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International Clinical Trials

Commercial Challenge

James Blakemore and Brennan Miles of Team Consulting Ltd discuss the value of a genuinely integrated approach to device prototyping for clinical trials

The rapid and effective completion of clinical trials is a prerequisite for the commercial viability of any product. Early adoption of an iterative design process is vital to this success as the approach insists that both the environment in which the product will be used and the end user is considered from the outset. The process also encourages a practical view to be taken on the balance that needs to be struck between engineering functionality for clinical trial and design, and the management of specification creep.

THE CHALLENGE

For emerging medical technology companies, getting devices through clinical trials represents a key and often fundamental milestone, not just in the product development cycle but also in the development of the business itself. Achieving a clinical proof-of-principle often represents the basis upon which follow-on funding or business exit strategies depend. Hence, in order to bring products closer to market, while adding value to their business, organisations – particularly those backed by venture capital – are driven to seek the fastest route for the production of devices suitable for clinical trials.

By contrast, the approach for developers in the consumer products industry, for example, has been to create a limited number of finished devices for the purposes of demonstration or for marketing support. This type of prototype is often produced in low numbers, using specialist manufacturing methods. And, although costly, it represents the most rapid route to a ‘looks-like’, ‘works-like’ demonstrator that is perfectly acceptable for this industry sector.

Outside the medical and life science industries, market acceptance of these ‘demonstrators’ is suitable justification to proceed with the capital investment in production tooling and manufacturing facilities. This is possible for two main reasons. First, these industries are often led by current market trends and, therefore, the need to get products on shelves rapidly is paramount to their success. Second, the regulatory requirements are generally far less stringent, so the need to ‘statistically prove’ a product’s robustness is reduced.

However, this method of prototyping does not always fit with the requirements of the medical device industry where, more often, ‘prototype’ devices are required in greater numbers in order to show, statistically, that the device fulfils the regulatory requirements of a clinical trial.

Only when acceptance has been proven against all relevant standards would a medical technology company make a highvalue investment in production tooling, assembly and manufacturing. Therefore, the ability to maximise the function and usefulness of medical prototypes is important, in terms of cost and time savings.

Theory in practice

Dutch biotech firm, ProFibrix, is developing a dry powder fibrin sealant, based on a mixture of the proteins fibrinogen and thrombin, which occur naturally in blood. When applied to a wound, the sealant precipitates clotting and stops bleeding that occurs during surgery or after injury.

However, applying a powder – which comprises fine particles that become sticky when moist – to bleeding sites presents many technical challenges. ProFibrix conceived a method of application by which a hand-held device ‘blows’ the sterile product onto the wound. The company sought a partner to define a technical design and produce prototypes that would enable ProFibrix to move to Phase II clinical trials. A medical device company was selected to develop a prototype device, compliant with ISO13485 – the quality standard which governs the design and manufacture of medical devices.

The company took conceptual ideas and, in conjunction with clinical users, developed them through a series of product definition and technical workshops. User feedback enabled refinement of a design and, following rigorous testing and development, the project team arrived at a proof-of-principle design. In four weeks, the company had procured the fully automatic injection mould tooling needed to produce components for the device, enabling the rapid manufacture of disposable prototypes. ProFibrix has now entered Phase II clinical trials using the device.


UNDERSTAND THE REQUIREMENTS

When embarking upon a medical device development programme, a sound understanding of which regulatory requirements apply to that specific device and, in turn, what the regulatory obligations are likely to be, is of critical importance. The appointment at an early stage of a regulatory advisor to shed light on regulatory compliance will, therefore, have a significant impact on the shape of the development programme. And while there is variation in the regulatory requirements between different authorities (with US regulations often being perceived by developers as more stringent than those in other countries), certain key device considerations need to be demonstrated through clinical trials.

Successful trials depend on some important questions being answered. These include:

  • How do you make a device safe?
  • How do you ensure the device always operates as users expect?
  • How do you know what user’s expectations are?

PUT THE USER FIRST

At the earliest possibility – often at the concept generation stage – thought should be given to the intended users of a device and the situations in which they will use it. It is not unusual for medical device developers to focus almost exclusively on achieving a technical proof-of-principle without the user-related aspects of the device being considered properly. This lack of forethought might be as a result of funding limitations or simply that the value placed on this aspect of a design was not high enough at the early stages of development. While there might be an intention to revisit these design considerations at a later date, delaying their evaluation just defers usability and design problems to a time when it can be extremely costly to modify a device.

INTERACTION DESIGN

This ‘interaction design’ approach can result in creative tension between various functional groups (see Figure 1). However, it is a vital element in integrated product development. It is important to remember that the level of detail of interaction design should be appropriate to the specific project, and that it should be undertaken with a view to it becoming part of the device specification.

It is important that throughout concept generation and into the proof-of-principle, the views of stakeholders, beyond the design and engineering team, are included in order to inform each design response and iteration loop. Among these stakeholders should be relevant healthcare professionals and patient representatives.

Design control – essential for maintaining a design history file for the purposes of regulatory submission and approval – starts with the user requirements specification (URS).

The URS should be a succinct document that describes what the product must be at a level that is easily understood by any reader. The URS comprise the objectives, goals and functions of the required product and should:

  • Not normally have precise limits
  • Describe the product aims, which should be as specific as possible, without indicating solutions or limiting the scope of alternative options
  • Set out what is not yet known, or is still unclear, within the context of the product overview. This is a task that many projects fail to factor in, neglecting to specify correctly what the system should do

Once the URS has been written, a product requirement specification (PRS) should be drafted. The PRS is a more detailed document written with the intention of defining the characteristics (such as performance, functional parameters, cost and production volumes) for the product concerned. Requirements are stated clearly, covering ‘must’ and ‘want’ metrics or attributes. A means of verification for any characteristics must be included, and this forms the basis of the design verification plan (DVeP). It is verification activities that often form the basis of the design iteration loop. An example of a developmental process for medical device development is shown in Figure 2. Defining and achieving clear development milestones is important in transitioning from one development phase to the next and then through to industrialisation of the product.

It is important to remember that, while the PRS will capture all the requirements for a product, it might not be practical nor necessary to incorporate all these features for the purposes of clinical trials. And it may be that device development programmes that choose to carry forward all the features detailed within the PRS become financially untenable.

For example, in the case of an in vitro diagnostic product, the primary endpoints relate to demonstrating safety and the effectiveness of the assay. In this case, all target product profile considerations should be prioritised, for example incorporation of a printer or docking station, or communication with a laboratory information management system (LIMS).

These product requirements may be added to the device as part of a post-marketing authorisation modification. Additional, but limited, clinical trials will be required, but their focus will be the ability to demonstrate that there is no change to the performance of the system, in terms of safety and effectiveness.

RAPID PROTOTYPING

The use of rapid prototyping resources, now commonly available, enables device concepts to be evaluated and iterated by designers in days rather than months. This enables accelerated iteration cycles prior to the design verification and early entry into certain trials, such as user validation studies.

Following an initial concept selection process, nominated designs can be rapidly worked up in silico using a combination of 3D computer-aided design (CAD), moving swiftly to low-level ‘semi-functional’ prototyping using rapid 3D printing techniques, such as stereolithograpy (SLA). It is also possible to evaluate and select the final materials from which the product will be manufactured. The significance of this is that the expected performance, robustness and, ultimately, the cost of the device, can be determined early in the development process.

The next step towards a clinical trial device is the generation of rapid prototype tooling to enabling low-volume production of devices representative of the final design. While the tools used to make the final production components are complex and create many components at a time, the rapid injection mould tools produce one single component at a time. This would be inefficient for production, but it enables prototypes to be produced rapidly for trials. It is worth noting that high-quality prototype tooling can be capable of producing many thousands of parts, and is often sufficient for initial production volumes.

While there is no way around the need to implement welldesigned and adequately controlled clinical trials that support the development, verification and manufacture of medical devices, the commercial risk associated with market access can be reduced significantly by taking a genuinely integrated approach to device design and prototyping.


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James Blakemore, a molecular biologist by training with an MSc from Edinburgh University, joined Team Consulting in 2008 to lead its work in the area of in vitro diagnostics as a Senior Consultant. He has worked in the biotechnology and pharmaceutical industries for 10 years across a range of R&D, IP licensing and business development positions.

Brennan Miles has a BSc (Hons) in Product Design and was a Senior Scientist in Pfizer’s Inhalation & Device design group before joining Team Consulting as a Product Design Consultant. Bridging the design and engineering disciplines, he has a passion for product detail, usability and engineering mechanical systems, as well as managing development projects.

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James Blakemore
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Brennan Miles
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