Regulation and compliance in medical device development

Speaker: Brendan Hogan, director of engineering, Aerogen Ltd So, you came up with an amazing idea for a medical device that could save lives and improve patient safety, while also generating a tidy profit. You have consulted with clinical experts and patients alike in the development process to create the perfect model. Now, all you need is to get your device to market – and so begins the regulatory approval process. At the Engineers Ireland Annual Conference last week (15-16 May) in Sligo, Brendan Hogan, director of engineering with Aerogen, explained the issues surrounding regulation and compliance when it comes to developing a medical device and advised engineers on how best to negotiate the ‘red tape’. Aerogen is an Irish medtech company that produces nebulisers for acute care and homecare. It manufactures and ships from Galway and Shannon, and employs over 70 staff. Its products are sold in 68 countries and have been used to treat over one million patients. It also holds 40+ patents across major markets. “When it comes to regulation and compliance, the frameworks are complex and can significantly delay product approval – and these delays can have consequences,” Hogan explained. “If you can’t offer a product for sale, then there’s obviously no income from product sales and there’s a delayed return on investment. It also means that patients aren’t getting the benefit from newer medical treatments. Understanding these complexities helps avoid unnecessary delays and allows for better forward planning for the time periods involved.” [caption id="attachment_14093" align="alignright" width="1152"] The healthcare product lifecycle (click to enlarge)[/caption] The regulatory affairs profession is integral to the healthcare product life-cycle (see right). To put a medical device on the market, one must comply with the relevant regulatory authority in the geographical market region of interest. In Europe, CE Mark approval is necessary. This is governed by the European Council Directive and is known as the Medical Devices Directive (93/42/EEC). In the USA, the Food & Drug Administration (FDA) provides approval through the Code of Federal Regulations (21 CFR 800-1299). “The cost, timing and complexity of navigating through such processes depends on the level of risk associated with the device,” Hogan explained. For an Irish company trying to break into the medical-devices market, the European Commission is responsible to proposing legislation. The ‘competent authority’ acts on behalf of the Member State Government – in this country, this is the Irish Medicines Board (IMB). The National Standards Authority of Ireland (NSAI) is the ‘notified body’ – the certification organisation on behalf of the State that is responsible for ensuring compliance. Finally, the legal manufacturer is the company that places the product on the market (although it may be manufactured by a different entity). CLASSIFICATION, DESIGN AND DEVELOPMENT “Classification is generally risk based and depends upon a number of factors, such as: the intended purpose of product, how long the device is intended to be in continuous use, the degree of contact with the body or with a fluid which is administered to the body, or whether or not the device is invasive or surgically invasive,” said Hogan. “It must also be considered whether the device incorporates a measuring function or not, whether it’s implantable or active or whether or not it contains a substance which, in its own right, is considered to be a medicinal substance and has action ancillary to that of the device. “In general, the higher a medical device on the EU’s classification system, the greater the implied risk,” continued Hogan. “Therefore, greater data is generated to support the regulatory approval – which all means more time, money and resources.” The EU classification of medical devices is as follows:

Class 1 (basic) – e.g. tongue depressor;
Class 1 (sterile) – e.g. surgical glove;
Class 1 (measuring) – e.g. thermometer;
Class 2a – e.g. surgical blade, blood-pressure monitor;
Class 2b – e.g. ventilators, orthopaedic implants;
Class 3 – e.g. pacemakers.

When it comes to the design and development of a medical device, Hogan explained that there is a formal development process that meets requirements such as ISO 13485. “You have to be specific on the intended use and identify applicable standards,” Hogan advised. “For example, when it’s product based, it’s ISO 27427; risk based are ISO 14971; for biocompatibility, it’s ISO 10993; for electrical safety, there’s ISO 60601; and for usability (ergonomics), ISO 62366 will apply. This is a ‘stage gated’ development process with the cross-functional team. Product conceptual testing, verification and validation must all demonstrate that the product is proven and safe to use.” Hogan explained that medical devices have a staged development – clinical input from a practising specialist in the intended use application is required throughout the process. “Phase I deals with initiation, opportunity and risk analysis; Phase II deals with formulation, concept and feasibility; Phase III looks at design and development, verification and validation; Phase IV examines final validation and product launch preparation; and Phase V deals with product launch and post-launch assessment,” said Hogan. Product approval testing must demonstrate fitness for purpose and compliance, and there are many different product tests to be passed. Some are to recognised standards, while others are to specifically developed test methods.

Mechanical – tensile, compression, leak etc;
Metallurgical – grain structure, composition and hardness;
Accelerated ageing – specify a shelf life;
Electrical – resistance, frequency, dissipation, electromagnetic compatibility, safety;
Aerosol science – particle size and distribution;
Environmental – humidity, temperature;
HALT – High Accelerated Life Testing;
Medical – ventilator with artificial lungs;
Human factors – usability and ergonomics of use;
Software – verification and validation;
Biocompatibility – effects of materials on body and effect of body on materials.

REGULATORY APPROVAL OF PRODUCT When it has been demonstrated that the product design meets its intended requirements, approval file must be submitted to the regulatory authority. In Europe, this means the notified body (such as the NSAI). “Feedback can be provided in a few weeks, if a review slot is pre-booked, but you can expect many questions to be asked,” said Hogan. “If it’s risk based, they may want to push you to a higher risk classification, which generally needs more data, with added time and cost.” In the USA, the FDA regulatory approval process can cost around €500,000 and it must cite a ‘predicative’ device. Depending on degree of change, different time frames are involved: special review, which is feedback within 30 days or traditional review, which means feedback in 90 days. “Generally, ‘feedback’ means more questions rather than approval,” added Hogan. “Authorities are normally trying to narrow the field of use or claims to mitigate against risk.” [caption id="attachment_14096" align="alignright" width="660"]

FDA approvals time (click to enlarge)[/caption] According to Hogan, FDA approvals can take from two to 12 months. CE Marking generally takes a little less time – typically from two to six months, although some approvals can take considerably longer. “There can be active written communication between manufacturer and regulatory body during this time – you can arrange conference calls and the like,” said Hogan. “Often more data is requested, which involves carrying out more testing.” Nonetheless, he added, costs are significant and can mount up. Typically, it costs €500,000 to €1 million to develop a next-generation, Class II product – and this s before the cost of tooling is taken into account,” said Hogan. The typical development of a device would require:

A team of engineers (five full-time equivalents x one year) – mechanical/electrical/software/materials; project manager and design assurance; quality and regulatory specialists;
Materials & jigs/fixtures – approximately €30k to €80k;
External specialist testing (biocompatibility €20k to €75k) and electrical safety (€40k to €80k).

But the work is still not completed, Hogan continued. After the launch of the device, post-market surveillance must be carried out. “This is a regulatory requirement to improve the protection of health and safety of patients, users and others by reducing occurrence of adverse events,” he said. “It involves customer surveys, monitoring customer complaints and warranty claims, user reaction during training, device tracking, maintenance/service reports and failure analysis.” In summary, developing a medical device is a complex, time consuming and expensive processes. “The key thing is to understand medical device regulation as it pertains to your intended product and target market. Have key experienced people on the team who’ve been through process before and be aggressive, but realistic, with target dates and deliverables. Also, be prepared for a few iterations of product design and feedback questions from regulatory authorities “In the end, it’s worth the effort – a new device can improve patient safety and patient care as well as underpinning a sustainable and profitable business,” Hogan concluded.