See a need, fill a need: medical invention in the 21st century
See a need, fill a need: medical invention in the 21st century
Dr. A. Shaikh
The historical article on the development by Dr Brain of the laryngeal mask airway  shows for the first time what the processes were for the introduction of a new airway device some 30 years ago. The authors of the paper state that it would be ‘interesting to speculate whether such research would be possible under today’s more stringent conditions’. This paper is written in response to this statement and will describe current research when compared with the conditions and environment that Dr Brain worked in. New airway devices are such as the Tulip® airway (The Age of Aquarius™, UK) are manufactured and researched under stringent conditions and the time taken from seminal thoughts to production has taken some 18 years. Texts on the process of invention are limited and must serve to describe the process of medical technology development to practitioners as invention is not taught but must be self-learned by trial and error so a comparative update is timely.
The changes that effect such new developments in the modern world are many and include new ethical systems and guidelines, new research and development requirements, the changing faces of the patent application and grant processes, new material sciences, the role of companies and the validation of manufacturing and production systems for international device regulation. It must be noted early that absolutely none of these new developments are helpful in fast-tracking superior medical technology to anaesthetic practice and all have added significantly to the time and expenses consumed in producing and testing a new airway device for clinical trial and peer review.
The historical article describes for the first time why and how the LMA was invented and it beautifully justifies why the name Laryngeal Mask was adopted as it was eminently suitable for a (Goldman) mask placed over the larynx. The article also clearly describes the mechanics of the engineering solution for the problem adopted by Brain, again for the first time. Brains clear objectives are a standard of invention, as is the process of prototyping by self-construction and model building by the inventor. The article describes that the LMA did function well when first used in 1981 at the William Harvey Hospital, Ashford, offering Brain a welcome ray of hope and justification to continue in his endeavours. Such an event would be considered anecdotal these days but in the light of the LMA’s success globally we can clearly see that it was an important event in the history of Anaesthesia as a science, so much so that a retrospective account of the LMA defines the moment in a peer-reviewed journal.
What does the modern inventor have to do now to achieve the same objectives and develop a new airway device?
See a need; identify a problem in existing practice
Our premise for the Tulip® airway was that the Guedel airway and face mask is difficult to use so largely cannot be used by non-anaesthetic inexperienced users, is not hands free, cannot be secured in-situ and is not directly connectable to any breathing circuit or ventilator. The LMA addresses this issue but largely only does so in the hospital with experienced users for elective surgery. In the last 30 years the LMA has largely been unsuccessful in extending its capabilities outside the hospital environment. This is because the research [REF JAMA/BMJ] shows that endotracheal tubes and supraglottic airways increase the incidence of a poor neurological outcome when compared to the Guedel/Mask technique when used in out of hospital cardio-respiratory arrests. We still need an airway that anyone can use and use well on anyone in an out of hospital or home resuscitation scenario.
Fill a need; Prototypes
The early indications of any new idea set the trend and are clearly important but every idea, even good ones like the LMA, take time to perfect. Would it be possible to emulate the very best and test a new technology sequentially using the described 130 LMA Classic prototype method in the modern day? We think the chances of success using this method are more limited than they once were because of escalating costs and because modern practitioners are now told to resist new developments at a similar stage of development until a greater volume of published and statistically significant evidence is available. This is unlikely with prototypes and is in effect an authorized resistance to new technology. We believe that this recommendation desirably raises standards, but we also believe that the recommendation leads to an expectation of new technology being perfect from the outset. Sequential testing, like the LMA, would now be more difficult as a direct result of the very reasonable suggestion that new technology be backed by published evidence before its use can be considered for the very first time. This is expectation is unrealistic for device development, as the LMA’s development process reveals. Even the account of the LMA’s development says that “in practice” developing a “suitably effective device…took several years” and it must be remembered that its use at this time was not supported by any significant publications but the anaesthetic collective was still contributing to its assessment. This no longer occurs. With the LMA many people used it and researched it so many were quickly convinced of its advantages. They then passed the LMA knowledge on by word of mouth and personal recommendation, something that is not given easily. This is no longer possible.
Development issues similar to those still suffered by the LMA after 60 prototypes may today limit the use of the new technology and therefore reduce any research in to it. Mistakes are less well tolerated than once they were. That is in no small part because of the increase in litigation, which is another key escalation since the days when the LMA was developed. Indeed most of the extra regulation that now exists is because of this single factor. It is clear that even with a globally effective device such as the LMA, the idea took time to perfect. Intuition is important in invention but it is unlikely that any inventor gets everything right first time. In invention mistakes will be made, even if you’re Archie Brain making the LMA.
Collective and research
The anaesthetic community is the research tool of choice. Without it the research cannot happen because the collective is part of the research process, as shown by Brains LMA and its uptake by self-assessment once access was granted to all. The collective will self-select those who are happy to use the new technology and act as opinion leaders for any research of the new technology and teach others. That is the normal way of things but the normal process has now been interrupted in the modern era by the demands for evidence before it is engaged for new technology. If engaged, the collectives combined publications will reveal both benefits and complications of new technology through experienced hands and the meta-analytical view will reveal the truth, as it did for the LMA. The recommendation is that the collective be re-engaged for new technology so that the facts can be accurately ascertained by assessment by those who are happy to do it. The historical article accepts that it would be “difficult to do this today”, yet it still needs to be done.
Essentially, this publication threshold limitation of new device access for use prevents those who can and would from using the new technology, limiting any further research opportunities and adding to the delay in further use. This broad availability was essential to the LMA’s success and this consequently reduced patient mortality and morbidity. The most essential of objectives was achieved through self-regulation not over-regulation.
We must be aware that unrealistic expectations effectively close the door on new technology for the next 10 years as it laboriously gains traction and accumulates data and that this will be the case even if the new technology is very much superior to its contemporary devices. We do not disagree that evidence is safer and optimal but this situation needs addressing if new technology is to be allowed to develop for without it the research team closely associated with any new development will have to manage on their own, increasingly isolated and laboured down further with the other significant hurdles that now exist that we will describe further.
The LMA pilot study (REF) was conducted after ethical committee approval but there was “no constraint with regard to the numbers of patients studied, so that Brain felt able to continue his investigations until he reached what he felt was a suitably effective device”. This is possibly the greatest difference between the times when Brain developed the LMA and our current position developing the Tulip®. The Tulip® was first approved for clinical study by the ethical committee in March 2007 but it was still not authorized for clinical use as it was classed as an experimental device.
Medical Healthcare Regulatory Authority (MHRA) and CE marking
Only after a lengthy and detailed MHRA approval process involving 6 months gathering the relevant evidence from multiple companies (device manufacture, sterilization, bio-burden assessments, bench-top testing, valve manufacture, computer aided design etc.) plus a 9 month MHRA grant process was the Tulip® finally given the required authorization for clinical testing but no mention is made of any such regulatory hurdle for the LMA.
The MHRA approval process for clinical use included the manufacture of specifically dedicated experimental devices printed and labelled with the words “Exclusively for Clinical investigation”, the bench-top testing of the Tulip® to destruction (MeDEC 2007, £450 fee) with a test report, a comprehensive validation of the manufacturing processes, plastics, inks and clinical bio-burden, which is the post-sterilization microscopy and culture examination of bacterial indicators placed into the device before sterilization. Only after submitting a file of some 242 pages and submitting a fee of £1600 was MHRA approval given for the Tulip® to be used in clinical investigation for the first time (2007). In addition to this regulation the Tulip® was CE marked at a cost of approximately £15,000 and 6 months in 2009, again no mention is made of the LMA being CE marked, though the article does delineate the LMA’s 3 year USA FDA approval process. The modern inventor must be “as one” with these MHRA and CE marking requirements before there can be any possibility of clinical testing in Europe these days.
Model changes impact CE marking if the device is CE marked and not MHRA approved, as MHRA approval is not required if the prototype technology is CE marked. This CE process is even more complex as it involves a third party called a Notified Body. The Notified body is authorized to manage the CE marking process and regulates the technology and authorization of the new technology for a sizeable fee (£15,000 approximately). Certain international standards such as ISO 9001, ISO 868, ISO 10993 and ISO 13485 have to be met in any such CE mark application with documented evidence required for every aspect of device construction and packaging. The new devices plastics and printing inks must be approved for biocompatibility, production techniques must be known or new technologies described in detail, sterilization and packaging must be validated, tested and proven to be effective. It is not uncommon for many parties and contractors to be involved in the process of evidence submission as components such as plastic and printing inks are not usually supplied from the same sources so the certification required must come from the many suppliers of the devices individual components. Interactions with the Notified body are likely to incur costs to the inventor and as such 130 different prototypes for consideration would be expensive almost irrespective of the costs per discussion, hence the ability to manufacture 130 prototypes is considered improbably expensive today, but it is not impossible.
Cost and delay
Whilst we accept the need for such searching questions for medical devices in the modern era, the time spent (+/-1 year) is of the greatest detriment to new technology. At this stage the Tulip® patents had been applied for with initial grants having being received but significant annual patent fee costs having accrued since 1994 in addition to manufacturing and design costs. Regulation is expensive because new technology is very time sensitive. Time really is money when intellectual property is involved, not in terms of lost profit but in terms of the actual bottom line costs to the inventor as patent fees are payable annually and are in the tens of thousands of pounds per year. It must be remembered that it is unlikely that enough evidence exists at this stage for any new technology to have achieved industrial backing prior to its first clinical use, so these extended costs are likely to be bourne by the jobbing inventor personally whilst running on a family mans salary. A similar problem was faced by Brain when the reticence of UK companies forced him to consider the Seychelles and Robert Gaines Coopers plastic bottle factory. Modern day companies require the same kind of evidence we as Anaesthetists do before they support a device, but then how is the inventor supposed to achieve those results without access to manufacturing? The only possible answer is for the inventor to invest in themselves, just as Brain did. It becomes apparent that the inventor is one of “us”, and not one of “them” and may require assistance and support from our community if we are to advance as a collective. It is natural for a Surgeon to develop a new method of surgery so how is an Anaesthetist developing a new method of airway management any different?
Expertise and inventors as authors
The article describes the inventor’s role as “expert”, in inverted commas, but in the modern UK the sentiment is against the inventors papers as they are considered to be in some way biased. This is considered an injustice because the inventor is the expert, as Archie Brain is the undeniable expert of the LMA, without inverted commas. The inventor must describe the new technology in detail, outlining their theory first and then their solution backed by clinical evidence if the reading world is to fully understand their objective, so tainting their work as biased in some way is in itself prejudicial and as such should be considered unacceptable. As expert the USA prefers the inventor’s papers as the fullest description of the method but in the UK the same is not the case. This is a problem faced by the modern inventor in our territory, how do you write a worthy paper without doing it yourself? That is quite a hurdle as the inventor cannot now work alone in the modern era and needs an open minded and particularly dextrous individual with the ability to visualize to be the first independent user free of the inventor. The inventor then has to work through a series of improved prototypes with that very specific individual in order to perfect the new technology second hand. This was very much not the case with the LMA that in a short sentence describes the many years of ethical approval and paperwork that are now required.
Study numbers and statistics
The first study of the LMA in 1982 was only in 23 patients and the device demonstrated a 3/23 (13%) sore throat incidence. Such a study would not be published now as the protocol would not have passed the ethical approval stage as it would be considered inadequate to provide any statistical significance in its analysis. The second study was of just 6 patients. Our objective is not to criticize Brain in any way but to highlight the adequacy of his investigations despite none of them matching our contemporary expectations of what constitutes a sufficient due process and yet the results of his work are exemplary. If the LMA can be achieved with Brains process perhaps we should study the LMA process as well as the LMA device because new ideas are easily suffocated.
NHS Research and Development Departments
For the Tulip® an independent statistical analysis plan was required by the ethical committee at a cost of £2500 and this stipulated a minimum cohort of 75 patients for the very first Tulip® Pilot Prime study. This analysis was then further supported by an independent statistician and by a peer-review, both of which were submitted with the ethical committee application for the Tulip®. Such statistical reports and analysis are now required by the ethical committees to show the very minimum patient numbers that are required to achieve any statistical significance in result analysis in order to minimize patient exposure to study. It should be revealed that the ethical committee received 3 applications and 2 amendments for the Tulip Pilot Prime Study before it was finally completed in September 2012. The first ethical grant was received in 2007 but the implosion of research and development as a hospital department nationally at that time significantly hindered research applications and we could not commence our clinical study as had previously agreed with the Research and Development (R+D) departments at the relevant hospitals. This meant relocation, reapplication and some 3 years lost prior to a recommencement of research in-vivo. No research and development authorisation was required at all in the LMA’s era it seems.
Ethics, resubmissions and research
Ethical and R+D approvals increase time expenditure but they also hinder new technology by deliberately seeking to reduce experimental patient numbers, which is an issue for any device like the LMA requiring sequential assessment during its development. Contemporary recommendations suggest that approximately 250 patient subjects are required for evaluation in any study before its results can be accepted as reasonable, but statistical analysis plans are now required by ethical committees to show the minimum numbers of patients needed to achieve possible statistical significance in any study not the maximum number. So these two requirements act as being mutually exclusive.
After that first cessation of in-vivo study we published a manikin study that was presented at the AAGBI, Torquay 2008 and published in “Anaesthesia” (REF). A second in-vivo Tulip® study was then authorised with new clinical investigators and a new investigation site. However after commencing the study it was noted that the Tulip® performed much better than expected with a very good airway seal and hence a ventilation pressure and tidal volume well in excess of other comparable technology. This meant that tidal volumes were in excess of 1000mls in some patients at the protocol stipulated ventilating pressures (20cmH2O). This then meant in order to change the protocol we had to suspend the in-vivo investigation after studying 18 patients and resubmit an ethical application with a modified protocol and ventilating pressure, despite the Tulip® performing better and not worse than expected. From the historical article it seems that the LMA was still on its first ethical approval grant for clinical investigation at a similar time in its development. The time spent on the writing and preparation of any ethical application is known by those who’ve spent time doing such applications and should not be under estimated by those who have not. The Tulip® also out-performed in its first clinical uses but the time getting to such a stage of evidence took considerably longer as thus far we can account for at least 4 years of delay for the Tulip® through additional regulation alone. In a similar time Archie Brain made significant headway with a life saving device.
The LMA was first used in the summer of 1981 and Brain published his first descriptive study of 23 patients in 1982. By February 1983 the LMA “had been used in about 1000 routine patients” despite still being a prototype, yet even after 1000 patients and 70 prototypes the article describes that the LMA’s “most pressing problem was to understand the cause of airway obstruction and leaks”. This is not unexpected by the inventor because all airway components such as the inflatable cuff and breathing tube need separate assessment, consideration and modification which takes both time and accurate investigation, but these residual issues could be considered unacceptable underperformance for any new device after 70 prototypes in the modern world seeking instant perfection. This many multiple failures, in a modern world, could even be used to stop any further assessments of the new technology based upon any such underperformance as it could be argued that these two parameters are the most basic requirements from an anaesthetic airway device and failure in either parameter increases patient risk, unacceptably so, especially after 70 attempts. Such a decision could be viewed as entirely reasonable by all those who do not subject themselves to the process of invention. In the case of the Tulip®, such data is required by the ethical committee on an annual basis as a written report on progress of the clinical study as part of the conditions for ethical grant which was not required with the LMA to best our knowledge.
This performance of using the LMA prototype technology in 1000 patients over a 20 month period is not considered possible now. With current regulation as it stands, it is considered unlikely that the invention team would be able to jump all the regulatory hurdles, provide enough published evidence in order to extend the research to other teams or cover those patient numbers alone in a similar 20 month timeframe. Even to date the independent team assessing the Tulip® at Northwick Park Hospital has been unable to cover 1000 patients despite 3 years of regular clinical work, with some 750 patients having used the Tulip® at Northwick Park Hospital over the last 3 years and some additional 200 being investigated in Germany, Belgium and France by other independent teams. Patient consent existed in Brains LMA development days but is considerably more informed now with the requirement for patient information sheets and signatures in triplicate for studies.
By late 1983 the 70 LMA Goldman prototypes had become “obsolete as the design changed”, with Brain testing “more than one different design in a day”. Later the article states that the following latex prototype was first tested in August 1986 with another 60 different latex designs being constructed for clinical testing over the next 6 months. This then gives us a minimum prototype count of 130 LMA prototypes by the end of 1986 for the LMA Classic alone. The Tulip®, in contrast, was both manikin tested and clinically tested with its first prototype, which was multi-sized and had a fixed angle on its PVC breathing tube. This first prototype was first used by Dr. Sally Harrison in 2007 at the Royal Free Hospital, London. The following year we published (REF) and presented a manikin study (AAGBI September 2008) from the same site using the second preformed silicone tubed Tulip® prototype, which was now a one-size-fits-all-adults device with a smooth, non-angled silicone breathing tube to counter any airway obstruction. Just like the LMA the use of a smooth preformed silicone tube made a significant difference to the Tulips performance but this prototype was never clinically tested in-vivo due to regulation issues with local research and development departments. Then both a manikin Guedel cross-over study with inexperienced users and the first clinical pilot study were completed using the 3rd prototype which now had the same type of smooth, preformed breathing tube as the second prototype but it was now made of non-phthalate (DEHP Free) PVC. This 3rd prototype was first used by Dr. Neville Robinson in January 2010. A clinical pilot study was attempted but aborted because of the Tulips over-performance in 2011 after the study of 18 patients, with a manikin Guedel cross-over study and the first clinical study being completed in May and September 2012 respectively in the hands of Dr. Neville Robinson at Northwick Park Hospital, Harrow.
The manikin Guedel cross-over study was presented at the AAGBI in September 2012 and was still awaiting publication at the time of writing. The first in-vivo clinical study was submitted for publication in December 2012 using the third prototype. The Tulip® is now in its 4th generation of the one-size-fits-all-adults Tulip ® with a shorter, smooth, preformed oval tube and dedicated improvements to the cuff, connector and tri-coloured guide markings. This is likely to be the last prototype as the performance of the device is now as theoretically expected, so much so that in 2012 after sufficient testing and analysis a second sub-type of Tulip® similar to the first prototype with a fixed angle bend on its breathing tube was produced with the introduction of the Tulip GT® (Tulip Guedel Type) specifically for inexperienced users. Both the one-size Tulip® and the Tulip GT® are now in their final form and await the fitment of a pressure release valve (PRV®) to assist in cuff pressure regulation and ease of fitment for inexperienced users.
Such prolific prototyping with 130 LMA Classic prototypes is considered unviable these days with design changes having to be costed and constructed. But these prototypes must also now be resubmitted for approval by both the ethical committee and the MHRA prior to any use, so in the LMA’s case at least 130 MHRA and 130 ethical committee written notifications of some kind would now be required with it being considered unlikely that any two such grants could co-exist to allow “more than one different design in a day”. Both the MHRA and the ethical committee are unlikely to grant any 2 simultaneous devices for use like this as they are likely to argue, reasonably so, that the results from the first investigation should be known before the second is authorized. The MHRA is also unlikely to authorize anything other than professionally constructed equipment. We do not wish to unfairly condemn the MHRA in any way as it was eminently helpful in the preparation and process involved with the Tulip® application but it must be understood that the investigation is detailed, contrary to what we are sometimes lead to believe by those who have never had to write one.
There are additional expenses incurred in these 130 prototype changes but their magnitude depends not only upon their frequency but also upon both the modifications made and the technology involved in the design changes. Both tubular and inflation line modifications are relatively inexpensive as they are based upon extrusion technology that can be bought from suppliers “off the shelf” but blow-moulded cuffs are usually unique, as they are for the LMA and must be custom made. Blow moulding technology changes carry an additional premium to being custom made because of the re-tooling that is required to modify or change completely the solid metal moulds that are needed for the manufacture of different inflatable cuffs. It is possible to enlarge the cavity within the tool to create a larger cuff but it is not possible to reduce it in order to make a smaller one. The tools are metal moulds into which hot plastic is blown to create a balloon of differing forms and are created in aluminium first at a cost of approximately £2-3000, depending upon the size, and then in steel when the design has been confirmed for production (£5-6,000 approximately). This two stage manufacture of tools occurs because the hot injectable PVC used in blow moulding is very corrosive to the aluminium of prototype metal tool moulds causing the mould surface to degrade after about 1000 units, making harder steel tools necessary for larger production runs. Such costs have probably become fractionally cheaper due to computer assistance for design, emerging markets and additional competition.
Computer and technical equipment advances
It is interesting to note that the use of modern silicone technology by the Dunlop Rubber Company for the LMA’s cuff and by the Bivona company for the LMA’s breathing tube in 1984 made such a big difference in the performance of both the LMA’s cuff and its tube. This is a place where the modern inventor has an advantage. The use of new technology in all aspects of manufacture has advanced greatly with the introduction of silicone and phthalate free PVC (DEHP Free PVC) and the concurrent cessation of vulcanized rubber and latex based materials. Additionally the modern inventor has access to significant new computer based technology such as brand new 3D printing technology at high speed and low cost for prototyping solid samples and they now have access to Computer Aided Design (CAD) which enables good visualization prior to the expenditure of manufacture. These are accepted advantages that did not exist in the early development of the LMA.
The need for new technology and its role in accelerating further new innovation is proven by the significant role of video able smart phones, digital photography, laptops, colour printers, home broadband and software packages such as ADOBE’s Photoshop™ and Microsoft’s Word™ for the modern inventor, as for all of us. Such global developments allow the production of professional scripts, presentations and illustrations from home now but this was practically impossible during the development of the LMA. In delineation of the design and the theory the modern day inventor has significant advantages over what was on offer to Dr. Archie Brain. The global communications revolution now provides the inventor with the ability to communicate world-wide via the internet and text messaging in real time to remote locations at a much reduced cost but greater speed.
Manikin and simulation advances
Other technology has also become manifest with the availability of more realistic manikins (Trucorp® AirSim, Ireland), which is also an advantage over Brains position 30 years ago. The availability of a wide range of different manikins (Trucorp®, Ambu®, Laerdal®) allows the inventor to simulate the function of the device and extrapolate the findings for Human use. These studies have been negatively received by some members of our community (REF) but we feel that this is unduly prejudicial as the use of simulation has been confirmed in a number of professions requiring accurate training and performance. The Tulip® manikin studies (REF) demonstrated good correlation with its actual in-vivo functions in the Pilot Study by demonstrating a good seal and high tidal volumes with a high ventilating pressure, so much so that we had to stop the initial in-vivo clinical study and down-regulate the ventilating pressures and tidal volumes for patient safety before we reapplied for ethical grant. These manikins safely allowed the Tulip® to be tested to its limits by generating in excess of 100cmH2O IPPV with a complete ventilating seal in manikins without exposing real patients to such excessive and possibly fatal ventilating pressures. Additionally, the manikin studies demonstrated ease of use (REF) and inexperienced user viability (REF) when compared to the Guedel and Facemask combination with statistical significance seen for the reduction of assistance required for the Tulip® and the increased tidal volumes delivered by it. Whilst actual in-vivo investigation is still seen as superior the manikins did allow the study to be conducted without any harm to patients from inexperienced users. This is another accepted advantage over Brains LMA process.
The LMA was first independently studied in the same department as the Tulip® is being studied in now, Northwick Park Hospital, Harrow. Professor Nunn published its first wholly independent clinical trial in 1989 from this location and like the LMA Classic, the Tulip® is exceeding all expectations 23 years later, but what is the implication? Within 3 years the LMA had been used in “at least two million patients” and word of its efficacy had spread by word of mouth and personal recommendation peer to peer. This is the essential reason that the LMA became so successful but it isn’t possible now. It was independently tried and tested by thousands of anaesthetic users who tried the science for themselves to see what it was that they could achieve with the new technology now on offer freely. This is a significant difference from our modern world as similar access granted to the LMA has now effectively been denied to new technology. It must be remembered that in our era regulation alone has delayed the Tulip® by at least 4 years in the last 6 before any further delays are added to the developmental timeline. It is always possible to do better, even with regulation, but this is an article of actual events in a contemporary world which is increasing its regulatory hurdles.
This lost time is important because regulation is not the only source of delay now to be experienced by new technology and its modern inventor. Significant additional time losses were incurred by the Tulip® through the anti-competitive actions of companies who acquired the Tulip® intellectual property in order to deliberately “put it on the shelf”, a sharp business practice that any inventor focusing on patient care may be ill prepared for. Such behaviour is common in industry to protect profit margins from competitive devices that may threaten a defined market. Whilst it is common, the ethics of suppressing potentially safer medical technology for financial gain is very questionable. Such action is in fact illegal through anti-competitive laws, if the inventor can afford to prove it. The Tulip® lost a total of 8 years through such practices as companies recognised the possible threat the Tulip® posed to the marketplace with its one-size-fits-all-adults ability, its unique pressure release valve (PRV®) and its ability to generate lower cuff pressures and higher IPPV pressures than any contemporary device. The biggest threat to the status quo, as recognised by the companies involved, was the significantly smaller size of the Tulip® design, because with a small size comes a cheaper production and sale price. Such engagements, however, can be used to inventor’s advantage with some on-going activity to assist the development of the new technology still occurring. Companies are useful in assisting with a number of procedures which may include patent applications, computer aided design work, tool construction, manufacturing, MHRA applications and the CE marking process. Once contracts are signed it is difficult for any anti-competitive company to do absolutely nothing so this can be used to the advantage of the new technology. Costs of patent applications may still be met and early development paid for so progress may still be made, even if it is at a deliberately reduced rate. The modern day inventor needs to be prepared for their work to be used against them, be aware of such actions and adjust accordingly.
Companies vs. self manufacture
Comparing modern times with the LMA era, this type of anti-competitive action could happen at any time in history. Brain was not actively held back by any companies, but he was rejected by most of the world’s largest medical companies despite approaching them with the LMA idea. He in fact engaged with a plastic bottle producer in the Seychelles called Robert Gaines Cooper, who made his fortune with jukeboxes in the 1950’s and 60’s. It is this company started by Robert Gaines Cooper for manufacturing the LMA that we now know as LMA®, the company that was listed on the Singapore stock exchange in 2005 and the company that is still the supplier of the original LMA world-wide.
The story demonstrates that the inventor may well be rejected by a number of appropriate companies because it is unlikely that the company board will fully comprehend the full complexities of inventive Anaesthesia, even if it is the LMA. In fact, it now seems to be an odd boast in medical industrial circles to say that they were one of the companies Archie Brain approached. The implication is that they declined to manufacture the LMA, which is not something we consider worthy of pride or publicity, yet is a story told regularly by people working for many global companies. It seems that irrespective of the idea the inventor should be prepared for rejection at any date in time.
Consequently any company relationships should be considered carefully, with the inventor concentrating upon what happens after any possible signing of contracts with an interested third party, rather than the signature itself. Commercial sharp practices continue in other forms, such as requests for copies of patents and detailed grant dates, a request for a full briefing about the technology and requirements to do “due diligence”. Caution should be applied prior to any engagement with commercial interests as the “knowledge” has significant fiscal value which may be given away by ill prepared inventors. Nothing whatsoever should be revealed without a detailed and professionally sanctioned non-disclosure agreement (NDA) that stipulates what is protected and for how long being signed before any discussions take place. Lawyers don’t come cheap so prospective inventors should expect significant costs in order to communicate with industry. Additional costs will be incurred if the intellectual property (IP) development is run as a business, such as accountancy and set up fees.
Popular culture shows reveal some of the possible routes to success but venture capital and business angels are best avoided. These relationships tend to be prejudicial to what actually needs to be done and tend to significantly undervalue the IP and any possible future benefits, to the detriment of the inventor. Investors of any form tend to stick with what they know and are therefore unlikely to understand the nuances of a particular medical technology irrespective of how many advantages it demonstrates. A better solution is for the IP holder to partner a medical manufacturing company with world-wide distribution, but this also has its pitfalls as large international companies have thousands of products and the new technology will be just another. Communication with mega-companies is slow and can take years, even after which success is still not guaranteed.
A possible better solution is to contract manufacture your own product, which is a beneficial stance for any inventor as it gives manufacture control to the inventor as customer to the firm contracting the manufacture of the new technology, but finance will be required. Finding such a manufacturing partner is easier today than in Brains LMA days with internet availability and cheap commercial flights but finding the right partner remains as elusive as ever it was. Any sub-contracted manufacturing must also be done under NDA because the inventor must remember that any company involved will hold the “crown jewels” of their intellectual property in the form of the actual know-how involved in the manufacturing, as well as any CE mark required for its clinical use. Personal investment will be required unless the inventor signs an agreement with an industrial partner on the first day of the ideas conception so multiple strategies are best employed early.
Costs of invention
The development team suggested that a more detailed outline of actual invention and development costs may be useful to any other medical practitioner in the position of embarking upon the creation of new medical technology and as such may assist in that endeavour. It must be made clear immediately that the potential financial costs are significant and that any such undertaking may be potentially threatening to the fiscal balance of a working Doctor. It is unlikely that the inventor chose to invent and as such is unlikely to have access to the funds required. This usually means that support must be sought from the outset, at the moment of conception, once such discussions are covered by a legally binding NDA (non disclosure agreement), otherwise the lone inventor may well run out of money, which will jeopardize any patent protection that may have been achieved.
Initially, the inventor will meet the concept of intellectual property (IP), the patents that protect it and their application and grant processes. The IP and patent costs are multiple because Patent Attorney, patent application, patent grant and patent annual renewal fees are payable in an on-going manner because without annual renewal fees being paid all granted patents will expire. Initial patent applications require the assistance of a competent Patent Attorney, but this engagement is critical as this relationship may span the full duration of the 20 years patent so must be managed effectively. The Patent Attorney must understand what it is the inventor is trying to convey and write a specific and strong patent application claiming the outlined benefits, with exact technical features outlined in detail, including dimensions and methodology for the new technology to protect the inventor’s new claims. The initial set up fees for patents include international searches of other patents world-wide to make sure that the idea is viable and has not been applied for before. These searches are conducted by the Patent Attorney at a cost to the inventor (£1-5,000) and such costs are defined by the extent and thoroughness of any searches conducted. Once the inventive claims for the new technology have been confirmed a patent application must be written. This usually requires the assistance of graphic artists as even a talent in art will not be enough for the inventor to outline the details required in the professional manner that is required. In total the inventor can expect to spend approximately £5-10,000 in writing their first patent application and submitting it for consideration. Annual renewal costs are in the region of £10-20,000 per year for maintenance of patents on a global scale. If company contracts have been signed, any such patent and intellectual property (IP) costs may be charged to the company assisting the inventor. Total patent costs over the duration of the project (5-10 years) will be in excess of £100,000 approximately, depending upon the range of territories covered by the IP protection.
For extending the initial patents from a single geographical territory to a global IP grant involves individual applications being filed in each country, with the European Union using a combined application process. Each application carries a cost and each cost is annual. It must be understood that the patent process is slow as the patents are granted in each territory individually after examination. By way of example, the Tulip® Japan patent took 13 years to achieve grant. In the process of inventing the Tulip®, international patent and IP laws were changed. It is now the case that patents extend from the moment of the first application date so the inventor now has less time than ever to develop their technology than in the days when the LMA was invented, despite it now taking another 3-5 years before any new technology can become available for practitioner assessment.
If the inventor funds the initial development and production of the new technology, the costs will be in the region of £50-100,000 for a production of a clinical prototype and certification alone. This large sum includes travel, meetings, flights, petrol, parking, hotels, telephone and broadband costs, computers, printers and their expensive inks, paper and reproduction costs. The total sum includes initial samples, bought volumes (£1-10,000 depending upon unit price), changes in tooling (£2-5,000 per change, LMA 130 changes), changes to packaging and printing (£1-5,000), MHRA application preparation (£3-5,000 approx.), CE marking (£15,000 approx.) and numerous other costs which include legal representation for NDA’s and other contracts (£20,000 approx.). The total cost of development may well run into hundreds of thousands of pounds and when patent costs are included the expenditure is in significant fractions of millions that rise with the duration of development at a rate of £10-50,000 per year approximately, depending on the technology being developed and the extent of its IP protection.
It must be noted that the costs of advancing medical science may be bourne personally by the inventor, much as Dr. Archie Brain did, so should not be taken lightly as private capital outlay has its reasonable limits. The business case for invention in medical technology is now contracting fast so financial considerations are unlikely to be the motivating factor in such endeavours. This should be recognised.
Manufacturing and Companies
After the IP has been adequately protected, the process of development may begin. Usually the inventor has no access to manufacturing. This may be challenged by teaming up with a company with such capabilities, but it is unlikely that industrial support is available for an idea on paper. This dilemma is not insignificant and will be solved by self-financed options. The only realistic way to manufacture the new technology for certification and testing is to contract the manufacturing requirements to a company with the relevant manufacturing technology. As such the inventor must now involve themselves in production engineering for the next 3-5 years. These skills must be self-learnt and all mistakes have a significant financial and time cost.
The manufacturing method and the technology specifications must be understood by the inventor, in detail. This means the inventor needs to understand how the various components of their new technology are actually made and which types of process are used. For example, the airway inventor will have to find a blow-moulding manufacturer for inflatable cuffs, a plastics extruder for tubes, a supplier of check-valves that may be bought off the shelf, connectors of the right specification and then someone to assemble them, package them and then sterilize them effectively whilst proving it. This may be available at one site and by one company but each new technology will require different components and each may be made or supplied by a different company.
Companies with all the relevant technology in one place are likely to be manufacturing and selling the current, profitable, competitive devices to the inventor’s new technology, so these companies are likely to be the inventor’s greatest rivals. This then means that any such company conversations are highly dangerous because the new technology needs to be explained to the competition before manufacture, but the inventor is dealing with their greatest enemy, who may well take an anti-competitive approach. Caution and legal expenses are indicated.
Effectively this production and pioneering process is assistive as it informs the inventor of the possible benefits that the production technology may bring and usually serves to improve the new technology in some way. This is also the sole opportunity to reduce manufacturing costs and hence sale price to everyone’s benefit, but this improvement and simplification process can only occur if the inventor engages with their production team and learns their language and skills. This manufacturing information, once understood and collated, must be transferred to the manufacturer when one is found. Once manufacturing relationships have begun, the expected time from drawing to device will be approximately 6-12 months for the first prototype. In medical technology quality will be the deciding factor, not price.
The extra time that is now required is most valuable because time is exactly the commodity that is limited by the expensive patent process which imposes those commodities limits stringently. The extra time now required adds to the costs incurred in achieving manufacture, regulatory certification, in-vivo testing and clinical study in order to prepare clinical data for peer review. We now estimate a minimum of 3-5 years initial development time for new technology in the modern medical world, and that time-line may extend to some 10-20 years research and development work and some £250-500,000 costs without any inclusion of the inventor’s time and effort. If the inventor was to add the costs of their own time, at their usual professional rate, it is likely that total costs could exceed £1 million sterling comfortably for a 5 year project. Time off to work on the new technology will be required and may be difficult for the inventor, who like Archie Brain may have to move out of mainstream medicine in order to get the job done, increasing professional isolation. The time used by the inventor to develop new technology is lost at the inventors normal professional rate but it cannot be invoiced for at the same rate, despite the inventor deserving a higher than standard professional rate for what they are actually doing. The inventor’s time is considered free until such a time as a company agrees to support the development project.
Peer review and acceptance
After the LMA’s effective introduction in 1988 “clinical practice with the LMA was frequently suboptimal, giving rise to a higher than necessary complication rate so only 5 LMA papers had been published by 1988, of which 2 have been described as independent. This expanded to 16 independent publications by 1991 despite on-going clinical complications. However even such modest expansion is considered unlikely now within 3 years for the reasons previously outlined. If only 16 independent papers were written when there was free access to new equipment then how many can we reasonably expect to be published if that access to new equipment is now restricted to just the few by the absence of the required “passport” of published evidence?
The problem confounds itself.
Everybody wants published evidence but this must to be done as a collective and is not a task that is specifically for others to do. If you want the evidence on new technology, why not do the research yourself? It is the request for evidence before first use from the collective that prevents the evidence from being gathered in the first place. We believe it is the inventor’s responsibility to demonstrate competence of their theory in practice but then we think the new technology should be delivered to the collective for further investigation bringing about a large scale test leading to a meta-analytical consensus on the new technology. This then reduces timelines and therefore patient exposure to any possible harm, whilst simultaneously advancing better, safer technology. The ADEPT recommendations (REF) are a reasonable place to start but should not be seen as an authorized resistance to new technology because achieving similar goals to the LMA now takes approximately 3-5 years longer in modern Anaesthetics than it did in Brains development days. The anaesthetic collective has an interest in reducing the developmental timeline for better equipment in order to hunt out the very best technology and reject the rest quickly so as to benefit both practitioners and patients as best they can. Otherwise doing nothing could be considered a thing in itself.
New devices should be introduced using discipline and method and that process should be based upon experimental results. The Tulip® airway (The Age of Aquarius Limited, UK) has already almost completed the full remit of the lately recommended ADEPT processes (2011) that we began in 2007, including the multiple hurdles of bench-testing to destruction (MeDEC, Wales School of Medicine, 2007), manikin testing (TRUCORP AirSim Multi, TRUCORP AirSim Advance, AMBU Intubation Trainer, Laerdal [4, 5]), M.H.R.A. approval, component testing in-vivo and C.E. marking. The Tulip® airway has been studied in-vivo for at least 36 months and now the Tulip® airway has completed a human pilot study on 75 patients before undergoing observational and comparative clinical trials in 2013 for which ethical committee grant has already been given. The Tulip® airway has also been independently tested by Consultant Anaesthetists in Germany, Belgium, France and the United Kingdom yielding a body of knowledge about clinical efficacy that was clearly never matched by older equipment such as the LMA when it was first introduced. Additionally, there is no record of any MHRA or CE marking assessments, or similar regulatory procedures, being completed by the LMA during its early development and introduction to Anaesthesia. This entire Tulip® testing and evaluation process began in 2006 and was underway well in advance of any external suggestions as to an appropriate method for such an introduction. The inventor can longer claim that there is “simply no time to go through the lengthy process of publication”.
We feel that a massively successful development such as the LMA may have more to teach us about airways than previously considered and that other parts of the method applied should be studied for replication. Dr. Archie Brain teaches us that experimentation is required and that a broad based investigation of new technology is advantageous in the selection of good technology. We do not like human experimentation because it is undesirable but the ethical supervision and industrial regulation as described is now here to assure a much higher level of safety than in the early days of LMA development. This regulatory supervision applies to all teams within the UK so these teams can and should be safely used to investigate new technology as all of them must conform to the necessary requirements. This additional regulation is time consuming but is accepted as a desirable part of the essential landscape by the modern inventor now but this timeline may be effectively shortened by wide-spread examination of the new technology. This desirable to both patients and practitioners.
Seeing a need is easy but is it still possible to create an airway device similar to Archie Brains LMA? Yes it is, but in the modern world the inventor must be prepared for a 20 year project that needs hours of work every day, disruption to their career and possible personal bankruptcy.
The introduction of new technology is being slowed down at multiple levels so we must consider if we are actively preventing new technology from being introduced through increasing demands on the inventor, ballooning developmental costs, stretched timescales and repetitive regulation processes that have risen exponentially from effectively nothing. Invention in the modern era now needs significantly more time, more hard work and much more money than it once did. It can still be done but filling the need is not getting any easier.
Inventor of the Tulip® airway.
Northwick Park Hospital,
North West London Hospitals NHS Trust,
Dr Shaikh is the inventor of the Tulip® airway. No external funding and no other competing interests declared.
- Shaikh A, Robinson PN; An ADEPT apology. Anaesthesia 2012;67:
- Pandit JJ, Popat MT, Cook TM, et al. Corrigendum: The Difficult Airway Society ‘ADEPT’ Guidance on selecting airway devices: the basis of a strategy for equipment evaluation. Anaesthesia 2011; 66: 1080.
- Pandit JJ, Popat MT, Cook TM, et al.; The Difficult Airway Society ‘ADEPT’ Guidance on selecting airway devices: the basis of a strategy for equipment evaluation. Anaesthesia 2011; 66: 726–37.
- Harrison S., Robinson N.P., Shaikh A., Yentis S.M.; Manikin evaluation of the Tulip®, a new supraglottic airway. Anaesthesia 2009; 64: 807.
- Robinson N.P., Shaikh A.; Manikin studies are essential in airway research. Anaesthesia 2011, On-line correspondence: http://www.respond2articles.com/ANA/forums/thread/909.aspx
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