Clinical drug trials: Tests of progress

WALK into the gloomy lobby of Groote Schuur Hospital's "old main" building and you could be forgiven for thinking you were entering a municipal bureaucracy, rather than the home of a cutting-edge research facility for experimental medicines.

Financial Mail, 11 December 2014

The paint is faded, the floor tiles scuffed, and a visitor faces a bewildering journey through a warren of dark passages before entering a creaking lift that rises to the J floor, where the University of Cape Town (UCT) recently opened a high-security 24-bed ward for sophisticated "first-in-human" studies. These are small phase 1 clinical trials, in which scientists take medicines that have been studied in animals and test their safety in people for the first time.

This kind of research is all too rare in Africa, according to Richard Gordon, director of Strategic Health Innovation Partnerships at the Medical Research Council (MRC). He said the continent is not the first port of call for brand-new medicines, because typically they are destined for bigger markets such as Europe and North America. But for diseases like malaria, TB and HIV there is a very strong case for saying Africa should be the place for doing the first-in-human studies because this is the population the drug is ultimately going into. Researchers use phase 1 trials to determine whether an experimental drug is safe, gauge a dosage range, and identify side effects.

They then move onto larger phase 2 and 3 trials to see if it is effective, learn more about its safety and side effects, and compare with to other treatments. Regulators such as the Medicines Control Council require data from clinical trials before they will approve new drugs for use in patients. Local scientists regularly do phase 1 clinical trials for candidate HIV and TB vaccines, but there is limited scope in SA to conduct hospital-based first-in-human drug studies that require close observation, said MRC president Glenda Gray. Both universities and the private sector have the capacity to do this work, but on a very limited scale, she added.

Parexel Early Phase in Bloemfontein has the most extensive first-in-human trial experience, after the closure in 2012 of Qdot Pharma. Local generics manufacturer Adcock Ingram had a clinical trial facility to work out what is safe and effective called AdClin, with a four-bed facility at Universitas Hospital that was capable of doing first-in-human studies, but it never did any, according to the company spokesman, Vicki St Quintin. She said it was necessary to attract research to the unit and proposals were sent out, but this effort was negatively impacted by the death in the UK of a clinical trial subject and consequently a lot of clinical trial work in developing countries was cancelled.

The unit has been closed, as it was not economically viable, she said. Groote Schuur's new clinical trial ward is one of SA's biggest. Its highest-profile study is a phase 1 trial for a candidate malaria drug called MMV390048, which was identified by Kelly Chibale, director of UCT's Drug Discovery & Development Centre, in collaboration with the nonprofit Medicines for Malaria Venture. Tests in rodents and monkeys found the compound was safe and effective against a variety of malaria parasite strains, and required only one dose to cure the animals of the disease. It is currently being tested in 40 healthy human volunteers and results are expected next year, said UCT professor of clinical pharmacology Karen Barnes.

She said it is a complex science to move safely and responsibly from animal and test tube studies to studies in people. This kind of work is not for the fainthearted. Not only is the success rate low - as few as five out of 10 000 compounds that look promising in the lab will make it onto the market - but moving from an animal model into a human is not entirely predictable. Occasionally things go spectacularly wrong and a drug that is safe and well tolerated in animals turns out to be dangerous for humans, as was the case in a widely publicised and much-criticised phase 1 clinical trial in the UK in 2006, when six healthy young men suffered organ failure after taking an experimental drug called TGN1412. The event sent a shock wave trough the research community and first-inhuman studies are now done much more cautiously, said Barnes.