During the congress on clinical trials for medical devices in Berlin, I spoke on the mutual acceptance of clinical trial data. A short version of my presentation you can find on SlideShare:
Clinical trial environment
Probably one of the main developments over the last decades has been the introduction of electronic data capture, making the process of data collection, processing, and cleaning much more efficient in comparison with paper. Besides enhanced efficiency of data-processing, this opened up the world for clinical trials as the collection and cleaning of the data can be done from any location provided there is internet. In parallel we see that over a period of 5 years the proportion of clinical trials run in the US declined with almost 20%, whereas the proportion of clinical trials run in Japan and Europe rose with an ~8%.
Running your clinical studies elsewhere only is efficient when foreign clinical data are accepted in the intended region, so looking into the
an analysis by RAPS indicates that mutual recognition is facilitated by the fact that the different GCP standards for running clinical studies are becoming alike. The differences that still exist are minor and should not be a barrier for acceptance of clinical trial data collected elsewhere anymore. For medical devices studies it is worthwhile noticing that this includes ISO 14155: 2011, which in 2015 was acknowledged by the ICH regions to be able to serve as a global standard in that respect.
Standards specifically addressing acceptance of foreign clinical data include the ICH E5(R1) on Ethnic factors in the Acceptability of Foreign Clinical Data for medicinal studies, which to my opinion is also of interest for medical device studies as for example it mentions the use of bridging studies,
a clinical study in the new region aiming to provide information on pharmacodynamics, or clinical data on safety, efficacy, dosage and dose regimen in the new region to allow extrapolation of the foreign clinical data to the population in the new region.
What makes it interesting is that this can help to extrapolate clinical data from the complete clinical evidence package collected elsewhere to the new region at relatively low cost.
Standards specifically for medical devices standards are the FDA guidance’s for drugs and devices in March 2001, and one (draft) specifically for medical devices in April 2016, and the Japanese notification #479 issued in March 2006. In Europe the new version of MEDDEV 2.7/1, a topic recently blogged on, addresses that in case a clinical trial is conducted outside of the EU, an analysis whether data are transferable to the EU population is needed.
What the different standards have in common regarding the requirements for mutual recognition of clinical trial data are that
- Trials should be performed according to internationally acknowledged standards
- Clinical data should be transferable to the local population and clinical condition, and the
- Methodology should meet the local standards including scientific appraisal
With the GCPs becoming alike, conformance with international standards has become relatively speaking easy, but other factors such as ethnic differences may well hinder data transportability.
Anatomical factors such as growth, muscularity, and size may well impact safety or efficacy, and underlying disease or different physiology could cause a different tolerability or allergy.
It is known, for example, that Asian eyes, or more specifically the anterior parts of the eye, are smaller than those of Caucasians. So clinical data from Asians on the performance of intra ocular lenses are not 1:1 transferable to Europeans as a lens suitable for an Asian may be too small for a European and start rotating. Thereby impacting efficacy, so size does matter.
Also the efficacy of barrier creams has been shown to depend on the type of skin applied to: Caucasians respond different to the same barrier cream as compared to Africans, indicating that physiological differences can affect the performance of a device.
Another aspect that can affect acceptance of foreign clinical data concerns the study methodology. The local Standard of Care can impact the choice of the treatment in the comparator arm of a RCT and such may well differ from one region the other. In addition, study endpoints may differ depending on local requirements, the FDA for example requires effectiveness data whereas the EU requires performance data.
So with the above in mind what is it that we actually see happening with respect to the use of foreign clinical data?
Mutual acceptance in practice
Interestingly data from the Japanese Pharmaceuticals and Medical Devices Agency indicate that the acceptance of sole foreign data for PMDA submissions in the period from 2006 to 2011 is substantial, and after an increase in the first 2 years seems to stabilize around 60%.
Which contrasts with US data on PMA approvals (personal analyses, see above figure) in May, June, and July in 2001, 2006, 2011 and 2016, as that indicates that the use of foreign data, although slightly increasing over that period, is still less than 40%. This in spite of the fact that the overall proportion of clinical trials executed in the US declined to less than one third.
The challenge in Europe is that the medical device regulatory bodies are far less transparent on the (origin of) clinical data used for CE marking, so I can only speak of own experience that under MEDDEV 2.7/1 the approach has been much more the applicability of the clinical data rather than its origin. Subsequent local implementation, however, is often hindered by lack of local data, as global trials typically are not taking into account the local health care system and/ or reimbursement requirements, and you often end up doing another local post-market study for the same reasons as to why foreign data are not considered acceptable for market approval outside of Europe.
In conclusion, the clinical trial environment as well as the regulatory environment favors mutual use of clinical data. Internet and electronic databases facilitate clinical trial globalization, and standards address the way to deal with foreign data. The changes and proportion of clinical trials as they are seen in the trial execution, however, are not identical to those seen in the acceptance of medical device foreign data in Japan but especially the US.
It seems that factors such as differences in the population, local practice, and requirements still outweigh the possible benefits of reduced duplication and faster access to innovative care. Although the system is slow, I doubt whether we will see further substantial changes and wonder whether in medical devices we should formally implement the concept of bridging studies similar to pharma.
February 21, 2018, the FDA published its final ruling on the acceptance of data from clinical investigations for medical devices. This will open up the options for use of clinical data collected outside of the US to support an IDE, 510k, or PMA submission. The rule will take effect February 21, 2019.