Deharmonization (alas) in Drug Safety

Jul 10, 2013
Bart Cobert

Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert

Today’s posting is something of a lamentation.

For 15 years I was a member of the International Conference on Harmonisation which begin in Brussels in 1989 and continues to this day.  The initial goals were highly laudable and revolved around making pharmaceutical research, development, and regulatory submissions as harmonized, efficient and non-duplicative as possible.  As the ICH itself (see: http://www.ich.org/) puts it:

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe, Japan and the US to discuss scientific and technical aspects of drug registration.”

Note that it refers to Europe, Japan and the US.  It started out rather non-democratic with only Europe (the European Union actually as this was before the fall of communism and the opening of Eastern Europe and the rise of China, India and other pharmaceutical players), Japan and the US.  There were several non-voting observers from Switzerland, Canada and elsewhere.  Each of the three regions were represented by the government/health authorities and the main pharmaceutical industry association.  For the US, this was PhRMA (actually called something else then but the same folks) and the EFPIA in Europe.  For the governments, FDA and the major national health agencies were the key players.  Note the EMA/EMEA did not yet exist then.  The key groups (US, EU, Japan industry and governments) were called the “six pack” and the decision making, though complex and bureaucratic, moved rather quickly.  Many documents were put forward which changed the face of our industry.  There was significant cooperation, compromise and a strong desire to make things work better.  Working groups were created to tackle the many many areas of pharmaceuticals.  They are broadly broken down into Efficacy, Safety, Quality and “Multidisciplinary” areas.  Pharmacovigilance actually falls under the “efficacy” group as the “safety” area refers largely to non-clinical matters.  This is a bureaucratic technicality (one of many).  Much of the ICH work was based on earlier CIOMS work.  Much of the early work (e.g. E2B) was done before the internet existed.

Nonetheless, over about 15 years ICH produced many outstanding, workable and useful documents which governments slowly adopted as official regulations.  Sometimes the ICH documents were never fully adopted by governments but were, de facto, put into effect.  For example, the PSUR is not required in the US but is accepted by FDA instead of an NDA annual report (PADER).  Much of what we do today in post-marketing drug safety and pharmacovigilance is thanks to ICH.  The newish field of risk management owes much to CIOMS and ICH.  There is less duplicative animal testing done.  The CTD has largely been harmonized.

However, we are now slowly but inexorably starting to unravel the intricate systems proposed and adopted from ICH.  This, in my view, is unfortunate and is not a beneficial develop for the pharmaceutical world except in the narrow sense of creating more work and thus more jobs and less unemployment for us.

In addition, ICH has changed and democratized.  There are many more players as the original six pack, though still dominant, is not as fully in control and more and disparate stakeholders must be accommodated.  Like many international consensus organizations, this works well on paper but less so in practice.

I’d like to focus on the deharmonization occurring in the world of drug safety and pharmacovigilance (PV).  First, of course, we have not harmonized on the spelling of the key word:  harmonization (US) vs Harmonisation (UK & most of the rest of the English speaking world). The official spelling is the UK version but with the US being such a strong influence, American spelling spills over every now and then.  The same in MedDRA where the official spelling is that of the UK but the computer systems must accept and “correct” the US spelling variants.

In 2013 the EU and the EMA put forth its new Good Pharmacovigilance Guidelines (GPVP).  They started taking effect in January of 2013 and have changed the landscape of much of PV in Europe.  I’ve discussed many of the changes in these blog postings.  Here are some comments, though, from the harmonization point of view.

Reporting of serious adverse events (SAEs) as “expedited reports”

This concept has largely disappeared in the EU for spontaneous reporting.  The 15 calendar day report of spontaneous, serious, unlabeled AEs is largely gone.  Now, instead almost all serious adverse reactions from the EU are reported in 15 calendar days.  No more checking the SmPC to see if the SAEs are labeled or not.  The idea behind this is that it is easier and more routinized for companies to simply send all SAEs in straightaway to EudraVigilance rather than only a subset of expedited reports.  This obviates the need for line listings in the PSURs.  All the cases are now in EudraVigilance and there is no need anymore to slice and dice the cases to produce line listings for the PSURs.  The PSUR (now also called the PBRER-Periodic Benefit Risk Evaluation Report) now is more analytical document and doesn’t need to repeat the reporting of the individual cases as line listings.  So far so good.  The theory behind this is fine.  The EU maintains that this is better and more analytical PV than what we previously had.  Also note that non-serious cases must be reported in 90 days.  Previously they were reported in the PSURs not individually as they must be now.

The big “however” is that the idea of reporting all serious and non-serious AEs is uniquely European for now.  The FDA, Health Canada and the other health agencies have not adopted this concept.  Thus, for the companies, life has gotten much more complex as we still must report expedited cases (serious, unlabeled reactions) to FDA and most other health agencies in 15 calendar days.  And non-serious cases in the line listings in the PSUR.  The consequences of this are essentially “one off” procedures for companies to handle the EU, US and multiple other regions of the world.  Much less harmonization.

We in the industry are now reporting different cases to different countries and no longer speaking with “one voice” to all regulatory agencies as we should.  Clearly the FDA is getting fewer cases that the EU. Does this matter? We shall see.  From an operational point of view, this adds to complexity and makes it harder to do routine SAE and non-serious AE reporting.  Tracking is harder and there are more chances for error.  Quality control similarly becomes more complex.  To make matters worse, many countries in the EU as well as EudraVigilance are not ready to adopt the new PV requirements in the EU and the full system will not be in place for many years.  The new system was launched before everyone was ready.  So there is now an interim and changing system which is incredibly complicated submitting individual case safety reports in the EU.

PSURs

As noted above, the PSUR (now the PBRER but still called, unfortunately, the PSUR) has changed for the EU.  It how is analytical, does not contain line listings and has several new features including an efficacy/effectiveness section and an overall benefit-risk analysis.  It has also become a more cumulative document rather than a summary of what happened with the drug over the last 6 months, year or 2.5 years.

Unfortunately, the other countries of the world have not adopted the EU PSUR and require the old style PSUR.  Thus they require line listings and other, older features.  Companies then must still produce old style PSURs for the rest of the world, or hope that the rest of the world will accept the new PBRERs (probably with line listings added) and any other local requirements.  This, for example, is what FDA does.  They have accepted PSURs instead of the PADER for several years so long as the company adds on appendices that meet the US regulatory requirements.  This produces a sort of hybrid PSUR/PADER.  FDA has just indicated that they will accept the new PBRERs again with the US required appendices.

In the “good old days” (before January 2013) the timing for the old PSUR submission was largely harmonized.  The basic rule was 6 monthly, then and then forever every 2.5 years.  The EU changed this to the Union Reference List which contains over a thousand products and their periodicity.  Some products (some generics and old drugs) don’t require PSURs any more (e.g. generics); others have 12 or 15 year time frames.  A big “however” though is that the EU will review this listing monthly and may change your periodicity as it wishes/requires.  Thus companies must check this list monthly to see if their obligations have changed.  Again the problem here is that no one else has adopted the new schedule outside of the EU.  So, old or perhaps new style PSURs must still be produced on the old timetables for the US, Australia etc.  From industry’s point of view this is not necessarily a beneficial thing.

So these are just a few of my lamentations.  The somewhat harmonized pharmaceutical world has started to deharmonize in the name of better public health.  However, these new requirements for the most part have not been tested or piloted and it is something of a leap of faith to feel that they will pick up toxic drugs more quickly and save lives.  All of this at increased cost for governments that are deeply in debt and running out of money.

Of course, it does mean that those of us in PV will find it easier to get a job!  Every cloud has a silver lining I suppose.