Studying bacteriophages: catch-22

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:

  1. 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.

 

  1. 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.

 

  1. 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.

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3 thoughts on “Studying bacteriophages: catch-22

  1. Dear colleague,

    with our Belgian experience in human treatments with phage therapy, we can only agree that the success rate of the case-by-case treatment with phage therapy of eligible patients is almost 100% in the last years. We didn’t observe any side effects in our patients, treated with purified Belgian phage productions.

    Knowing that most of these patients suffered for many years of chronic infections and that a single treatment course of this targeted phages is mostly successful (and reducing hospital costs), makes it even more difficult to understand why this bacteriophages stay in the shade without sufficient funding.

    To my personal opinion, none of your three options to break this cycle are really realistic, but you never know…

    I learned from the Brussels’ phage research lab team (Dr Gilbert Verbeken and Dr Jean-Paul Pirnay) many years ago that an adapted regulatory framework, only for phage therapy (out of the medicinal product pathway) at EMA level would be the best solution for conducting the essential clinical trials… but this will be not for tomorrow!

    We in Belgium, feel really comfortable with this case-by-case treatment with “Magistral Phages”. However, we urgently need more sequenced phages for human application.

    Last but not least, I want to highlight an important error in your comment: “desperate patients pay thousands of euros for bacteriophages in Georgia, Poland and Belgium for self-treatment.”
    In Belgium, only some few Dutch patients are treated to my knowledge, as one of the responsible physicians, all in a standardized and ethical way with Good Clinical Practice procedures in place. Notably, when patients are treated with phages: this treatment is at the moment for free in Belgium (at the cost of the Belgian Defense department).

    Let us hope that Belgian phage productions will be very frequently used in the far future to help every individual patient suffering from MDR infections, not at the cost of the Belgian Defense department!

    Sincerely,
    Patrick Soentjens

    Med LtCol Patrick Soentjens
    Internal Medicine – Infectiology
    Head Center for Infectious Diseases
    Military Hospital Brussels

    Like

  2. Dear colleague,

    with our Belgian experience in human treatments with phage therapy, we can only agree that the success rate of the case-by-case treatment with phage therapy of eligible patients is almost 100% in the last years. We didn’t observe any side effects in our patients, treated with purified Belgian phage productions.

    Knowing that most of these patients suffered for many years of chronic infections and that a single treatment course of this targeted phages is mostly successful (and reducing hospital costs), makes it even more difficult to understand why this bacteriophages stay in the shade without sufficient funding.

    To my personal opinion, none of your three options to break this cycle are really realistic, but you never know…

    I learned from the Brussels’ phage research lab team (Dr Gilbert Verbeken and Dr Jean-Paul Pirnay) many years ago that an adapted regulatory framework, only for phage therapy (out of the medicinal product pathway) at EMA level would be the best solution for conducting the essential clinical trials… but this will be not for tomorrow!

    We in Belgium, feel really comfortable with this case-by-case treatment with “Magistral Phages”. However, we urgently need more sequenced phages for human application.

    Last but not least, I want to highlight an important error in your comment: “desperate patients pay thousands of euros for bacteriophages in Georgia, Poland and Belgium for self-treatment.”
    In Belgium, only some few Dutch patients are treated to my knowledge, as one of the responsible physicians, all in a standardized and ethical way with Good Clinical Practice procedures in place. Notably, when patients are treated with phages: this treatment is at the moment for free in Belgium (at the cost of the Belgian Defense department).

    Let us hope that Belgian phage productions will be very frequently used in the far future to help every individual patient suffering from MDR infections, not at the cost of the Belgian Defense department!

    Sincerely,
    Patrick Soentjens

    Med LtCol Patrick Soentjens
    Internal Medicine – Infectiology
    Head Center for Infectious Diseases
    Military Hospital Brussels

    Like

  3. For clarity: Patrick Soentjens replied and I pasted that reply here.

    But in response to that reply:

    I sincerey apologize for putting our Belgian colleagues in the same bin as Georgia and Poland. As a matter of fact, our Belgian colleagues have been very collaborative and helpfull in all our steps in trying to set up clinical studies with bacteriophages.

    Yet, I am surprised by the statement of almost 100% effectiveness of a single treatment course with bacteriophages – without adverse events – in patients that repeatedly did not respond to antibiotics. That would make phages more active than even our best antibiotics – say carbapenems – to infections caused by suspceptible bacteria. And I must say that I have also received documentation of failed treatments with bacteriophages (which I would expect to happen).

    To me, this only emphasizes the need for clinical trials, as case reports, no matter how succesful, will not provide the evidence that is needed. The good news, though, is, that if treatment effectiveness is close to 100% a few small-sized studies would be sufficient.

    Like

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