Category Archives: Efficacy

Prequalification of Malaria Medicines Needs to be Taken More Seriously

The Leadership newspaper in Nigeria reported on Sunday the launching of a new artemisinin-based combination therapy (ACT) drug knwon by the trade name ‘Artiquick.’  In order to ensure that it is not just another route to ‘profit-quick’, we looked into the WHO prequalification list to see if the Chinese company ArtePharm that makes the drug was listed.

Prequalification is based on a comprehensive evaluation of “the quality, safety and efficacy of medicinal products, based on information submitted by the manufacturers, and inspection of the corresponding manufacturing and clinical sites.” The resulting lists of malaria, TB, and HIV drugs and diagnostics is meant to guide various national and international health agencies in their procurement of medicines.

dscn7285sm.JPGThough not stated and often not practiced, it would be ideal if these lists also guided various drug regulatory agencies in malaria endemic countries. Although it is a somewhat arduous process to get prequalification, it is possible and necessary – two new medicines containing artesunate-mefloquine were just added in 12 September.

The prequalified list as of today contains 25 anti-malaria products from only 10 companies. ArtePharm is not among them.  Yet the manufacturer made it known that, “the   new  drug   which  has  proven  very  effective  since  early  this  year  when  it  underwent additional clinical trials, Nigeria can, thus, be very hopeful, on attaining the Millennium Development Goals (MDGs) target on malaria come 2015.”  In addition the manufacturer mentioned to the press that ACTs generally were recommended by WHO, implying that any ACT, including their own, was approved by WHO.

Finally the ArtePharm representative made it know that their product was tested and approved by Nigeria’s food and drug agency NAFDAC. NAFDAC does ensure that products contain the labeled ingredients in the labeled amounts and that the drug is safe to use. It is important in the fight against counterfeit drugs. But NAFDAC has approved hundreds of ACTs for sale and use in the country. Unlike WHO, NAFDAC and other national agencies do not have the reach to inspect the production processes at the root.

Hopefully ArtePharm will begin the journey of the prequalification process soonest, and that countries where it sells its product will also encourage that company and many others to take the responsible steps needed to ensure we have quality antimalarials that will actually eliminate disease and not just eliminate money from patients’ pockets.

Tanzania: fake drugs, wrong drugs, more drugs

Selling malaria medicines in Tanzania and elsewhere in Africa is a big business. The market is not one that is easily dominated by a few brands, although the Affordable Medicines Facility malaria (AMFm) would hope otherwise. It appears that volume of relatively low or lower cost malaria drugs is the path to profit, not sales of a pricey mega-drug.

New from Tanzania is that this vast market is attractive to all sorts of manufacturers, even those making fake drugs. According to The Citizen, “The Tanzania Food and Drugs Authority (TFDA) yesterday issued a public warning against the sham product marketed under the name Eloquine (Quinine Sulphate 300mg USP) and packed in a bottle containing 1,000 tablets each.”

IPP Media reported that, “the authority has seized 155 tins of the fake drugs in Dar es Salaam which were yet to be distributed” and a suspect has been detained. The company headquarters in Nairobi helped point out differences in packaging between their products and the fake ones. A major concern of course is that role the fake drug was supposed to play. Normally quinine would be used in a limited way such as for pregnant women, so it is unclear how the fake drug would have been marketed to make a profit.

All of this comes amid efforts of AMFm to ensure that prequalified anti-malarial drugs reach the market (public and private) at prices people can afford. Cheap fake drugs threaten this effort.  A Tanzania study sponsored by the Clinton Foundation/CHAI, “showed promising results: subsidizing the ACTs at the top of the supply chain successfully increased the stocking of ACTs in drug shops and brought down the price of ACTs significantly.”

Prior to AMFm, but after Tanzania changed its malaria drug policy from SP to ACT, “the saleability of ACT was negligible. SP was best-selling.” Pre-AMFm price differentials between ACTs and cheaper but less effective medicines, put ACTs at a disadvantage.
addo2.pngPart of Tanzania’s approach to improving quality of malaria case management in medicine shops is upgrading the quality of these.  Accredited drug dispensing outlets (ADDOs) are places where the sales people and the products are both upgraded. When Tanzania changed its malaria drug policy from SP to ACT, access to ACTs in the private sector was low, while focus was on the public supply of ACTs.  It appears that with the event of AMFm ACT supplies in ADDO shops and other private outlets, but this does not preclude the presence of inappropriate or substandard drugs in non-accredited shops known as duka la dawa baridi.

Despite improved access to ACTs and improved quality of front line medicine store outlets, Tanzania cannot let up on its pharmacovigilence. As we move closer to malaria elimination – for example in Zanzibar in Tanzania – the importance of appropriate parasitological diagnosis and prompt treatment will increase. We cannot afford to have fake and inappropriate drugs compete with ACTs.

Nigeria continues to test malaria drug efficacy

At present artemisinin-based combination therapy medicines for malaria are our best hope for treating malaria and have the added benefit of reducing parasite transmission.  If these drugs lose their power, we are in trouble; hence there is need for continued testing to ensure that drug efficacy remains high.

The Nigeria National Malaria Control Program has just circulated its latest malaria drug testing results. All endemic countries should see this as a model for their own continued monitoring of malaria drugs.

nmcp-nigeria-2.jpgA total of 747 children were enrolled in the two treatment arms – artemether-lumefantrine and artesunate-amodiaquine. The sample was drawn from investigations at seven sites in different geographical settings.  Below we find the main points as summarized in the Executive Summary.

1. The Therapeutic Efficacies of two Artemisinin-based Combination Therapies (ACTs) – Artesunate-Amodiaquine (AA) and Artemether-Lumefantrine (AL) were evaluated in 724 children <5 year-old drawn from 7 sentinel sites; Lagos, South-west, South-east, South-south, North-central, North-west and North-east located in 6 geographical zones of Nigeria.

2. All children recovered clinically from their illness. Fever clearance was significantly faster in children treated with AA than in those treated with AL (1.19 ± 0.49 versus 1.33 ± 0.7 d, P= 0.006).

3. Compared with AL, AA significantly reduced the proportion of children with parasitaemia 1 day after treatment began (P=0.016), but parasite clearance times were similar in AA- and AL- treated children (1.13 ± 0.4 versus 1.11 ± 0.34 d, P= 0.47).

4. Overall, adequate clinical and parasitological response (ACPR) on day 28 was 97.4%, and was similar for both AA (95.1%) and AL (96.3) P=0.108). Early treatment failure occurred in one child treated with AA.

5. Overall, PCR-corrected parasitological cure rate on day 28 was 98% and was significantly higher in AA- than in AL- treated children 99.1% (343/346) versus 96.9% (311/321), P=0.048. The cumulative probability of a reappearance of asexual parasitaemia after treatment with AA or AL were similar (Log-rank statistic = 0.027, P=0.869)

6. Recurrent infections were not age or drug dependent. Overall, recrudescence occurred in 5.3% of the children (38 of 711), and was unrelated to age or drug treatment. Recrudescent infections were significantly more common in the eastern flank (North eastern, North central, South eastern than the western flank (North-western, South-western and Lagos) of the sentinel sites [32 of 311 children (10.3%) versus 6 of 319 children (1.9%), P<0.00001].

7. Overall, gametocyte carriage after treatment with both drugs was significantly lower compared with pre-treatment [16 of 491 children (3.3%) versus 46 of 620 children (7.4%), P=0.005].

8. Anaemia, defined as haematocrit <30%, was present in 294 of 672 children (43.8%) and was significantly more common in the eastern than in the western flank of the sentinel sites. Anaemia resolved completely in all anaemic children within 14 days in 93% of the chilldren.

9. In anaemic children, anaemia resolution time was approximately 10 days for both drugs.

10. In the few sentinel sites where adverse drug reactions were monitored, both drugs were tolerated; the reported adverse drug reactions were indistinguishable from the symptoms of malaria.

11. AA and AL are safe and efficacious treatment of uncomplicated P. falciparum malaria in <5 year old Nigerian children.

The full study will be made available at the NMCP’s website.

Will malaria parasites defy elimination?

Three new articles in Malaria Journal plus a news release from the Commonwealth Games in India remind us that like any other organism, the malaria parasite will fight for survival.

Yvonne Lim and colleagues document a rare case of P. ovale imported into Malaysia. They note that local vectors are capable of transmitting this parasite as well as an “exponential increase in the number of visitors from P. ovale endemic regions.”

A Nigerian table tennis player at the Commonwealth Games in India withdrew after coming down with malaria. The Times of India implies that the illness may be a result of “The Capital’s dreaded mosquitoes.” Depending on when he arrived in India, Ekundayo Nasiru could have brought the disease with him. In either case the potential for importing and exporting malaria exists.

Now under way in several pilot countries, “The Affordable Medicines Facility-Malaria (AMFm) is a mechanism to increase access to quality assured ACT.” AMFm hopes that with approved and cheaper artemisinin-based combination therapy (ACT) drugs monotherapies will be driven from the market and the lifespan of ACTs will be prolonged, thus “reducing the likelihood of resistance to artemisinin.”

artequin-child2.jpgUnfortunately, another article in Malaria Journal reviews “Declining in clinical efficacy of artesunate-mefloquine combination has been documented in areas along the eastern border (Thai-Cambodian) of Thailand.” After identifying cases of recrudescence after treatment, the researchers concluded that …

Although pharmacokinetic (ethnic-related) factors including resistance of P. falciparum to mefloquine contribute to some treatment failure following treatment with a three-day combination regimen of artesunate-mefloquine, results suggest that artesunate resistance may be emerging at the Thai-Myanmar border.

These experiences show how important it is not only to document drug resistance and imported cases but also to help countries plan “Robust Malaria surveillance systems towards malaria pre-elimination and assessing Roadmaps achievements,” which is the theme of a meeting of the East Africa Regional Network (RBM) underway in Kigali. More technical assistance is needed in “strengthening Malaria surveillance in high and low burden countries,” if elimination goals are ever to be achieved.

What if available malaria tools actually reached people?

Tachi Yamada of the Gates Foundation told Discover Magazine (October 2010) that, “… childhood deaths … could fall by half by 2025 if we could deliver existing vaccines, malaria treatment, and today’s other lifesaving tools with 90% penetration to those at risk.” During the push towards Universal Coverage, it is good to ask whether we can really reach people with our existing tools.

efficacy-to-effectiveness-sm.jpgThe INDEPTH Effectiveness and Safety Studies (INESS) offers a conceptual model as to what happens when a when efforts are made to ensure that a highly efficacious tool – malaria medicines, LLINs – actually reaches people. This ultimately impacts on the effectiveness of the tool. Thus a drug that is 95% efficacious, may be less than 50% effective if the right people do not take it at the tight time.

First people need access to the tool – in the INESS case ACTs. We must deal with all the procurement and supply chain management issues that determine whether the medicines will reach the sick people in good condition beyond the end of the tarmac road.  Then targeting must be considered – do the right people get the medicines? Next the health workers themselves must comply with treatment guidelines, and finally, if the person with malaria gets his/her drugs, will he/she adhere to the treatment regimen?

Peter Moszynski in the British Medical Journal also expresses concern about the access and compliance issues:

Despite the widespread availability of effective new (malaria) drugs and diagnostic tools … major problems remain. Issues such as misdiagnosis and overprescription of treatments, counterfeit drugs, problems in supply and delivery, and emerging resistance to drugs “all hamper effective treatment.” A lack of awareness among donors and the public of some these basic problems “threaten the success of global malaria control efforts.“

Beatrice Wasunna, et al. addressed the provider compliance issue when they found that, “In-service training and provision of job aids alone may not be adequate to improve the prescribing, dispensing and counseling tasks necessary to change malaria case-management practices and the inclusion of supervision and post-training follow-up should be considered in future clinical practice change initiatives.”

Many resources are flowing through health systems right now, especially with the pressure to achieve Universal Coverage and the enthusiasm generated by the MDG Summit. Can we ensure that the health systems in place can bring the effectiveness of these tools closer to their actual scientifically tested efficacy?