Astute BioSolutions Blog

In the last six years, over 80 external infusion pump models have been recalled by the FDA.  Additionally, numerous significant adverse events have also been reported (translation:  increased healthcare costs).

External infusion pumps are used to deliver nutrients, biologics, analgesics or other medication to a patient.  Pumps may be used in a clinical setting or home setting (eg. insulin infusion pump).  Most infusion pump problems can be catalogued into one of the following groups:

• User error and user interface difficulties
• Mechanical/electrical failures
• Software defects

An FDA investigation determined that most errors encountered could have been prevented through better manufacturing and product development practices.  Additionally, better application of human factors engineering could have precluded several user interface difficulties and errors.  One suggestion is that perhaps pump manufacturers can model their interfaces after the iPhone or the iPad interfaces.  These revolutionary products boast interfaces so transparent that technical neophytes can navigate the screens without much difficulty.  (This Businessweek article highlights how medical device manufacturers are modeling smart phone interfaces.)

When reviewing the status quo, one may question how the situation reached its current state.  One explanation may be related to the nature of the 510(k) process.  Clearance of earlier generations with limited data may have paved the road for clearance of future generations of pumps on the basis of the substantial equivalence.  Additionally, many infusion pump 510(k) submissions were reviewed by third parties, as opposed to FDA evaluators.  It is currently unknown whether third parties evaluated the medical devices with the same rigor as the FDA.   For the additional information on infusion pump recalls, visit the FDA website.

Ben Franklin said “Nothing is certain but death and taxes.”  This means that there is a non-zero probability that a medical device manufacturer, despite its best efforts, will face the grim prospect of conducting a product recall.  Product recalls increase company expenditure through repair and/or replacement costs, augmented staff support, and increased liability insurance.  Product recalls can also be deleterious to a company’s reputation as competitors seize lost market share.

Product recalls may be initiated by a medical device manufacturer when it deems that defective or harmful products have been released to the public.  Alternatively, the FDA may require a company to conduct a recall if the company refuses to cooperate.  Recalls can be categorized into one of three categories:  Class I, Class II, Class III, with Class I being the most severe and Class III being the least severe.  To initiate a recall, a company submits a recall notice to the FDA with the following information:

• Identification of the product to be recalled
• Reason for the recall
• Date and circumstances under which deficiency was discovered
• Evaluation of risk associated with the deficiency
• Total number of deficient products produced and time frame during which they were produced
• Total number of products in distribution
• Recall communication to customers
• Strategy for conducting recall
• Contact information for company representative to address recall questions

Recently, there has been speculation over some companies bypassing these procedures and surreptitiously removing compromised product from store shelves.  Such deviations from protocol only worsened company woes as the FDA intervened. While product recalls are an undesirable outcome for any medical device company, assuming responsibility and remedying the problem promptly may be a company’s best strategies to salvaging its reputation.

The last two entries described regulatory and business challenges faced by foreign medical device manufacturers that wish to enter the US market.  This entry will consider the reverse scenario: requirements for US medical device manufacturers that wish to enter foreign markets.

Most developed countries have regulatory agencies and processes in place to accommodate foreign medical device imports.  Upon evaluating the processes among nations, certain universal requirements become evident for US device manufacturers to export their devices to any foreign nation.  Regardless of the country for entry, device manufacturers must comply with:

• Assigning a local representative (through a local office or distributor)
• Product and/or company registration
• Implementation of QMS by device manufacturer (Hint:  ISO 13485 is a good start)
• Risk Management assessment
• Labeling and technical documentation
• Device classification

Compliance with these requirements is a lofty achievement towards obtaining market clearance in foreign countries.  However, the aforementioned list does not cover all requirements for entering all foreign markets.  Ultimately, each nation possesses some distinctive requirements for medical device market clearance.   Device manufacturers must research these or consult with appropriate regulatory authorities in order to enter the desired foreign market(s).

Foreign companies seeking entry into the US market can sometimes be overwhelmed not just by the FDA, but also by idiosyncrasies in the culture, business regulations, and other practices of the US.  Partnering with a business that has roots in the US can often facilitate the entry process.  Boston Denmark Partnerships is a US based organization that assists foreign companies establish a footprint on US ground. Entry into a new market can be a costly process, but third-party organizations can offer expert advice that translates into cost-saving strategies and expedited realization of a client’s business goals.

Whether a company is domestic or international, dealing with the US FDA can be a daunting task for many medical device manufacturers.  Regulations surrounding medical devices continue to evolve in response to technological advances, customer complaints, adverse events, etc.

Foreign medical device companies may view the US as a lucrative market for entry.  Larger multi-billion dollar companies usually have well-versed regulatory staff to facilitate market entry into the US market.  Smaller foreign companies, on the other hand, may be resource challenged in this area.  These companies may turn to regulatory consultancies for guidance.

Device manufacturers should be aware that market entry into the US does not culminate with FDA clearance and product/company registrations.  Foreign companies must assign a US agent who will facilitate communications between the device manufacturer and the US FDA.  US agents may be distributors, consultancies, or the companies themselves as long as these entities have established offices in the US.  A company should consider the overall business advantages and risks when evaluating each of these options.  Finally, device manufacturers must obtain reimbursement code(s) from the Center for Medicare and Medicaid Services (CMS) for use by the clinics and hospitals that will ultimately use the medical devices.  Only after accomplishing these tasks is a device manufacturer positioned to compete in the US market.

The implementation of a quality management system equips medical device manufacturers with the tools to maintain a quality product and detect problems during the development, production, and post-production stages of the product life cycle.  Defects that are detected earlier in the product cycle are cheaper to correct than those detected later in the product life cycle.  For example, a design change to a software drawing costs virtually nothing.  As the device advances through the prototype, production, and post-production stages, a general rule-of-thumb is the cost for defect fixes increases tenfold with each stage.

Last month, a major manufacturer of blood glucose meters initiated the recall of 359 million blood glucose test strips.  The test strips may report inaccurate results that are lower than actual blood glucose levels.  The speculated cause of the problem may be the test strip’s inability to draw an adequate blood sample volume.

The cost associated with this recall will be magnanimous.  At approximately $25 per vial of 50 strips, the company will lose about $180 million on the recalled strips.  The company will also replace the recalled product at no cost to the end user.  Thus, the cost of the recall will be $360 million.   Since the defect was uncovered post-production, the cost for correcting the problem is orders of magnitude greater than had the problem been detected during the earlier stages.  One can speculate this company will be vigilant to modify its quality management system in an effort to rectify the problem and eliminate future occurrences to avoid further profit loss.

On the grand scale, the 510k and CE mark acquisition processes share the same scope:  regulation of medical devices in specific geographical areas.  However, upon further inspection, it becomes evident that while the two processes share a number of similarities, each process has its own idiosyncrasies.

This entry will elucidate similarities and the differences between the 510k and CE mark acquisition processes.

Both the 510k and CE mark regulatory processes categorize medical devices into classes based on the complexity of the devices.  There are three main classes:  Class I (least complex) to Class III (most complex).  However, the EU further sub-divides Class I and Class II devices.   The rules listed in the EU MDD can be used to correctly identify the class of a medical device.

Both the 510k and CE mark regulatory processes also mandate the implementation of a Quality Management System (QMS) with the exemption of devices listed under the MDD Class I non-measuring/non-sterile subdivision.  However, the terms of the QMS vary between the two systems.  The MDD outlines compliance for the CE mark, while 21 CFR 820 outlines compliance for the US FDA.  These are not identical!

Lastly, preparation and processing of the technical files are also handled slightly differently.  The US 510k paradigm relies on demonstration of substantial equivalence to an existing, FDA-cleared medical device.  There is no such requirement for CE mark acquisition.  Technical files are prepared in accordance to the MDD for review by a Notified Body.  Upon review, a legally-binding Declaration of Conformity is prepared by the manufacturer indicating that the product is in compliance with the MDD.

These are high-level, notable differences between the US FDA 510k and EU CE mark acquisition processes.  Has your organization encountered other differences that are not mentioned here?

The pathway towards obtaining US FDA regulatory clearance for new medical devices can be enigmatic process.   Hundreds of federal regulations delineate guidelines for product development, manufacturing, quality, and marketing.  Sifting through a multitude of federal regulations to find those relevant to a specific product type can be a time consuming process for time- and resource- strapped organizations.

As the FDA evaluates the state of the 510(k) process, it is likely that important changes to these regulations will ensue.  An internal FDA report lists shortcomings of the regulatory process and proposes corrective action.  Some of the major proposed changes that will affect device manufacturers are:

• Streamlining the regulatory process for de novo products (which can currently take years)
• Introduction of Class IIb medical devices which will require clinical, manufacturing, and post-market setting information to demonstrate substantial equivalence
• Changing rules for predicate device usage:  Removing recalled/obsolete devices and a limit of ONE predicate device for each 510(k)
• Internal changes within the FDA to obtain consistency among reviewers.

Additionally, an independent evaluator, the Institute of Medicine, will also provide input regarding the 510(k) process.  That report is due out in July 2011.

It is too soon to speculate which changes will ultimately prevail, and the timeframe for implementing those changes.  Stay tuned for the updates.  In the interim, is your organization concerned about upcoming FDA regulatory changes?  If so, what steps is your organization taking?