Prof. Peter Saunders raises a number of key questions on the way the drug trial was conducted
On March 13, 2006, six volunteers at Northwick Park Hospital in London were given small doses of a new drug TGN1412 that had been developed by the German biopharmaceutical company TeGenero. As is common nowadays, the trials were run not by the manufacturer but by a company that specialises in clinical trials, Parexel International Limited.
The subjects all became so seriously ill that they had to be placed in intensive care. There were fears that at least two of them would die, and while in the end all survived, at the time of writing one is still in hospital and it is not known how much permanent damage any of them has suffered (“London drug trial catastrophe, the collapse of science and ethics”, this series).
So long as new drugs are going to be developed, they will have to be tested, and it is always possible that something will go wrong. But that’s all the more reason for asking whether everything was done to protect the six volunteers (actually there were eight, but the other two were given a placebo) and what are the lessons for the future.
As explained in Box 1, a drug is tested on animals before it is given to humans. Unfortunately, all species are different, and even if rodents or monkeys suffer no adverse reactions, or only at very high dosages, we still can’t be sure it will be safe for humans.
Developing a new drug is a very long and expensive process. When a candidate has been identified, it is tested first in the laboratory and then in animals. If all goes well, the next step is clinical trials, in which it is tested in humans.
Clinical trials are conventionally divided into four phases that a drug must pass in order:
Phase I: These are primarily to discover whether the drug is safe. They are conducted with small numbers of individuals, seldom more than about 60. The subjects are usually healthy, but if the drug is known or suspected to be toxic it may be tested on patients; this is most common in treatments for cancer.
Phase II: Next, the drug is tested with a larger group, generally patients. The chief aim is again to determine whether the drug is safe, but efficacy will usually also be tested.
Phase III: The drug is now tested in a much larger group of patients, perhaps several thousand; the issue is primarily efficacy. Because the effect of a drug will vary from patient to patient, this phase generally involves careful statistical analysis, especially as the question is often not just whether the drug works, but whether it works better than an existing competitor.
Phase IV: After a drug has been approved for use, it must still be monitored for effects that did not become apparent during the first three phases. The sample is now all the patients who have used the drug. This phase can be highly contentious, because to withdraw a drug that is already on the market is obviously very expensive.
TGN1412 is different from most drugs, however, and there was even more reason than usual to be cautious about the first human trials. It is not a molecule that has been synthesised by conventional chemical processes but a monoclonal antibody, based on an antibody produced in a mouse. It had to be “humanised”, i.e. genetic engineered so that it will be immunologically accepted in humans, which means that the drug given to humans is not the same as the one used in animal testing.
Before the trial began, Parexel submitted a protocol to the regulator, the Medicines and Healthcare Products Regulatory Agency (MHRA). The protocol can be seen on the MHRA web site , though with some parts censored on grounds of “commercial sensitivity”. It gives the background to the trials including a description of the drug and the results of the pretrial tests, and details of how the trials are to be carried out and the results assessed. As is usual with submissions from industry, the results of earlier work, on which the regulator – and the subjects – relied, had not been published in peer-reviewed journals.
According to the protocol, a variant of TGN1412 had been found to be safe and effective in rats. TGN1412 itself had been given to “non-human primates”, which TeGenero argued would be a good animal model for testing safety and efficacy. No serious adverse reactions were observed, though the monkeys did develop swollen lymph glands at a high dosage, but the protocol does not say how many animals were used. There is also no mention of efficacy, and it may well be that the reason the monkeys did not suffer the same side effects as the human volunteers is that, contrary to the assumption made by TeGenero, TGN1412 does not act in monkeys in the way it does in humans, and the non-human primate was therefore not a good model.
The other inherent danger in TGN1412 is that it acts on the immune system. The immune system differs from species to species more than other systems. Its operation is highly complex and not well understood. It typically involves a large effect being triggered by a relatively small stimulus, so we cannot assume that a low dosage will have only a small effect. What is more, unlike many other monoclonal antibody drugs whose function is to reduce or suppress the immune response, TGN1412 is designed to stimulate it. According to the protocol it “induces profound in vitro T-cell proliferation”. That’s important for the purpose for which it is intended, but it also opens the possibility of a runaway effect, which is almost certainly what happened.
These are not merely theoretical points. Monoclonal antibody drugs have been found to present characteristic dangers, and the USA Food and Drug Administration (FDA) has issued warnings for practically all of the ones it has approved (see “FDA warnings on monoclonal antibodies”, this series). For example : “Orthoclone OKT 3 mouse monoclonal antibody, Ortho Biotech, Transplant anti- rejection
Safety information: Anaphylactic or anaphylactoid reactions may occur following administration of any dose or course of ORTHOCLONE OKT3. In addition, serious, occasionally life-threatening or lethal, systemic, cardiovascular, and central nervous system reactions have been reported following administration of ORTHOCLONE OKT3. These have included: pulmonary edema, especially in patients with volume overload; shock, cardiovascular collapse, cardiac or respiratory arrest, seizures, coma, cerebral edema, cerebral herniation, blindness and paralysis.”
There are warnings of serious adverse side effects for at least 17 other mouse monoclonal antibodies that are on the market (“Warnings on FDA approved monoclonal antibody drugs”, this series).
Despite this, TeGenero and Parexel decided to go ahead with the Phase 1 trials. It’s not possible to know the factors they did and did not consider in reaching this decision, but it is disturbing that the FDA notices are not referred to in the protocol. Surely they should have served as a warning that the drug might be especially hazardous, and we have no evidence that the company realised this or took it properly into account.
When potentially hazardous drugs are being tested, it is common to use patients rather than healthy volunteers. That is often done in proposed treatments for cancer, where the new drug may be seen as a last resort. It is one thing to recommend something very risky to a person who seems likely to die soon if nothing is done (although the ethics of that is also debatable); it is quite another with an individual who is in good health.
It is also usual practice to try the drug on a single individual first, and not to give it to others until it seems safe to do so. That does not appear to have been the case in the TGN1412 trials, which is why all six volunteers suffered the violent reactions. Unfortunately, while the protocol did include a “time and events” table, this has been omitted from the version posted on the MHRA website .
In place of the table, there is a handwritten note referring the reader to an earlier statement (which is used to justify a number of other omissions as well): “Section withheld under section 43(2) of the FOI [Freedom of Information] Act as, in the MHRA’s view, disclosure would, or would be likely to, prejudice the commercial interests of TeGenero or associated third parties. In the Agency’s view the public interest in disclosure does not outweigh the private interest in withholding the information.”
It is hard to see how anyone’s legitimate commercial interests could be harmed by releasing the information. On the other hand, it is highly relevant to deciding who is at fault for what happened – and presumably who will have to pay compensation.
If the protocol said that the drug would be administered to one volunteer first, then Parexel did not follow the protocol and could be held to be negligent and therefore responsible for the harm done to at least five of the volunteers. On the other hand, if the protocol specified that all six were to receive the drug at the same time, or at intervals too short for safety, or if it said nothing about the timing, then Parexel are open to criticism for not exercising sufficient caution in the Phase 1 trial of a possibly hazardous drug, and the MHRA can be criticised for not insisting that they did. (According to the TeGenero website  the protocol specified that the drug should be given to the volunteers “within a period of two hours” and this was done. That does not tell us how long the time interval between the first and last actually was; from newspaper reports it certainly seems to have been considerably less than two hours. We also do not know whether they followed the procedure of giving the drug to one subject first and waiting before giving it to the others.)
We also have to ask what the volunteers were told about the drug. Anyone who participates in a drug trial is supposed to give “informed consent”, which means they should know as much as possible about the risk they are running. According to the reports, the volunteers were given only ten minutes to read the relevant document. This is apparently not unusual, but that does not make it acceptable, especially given what was known about drugs of this kind.
Parexel and the MRHA have refused to release the document that each volunteer was given, but one page is available. It does indeed mention the possibility of anaphylaxis, and even that this can be life-threatening, but it plays it down by saying that it and other unintended effects “may theoretically be encountered” [emphasis supplied] and pointing out that it can also be caused by common foodstuffs like peanuts and shellfish. In fact, what actually happened appears to have been something different; a cytokine storm (see Box 2). This was not mentioned in the document; perhaps the investigators did not consider the possibility, though clearly they should have.
Anaphylaxis and Cytokine Storms:
Anaphylaxis occurs when a person is exposed to a trigger substance, called an allergen, to which they have become sensitised. Even minute amounts of allergens may cause a life-threatening anaphylactic reaction, which is why there are warnings on foods that may contain only traces of nuts. Anaphylaxis may occur after ingestion, inhalation, skin contact or injection of an allergen. The most severe type of anaphylaxis—anaphylactic shock—will usually lead to death in minutes if left untreated.
A cytokine storm is a potentially fatal immune reaction consisting of a positive feedback loop between cytokines and immune cells. When the immune system is fighting pathogens, cytokines signal immune cells such as T-cells and macrophages to travel to the site of infection. In addition, cytokines activate those cells, stimulating them to produce more cytokines. Normally this feedback loop is kept in check by the body. However, in some instances, the reaction becomes uncontrolled, and too many immune cells are activated in a single place. The precise reason for this is not entirely understood. Cytokine storms have potential to do significant damage to body tissues and organs. If a cytokine storm occurs in the lungs, for example, fluids and immune cells such as macrophages may accumulate and eventually block off the air passageways.
Many monoclonal antibodies, both humanised and human, provoke anaphylaxis, but only the ones directed towards regulation of the primary immune response seem to cause cytokine storms.
It is also interesting to go to the Parexel website where, under FAQ for clinical trials, we read:
“How safe is it?
“Before any volunteer can take part in a clinical trial, we take great care to ensure that you are suitable to do so. Volunteers are required to undergo a thorough medical examination which includes taking blood samples for a variety of tests (including Hepatitis and HIV) as well as performing a tracing of your heart (ECG) and blood pressure. Clinical trials are carried out under the strict supervision of qualified doctors, nurses and other health professionals. All our trial protocols are reviewed and approved by the Independent Ethics Review Committee.”
That does not, of course, answer the question. It’s nice to know that a Committee has looked at the protocol and that there will be lots of qualified people to help you if things go wrong, but what you really want to know is the chance that they will.
The health correspondent of the newspaper Scotland on Sunday asked the MHRA, and was told that since 2001 there have been 2 088 volunteers who have needed hospital treatment as a result of drug testing . In 2005 alone, there were 359 people in the UK who suffered what are called “suspected unexpected serious adverse reactions” (SUSARs). Now there are about 3000 drug trials a year in the UK, and most SUSARs are nowhere near as serious as those experienced in the TGN1412 trial, but it is still not what a prospective volunteer is likely to imagine from reading the Parexel website.
The MHRA has produced an interim report on the incident . It concludes that:“… an unpredicted biological action of the drug in humans is the most likely cause of the adverse reactions in the trial participants. Monoclonal antibodies are a relatively new type of biological drug although there are a number of them already licensed and in use. However, TGN1412 is a new class of monoclonal antibody which has a stimulatory mode of action affecting certain types of cell in the immune system. In this case the resulting activity seen in humans was not predicted from apparently adequate pre-clinical testing. This is a complex scientific issue which raises important scientific and medical questions about the potential risks associated.”
The MHRA appears satisfied that as the drug was properly produced and the agreed protocol was followed, however unfortunate the incident was, no one was to blame. They write that what happened was unpredicted, but the real question is not whether it was predicted, which it obviously was not, but whether it was so unpredictable that no special precautions were called for. Cytokine storms have been observed before, and where there is positive feedback we always have to consider the possibility that the system will run out of control. An important part of the design of nuclear reactors is precisely to ensure that this cannot happen almost no matter what goes wrong.
The report acknowledges that TGN1412 is a new class of what is itself a relatively new type of drug, and we must assume that both TeGenero and the MHRA knew this before the trials began. Did Parexel and TeGenero take it into account when they drew up the protocol? Did they specify that the trials were to be run with greater than usual caution? Did the MHRA take it into account when they agreed the protocol? Was it made clear to the volunteers that they were being given a drug that was significantly different from almost all existing drugs?
It cannot be right for the investigation to be carried out by the MHRA, when one of the key questions to be answered is whether the MHRA carried out its own role properly. In its 2005 report on the influence of the pharmaceutical industry, the UK House of Commons Select Committee on Health recommended a large scale independent review of the MHRA, but this was not accepted by the Government in its response. The TGN1412 incident and its aftermath should make the Government think again.
The Secretary of State for Health has now agreed to set up an international group of experts under the chairmanship of Professor Gordon Duff of Sheffield University. Its brief is to consider what should be required in the transition from pre-clinical to Phase I trials especially in the case of biological molecules with novel mechanisms of action, new agents with a highly species-specific action, and new drugs directed towards immune system targets. In other words, drugs like TGN1412.
TGN1412 is not the only drug to have caused serious problems in Phase I trials, and Phase I is not the only stage at which there have been serious problems. In cases such as Vioxx, the harmful side effects were not observed until after the drug was on the market, i.e. in Phase IV, and the many law suits hinge on the question of how fast the producer, Merck, was to accept that there was a problem. What is needed is an investigation into the whole process of drug development and testing, from preclinical trials to monitoring after it is being sold.
Acknowledgement: I am grateful to Joe Cummins and Mae Wan Ho for their advice.
Article first published 23/05/06
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