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Science Alert: Experts Respond

Man dies after taking clinical trial drug- Expert reaction

Posted in Science Alert: Experts Respond on January 18th, 2016.

bedA man died today after several days in a brain-dead state, after having an adverse reaction to a drug taken as part of clinical trial to establish the safety of the compound.

The drug in question was a FAAH (Fatty Acid Amide Hydrolase) inhibitor, manufactured by the Portuguese company Bial as a potential pain treatment.

Ninety volunteers took the drug as part of an early stage clinical trial in the French city of Rennes, and six of the participants – including the man who died –  suffered severe side effects.

You can read more about the trial in coverage from RNZABC News and the New York Times.

Updated comments from the AusSMC:

Dr Ian Musgrave, Senior Lecturer in the Faculty of Medicine, School of Medicine Sciences, University of Adelaide, comments:

“The disastrous results of a clinical trial for a new pain killer has sent shockwaves around the world. As yet, we do not have enough information to understand why this drug caused brain damage and death, or why these effects were not seen in preclinical testing of the drug. Before a drug is tested in humans, it undergoes testing in tissue culture and animals to determine both if the drug works and if it has toxic effects. No drug goes into a clinical trial until we have a clear idea of its toxicity in animals (and potential toxicities using tissue culture).

“Serious adverse effects to experimental drugs are exceedingly rare, and this may be the worst ever under modern safety procedures. We don’t know the extent of animal testing for this drug at the moment, but we know that the drug was tested in chimpanzees, in case there were primate specific toxicities that would not be picked up in other animals.

“When drugs are first tested in humans, the first thing that is looked for is human toxicity. Doses are typically low and increased carefully with monitoring. In this particular case, the drug prevents the breakdown of endocannabinoids, substances that our own body produces but have actions similar to cannabis. Other drugs that act in the same way have been through preclinical and clinical trials with no evidence of the devastating side effects seen in this clinical trial. At the moment we can only speculate about why this has occurred, and why our clinical trial safety measures failed, but this will be actively investigated and clinical trial procedure reviewed in the light of these investigations.”

Professor Barbara Workman, Medical Director of Rehabilitation and Aged Services at Monash Health and Director of a Pain Clinic. She comments:

“Globally there are many guidelines for good clinical practice to ensure research is ethical and rigorous in conducting clinical trials to prevent harm to the participants and in the vast majority of drug developments the safeguards are effective.  This is a tragic event and requires detailed investigation to ensure all quality controls were in place. In my experience drug companies are meticulous in monitoring clinical trials and it will be of interest to the global research community to identify what happened in this instance.

“Our availability of analgesics for management of pain has improved over the last few decades but there are significant adverse effects from all strong analgesic so further drug development and research is essential and this event will impact on drug development in this area of clinical practice for a long time.”

Our colleagues at the UK SMC collected the following expert commentary.

Prof Alan Boyd, President of the Faculty of Pharmaceutical Medicine, said:

“It was very sad to have read in the media about the death of the subject who had previously been reported to have suffered severe brain damage as a result of their participation in this clinical trial. In relation to the other five subjects who remain in a stable condition in hospital, some of whom have neurological problems, until we have more information about the possible cause of these events and their specific clinical signs and symptoms, it is not possible to comment on the implications of this subject’s death for the other subjects.”

Prof Carl Heneghan, Professor of Evidence-Based Medicine, University of Oxford, said:

“With so many other people having received the experimental treatment, and given that similar FAAH1 inhibitors have been tested within this class, there is an urgent need for transparency that transcends the prosecution: detailing what has gone wrong and the nature of the medical complications that the volunteers developed and which led to one individual’s death.”

Comments from Saturday 16 January:

Prof Sir Munir Pirmohamed, David Weatherall Chair of Medicine, University of Liverpool, and Vice President Clinical, British Pharmacological Society, said:

“Pain medicine is an important area of research and clinicians have a limited number of options for treatment of pain, many of which are associated with their own adverse reactions (as evidenced by withdrawal of COX-2 inhibitors such as rofecoxib (Vioxx) which was associated with heart attacks) and problems with addiction (for example opiates). There is therefore a need for new analgesics.

“Fatty acid amide hydrolase (FAAH) inhibitors are being developed by a number of pharmaceutical companies as novel drugs for the treatment of pain and inflammation.  This is therefore an important area of research which could have major benefits for patients.

“FAAH are enzymes that break down endogenous compounds that act as neurotransmitters via the cannabinoid receptors (CB).  The idea behind the development of FAAH inhibitors is to preserve the analgesic effects without having the negative effects of cannabinoids.  There are two FAAH enzymes, FAAH1 and FAAH2.  The majority of drugs developed inhibit FAAH1 but can also have effects on FAAH2.

“Some FAAH1 inhibitors have already been tested in humans, without the adverse effects seen with BIA 10-2474.  As per the current paradigms for development, the testing programme has included phase I trials – the first one was with PF-04457845 (produced by Pfizer), which was studied in 77 subjects, at different doses (single and multiple), and was well tolerated by the volunteers (British Journal of Clinical Pharmacology; 2011; 73: 706-716).  Indeed PF-0445784 has also been trialled in 74 patients with osteoarthritis and was unfortunately not effective, but was well tolerated and did not have the cannabinoid-type adverse events (Pain. 2012 Sep;153(9):1837-46).

“FAAH inhibitors can be reversible or irreversible.  There are reports that BIA 10-2474 was an irreversible inhibitor, but I have not been able to find any scientific publications by searching the literature databases.  I presume BIA 10-2474 is a FAAH1 inhibitor, but again unverifiable at present, as nothing has been published.  It is interesting to note that reviews of FAAH inhibitors mention many drugs in development by many companies, but BIA 10-2474 is hardly mentioned.  The lack of information on BIA 10-2474 in the peer reviewed scientific literature from the manufacturer is surprising.

“From the information available on websites since the reported incident, BIA 10-2474 has undergone the conventional and regulated process of drug development (including testing in chimpanzees as has been reported by some), and the number of volunteers exposed would be consistent with phase I studies, initially starting at low dose and progressing to higher multiple doses.  There are suggestions that this might have been a contaminated batch, but this would be surprising given the stringent quality control procedures which are utilised in drug manufacturing. Nevertheless it is an important potential reason which needs to be excluded through careful analysis of the batch given to the volunteers.

“It is possible that the serious adverse reactions suffered by the volunteers were an off-target effect of the drug (i.e. it was interacting with another receptor, enzyme or target in the body), but without further information on the drug and its pharmacology, it is difficult to be sure.  It is therefore vitally important that as much information as possible is made available to the scientific community as soon as possible by the manufacturer.  The independent enquiry announced by the French Government is also extremely important – it is vital to identify the reasons behind this tragedy so that lessons are learned for future drug development in this vital area, but also more generally.

“Finally, it is important to state, as many commentators have already done so, that the safety record for drug development is good.  The 2012 ABPI report stated that the overall incidence of serious adverse events in phase I trials is 0.02%.  Phase I trials remain a vital part of the drug development process and without such trials, we would not have any new drugs, which are still very much needed to treat the many diseases and symptoms for which we currently have few choices.”

Prof Max Parmar, Professor of Medical Statistics and Epidemiology at UCL, and Director of the MRC clinical trials unit at UCL, said:

“We really need more information as to what has happened in this trial, especially in terms of the dose of therapy given to these six volunteers, compared to the 84 or so who have received this treatment and (presumably) have not experienced such side effects.

“I would just re-iterate the points that clinical trials are key if we are going to cure diseases such as cancer and Alzheimer’s. In clinical trials usually every effort is made to minimise the risk to participants, however inevitably some risks are just unavoidable. It is too early to say whether the horrible side effects experienced by these individuals was down to avoidable or unavoidable risks.”

Prof Alan Boyd, President of the Faculty of Pharmaceutical Medicine, said:

What is an FAAH inhibitor, what do they do and how do they work?

“FAAH stands for Fatty Acid Amide Hydrolase and it is an enzyme that is responsible for the degradation of endocannabinoids found in the brain and the peripheral nervous system. The endocannabinoid system (ECS) is a group of endogenous cannabinoid receptors located in the nervous system and other body systems and essentially it is human body’s own “cannabinoid system”. The ECS is involved in a variety of body processes such as appetite, pain-sensation, mood, and memory. It is also involved in the psychoactive effects of cannabis when this drug is taken. Giving drugs that are inhibitors of FAAH, theoretically should lead to an increase in the concentration of the body’s natural endocannabinoids in the brain and hence reduce pain, stimulate appetite and enhance mood and memory.

What kinds of diseases or conditions are they already used to treat or known to be effective at treating?

“There are no approved medicines that are FAAH Inhibitors but compounds that are FAAH Inhibitors have been in development. For example Pfizer have had a clinical development programme for a compound known as PF-04457845 and they have conducted and completed both a human volunteer study and a clinical study in patients with osteoarthritis for pain relief with this product (details can be found on the Clinical Trials.gov website by searching for the respective study identifiers NCT008360082 and NCT00981357). Other companies are also known to have FAAH inhibitors in their portfolios.

Some media reports suggest the drug was tested in chimpanzees. If the drug in this case had been tested in chimpanzees, what might that mean?

“Chimpanzees are only rarely used these days for animal experiments – this fact, given it has been reported by the media and not by the company, would need confirming by them.

Is it too early to know what might have gone awry with this drug in this group of volunteers?

“Until we have more information about the study it can only be speculation.

Is it possible it may have been a contaminated batch, or more likely to be a problem with the mechanism of the drug?

“Batch contamination could be the issue but the most likely issue is probably a toxic effect of the drug at the dose that has been given to this group of volunteers. Given this was a Phase 1 study and, although the actual design of the study has not been disclosed publically, typically it would have involved the administration of initially single doses of the product in increasing amounts to individual groups of the human volunteers, followed by repeated doses again with increasing amounts to separate groups of volunteers. As you move through these various doses and amounts of drug given to these separate groups you would monitor them closely for side effects – it would appear that this last group have experienced these very severe effects at the does that received. From the press release that the company Bial have issued they have stated that prior to this group of volunteers they have not observed any moderate or severe reactions to date – so what has happened is clearly a surprise to them. (Please note this is speculation on my part in relation to what might have happened).

Now we know that the drug is an FAAH inhibitor, is there any more you can say about why 108 patients were administered the drug and so far five have been reported to have suffered side-effects?

“In my previous comment I have suggested a typical design for the study that has been performed – a figure of 108 volunteers involved in the study has been given by the company – and although this is larger than would normally be exposed, if the study covered several different escalating doses then this number can be accounted for. In addition following what has just happened to these final six volunteers, all the other volunteers who have been treated in the study need to be checked for any clinical issues and it would appear that this is what is happening now.”

Prof Jackie Hunter, Chief Executive of BBSRC, said:

“FAAH stands for fatty acid amide hydrolase. FAAH is a membrane bound, intracellular, enzyme which belongs to the serine hydrolase superfamily. It is known to regulate the endogenous concentrations of several important and pharmacologically active molecules called fatty acid amides (FAAs). It mediates the breakdown of FAAs such as anandamide (AEA), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). These FAAs are agonists at a range of receptors but AEA for example has been shown to be important as an agonist of cannabinoid (CB) receptors, CB1 and CB2.

“Given that agonists for CB receptors have been shown to be involved in a range of activities including pain, increasing the levels of AEA by blocking its degradation through inhibiting FAAH would be postulated to be analgesic. Pre-clinically FAAH inhibitors have been shown to be active in a range of models of chronic, acute and neuropathic pain. They have also been postulated to be of use in Post-traumatic stress, Parkinson’s disease, depression and inflammation.

“There are no FAAH inhibitors on the market.

“The following table shows that other compounds with this mechanism have been trialled in man over a period of weeks with no adverse effects:

Other compounds that are FAAH inhibitors include:

Compound Clinical status Comment
PF-04457845 Failed Phase II trial in pain Well tolerated and in multiple dose phase I and Phase II
IW-6118 Phase II trial in dental pain completed Acute dosing – no data reported so unlikely to be efficacious
SSR-411298 Phase II depression completed 2010

Phase II trial in begun in 2011 for adjunct in persistent cancer pain

Likely to have failed in depression as not progressed

Patients dosed for 8 weeks.

JNJ-42165279 Preclinical
MK-4409 Phase I Stated to be in Phase I in 2009 but no clinical trials posted on USA or EU databases

“In response to suggestions in media reports that this drug had been tested on chimpanzees: companies would normally only test in primates if the compound only worked on a human version of the protein in question – in this case FAAH. Other molecules work on both rodent and human versions although the potency might not be the same so this is odd. Also if one went to primates one would usually test on macaques rather than chimpanzees so it appears to indicate that there is something different about this particular compound if this report is true.

“We have no information as to whether this is a reversible enzyme inhibitor – if it was an irreversible inhibitor then this would be different to the other compounds. We also know nothing of its off-target profile or its metabolic profile.

“The compound was clearly safe in single dose and it appears that the problems arose on multiple dosing. The standard protocol for Phase I is single doses in groups of volunteers with placebo controls, increasing the dose with each cohort until either adverse effects are seen (which could be mild e.g. nausea) or until the exposure limits of the drug in the blood defined by preclinical toxicology are reached. Then cohorts are dosed on multiple days i.e. receive more than one dose of the compound. The duration of dosing and dose amount in this phase is defined by what has been done preclinically i.e. how long animals have been dosed for. This explains why so many people have received the drug as most of these would have been singe doses.

“The fact that side effects are apparent on multiple dosing might be due to an accumulating metabolite that is not present in animals, some off-target action of the molecule or some other mechanistic reasons. The fact that a number of selective FAAH inhibitors have been dosed for weeks in the clinic does suggest that it isn’t due to reversible inhibition of the enzyme.”

Prof Stephen Alexander, Fellow of the British Pharmacological Society & Associate Professor in Molecular Pharmacology at the University of Nottingham, said:

What is an FAAH inhibitor, what do they do and how do they work?

“FAAH is an enzyme which inactivates a series of naturally-occurring compounds in the body, the most recognisable of which is anandamide.  Anandamide acts as an activator of cannabinoid receptors, the same targets as one of the active ingredients of the Cannabis plant, Delta9-tetrahydrocannabinol, THC.  Inhibition of FAAH allows accumulation of these compounds, including anandamide.

“The expectation is that these FAAH inhibitors allow an amplification of signalling through the cannabinoid system, which could have subtle but important differences from treating with a direct activator of the cannabinoid system.  THC does have pain-relieving properties, but its other psychoactivity (including acute memory loss, dissociation from the environment, and further effects on chronic usage) limits its usefulness.  In pre-clinical models, THC and other direct activators of the cannabinoid system evoke a characteristic series of symptoms which includes catalepsy (a rigidity or stiffness of posture).  The use of FAAH inhibitors in these same models is not associated with this symptom.

What kinds of diseases or conditions are they already used to treat or known to be effective at treating?

“As yet, there are no diseases or disorders which are treated with FAAH inhibitors.  The most advanced area associated with the use of FAAH inhibitors is in the treatment of chronic pain (currently, things like non-steroidal anti-inflammatory drugs, such as ibuprofen and aspirin, are effective, but they suffer from issues including gastric ulceration, which can be severe.  Opiates, such as morphine and codeine, are effective in many individuals also, but suffer from issues including tolerance and addiction).

“There are numerous studies from many different labs around the world (including US, Europe, Australia) which have shown good pain-relieving properties of FAAH in pre-clinical models.

What other drugs do we already use safely that use the FAAH mechanism?

“At the moment, there are no other drugs in the clinic which directly target this enzyme.”

Is there history of FAAH inhibitors being successfully and without incident taken past the phase 1 stage of clinical trials?

“In 2012, Pfizer published the results of their Phase II clinical trials (small scale, patient-based investigations). This compound was very similar to the BIAL compound in that it was an orally-active, irreversible FAAH inhibitor, PF04457845, which was being investigated for pain relief (in this case, associated with osteoarthritis).  Pfizer ended the trial because the compound lacked efficacy – no difference from the placebo.  There were no reports of the unfortunate severe adverse effects described yesterday.

Now we know that the drug is an FAAH inhibitor, is there any more you can say about why 108 patients were administered the drug and so far five have been reported to have suffered side-effects?

“If the report is correct in that the severe adverse effects were only observed in those individuals that received repeated cumulative doses of the compound, there is a possible explanation. While this is just speculation, one possibility that presents itself is that the compound has low level effects at another target very different from FAAH, the primary target. This would need further investigation, but the logic suggests that low doses or short term exposure to the drug would lead to the expected effect of inhibiting FAAH and potentially some benefit. However, with repeated dosing, not only would the primary target, FAAH, be affected, but also some secondary, as yet unidentified target.  Maybe it is this secondary unknown target which is responsible for the unfortunate severe adverse effects which have been reported.  This obviously requires further investigation, and such evidence is only likely to be forthcoming after a number of months of study.”

Prof David Nutt, Edmond J Safra Chair and Head of the Centre for Neuropsychopharmacology, Imperial College London, said:

What is an FAAH inhibitor, what do they do and how do they work?

“Preventing the breakdown of endogenous cannabinoids such as anandamide to enhance the effect of this widely spread neurotransmitter system.

What kinds of diseases or conditions are they already used to treat or known to be effective at treating?

“No proven indications as yet – Pfizer compound failed in pain control but there are many other possible target indications as cannabis receptors are the most prevalent GABA-protein coupled receptors in the brain (more than dopamine, noradrenaline and serotonin together).

What other drugs do we already use safely that use the FAAH mechanism?

“None as yet but has long been a target – the first research was over 20 years ago.

Is there history of FAAH inhibitors being successfully and without incident taken past the phase 1 stage of clinical trials?

“Yes – Merk and Pfizer have done this and clinical trials I think also. The fact that these didn’t have significant adverse effects and the fact that this occurred only at the highest dose means that it is likely this is an off-target effect i.e. interferes with another enzyme system of maybe brain or more likely vascular system.

Some media reports suggest the drug was tested in chimpanzees. If the drug in this case had been tested in chimpanzees, what might that mean?

“Best way to assess likely safety in humans.

Is it too early to know what might have gone awry with this drug in this group of volunteers?

“Yes, we’ll need proper and detailed pathology studies though it won’t be easy as the patients are still alive so getting brain material will not be easy if possible at all.

Is it possible it may have been a contaminated batch, or is it more likely to be a problem with the mechanism of the drug?

“Could be either though the former is more likely.

Now we know that the drug is an FAAH inhibitor, is there any more you can say about why 108 patients were administered the drug and so far five have been reported to have suffered side-effects?

“This is a standard way of testing the safety of new drugs.”

Prof David Webb, President, British Pharmacological Society, said, commenting on the information that the drug is an FAAH inhibitor:

“FAAH (fatty acid amide hydrolase) degrades neurotransmitters that can influence eating, sleep and pain. It is possible FAAH inhibitors, such as BIA 10-2474 using in the clinical study in France, might, therefore, be useful in disorders affecting these functions, as well as in anxiety and neuro-psychiatric disease (including Parkinsonism), though none have yet been developed into treatments.

“Animal studies (which media reports suggest may have included chimpanzees) and studies with single doses of the drug in humans did not appear to raise concerns, and it appears that the study that caused severe and critical illness was the first to use multiple doses of the drug. Levels of the drug, and/or of the neurotransmitters that are degraded by FAAH, may have accumulated with multiple dosing, and potential cumulation of high concentrations of these neurotransmitters may have caused the current problems, which reports suggest appeared after several days of dosing.

“Other companies have also been exploring FAAH inhibitors, but have discontinued their studies. I am not sure whether this was through lack of efficacy (in which case it is possible they did not get to multiple-dosing) or for other reasons.”

Dr Ben Whalley, Professor of Neuropharmacology, University of Reading, and member of the British Pharmacological Society, said, commenting on the information that the drug is an FAAH inhibitor:

What is an FAAH inhibitor, what do they do and how do they work?

“FAAH inhibitors block the activity of the enzyme in our bodies that is responsible for breaking down endocannabinoids, compounds that our bodies produce naturally and act at the same receptors as some of the components of Cannabis.

What kinds of diseases or conditions are they already used to treat or known to be effective at treating? 

“None. Some went to Phase II trials some years ago without any associated problems but none became medicines.

What other drugs do we already use that use the FAAH mechanism?

“None, other than research compounds used in non-human animal or test tube studies.

Is there history of FAAH inhibitors being successfully and without incident taken past the phase 1 stage of clinical trials?

“Yes, Pfizer took a FAAH inhibitor to Phase II trials some years ago without incident.

Some media reports suggest the drug was tested in chimpanzees. If the drug in this case had been tested in chimpanzees, what might that mean?

“Too early to say since we do not know the doses used, how long they were treated for etc.

Is it too early to know what might have gone awry with this drug in this group of volunteers?

“Given that there have not been previous problems with a FAAH inhibitor in humans, it is possible that the Bial compound has caused its unwanted effects by interacting with a target that is not FAAH (termed an ‘off target effect’). Another option is a dosing accident where patients were given far more than clinicians thought was in the dosage form.

Now we know that the drug is an FAAH inhibitor, is there any more you can say about why 108 patients were administered the drug and so far five have been reported to have suffered side-effects?

“Those who have experienced side effects appear to be the only patients who have received repeated doses of the drug. This may be a factor. Alternatively, the reasons above may also apply”.

Comments from Friday 15 January:

Prof Sir Munir Pirmohamed, David Weatherall Chair of Medicine, University of Liverpool, said:

“Phase I trials are usually small, particularly when the first volunteers are dosed when the lowest doses are used.  However, if the lower doses are tolerated, there may be some dose escalation studies undertaken, again in healthy volunteers.  Depending on how many dose escalations are undertaken, this can add up numbers in the overall phase I study.  So it is unusual for a phase I study to have these many volunteers at one dose, but my guess would be that in this case, they were in dose escalation phase, and hence the cumulative numbers doses would have gone up to 90.  Of course, without having read the protocol, one cannot be sure of this, and it would be good to get more information to either reject or confirm this hypothesis.

What safeguards are put in place for clinical trials?  Following Northwick Park, guidelines have been strictly adhered to in terms of the type of drug being assessed, ethics approvals, approvals by national regulatory authorities.  Before starting any study it is important to ensure that the need to undertake a clinical trial is scientifically sound and robust, and this should be assessed as part of the regulatory approvals.

How common are trials like this and how common is it for there to be side-effects? Phase I trials are very common and essential for drug development. The safety record is very good, with 0.02% developing a serious adverse event (I should explain an event is anything that occurs in relation to taking a drug but it may not be causally related).

Are there regulations that people have to follow? Will they be the same in France as in England?  See above.  The regulations in France will be similar to the UK as we are all part of the EU, and have to follow the guidance set out by the European Medicines Agency.

This apparently took place in a private establishment – will that mean they are under different regulations/ethics approvals?  The majority of phase I trials are undertaken by Contract Research organisations which are private.  They also have to abide by the regulations described above.

If this is a trial being conducted on healthy patients then does this mean it is likely to be a trial for safety in humans, or is it not possible to say at this stage? Phase I trials are designed to test the pharmacokinetics and tolerability of the drug.

Will this drug necessarily have been tried on animals before? Impossible to say this without more knowledge of the drug.”

(Second comment in response to reports that 90 people received the drug) Mr Les Rose, Clinical Science Consultant, said:

“90 subjects is a lot for phase 1, but not by any means unknown. I ran one such study about 10 years ago, but it was a pharmacodynamic study (i.e. finding out if the drug has any effect in humans) and not first in man. It would be very odd to dose 90 subjects in a first in man study.

“It would be more usual to give ascending doses to small numbers, monitoring carefully between escalations. That was a recommendation of the TGN1412 report.

Prof Trudie Lang, Director of the Global Health Network, University of Oxford, said:

“Phase I trials, as with all clinical trials are highly regulated across the globe and when we plan phase I trials we, as the researchers, need to demonstrate to ethics and safety committees that we understand enough about the drug to predict confidently that it will be safe when given to a human volunteer for the first time. This would have been the case with this drug because there are a common set of EU requirements.

“Clinical trials are essential for determining whether a drug works in the target disease and whether it is safe. The safety question is often harder one to answer. It can be the case that rare adverse events only become evident after the drug has been given to many thousands of patients. Phase I trials explore how the drug acts in humans and can tell us many things about dose and how long any therapeutic effect might last. Rare and serious events such as this are so unusual because so much as already been learnt about the drug in the laboratory and in animal studies and so problems can typically predicted. Phase I trials usually involve quite small numbers of patients who are very closely monitored. This trial seems unusually large for a normal phase I trial and so it will be interesting to learn why there where so many volunteers and whether they were dosed slowly and sequentially and how closely they were reviewed.”

Prof David Webb, President, British Pharmacological Society, said:

“This is a tragic and thankfully extremely rare event in the development of a new medicine. Nothing like this has occurred since 2006, with the Northwick Park tragedy in the UK, and before that few early clinical studies have led to devastating harm since the mid-20th century.

“A very effective regulatory system (provided by the Medicines and Healthcare products Regulatory Agency in the UK) now requires a substantial number of well-defined studies in tissues and animals to explore toxicity and potential side effects before a potential new medicine is given to people. The first studies, so-called phase 1 studies, use low doses of the medicine, based on the pre-clinical work, and provide a reasonable assurance of (but cannot promise) safety. With an oral medicine, as in this case, with up to 90 patients already treated (as been suggested), then an unanticipated critical illness in 6 subjects caused by the medicine is unheard of. This raises the possibility that there were issues with dosing or manufacture, though we will not know until more information emerges.

“Involvement in clinical trials is critical for the development of new medicines that cure diseases, alleviate pain and illness, and prolong life. It must be hoped that a better understanding of the problem that occurred here will help ensure that phase 1 studies continue to maximise safety for patients and healthy volunteers.”

An MHRA spokesperson said:

“There is no clinical trial taking place in the UK with this product nor has it been used in a clinical trial in the UK in the past.

“Clinical trials in general have an excellent safety record and hundreds of phase 1 clinical trials are authorised each year by MHRA.

“Before any trial of a new medicine begins in humans, the product will have undergone extensive pre-clinical testing, both in the laboratory and in animals as appropriate.

“Safeguards for clinical trials are well-established and regulations are in place, which specifies how clinical trials should be conducted.”

Background

  • Clinical trials in the UK are regulated by The Medicines for Human Use (Clinical Trials) Regulations 2004. Clinical trials of medicines on people requires authorisation by the competent authority (MHRA in the UK) and a favourable opinion from an ethics committee.  This authorisation is granted in the form of a clinical trial authorisation (CTA).
  • In 2007 following on from the recommendations of an independent Expert Scientific Group which was brought together to examine the design of phase 1 clinical studies. It was convened by the Secretary of State for Health to look at how to improve the safety of drug trials following adverse reactions experienced by participants in the clinical trial of TGN1412.

http://webarchive.nationalarchives.gov.uk/+/www.dh.gov.uk/en/consultations/closedconsultations/DH_4139038

MHRA implemented an accreditation scheme for companies running Phase I clinical trials in the UK.  This scheme is voluntary and aims to make sure trials are as safe as possible and to create public confidence in the regulation of these trials. 

  • Organisations in the scheme have to exceed the basic regulatory good clinical practice (GCP) standards by having additional procedures that include the highest standards for avoiding harm to trial subjects and for handling any medical emergencies. Further information can be found here: https://www.gov.uk/guidance/mhra-phase-i-accreditation-scheme
  • In the UK all Phase 1 clinical trials need be have been authorised by MHRA.

(Second comment in response to reports that 90 people received the drug) Prof Carl Heneghan, Professor of Evidence-Based Medicine, University of Oxford, said:

“In phase 1 trials, usual practice dictates that patients are recruited slowly, with only a few patients in the first instance. These first patients are given a small dose and if this proves to be safe, with no adverse effects, then a next group is given a slightly higher dose – referred to as a dose escalation study. This new information suggests that the dose reached a toxic level – and why problems are now emerging. The key with phase 1 dose escalation trials is that they should generally take a long time, as at each stage of the dose increase you have to be sure sufficient time has passed for the adverse effects to have manifest themselves.

All of the people involved will now likely need to be traced and monitored for adverse effects.

“Why this is still a phase 1 trial, is it is carried out in healthy volunteers. Phase 2 trials generally involve those with the disease of interest, for which the treatment is intended for.”

Prof Alan Boyd, President of the Faculty of Pharmaceutical Medicine, said:

“It is very sad that the clinical trial of a new medicine has caused serious illness to healthy volunteers. Over time we will learn the full facts about this case. There are very clear regulations and controls in place around the conduct of clinical trials and this includes both patients and healthy volunteers.

“It is not currently possible to speculate on the causes of illness in this instance. All new medicines under investigation in humans will have previously undergone extensive investigation both in the laboratory ‘test-tube’ setting and then with animals, collectively these are called ‘preclinical tests’. All clinical trials are subject to strict regulatory and ethical controls.

“In phase 1 clinical trials or ‘first-in-man’ studies the experimental medicine or treatment (an Investigational Medicinal Product or ‘IMP’) is tested in a small group of people (usually healthy volunteers) to evaluate its safety, determine a safe dosage range, and identify side effects. Pharmaceutical physicians are responsible for the design, performance and interpretation of phase 1 studies. The trials are often carried out by privately run Clinical Research Organisations (CROs).

“The Faculty of Pharmaceutical Medicine’s (FPM) role is to set and raise standards in Pharmaceutical Medicine and to help ensure the safety and wellbeing of the general public and the participants in clinical trials. The FPM works for the continuous improvement of standards in phase 1 clinical trials and sets the curricula and administers both the Diploma and Certificate in Human Pharmacology with this purpose.”

Dr Anna Smajdor, lecturer and researcher in biomedical ethics, University of East Anglia’s Norwich Medical School, said:

“Each country has its own rules and regulations to protect people involved in clinical trials. Trials involving human beings have to be scrutinised by an ethics committee. France has several such committees, and I would expect that this research would have been approved by one of them.

“Occasionally, very severe side-effects are experienced by participants. In the UK in 2006, several men suffered organ failure following a phase one trial at Northwick Park Hospital in London. Phase one is the first phase after animal testing, usually involving only a few healthy volunteers. The purpose is to establish risk and side-effects. However safe animal studies have been, there is never a 100 per cent guarantee that it will not react unexpectedly in humans.

“Phase one trials often involve young participants who take part in return for payment. The nature of clinical research means that every so often, people will be seriously harmed or even killed in the process of research, there is no way round this.

“The question in this case is whether, as in Northwick Park, there were any failures of protocol that meant participants suffered more damage than necessary – in Northwick Park, they administered the drug to all volunteers at once instead of staggering it so they could avoid a bad reaction affecting all of the participants.”

Prof Jayne Lawrence, Chief Scientist, Royal Pharmaceutical Society, said:

“This type of incident is tragic but very rare in the world of clinical trials.  There are very strict regulatory standards across the EU for performing clinical trials and phase 1 trials, where a drug molecule is tested for the first time in humans, are subject to particular scrutiny to minimise any risk to human health.  Those in charge of the trial would have had to have shown they had done everything they could to protect patient safety before the trial was allowed to go ahead.  There are many commercial companies who run phase 1 trials on a regular basis to establish the effects of a new molecule in humans.  All medicines have side-effects, but these are generally mild and severe reactions are incredibly rare.”

Prof Carl Heneghan, Professor of Evidence-Based Medicine, University of Oxford, said:

“Phase 1 trials are usually the earliest trials of drugs in people and are used to discover if a drug behaves in a way researchers expect it to based on laboratory studies.

“They are used to determine toxic effects, adverse events and a minimal safe dose, and are inherently risky, as unexpected events can – and do – occur.  Phase 1 trials, therefore, pose significant practical and ethical issues – as an example, the Northwick Park drug trial of the drug TGN1412, in 2006, highlighted the disastrous consequences of phase 1 trials.

“Following on from the TGN1412 disaster the ‘Duff Report’ highlighted a number of changes that should be implemented improve the safety profile of phase 1 trials. With the increasing number of novel agents being tested, the current disaster highlights the need for regulators to be extremely vigilant; to ensure correct scientific procedures are adhered to at all times.”

Mr Les Rose, Clinical Science Consultant, said:

What safeguards are put in place for clinical trials?  There would need to be approval from the national medicines regulator, review by an ethics committee, and often there are additional approvals required by local bodies e.g. the institution hosting the research, or relevant specialist committees such as gene therapy or radioactive substances.  For high risk early stage trials there has to be immediate availability of a physician and facilities for emergency support e.g. resuscitation.  Serious adverse events have to be immediately reported to the regulator and the ethics committee, who will stop the trial if they are concerned.  Note that ‘serious’ doesn’t necessarily mean life-threatening, it could for example just mean an overnight stay in hospital. This is just a sample of the extensive safeguards in place.

How common are trials like this and how common is it for there to be side-effects?  If this was a healthy volunteer study, it would have been in phase 1 of clinical development, where pharmacology and safety are evaluated.  It is a very common type of trial, but serious adverse events are not common.

Are there regulations that people have to follow? Will they be the same in France as in England?  All clinical trials are governed by EU law. We are currently transitioning from member state transpositions of two main EU directives, to a new EU regulation which doesn’t allow for national interpretation. So yes, France would have to meet the same regulations.

This apparently took place in a private establishment – will that mean they are under different regulations/ethics approvals?  No – in fact most phase 1 units are private companies.

If this is a trial being conducted on healthy patients then does this mean it is likely to be a trial for safety in humans, or is it not possible to say at this stage?  Although safety is always assessed in all trials, this might have been a pharmacokinetics or pharmacodynamics study, or evaluating metabolism.  But a major focus of all early phase trials is safety.

Will this drug necessarily have been tried on animals before? If so then does that mean that animal trials are a wasted effort?  To get regulatory approval to go into phase 1 human trials a dossier of pre-clinical (i.e. laboratory and animal) studies has to be submitted. But it is ridiculous to say that animal studies are useless.  Most of the time they are a valuable guide to what can happen in humans, but science is not certain.”

Prof Malcolm Macleod, Professor of Neurology and Translational Neuroscience, University of Edinburgh, said:

What safeguards are put in place for clinical trials?  In the UK at least there are lots of safeguards, but no absolute guarantees.

How common are phase 1 trials like this?  Every new drug has to be first in human at some stage, so there are quite a few of these, but they are of very varying risk.

Are there regulations that people have to follow, and will they be the same in France as in England?  This apparently took place in a private establishment – will that mean they are under different regulations/ethics approvals?  Regulations are likely to be the same whether at a private or university establishment – this is certainly the case in the UK (journalists could ask the MHRA for more information).

If this is a trial being conducted on healthy patients then does this mean it is likely to be a trial for safety in humans?  Yes, either safety or pharmacokinetic (how the body handles the drug) or both.

Will this drug necessarily have been tried on animals before?  It is likely but not definite that the drug will have been tested in animals – these animal studies were not necessarily a waste of time if animal studies were well done, and if they’ve found a novel mechanism which is independent of the toxicity.

Dr Ben Whalley, Professor of Neuropharmacology, University of Reading, and member of the British Pharmacological Society, said:

“Safeguards for clinical trials are well-established and standardised regulation is in place, which specifies how clinical trials should be conducted. These are largely the same across Europe and the UK. However, like any safeguard, these minimise risk rather than abolish it. There is an inherent risk in exposing people to any new compound.

“Hundreds of clinical trials involving thousands of people are under way at any time. It is very common for there to be side effects since all medicines (approved or in testing) exert both the desired effect and unwanted effects. For the most part, side effects are limited and tolerable although, for some medicines, they determine the upper limit for a dose that can be used.

“The small number of people involved and the location suggests (but does not prove) that this is likely to be a Phase 1 trial. A Phase 1 trial is part of the standard development of a new drug, and is where a new drug is given limited and tightly controlled exposure to a small number of healthy volunteers. This is done to ensure basic tolerability and safety before exposing potentially more fragile patients (with a disease) to a new medicine. Since it involves healthy volunteers, it is most often not done in a hospital but at specifically designed, private establishments that have approval for such work. Such trials start with a small dose which is then steadily increased over a few days. Also, the doses are most often given to the patients in a staggered fashion in order to minimise the risk of all volunteers experiencing a serious adverse effect. It is therefore unusual for reports to mention that up to 6 people have been affected unless the adverse event has taken several days to appear.

“This drug will certainly have been tested on animals. It does not mean animal trials are a wasted effort because, in the vast majority of cases, animal testing does give vital information of safety and tolerability and prevents incidents such as this happening. It is in a very tiny number of cases where animal models are not predictive but it is only after the event that we are likely to find out why. The number of trials ongoing and the tiny number of incidents like this demonstrate the value of animal research in preventing major events of this sort occurring more frequently.”

Dr Daniel Hawcutt, Senior Lecturer in Paediatric Clinical Pharmacology, University of Liverpool, said:

“Phase 1 studies are the first tests of a new potential medicine in humans, and their purpose is to work out how the drug is handled by the body – and so what is the right dose to give to patients.  They only usually require a handful of patients.  As the purpose of the study is not to work out if the medicine will treat the condition it is aimed at, but how much to give to a patient, phase 1 studies in adults are usually done on healthy volunteers.

“There are strict regulations around how phase 1 studies are conducted. In the UK, a phase 1 study would have to be registered with, and subject to inspection by, the Medicines and Healthcare products Regulatory Agency (MHRA) in addition to the usual study regulations (such as getting research approval and ethical approval). These additional regulations for an early phase study mean it is called a “Clinical Trial of an Investigational Medicinal Product (CTIMP)”, and carry with them strict rules for how to report suspected adverse reactions. These tests are part of an essential series of tests (phase 1-3) that have to be done and approved by a European regulatory agency before a drug company is allowed to sell a drug within Europe. Each medicine that is licensed needs to have undergone some form of phase 1 study.

“Undertaking phase 1 studies is highly specialist work, and in the UK is usually done in a small number of centres that have vast experience. All patients in a phase 1 study will have contact information for the team running the study and if they are worried that they may have experienced an adverse effect of the medicine, they should get in contact with the team directly and let them know.”

Declared interests

Prof Max Parmar: “The MRC Clinical Trials Unit at UCL receives funding to conduct clinical trials from a large number of government and charitable funders. It also receives support in terms of free or reduced drug costs or educational grants from more than 20 different companies. I do not personally receive any support (financial or otherwise) from commercial companies.”

Prof Jackie Hunter: “I am CEO elect of a biotech company, Stratified Medical.”

Prof Stephen Alexander: “In terms of conflicts of interest, I have received no industry funding for my investigations associated with this enzyme.  I have been co-investigator on a grant received from the Wellcome Trust to investigate effects of long-term inhibition of this enzyme on pain behaviours in pre-clinical models.”

Prof David Nutt: “None related.”

Prof Munir Pirmohamed: “I am employed by University of Liverpool, and am a Commissioner on Human Medicines for the MHRA. I also chair the Pharmacovigilance Expert Advisory Group for the MHRA.  I was a member of the Duff committee following the Northwick Park incident.  I have grant applications from a number of sources including MRC, NIHR, medical charities and the EU. In addition, we have funding for training of clinician scientists jointly between MRC and GSK and Astra Zeneca, and a research grant with Pfizer.  These are all investigator initiated rather than contract research. I do not act as Consultant to any pharmaceutical company. I am still also NHS Chair of Pharmacogenetics.”

Prof Trudie Lang: “No interests to declare.”

Prof David Webb: Professor of Therapeutics and Clinical Pharmacology, University of Edinburgh.  Non-executive Director, MHRA.

Prof Alan Boyd: “I am the President of the Faculty of the Pharmaceutical Medicine of the Royal Colleges of Physicians of the UK, which provides the curricula for examinations and training programmes in medicines development. I am also the CEO of Boyd Consultants Ltd – this is a Consultancy that Specialises in supporting small pharmaceutical and biotechnology companies develop their ideas and turn them into medicines. I also help and advise several universities too in this respect.”

Dr Anna Smajdor: No conflict of interests to declare.

Prof Jayne Lawrence: Jayne has stated she has no declaration of interest to make.

Prof Carl Heneghan: “Conflicts of interests: none.”

Mr Les Rose: “I am retired and only do very occasional work for a trade journal (Pharmafocus) so no interests to declare.”

Prof Malcolm Macleod is a member of the Commission on Human Medicines and a member of the UK Home Office Animals in Science Committee but he is commenting here in his capacity as an academic at the University of Edinburgh.

Dr Ben Whalley: paid employment or self-employment: University of Reading;

Grant funding: GW Pharma, NC3Rs, UCB Pharma;

Voluntary appointments; UK Advisory Council on Misuse of Drugs;

Memberships: BNA, BPS;

Decision-making positions: None;

Other financial interest: None.

Dr Daniel Hawcutt: “My post is jointly funded by a) University of Liverpool, b) Alder Hey Children’s hospital, and c) the NIHR Alder Hey Clinical Research Facility (a unit specialising in undertaking phase 1 and 2 studies in children).”

 

None others received.

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