche bought Flatiron which developed the OncologyCloud, claimed by them to be the ‘industry-leading electronic medical record for oncology, advanced analytics, patient portal and integrated billing management’, [22] Medicom is handling the data services for Bayer’s BetaConnect device, and Redox is developing a way to share healthcare data between heterogenous technologies.  In effect, Redox can take data from any input, perform transformations and analytics on it, and convert it into a given Electronic Health Record format.

Business models

Payers are trying to reduce costs, so simply adding connectivity and expecting to be able to charge more is not a convincing strategy.  However, a holistic view of the health economics of a given indication can reveal compelling business models in some cases.

Example business models already in use include:

  • A collaboration between Amgen and Humana whereby Amgen analyses real-world evidence from Humana’s members with data from wearable devices, apps and smart drug delivery devices. [9]
  • A collaboration between Amgen and Harvard Pilgrim Healthcare whereby Amgen will fully refund the cost of Repatha if the patient is hospitalised by a stroke or myocardial infarction. Naturally, Harvard Pilgrim will need to show that the patient had adhered to the Repatha regimen and connectivity is a convincing way to do this.
  • Abbot did not get reimbursement initially when it developed the FreeStyle Libre flash glucose sensor, so sold it direct to patients. It has since been approved for purchasing by the UK National Health Service. [23]

Summary and final thought

From what Springboard sees in its day-to-day work, every company involved in drug delivery devices either has a connected technology or is developing one. Clinical evidence for improved adherence exists, and evidence for other clinical benefits is mounting.  The data infrastructure exists, although systems are not familiar to patients or healthcare professionals yet, and there are legal hurdles to overcome when transferring patient data between legal jurisdictions. Traditional business models have struggled, but innovative business models are progressing.

Connected drug delivery devices are already with us, and more are coming to market.  The idea that connectivity itself will solve the adherence problem is unrealistic.  However, for the first time, healthcare professionals will be able to identify who is adherent and who is not, which will allow them to refocus efforts on those who have the most difficulty adhering.

If you are from a pharmaceutical company or medical device manufacturer and wish to talk with us at Springboard about any medical device development questions, please get in touch.

References

[1] Iuga AO, McGuire MJ, “Adherence and health care costs”. Risk Manag Healthc Policy, 2014, Vol 7, pp 35–44.

[2] Forissier T, Firlik K, “Estimated Annual Pharmaceutical Revenue Loss Due to Medication Nonadherence”. Capgemini and HealthPrize white paper, 2016.

[3] Tyer D, “Novartis Signs ‘Connected Inhaler’ Deal with Propeller Health”. PMLive, Feb 2017.  Accessed May 2018

[4] “Network Connected Inhaler for COPD”. myAirCoach. (Accessed May 2018)

[5] Pai A, “Novartis, Qualcomm Life to Develop Connected Inahler for COPD”. MobiHealthNews, Jan 2016. (Accessed May 2018)

[6] H&T Presspart eMDI product webpage. (Accessed May 2018)

[7] Comstock J, “Propeller Health, Aptar Partner to Create Connected Metered Dose Inhalers”. MobiHealthNews, Feb 2016. (Accessed May 2018)

[8] Krebs P, Duncan DT, “Health App Use Among US Mobile Phone Owners: A National Survey”. JMIR mHealth uHealth, Nov 2015, Vol 3(4), epub.

[9] Handschuh T, “Smart Devices – How to Unlock Their Potential in the Real World.” Presentation at PDA Universe of Prefilled Syringes and Injection Devices, Vienna, Nov 2017.

[10] “Merck Serono Launches easypod™ Connect in Europe”. Merck Serono press release, Oct 2011. (Accessed May 2018)

[11] easypod® Connect product webpage. (Accessed May 2018)

[12] RebiSmart MSdialog product webpage. (Accessed May 2018)

[13] Merchant RK, Inamdar R, Quade RC, “Effectiveness of population health management using the Propeller Health Asthma Platform: A randomized clinical trial”. J Allergy Clin Immunol Pract, May-Jun 2016, Vol 4(3), pp 455–463.

[14] Merchant RK et al, “Interim results of the impact of a digital health intervention on asthma healthcare utilization”. J Allergy Clin Immunol, Feb 2017, Vol 139(2), p AB250.

[15] “The Medication Nonadherence Epidemic”. (Accessed May 2018)

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Consultancy or manufacturer?

Let us suppose you need a new product developed.  You have 3 choices:

  1. Develop the product entirely in-house.
  2. Contract a consultancy to develop the product for you.
  3. Contract a manufacturer to develop the product for you.

In the past, companies would develop products themselves, entirely in-house.  In recent years, that model has become less common as companies have reduced their internal R&D teams and looked for collaboration to bring new products to market.

In some markets, engineering and design consultancies have delivered development projects as a service.  More recently, manufacturing companies have hired development engineers and set up development labs.   This article discusses the pros and cons of each method.  If you would like to know more, or have any feedback, do not hesitate to get in touch.

Development strategy Pros Cons
In-house
  • Knowledge stays in-house.
  • Limited IP leakage (other than employees leaving, indiscretions etc.).
  • Lower cost if, and only if:
    • Team and facilities are already in place, and
    • Recruitment, training, site and maintenance costs are not in your budget, and
    • Your team is fully utilised on productive projects at all times.
  • Limited to the skillset of the existing team.
  • Psychological inertia due to historical products and constraints.
  • Large expense of keeping the team when they are not fully utilised.
Consultancy
  • Highly skilled people available. This can make all the difference between a device passing tests and getting to market on time, or languishing in endless cycles of fire-fighting modifications. Removing even one redesign-revalidate cycle can easily save far more money than using a low-fee-rate manufacturer.
  • Flexible team structures.
  • Best option for an impartial view of which technologies would work best.
  • Impartial as to which manufacturer to use: consultancies are the best option if you intend to have more than one manufacturing source for risk mitigation.
  • Some consultancies, particularly those that specialise in your industry, will have relevant up-to-date experience from other projects.
  • Can have high fee rates (particularly those with > 100 employees).
  • Might not have experience in manufacturing. You can ask who will be working on the project, and what their experience is.
  • Consultancies with internal projects might save the best ideas for themselves. Springboard does not have internal projects.
Manufacturer
  • Fee rate can appear lower than consultancies.
  • Sometimes, deep knowledge of a given manufacturing process.
  • Good at making incremental changes to existing products, but not at innovating new products.
  • It will be very difficult to transfer manufacture to another party because the design will be optimised
    for their processes, and there will be no documentation or data necessary for transfer to another company.
  • Manufacturing costs will be high because they will need to recover their costs and make more profit than otherwise to make up for Net Present Value, and their risk.
  • Most manufacturers are trying to build up their own IP portfolio. This might mean they save the best ideas for themselves, or put some of their IP into your product.
  • Limited to the skillset of the existing team.
  • Psychological inertia due to knowledge of their existing processes. For example, if the company is very experienced with aluminium tooling, can you guess what your tools will be made from, even if steel tooling would have been a better option?

Springboard moves into new premises

Fast-growing product and technology innovator Springboard has expanded into larger offices at St John’s Innovation Park in Cambridge, UK, having outgrown its space in the Innovation Centre itself.

A steady flow of new projects for international clients has required the scale-up and Springboard has built additional capacity into its new HQ.  Now, the labs and offices are under one roof in a 4,000 sq ft unit, which also has self-contained meeting rooms and reception area.

Springboard team

Springboard’s capabilities have been in strong demand, and its project portfolio has been international from day one, driven by recommendations (word of mouth) between major medical device and pharmaceutical companies, especially where they have run into problems with a medical device.  Its focus has already enabled a number of big-name clients to launch devices that they could not have otherwise, and in the process saved time and money in product development. Cul-de-sacs have been moulded into highways of success for a large number of satisfied clients.

The consultancy’s reputation for troubleshooting and technical excellence spread across Europe and the United States. We are proud to say that more than 80 per cent of Springboard’s work is repeat business.

Some problems with delivery devices – injectables for example – cannot be solved “simply by throwing man hours at it”; in-depth technical insight and world-class engineers are required. And that is exactly what Springboard has provided since opening its doors.

Springboard has put much time and effort into recruiting, mentoring and training the best team possible.  The diversity and depth of skills now far outstrips that of the founders and includes skills in physics, optics, thermodynamics, fluidics, materials science, biotech, mechanics, systems engineering, electronics and manufacture engineering. This means the company now takes on cross-disciplinary projects and creates teams that have the breadth of knowledge to ensure success.  Recruiting talented people is a time consuming challenge, but of even more importance is creating an environment in which they can flourish. The company’s focus on professional development means people have opportunities to take responsibility and grow their careers at the company.

This broad church of capability is exactly what the founders wanted to achieve – a turnkey capability in the segment, rather than being pigeon-holed simply for one area of expertise.

We believe another strength of Springboard is its open innovation culture. Springboard can provide a fully self-sufficient team to a project but welcomes input from clients either through brainstorming sessions or weekly updates.  This approach enables the client to retain control of the concept while giving Springboard full rein to suggest enhancements.  “They don’t have to hand-hold us but they get to contribute; we believe in a highly collaborative approach”.

Springboard is also renowned for its highly ethical approach to projects. Its mantra is to work on innovation that are technically challenging but also ethical and worthwhile.  Staff like to be able to say that they are working on a project that will certainly improve peoples’ lives and might, for example, lead to a cure for cancer.  This approach is helping the business recruit the highest calibre of engineers and scientists; the ongoing recruitment process is also enhanced by Springboard’s outreach activities with schools, colleges and Cambridge University.

If you would like to know more, please get in touch.

Strategies for faster R&D: Break it into manageable steps

When Edmund Hillary and Tenzing Norgay climbed Everest for the first time in 1953, they didn’t just take a giant leap for the top. Rather, they conquered the 8000 meter giant in a series of 10 centimetre steps with manageable milestones along the way.

Everest

An R&D analogy is a company who had spent years developing a new biopsy product in which a rotating blade advanced over a needle used as an anchor. The samples were small and unreliable, so customers were losing confidence. They had tried a bigger motor, sharper blade, different shape, but to no avail. Generation 4 was on the market but still too few customers.

Instead of leaping immediately for a whole new design, we broke the challenge down into a series of steps. How strong is the anchor force? How big is the cutting force? Which is larger? These could be measured simply on a standard piece of laboratory apparatus called a tensometer. When the graph was plotted, we could see that the cutting force was far greater than the anchor force, so the device was just recoiling every time it fired.

So the next steps were: how can I make the cutting force smaller? How can I make the anchor force larger?

Breaking down the problem into steps like this means you then spend your time solving the right problem. It might feel that pausing to do a sequence of scientific experiments adds time compared to aiming straight for the whole answer, but in reality it is often possible to find a much quicker route to success. If every step is in the right direction, you’ll arrive at the answer. But if you spend time solving the wrong problem, no matter how elegantly, you get nowhere.

This is an approach we’ve done for our clients many times over, and the savings can often be measured in years.

Please contact Keith Turner if you think we could help you or if you would like to be alerted to the next strategy.

Strategies for faster R&D: Save tooling for later

There’s a great quote by Thomas Edison when asked if he felt like a failure because of all his failed attempts to invent the electric light bulb. “Young man, why would I feel like a failure? And why would I ever give up? I now know definitively over 9,000 ways that an electric light bulb will not work. Success is almost in my grasp.”

Lightbulb

And not one of those 9,000 prototypes was made on a production line.

A situation that our clients commonly find themselves in goes a bit like this. “Yes, I know it’s not quite working yet but time is running out before the product launch next April and so we have to commission the tooling now. Management aren’t willing to let the launch date slip.”

It brings to mind a medical project in which the disposable part had been pushed through to injection moulding. The trouble was that revisions to the design were still being made. It was possible to modify the tool, but each time that happened, it took six weeks to get the next parts released before they could be tested.

Earlier in the same project, we had been prototyping the disposable component on our CNC mill. You could do a test, modify the CAD, set the mill running overnight and test the next iteration the next day.

Short development cycles demand flexibility, and for this it helps to delay tooling until you know the design works in all respects except for those specifically dependent on tooled properties. Even if you need 100 parts for a clinical evaluation, perhaps they can be machined? It might cost $10,000 and some planning ahead in validation, but that’s child’s play compared with a 12 month delay to a multi-million dollar programme.

There’s a whole suite of prototyping methods available today, such as additive methods (SLA, 3D printing, SLS, vacuum casting…) and subtractive methods (machining, laser cutting, EDM…), not to mention various ways of sealing, bending and so on.

In the next article we look at how to break down a daunting, complex problem into a series of manageable steps.

Please contact Keith Turner if you think we could help you or if you would like to be alerted to the next strategy.

Strategies for faster R&D: Change one variable at a time

 

When the Wright brothers were trying to make their great aeronautical leap forward, they didn’t just throw feathers and motors at the problem to see what happened. Rather they tried to determine which of the three key challenges to mastering flight was most critical: wings, engines or control? Looking at the effect of changing one variable at a time helped them to determine that the critical weakness was in control, meaning that they could innovate in this aspect and set the way to their landmark achievement.

Wright brothers

It brings to mind a project where we were developing a cryosurgery probe to kill breast tumours by freezing. We had a functioning system that worked off a heavy gas cylinder but had recently made the exciting discovery that a simple 1 litre flask could be used to drive the probe directly from liquid nitrogen. This was easier to use, smaller, and cheaper, and so a sure-fire commercial advantage for our client. However, when we scaled our new technology up to full size it didn’t work. It wasn’t just slow, it was completely hopeless, and failed to get even remotely cool to the touch. Yet the only difference was the size.

But was it? The new flask was bigger, that’s true. But actually, the bung that sealed it was also a larger diameter. It was also deeper. And it was a different material. And the dip tube was longer to reach to the bottom of the larger flask.

On reflection, there was quite a lot different about the new system, and we had changed it all at once. This meant we didn’t know which thing we had to change to resolve the problem. There was a deadline approaching, and it was tempting to just jump to the end and try stuff in the hope it would work, but with planning we figured that we had a chance to solve the problem in two weeks by starting with the working miniature system and changing one feature per day until we had created the large system. 10 days, 10 features- surely one of those would be the key?

On day 1, we machined a new bung for the small flask out of the same material as we were using for the scaled-up system. It worked perfectly. On day 2 we scaled it up to the larger diameter- still great. On day 3 we extended the dip tube- still chugging along nicely. On day 4 we machined a deeper bung… nothing. A complete failure to freeze. It was now a simple deduction that the deep mass of rubber was sinking heat into our cryoprobe and preventing it from freezing. We added insulation around the tube as it passed through the bung and made ourselves a perfectly working full-size system. All in less than a week, which means we still had time to write the final report for our client who was visiting the next week.

This technique is widely used in science, and is particularly powerful when you have one prototype that you know works, but can’t figure out why another comes up short. If changing one variable at a time does not reveal the problem, there is probably one or more interactions between the variables. We can use techniques in a field of engineering called Design of Experiments to reveal them, but that is a subject for another day.

In the next article we look at how to speed up the development cycle by saving tooling until later.

Please contact Keith Turner if you think we could help you or if you would like to be alerted to the next strategy.