As posted previously, bacteriophage therapy is making a remarkable come-back, if measured in media attention. It is portrayed as safe and effective in treating infections where antibiotics fail. Yet, well-designed controlled studies either lack or failed to demonstrate benefits. All we have are case reports, with – with no exception – spectacular results. But that doesn’t make bacteriophages part of our daily options for treatment. And thus, desperate patients pay thousands of euros for bacteriophages in Georgia, Poland and Belgium for self-treatment, while – at the same time – all of us seem to agree that efficacy and safety should be determined.
That necessitates that we do research with humans, and for that we have a law: “wetenschappelijk onderzoek met mensen (WMO)” (“scientific research with humans”), and a law has rules. What do we want to study? Combinations of lytic phages, carefully selected upon in vitro effectiveness in killing those bacteria that cause the infection in a specific patient. Isolation, purification and producing phages in high concentrations is easy and can be done in microbiology labs, and there are several labs with large phage collections available (phage banks).
Of note, the European Medicine Agency (EMA) decided some years ago that such a cocktail of phages is seen as a medicine.
Thus we want to study a medicine in humans. To protect these humans, the law requires any medicine to be studied must be produced according to Good Manufacturing Practices (GMP) to guarantee purity, concentration and stability. Adherence to the law, including GMP, is controlled by the Inspectorate. Therefore, medicine production according to GMP usually occurs in specialized laboratory facilities of pharmaceutical companies and it may take several years to fulfil all GMP requirements. Needless to say that this requires a financial investment (starts with a million €, I was told).
After the last round of pro-phage media attention our Secretary of Health was bombarded with questions from Parliament, to which he responded 2 weeks ago (May 14). To the question whether “studies with bacteriophages in humans were possible in the Netherlands?”, he responded: “Clinical research is indeed possible within the limits of the current law. I can tell you that in December 2018 representatives of my Department of Health, the Inspectorate and UMC Utrecht (that’s me and some others) met. In that meeting the Inspectorate has explained the possibilities and requirements. UMCU has asked for a second meeting. This will happen soon, and in this meeting the expectations of the Inspectorate regarding “good manufacturing practices” and “good clinical practices” will be addressed. After that it is up to UMCU to decide if and how they can meet these requirements and if they start studies with bacteriophages.“
That meeting was on May 21st. It started with that all parties united (Inspectorate, Department of Health and us (UMCU)) solemnly swore that it is of utmost importance to study bacteriophages in humans. One hour later, all agreed that such studies are currently (and in the not-to-foreseen future) not allowed in the Netherlands.
The Catch-22: The law (WMO) requires a GMP-approved medicine, but individual-patient based bacteriophages cannot be produced according to GMP.
Indeed, there currently is no one that produces bacteriophages for individual patients according to GMP standards. Some companies produce proteins derived from bacteriophages, but that is a different approach. Our search for laboratories with GMP capacity and willingness to start producing bacteriophages has yielded nada so far. Not surprisingly, considering the investment needed for something that cannot be patented and for which return of investment is not guaranteed.
What is possible, is to select phages for an individual patient, if the treating physician asks for it as he/she sees no other treatment options. This is called the magsitral procedure. The experience derived with that treatment can be reported as a case report. But don’t be clever and think “let’s do this with more patients and a protocol to monitor the effects”. That is prospective observational research with humans for which we have a law: WMO (and you’re back at GMP).
Our Belgian friends have a splendid facility for phage production, but also that is not according to GMP. So, good enough for individual patients, but not for research with humans. Ironically, this WMO law is there to protect patients from evil investigators!
How to break this circle?
There are 3 options:
- We find a company with a GMP facility willing to produce phages for research purposes. May take some years, will probably result in fixed cocktails per species, but whether these products are affordable (for researchers) remains to be seen.
- Create a GMP facility with public funding to produce phages for research. May also take some years, but affordable prices for phages can be secured.
- Our brave Health Secretary decides that we – in the Netherlands – do no longer consider bacteriophages a medicine (a Phagexit). Cost nothing and we can start studies immediately.
But don’t worry, we’ll find a (legal) way, once common sense has stepped in.