Yesterday we had another episode on the miracles of bacteriophage therapy on Dutch television. In the show I asked our minister of Health to modify the Dutch law, in order to make scientific evaluation of this approach in patients possible. Yet, the reasons why we need this change were not broadcasted. As several patients explained how they had been treated across Europe, this must have bee confusing, people not understanding why I – the knucklehead – failed to do studies. Let me explain.
For more background on this topic, see 4 previous blogs.
For clarity, Dutch law allows clinical studies with bacteriophages, but…
The EMA has decided that bacteriophages, though natural products, must be seen as a medicinal product, which implies that studies in humans need to adhere to all quality and safety criteria for experimental medicines. Which includes the fabrication of the medicine. Given the stringent safety criteria, this requires a long and costly procedure for a lab, which is typically done in pharmaceutical companies with the prospect of a future return of investment. For phages that prospect is uncertain (do they work at all?) or even unlikely (it’s a natural product that you cannot own). We tried, but didn’t find a lab willing to. Of note, we inhale and eat billions of bacteriophages daily and freely prescribe fecal transplantations (loaded with phages), but these are of course not medicines.
The Belgians fixed that problem, by allowing the so-called magistral preparation of phages, see. In short: from phagebank, phages are selected for individual patients (ordered by a physician), purified in a lab and controlled by another lab. This overcomes the stringent and obtrusive criteria. Just, needs adaptation of our law.
We –knuckleheads – thought: let’s have phages for our patients produced in Belgium. We are all in the EU, no problem. Yes, we are, but still that doesn’t allow us to use a medicine produced according to Belgium law. Unless, there is a pharmacist in the Netherlands that accepts all responsibility for safety and quality of the preparation process in Belgium. Possible, but again unlikely that this will work.
The last option on our list: collaborating with a Belgian hospital. Being explored.
So, all this would be easier if we would copy the Belgian approach. Now, you know why I made that plea.
Then about the patients in the show. Why could they be treated. One woman travelled to Poland to get phage inhalation treatment for chronic lung infection. She looked happy, chatting and sight-seeing with her husband in the Polish sun. The Polish doctor explained that it is allowed to treat persons with phages if there are no other treatment options left. Indeed, that is the article 30-something of the Helsinki declaration (we do know). But this woman? And this approach would not let you randomize patients or use a blinded (or any) study design. The woman was treated, and told (6 months later), that she had an immediate worsening of complaints for which she was hospitalized and treated with antibiotics. The reason: fatigue from the travel to Poland, she said, and she certainly wanted a second course of phage treatment. In a clinical study this would be labelled a Serious (possibly life-theatening) Adverse Event associated with the treatment under study. That’s why we do (need) studies!
A colleague of mine advertised for a Dutch approach of applying a lytic phage enzyme for S. aureus in a skin emulsion. Apparently, eczema is caused by a disturbance of normal skin flora, with dominance of S. aureus. Killing these bugs with the enzyme, cures the eczema. The product is labelled as a skincare supplement (and not as a medicine) and could, therefore, be marketed without any scientific proof of efficacy. It was good to hear, that after many years, a double-blind randomized trial has been performed. Question to the investigator: did it work? “Oh yes, we saw impressive improvements.” Question: “In the patients that received the phage enzyme?” Answer: “We don’t know, as unblinding has not yet occurred.”
And of course, there was the San Diego patient. Made a remarkable recovery from critical illness after intra-abdominal and intravenous bacteriophages against Acinetobacter. He really seemed to qualify for the Helsinki exception rule at that time. Yet, all seem to forget that he also received IV minocycline at the same time, for which the bug was susceptible. His treating physician, though, was remarkably nuanced: we were happy that nothing serious happened in the first 10 minutes after injection and we need studies!
And so, there were more case reports. Positive ones and disappointing ones. The latter with a clear explanation why the phages could not have worked in the first place (as they don’t cure the underlying disease). True….., but many potential eligibles for this treatment will have underlying diseases……
I thought the show was more nuanced than previous ones, and to me, it provided 60 minutes of the strongest justification for scientific evaluation of this (potentially very) interesting approach.