From its headquarters in the Belgian city of Turnhout, Dafra Pharmaceuticals co-ordinates the manufacture of malaria medicines that it sells across Africa but are not authorised for use in Europe.
It is one of a number of pharmaceutical companies that produce drugs exclusively for export, often to poor countries with weak regulatory controls, through legal loopholes that opponents would like to see closed. No data from clinical trials to prove that its drugs are safe and effective have been scrutinised by European regulators, for example. The issue raises broader concerns about the current international system of regulation of pharmaceutical producers and how best to reform it.
Dafra says that its drugs are safe and have been approved by local regulators, that it has respected all laws and saved many lives. The company produces a variety of drugs based on artemisinin, a Chinese plant extract widely seen by researchers as the most promising form of treatment for malaria, which has developed resistance to many older-generation drugs, and kills 1m a year world wide.
The dilemma is whether a drug that does not meet rich-country standards of safety is going to do poor countries more harm than good in the midst of an epidemic of such proportions. Lembit Rago from the medicines policy and standards division of the World Health Organisation says that almost no countries assess the safety of medicines produced exclusively for export. He says it is “almost impossible” to assess the scale of the problem but existing loopholes allow manufacturers to make a wide range of “essential medicines”, such as antibiotics, for developing countries without much regulatory scrutiny.
The result may be ingredients that are inappropriate, of inconsistent quality or variable concentration. Other concerns include drug formulations that may not be stable; generic drugs that have not been tested for “bio-equivalence” to ensure they have the same effect as the original patented versions on which they are based; and inadequate dosing and safety information.
Draft legislation under discussion by the Belgian government could provide a precedent for reform elsewhere. It calls for all medicines made for export to meet the criteria of “safety, quality and clinical effectiveness” that apply to those authorised for domestic use.
“This is a huge problem and people don’t realise how big it is,” says Inga Verhaert, a Belgian politician who has lobbied for change. She says companies export drugs close to their expiry dates, sell medicines with side-effects that in Europe are prescribed only with heavy health warnings and peddle herbal treatments for HIV/Aids that would never pass muster at home.
“The era of poor drugs for poor people is not over,” says Chris Hentschel, head of the Medicines for Malaria Venture, a Geneva-based charity developing treatments for the disease. “There has been plenty of pressure for new and affordable drugs but hardly any about the fact that there is a plethora of products out there ranging from the sub-standard right through to the completely counterfeit.”
An analysis published late last year by Kenya’s Medical Research Institute showed that more than 40 per cent of the most common anti-malaria drugs on sale in the country were sub-standard. That raised concerns both about poor treatment of patients and the danger of resistance making the drug useless in the long term.
Dafra complies with the Belgian government’s designated “good manufacturing practices”, producing drugs consistently in line with the contents specified on its packaging. But that is as far as the Belgian authorities’ inspections go.
The regulators do not pay heed to recent World Health Organisation advice designed to prevent the development of drug resistance by eliminating malaria “monotherapies” using a single drug. That includes some of Dafra’s medicines, which are based on artemisinin derivatives not combined with any other compounds.
More important, they do not require data on the safety and efficacy of the company’s medicines, as they would for any drugs designed for domestic use. The result is that Dafra sells in Africa an anti-malaria syrup for children and is planning to launch a pill which it claims to clear the parasite in just 24 hours, despite questions by scientists over whether such a treatment can work.
When Véronique Ghenne, another Belgian politician, raised concerns about Dafra’s approach in the federal parliament last November, the ministry for public health replied that it had no authority to make such assessments. The onus of such scrutiny lies instead on the African countries importing the drugs.
Recognition of the problem is beginning to increase. In recent months, both the US Food and Drug Administration and the European Medicines Agency (Emea) have given greater attention to certifying the safety and efficacy of medicines made for the developing world. Emea last November introduced a system for makers wanting approval for drugs to be used outside Europe. So far, two Aids drugs have been approved this way, providing reassurance for regulators in the developing world.
But Emea’s Martin Harvey Allchurch says: “The obligation is on developing countries’ regulators. At the end of the day, every national government has the authority and the responsibility to regulate drugs.”
The problem is that either manufacturers must submit their drugs for approval to Emea or another respected regulator or developing world authorities and aid agencies buying medicines must insist on such procedures being followed. In reality, many regulators in the developing world, with limited resources and expertise and subject to intense political and commercial pressures,
do not have the capacity or willingness to scrutinise new drugs in detail. “There is poor regulation and poor enforcement in Africa and also parts of Asia,” says Mr Hentschel.
The Belgian draft law could set an important international precedent in toughening standards in drug exporting countries. But it also risks pushing manufacturers simply to relocate to regions where they remain able to exploit loopholes.
Mr Rago at the WHO argues that, ultimately, the best solution is to strengthen the ability of developing-world drug regulators to help themselves. “Donor countries should not only provide good-quality medicines but local capacity-building. In the long run, that is the only thing that is sustainable,” he says.