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Reports are emerging from France that six participants in a phase I clinical trial are critically ill after taking oral medication.
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.”
Mr Les Rose, Clinical Science Consultant, said:
Second comment in response to reports that 90 people received the drug:
“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
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.
Prof. Carl Heneghan, Professor of Evidence-Based Medicine, University of Oxford, said:
In response to reports that 90 people received the drug:
“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 [1]. 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.”
Reference [1]: The TeGenero incident and the Duff Report conclusions: a series of unfortunate events or an avoidable event? Toxicol Pathol. 2009 Apr;37(3):372-83. doi: 10.1177/0192623309332986. Epub 2009 Feb 24. http://tpx.sagepub.com/content/37/3/372.full
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. 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).”