The Drug-Trial that went wrong!

Kartheek Dokka000543544

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Their Job!

• B-CELLS : They get activated in presence of the antigens. They produce antibodies thus becoming “Plasma cells”.

• T-CELLS : They need 2 signals to be activated a)signal 1-Antigen Receptor

b)signal 2-CostimulationT-cells produce cytokines!!

Human CD28 StructureCD28 is one of the molecules expressed on T-cells that provide co-stimulatory signals, which are required for T-cell activation.

THE TARGET MOLECULE

THE GENIUS…. TeGenero AG was a pharmaceutical research company in Wurzburg, Germany. It had 15 employees and was incorporated as an Aktiengesellschaft*[hmm…sound very interesting] from 2002. TeGenero was founded in 2000 as a spin-off of the Medical School of the University of Würzburg; it received 14 million euros in venture capital.*AG-Corporation owned by shareholders.

A super-agonist is a type of agonist that binds permanently to a receptor in such a manner that the receptor is permanently activated

TGN1412• Also known as CD28-SuperMAB• Superagonist for CD28 molecule• It was supposed to be an “immunomodulatory drug”

[it sure was except for it could not be controlled]• originally intended for the treatment of B cell chronic

lymphocytic leukemia (B-CLL) and rheumatoid arthritis.

• It is a humanized monoclonal antibody that not only binds, but is a strong agonist for the CD28 receptor of the immune system's T cells.[SUPER]

• The drug, which was designated as an orphan medical product by the European Medicines Agency in March 2005

• Company that does clinical trials on contract basis

• 200 West Street • Waltham, MA 02451-1163 USA • Tel: +1 781 487 9900

The clinical trials….ROLE NAME LOCATION

Sponsor Product TeGenro AG Wurzburg,Germany

Manufacturer Boehringher Ingleheim Germany

Contract Research Organisation for Phase 1 clinical trial

Parexel Northwick Park Hospital, Harrow, UK

• Parexel was contracted by TeGenero• MHRA -Medicines and Healthcare Products

Regulatory Agency -authorizes all clinical trials in UK

• The MHRA received an application for the authorization of the clinical trial of TGN1412 on 23 December 2005.

• The clinical trial was authorized on 27 January 2006.

• Brent Medical Ethics Committee gave a favorable opinion on 14 February 2006.

• This was a first in man clinical trial undertaken at one centre which involved the administration of TGN1412 and placebos.

• Eight healthy male volunteers were recruited by

Parexel Clinical Pharmacology Research Unit (CPRU).

• The trial was Double-Blind i.e. neither the healthy volunteers nor the physician could identify which subjects received TGN1412 and which received the placebo.

• The first date of screening was 22nd February 2006 and the first day of dosing was 13th March 2006.

• On 13 March Serious Adverse Events (SAEs) were reported in 6 of the 8 subjects. According to Parexel CPRU, the subjects experienced a life–threatening incident of “Cytokine Release Syndrome” or also called Cytokine Storm.

• The drug was given by intravenous infusion, starting at 8am, with an interval of around 10 minutes between patients, and each infusion lasting from 3 to 6 minutes

• Roughly five minutes after the last participant had received his dose, the participant who had received the first dose complained of headache, and soon afterwards fever and pain. He took his shirt off, complaining that he felt like he was burning.

• Shortly after, the remaining participants who received the actual drug also became ill, vomiting and complaining of severe pain.

• Parexel confirmed that the all 6 subjects who received the active drug experienced SAEs and developed catastrophic multisystem failure. The two subjects who received placebo did not experience any adverse events.

• The incidents were reported to the MHRA on the

afternoon of 14 March. The MHRA• Immediately suspended the Clinical Trials Authorisation• confirmed that the drug in question was not in use in any other trial anywhere in the world

• alerted international drug regulatory authorities of the events, in case any similar drug of this class might be in use• sent a team of inspectors to the unit in Northwick Park to secure documents, samples and other evidence (in liaison with the Metropolitan Police).

• Investigations were undertaken to ensure that procedures were in line with the internationally recognized standards for:

• Good Clinical Practice (GCP)• Good Laboratory Practice (GLP)• Good Manufacturing Practice (GMP)

• Inspections assure the integrity of the data being submitted.

• GLP:“4 week intravenous toxicity study in cynomolgus monkeys with a 6 week observation period”.

Possibilities under consideration during the investigations included:

• A dosing error, with all participants being given an overdose

• An error in the formulation or dilution of the drug (either in the clinical trials unit, or in its original manufacture in Germany),which could also potentially lead to an overdose

• Contamination of the drug with some other toxic substance

• A previously unknown biological effect on humans that did not arise in any of the animal testing phases.

Conclusion

• MHRA takes the view that the adverse incidents did not involve errors in the manufacture of TGN1412 or in its formulation, dilution or administration to trial participants.

• The MHRA therefore concludes that an unpredicted biological action of the drug in humans is the most likely cause of the adverse reactions in the trial participants.

• An article by The Sunday Times on July 30, 2006 reported lawyers' claims that the long-term damage to the patients may be worse than originally thought.

• TeGenero has apologized to the families involved, insists that these effects were completely unexpected, and said that all protocols have been followed.

Look Closer!!• Why was the drug tested on healthy volunteers rather than

patients?• Why were all eight volunteers given the drug at the same time?• A two hour protocol was approved by MHRA, but the drug was

administered to all participants within just twenty minutes.• We have been assured repeatedly that proper procedures were

followed, when the real question is whether they were the right procedures.

• Company should have known the drug would provoke this reaction in humans. WHERE IS THE STANDARD LAB-TEST??

• caused catastrophic systemic failure in the subjects, despite being administered at a supposed sub-clinical dose of 0.1 mg per kg, some 500 times lower than the dose found safe in animals.Reason given for this: Less antibody and hence lower infusion time.

• In case of Cytokine release syndrome, Steroid injections supposed to be administered immediately. But they were administered after 5 hours.

• The developing company, TeGenero Immuno Therapeutics, entered into insolvency proceedings later in 2006.

• Ryan Wilson to be monitored for next 10 years and his future is uncertain.

• “I cant even open a can of beans! I cant even wash myself! My mom helps me! What 20 year old wants his mom to help him wash?”

• http://CEO of Parexel!

..• • What is the purpose of the

trial? Is it to compare a new drug to an old one and, if so, why?

• • What is expected of you? How long will the trial last? Will you need to undergo blood tests, for instance?

• • If it is a randomised trial, what are the chances of receiving the experimental drug, and will you have access to your personal data afterwards?

• • Are there any known risks of the experimental drug? Any “discomforts” such as headaches and nausea?

• • What happens at the end of the trial? If the experimental drug works, will you have access to it? What support is offered for any problems?