Tag Archives: FDA

What the Implant Files Are Not Telling

The investigation.  The “Implant Files” is a global investigation carried out by reporters in 36 countries under the lead of the International Consortium of Investigative Journalists (https://www.icij.org/investigations/implant-files/). The project, which attracted significant worldwide attention over the last few weeks as articles and reports were published, purported to show how the medical device industry failed to place on the market safe products and ultimately harmed a significant number patients.

Regrettably the way the investigation has been reported by several media outlets and the conspiracy theories underlying certain articles leave the readers without a clear understanding of the issues on the table and the policies behind the current regulatory framework.

The approval process.  For instance,  while the investigation was conducted globally, many articles published by European consortium members focused their attention on the lack of a centralized authorization procedure for the marketing of medical devices in the EU and argued that a loose regulatory framework enabled manufacturers to sell unsafe devices on the European market.

The absence of a centralized marketing authorization procedure for medical devices in Europe is depicted as a failure of European lawmakers, influenced by the medical device lobby. However, none of the articles reporting on the investigation provides readers – who may not be familiar with the authorization process – a clear and complete picture of the rationale and public healthcare policies behind the current regulatory framework. Most notably, the Implant Files investigation fails to explain the benefits for patients of a faster launch of innovative devices on the market. Neither they show any meaningful and documented difference in terms of patient safety between the EU and the US, where a centralized authorization procedure administered by the FDA is in force. The fact that the investigation concerns the US as much as the rest of the world is probably a good indication that the type of approval procedure does not per se guarantee patients’ safety and an effective healthcare system.

The new regulation.  As to the timing of the investigation, it comes at a moment of transition when the new EU medical device regulation has already been enacted but has not yet begun to unfold its innovative potential in the industry.  Yet, the Implant Files investigation seems to assume that the new regulation will have no impact on the industry and the approval/vigilance system as a whole. The investigation does not really delve into the changes and improvements brought by the new regulation, which has in fact already addressed many of the issues raised by the Implant Files. Among such innovations, new and improved vigilance measures and an increased accountability for notified bodies should be certainly taken into consideration.

Further, the investigation neglects the public discussions and exchanges that occurred throughout the EU (and the world) in the years that preceded the enactment of the new regulation, when the truth is that its provisions have been at the center of the public healthcare discourse for years, have been debated among experts, stakeholders and lawmakers in full transparency, have been reported by newspapers and specialized media. The alleged “scoop” seems a few years late.

The current vigilance system.  Lastly, one of the major flaws of many articles reporting on the investigation is that they give readers the idea that no meaningful vigilance system exists today. This is of course not correct. Italy, for instance, has a long-standing nation-wide register of approved medical devices marketed in its territory kept by the Ministry of Health. The same Ministry transparently shows on its website all safety notices and field actions carried out in Italy. The tool is easily searchable and can be found on the very first page of the medical device directorate’s site. 

Not only the Implant Files investigation failed to accurately report the existing vigilance and transparency measures, but created their own medical device database, allegedly aimed at providing the public with full access to data submitted by patients and reporters. 

Does the Implant Files investigation really benefit patients?  At the moment one cannot but wonder if this project really does provide patients with complete, accurate and independent information that can be useful for their health and wellbeing.

Is a public database, entirely managed by a private consortium, really empowering patients? How the database is managed, how the uploaded information is vetted and updated, for which purposes the uploaded information can be used by patients? Shouldn’t we work on improving a public, transparent system, managed by officers and professionals who have the scientific and regulatory expertise that is needed to address all issues involved, rather than building on a new, uncontrolled and unaccountable tool that could potentially distort patients’ behavior? The media would do a better service to the public opinion by giving a balanced, informative and articulate picture of the facts, rather than spreading sensationalistic news that would make anyone with an implanted device panic (and click on the article!).


The Italian Administrative Supreme Court Opens New Perspectives for Therapeutic Equivalents

By rejecting an appeal from Novartis, the Italian Administrative Supreme Court, with its decision n. 1306 of April 1st, 2016, focused on the notion of therapeutic equivalence under Italian law. Having underlined the difference with the concept of bioequivalence and having broadened its possible future application, the decision is likely to push forward the trend of public health care institutions to increase competition between pharmaceutical companies in the context of public tender offers, possibly for the benefit of taxpayers and patients.

The controversy arose from an opinion issued by the Italian Medicines Agency (“AIFA”) which, in a tender procedure held by Tuscany region, evaluated the drug Lucentis by Novartis (active ingredient ranibizumab) as a therapeutic equivalent to Eylea by Bayer (active ingredient aflibercept). This allowed the regional public administration to have the said drugs compete against each other in the same tender offer.

Debates as to whether Lucentis and Eylea are equivalent in terms of functions are not indeed new in the pharmaceutical scene and have caused many headaches to Novartis, let alone the critical issues raised in relation to Lucentis by the Italian Antitrust Authority.  Not a surprise, then, that Novartis tried to defend its product, alleging the illegitimacy and erroneousness of AIFA’s evaluation, which stated that the cheaper option by Bayer (Euro 780) is equally safe and effective in the treatment of macular degeneration as it is its more expansive (Euro 902) drug.

Novartis, nevertheless, failed in its claims. The Italian Administrative Supreme Court confirmed the validity and correctness of AIFA’s evaluation, together with the decision of the lower court, affirming, inter alia, that:

  • therapeutic equivalence is different from bioequivalence because the latter implies the identity of the active ingredient whether the former does not (indeed, FDA’s indications on the issue are rather similar);
  • the authority of AIFA in determining therapeutic equivalence is legitimate under Italian law;
  • evaluations regarding therapeutic equivalence cannot be based exclusively on the products’ leaflet: they are instead well motivated if they verify that (i) the drugs belong to the same Anatomical Therapeutic Chemical class; (ii) the drugs are subject to a similar route of administration and (iii) the drugs release the active ingredient in comparable ways.

Therapeutic equivalence, as it has recently emerged from Italian legislation and case law (in particular, from the decision discussed herein), is seen as a threat by pharmaceutical companies, unnerved by the increased competition effects.

Indeed, the debate has been escalated to a more general level by the Italian association of pharmaceutical companies, which challenged in many ways AIFA’s guidelines on therapeutic equivalence. As a consequence, a few days ago AIFA precautionary suspended for ninety days the said guidelines.

It looks like the match has just begun. Nevertheless, pharmaceutical companies should consider carefully on which side they should play. In fact, the expansion of the application of therapeutic equivalence, as a general trend, does not seem to be stoppable in a constant spending review context. Perhaps pharmaceutical companies should positively contribute to shape, rather than to stop, therapeutic equivalence and exploit its potential for the business in terms of new opportunities to access tender offer procedures.

FDA’s Initial Thoughts on 3D Printing of Medical Devices Published Today

Curious about how regulations on 3D printing of medical device will evolve? Check out the draft guidance published today by the United States Food and Drug Administration (“FDA”). Comments and suggestions are welcome and should reach the FDA within the next 60 days.

The draft guidance looks interesting under a number of aspects. First of all, it provides a definition of additive manufacturing (“AM”), i.e., “a process that builds an object by iteratively building 2-dimensional (2D) layers and joining each layer below, allowing device manufacturers to rapidly alter designs without the need for retooling and to create complex devices built as a single piece.”

It also defines itself as a “leap-frog guidance” and clarifies that “leap frog guidances are intended to serve as a mechanism by which the Agency can share initial thoughts regarding emerging technologies that are likely to be of public health importance early in product development”, which is a nice way to say that the FDA recognizes that its thoughts are just initial and subject to change.

A number of caveats are singled out and manufacturers are invited to be careful about, and to design their quality systems so they take due account of:

  • device design, which can be altered in AM due to various factors (pixelation of features, various patient-matching techniques, effects of imaging, etc.)
  • software and software interactions;
  • machine parameters and environmental conditions;
  • material used (which can be raw material or recycled);
  • post-processing phase;
  • process validation and acceptance activities;
  • device testing;
  • cleaning and sterilization;
  • biocompatibility.

The FDA also believes that AM devices that are patient-matched should be subject to additional labelling information.

The draft guidance does not address the use or incorporation of biological, cellular, or tissue-based products in AM, which may require additional regulation. Also, point-of-care device manufacturing may raise additional technical considerations.

Medical Apps and the Law Part I – What is a medical app? Perhaps it is a medical device. Find out!

Technology often starts in a simple way, perhaps with a simple “click” on an “I AGREE” button on your smartphone. Once the technology has spread, lawyers and authorities start debating what it is and how it fits with the laws.

The following post is the first part of a legal analysis of medical apps attempting to establish what they are under current legislation (Part I), as well as what is wrong with them according to various authorities who have scrutinized them (Part II).

 I keep reading and hearing that apps are not regulated and that the European Union stands behind than the United States in that process. Both statements are wrong. Medical apps can be regulated, if they fall within the scope of the definition of “medical device”. The trick is to find out if they do…

It probably takes less time to download a medical app on your smartphone than to determine if it falls under the definition of “medical device”[1]. Where to look for guidance?

THE EU COMMISSION GUIDELINES. In June 2012 the European Commission has issued Guidelines (MEDDEV 2.1/6) in order to attempt to clarify when standalone software is a medical device. A 6-step decision diagram is also provided by the Guidelines as an aid to decide if a medical application is a medical device. If the medical app is indeed a medical device, then a conformity assessment is required and the app must carry the CE marking.

One key element stands out in order to decide whether a medical app is a medical device: its intended use. This has been further emphasized in the Brain Products GmbH case (Case C-219/11) decided by the European Court of Justice regarding an electro-technical system enabling human brain activity to be recorded. The Court stated that “a device used in humans for the investigation of a physiological process falls within the scope of Directive 93/42 only if the intended purpose of that device, defined by its manufacturer, is medical”, while specifying that the fact that the software is used in a medical context is not sufficient to trigger its qualification as “medical device”. Therefore, the intended use of a device is up to the manufacturer, although – as the influential medical device counsel and blogger Erik Vollebregt puts it – “you cannot disclaim an obvious intended purpose as this would amount to a contradictory label and consequently a non-compliant product”.

THE FDA’s VIEW. On September 23, 2013 the United States Food and Drug Administration tackled the same problem and issued a guidance documentto clarify the subset of mobile apps to which the FDA intends to apply its authority”, because while “The FDA encourages the development of mobile medical apps that improve health care and provide consumers and health care professionals with valuable health information.”, however “The FDA also has a public health responsibility to oversee the safety and effectiveness of medical devices – including mobile medical apps.

FURTHER HELP FROM THE UK. On March 21, 2014, the United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA) has also issued guidelines to help “healthcare and medical software developers who are unsure of the regulatory requirements for CE marking stand-alone software as a medical device”. The MHRA indicated that software functions that, e.g., analyze, alarm, calculate, control, convert, diagnose, measure, monitor, are likely to lead the app to be considered as a medical device.

REALITY CHECK! The intention of the EU Commission, the FDA and the MHRA to clarify the regulatory framework is commendable and guidelines abound (see also the D4Research guide), but how many mobile medical apps actually bear a CE marking? How many app developers, app stores and app users are even aware of such requirements? I have witnessed awards granted to apps and eHealth projects which showed no awareness of the regulatory aspects. Announcements to “crack down” on illegal apps have been issued (e.g., by the Dutch authorities). What is happening in Italy? While the Ministry of Health is developing its own apps, its general manager Dr. Marletta in December 2013 has announced that the explosion of medical app use is an area of concern, especially with regard to risks and liabilities, which will be monitored by the authority going forward. Actual enforcement action, however, is still to be seen.

THE PROPOSED MEDICAL DEVICE REGULATION: WHAT MAY HAPPEN NEXT.  If the Proposal Regulation replacing the Medical Device Directive sees the light, software will be expressly regulated and specific quality requirements will apply concerning the following aspects:

  • software design must ensure repeatability, reliability and performance according to the intended use;
  • appropriate means to eliminate or reduce as far as possible and appropriate consequent risks in case of single fault condition;
  • software must be developed and manufactured according to the state of the art taking into account the principles of development life cycle, risk management, verification and validation;
  • if intended to be used in combination with mobile computing platforms, software must be designed and manufactured taking into account the specific features of the mobile platform (e.g. size and contrast ratio of the screen) and the external factors related to their use (varying environment as regards to level of light or noise).CONCLUSIONS. Medical apps do not stand in a regulatory vacuum: if they fall within the definition of “medical device”, they are subject to essential requirements and should bear the CE mark.
  • INSTRUCTIONS FOR USE FOR MEDICAL APPS: IN WHICH FORM? We note that, under the e-labeling regulation (Regulation no. 207/2012) entered into force on March 30, 2013, stand-alone software that is deemed to be a medical device can have instructions for use in electronic form, provided that the devices are intended for exclusive use by professional users and that the use by other persons is not reasonably foreseeable. Instead, if the app is a medical device but intended for a patient, instruction for use in paper form must be provided. This requirement appears both unpractical[2] and unreasonable given that a patient downloading an app seems “digital” enough to be sufficiently protected by electronic instructions.

[1] The very definition of medical device included in Directive 93/42/EEC, as amended by Directive 2007/47/EC, includes software. In fact, “’medical device’ means any instrument, apparatus, appliance, software, material or other article, whether used alone or in combination, together with any accessories, including the software intended by its manufacturer to be used specifically for diagnostic and/or therapeutic purposes and necessary for its proper application, intended by the manufacturer to be used for human beings for the purpose of:

  • diagnosis, prevention, monitoring, treatment or alleviation of disease;
  • diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap;
  • investigation, replacement or modification of the anatomy or of a physiological process,
  • control of conception,

and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means;”.

[2] An average smartphone user downloads 37 apps, according to the Opinion 02/2013 on apps on smart devices by the Article 29 Data Protection Working Party, page 2.