Facts about Novo Nordisk's clinical trials with ragaglitazar (26 Jul 2002)
In its 9 pm newscast last night, Denmark’s DR TV-Avisen featured a story about a patient who had participated in a clinical trial with ragaglitazar (also known as NN622, which is the compound’s project name within Novo Nordisk). Monday, Novo Nordisk announced that all current clinical trials with NN622 have been suspended until it has been determined what caused the development of urine bladder tumours in a number of rats and one mouse that have been treated with the compound.
The newscast could leave the viewer with an impression that Novo Nordisk has not acted appropriately in connection with the ragaglitazar clinical trials, for example by not having informed patients about the risks involved in participating in the trials.
It is important for Novo Nordisk to emphasise that the company has conducted the trials in full compliance with all requirements for good clinical practice, and that any potential risk connected with participation in the clinical trials is both very small and known by the participants in the trials.
Below are answers to some questions that the TV story raised.
What is ragaglitazar?
Ragaglitazar is an insulin sensitiser for the treatment of Type 2 diabetes. Insulin sensitisers are substances that stimulate the body’s ability to utilise insulin. In pre-clinical animal trials and in clinical trials, ragaglitazar has shown the ability to regulate both sugar- and fat-levels in the blood.
How many people participated in the Phase 3 trials, which now are suspended?
2,500 people in 32 countries participated in the trials, including 42 people in Denmark. About 1,100 of the 2,500 trial participants received ragaglitazar, while the remainder received another diabetes medicine. This was done in order to compare ragaglitazar’s effect with that of another Type 2 diabetes medicine whose effects are well-known.
Why did Novo Nordisk decide to suspend all further clinical development with ragaglitazar?
Novo Nordisk decided to stop clinical development of ragaglitazar immediately after learning that one mouse treated with ragaglitazar had developed a urine bladder tumour.
Early this year, similar findings were found in a number of rats treated with ragaglitazar. Many of the pharmaceuticals on the market today have, however, been shown to cause tumours in trials involving rats. Therefore, the rat findings alone were not alarming. The American and European health authorities, including the Danish Lægemiddelstyrelsen, did not question the continuation of the clinical studies after having been informed of the tumour findings in the rats.
However, the fact that tumours have now been reported in two species led Novo Nordisk to conclude that it was not ethical to continue trials in humans until it can be documented that the mechanism by which these tumours develop is specific to rodents, and as a result is not relevant for humans.
Were all relevant stakeholders informed of the tumour findings in rats earlier this year?
Yes, all relevant stakeholders were informed in February: Health authorities, patients, investigators and ethics committees in all the countries in which trials were conducted. All patients were asked to re-assess their continued participation in clinical trials, and all signed a new Patient Informed Consent Form which included the information about the tumours found in rats.
After finding the tumour in the mouse, we immediately took steps to ensure that all trial participants were informed and that they would be called in to a visit with the doctor with whom they have had contact throughout the trial.
What could have caused the development of bladder tumours in the rats and in the mouse?
We don’t know for sure. Novo Nordisk has initiated a series of studies in animals to clarify the reason for the findings. The primary theory is that the finding is specific to rodents. Rodent urine is significantly different in composition than human urine. One possible explanation for the findings is that they were caused by a mechanism leading to the formation of crystals in the rodent urine. The formation of such macro- or micro crystals may eventually be found to be the cause of the carcinogenicity findings in the urinary tract system in the rodent. If this is the case, the mechanism would be of no relevance to man.
What is the risk that patients who have been exposed to ragaglitazar will develop a bladder tumour?
It is very small. Novo Nordisk performed genotoxic studies with NN622 prior to initiation of any clinical trials. All genotoxic studies were negative, which means there is very strong evidence that NN622 is not a genotoxic compound. (A genotoxic carcinogen is a compound that causes cancer by damaging genetic material).
Non-genotoxic carcinogens require long exposure time to pose a risk to humans; normally many years of exposure. When a carcinogen is non-genotoxic, the risk disappears when exposure to the risk factor is removed.
The tumours seen in rats and in the mouse only occurred after exposure of the animals for a period of time equivalent to from between half to all of their life expectancy.
The majority of patients have been exposed for less than six months and only very few have been exposed seven months.
According to regulations approved by international health authorities, long-term carcinogenicity studies are only required when the patients have a chronic disease. This is based on the general acknowledgement that it takes several years of exposure to a very potent carcinogenic compound for patients to even start being at risk.
Why were these animal studies initiated so late in the development programme?
They were not initiated late. Some types of animal studies must be performed before starting trials in humans, but according to the international guidelines, this type of long-term carcinogenicity study need not be conducted prior to entering Phase 3 development. The study data are only required at the time of submission of the application for approval of the medicine.
For medicines that are expected to be used for less than half a year, long-term carcinogenicity studies are not required at all.
How have you informed the patients about the termination of the trials?
Only the investigators conducting the trials are permitted to contact trial participants directly. Pharmaceutical companies do not know who the trial participants are, and cannot contact them.
Monday morning, we sent letters to the health authorities and to investigators informing them of Novo Nordisk’s decision to suspend the trials and the reasons for the decision. The investigators then inform the patients and the ethics committees. This process is currently under way, and Novo Nordisk is following it closely.
What kind of follow-up will there be for patients who have been exposed to NN622?
All patients will be called to an end-of-trial visit. In addition, Novo Nordisk will suggest that patients have a urine sample taken one year after they stop taking the drug in order to document that the patient has not suffered any harm.
Novo Nordisk is a focused healthcare company and the world leader in diabetes care. In addition, Novo Nordisk has a leading position within areas such as haemostasis management, growth hormone therapy and hormone replacement therapy. Novo Nordisk manufactures and markets pharmaceutical products and services that make a significant difference to patients, the medical profession and society. With headquarters in Denmark, Novo Nordisk employs approximately 16,000 people in 68 countries and markets its products in 179 countries. For further company information visit www.novonordisk.com
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