Morgan & Masterson Consulting
Medical Device Regulatory Submissions
Technological Aspects of Regulatory Submissions
For any medical device to be used in a patient, it has to be assessed by an appropriate regulatory authority. In the USA, this is the Food and Drugs Administration (FDA); in the European Union (EU), both individual member states and the European Medicines Agency are involved, while in the UK it is the Medicine and Healthcare Regulatory Authority (MHRA), in South Africa, the South African Healthcare Products Regulatory Agency (SAHPRA), in Japan by the Pharmaceuticals and Medical Device Agency (PMDA), in China by the National Medical Products Administration (NMPA), in Australia by the Therapeutic Goods Administration (TGA) and in Canada by Health Canada.
Many of these organizations have changed their structure and procedures radically within the last few years; most of these changes have been beneficial in terms of logic, but there are so many nuances related to regulatory approval that the processes involved in regulatory submissions, the maintenance of approvals and in monitoring adherence to them can be very complex. Most medical device companies of significant size have their own Regulatory Department, which is often tasked with oversight on quality control; indeed, most submissions to regulatory authorities for all but the highest risk products are dominated by adherence to quality control and risk management procedures. There are many consulting companies that provide expertise in these areas, but that is not where I am involved.
My experience and expertise is often sought in one of two respects; those situations, usually involving high risk implantable devices, where advice on how best to structure the technological parts of a submission, (rather than quality systems sections) is required, and, secondly, when submissions are not initially approved and where scientific, engineering and clinical input is necessary within the ensuing dialogue between company and regulator. A few anonymous examples may explain this.
Benefits and risks
With the initial submission, regulators, quite rightly, focus their attention on risk – benefit relationships. The documents should be able to classify and semi-quantify all imaginable risks (e.g., through Failure Modes and Effects Analyses (FMEA) or their equivalent) and describe risk management procedures that mitigate these risks, but the residual risks should be placed in the context of the potential benefit to patients. This requires a presentation of the potential clinical benefits and a thorough analysis of alternative therapies, via literature reviews and personal knowledge, so that the putative benefits can be compared to the risks. As within the scientific literature in general, and speaking as an ex-Editor-in-Chief, literature reviews are usually worthless since they often repeat what is found in papers without critical analysis. Risk-benefit determinations have to be objective and un-biased; otherwise a competent regulator will see right through them.
Classifications and borderline issues
All regulatory authorities publish their scheme for classification of devices, such lists being dependent on the level of risk. That is usually straightforward, not requiring external expertise. Increasingly, however, the classification of products, which determines the methods used for their assessment, has become more complex as the products may involve active biological species or drugs. Within the FDA, for example, because of these situations, there is a Center for Biologics Evaluation and Research (CBER), a Center for Devices and Radiological Health (CDRH) and a Center for Drug Evaluation and Research (CDER) and, whenever it appears that a product involves two or more types of component, that product is initially referred to the Office of Combination Products (OCP). It is not surprising that in many areas of tissue engineering products, bioactive materials and theranostics (combined diagnostic and therapeutic function) that highly skilled, fact-based, objective arguments have to be provided in order for the product to be assessed most appropriately.
A situation that faces many manufacturers can arise when regulatory rules are changed. If a product has been approved and is in clinical use, should there be a change in criteria for approval, then the manufacturer may have to demonstrate that there is no change to the risk profile. Under most circumstances, this should not be a problem If, however, there has been some minor change to the product, for example, moving to a new supplier, or a slightly different material formulation, this may require much more attention. This has been an important issue in Europe in recent years, through the significant transition from the old Medical Device Directorate (MDD) rules to the new Medical Device Regulations (MDR). Here, the Notified Body may require confirmation of equivalence of the product under consideration to the previous product. This is unlikely to be provided by a simple statement and usually requires clear and detailed scientific and clinical evidence of equivalence with respect to both functionality and risk. This can be a significant challenge, where external consulting advice is required.
Interactions with regulators
The majority of medical device submissions to regulatory authorities concern variations of products that have already been approved, for example, second or third generations that represent improvements on the first generation, or refer to products that have been approved within other jurisdictions; these are usually straightforward. Submissions that are not so readily dealt with often involve devices that are perceived to be of high risk, either using some part of the technology that is totally new, or addressing a clinical condition that has never been treated this way before. Also, in some situations, a similar, but approved, type of product has met with significant clinical failures, and the regulator is nervous about appearing to make the same mistake again. I have been involved with several situations where a submission concerning an innovative device has met with ‘non-approved’ status, even where the documentation has followed all the obvious rules. An independent observer may well be able to see both sides of the argument here, since we know that the regulator has the legal, and probably ethical, responsibility to protect, as far as possible, the safety of all patients, while the manufacturer has a genuine belief that their innovative product provides potential benefits that far outweigh the risks. While a consultant may not qualify as being ‘independent’ since he / she would normally be paid for the advice, they may be able to assist in finding common ground, showing respect for the regulator’s position, while explaining, on the basis of solid experience and expertise, why the risks perceived by the regulator are not unreasonably high, with suggestions of how these risks may be mitigated.