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Different methodology and some mistakes

Posted by PierreChirac on 30 Jun 2010 at 07:00 GMT

Upon recount, using Trouiller et al. methodology, we found that between 1975 and 1999 more NCEs (n = 32) targeting tropical diseases and tuberculosis were approved than reported in Trouiller et al. (n = 16).


Cohen et al. [ ] wrongly claim that, by using the same methodology as Trouiller et al. [2], more drugs were approved for neglected diseases during the 1975 to 1999 period than previously reported. Where Trouiller et al. count 16 new chemical entities (NCE) targeting "neglected diseases" and tuberculosis over this period, Cohen et al. identify 32 (for details see appendix S1 to reference [1]).

What exactly is a ‘new drug’? In regulatory jargon, a new drug is either a new chemical entity that contains an active substance receiving regulatory approval for the first time, or a new indication for a product that has already been approved. Registering a fixed-dose combination of already-approved drugs previously used together as loose combination thus fails to meet either requirement.

21 NCEs were included by Cohen et al. but not by Trouiller et al. Of these, eight are not NCEs but are in fact fixed-dose combinations of drugs already in use both individually and concomitantly: five for tuberculosis (ethambutol + isoniazid; isoniazid + pyranizamide + rifabutin; isoniazid + rifabutin; isoniazid + rifampicin + pyranizamide + ethambutol; thiacetazone + isoniazid); one for malaria (sulfadoxine + pyrimethamine, marketed in France as Fansidar® since 1971, i.e. prior to the 1975-1999 period under consideration [3]); and two for leprosy (dapsone + rifampicin; clofazimin + dapsone + rifampicin). Admittedly, the fixed-dose combination artemether + lumefantrine for malaria may be considered a new drug, because lumefantrine was not previously available. As such, it is included by Cohen et al. who consider it to have been marketed in 1999 (in Kenya) but excluded by Trouiller et al. who dated its registration to 2000 – perhaps wrongly, as this drug seems to have been approved in 1999 in Switzerland. [4]

Of the remaining 12 NCE included by Cohen et al.:
- Two target malaria: amodiaquine, which Cohen at al. count as having been approved in Kenya in 1998, although it had already long been on the market as Flavoquine® and Camoquin® since the 1950s [5]; and artemisinin, considered by Cohen et al. to have been launched in France in 1996, although this moiety is not marketed as such but only as a derivative (e.g. artesunate, arthemeter, etc. which are already counted).

- Five target tuberculosis: kanamycin, amikacin, ofloxacin, ciprofloxacin, moxifloxacin. All of these antibiotics were first launched for indications other than for anti-TB drugs, and therefore cannot be considered as NCEs targeting a neglected disease, even if they may have indications against multidrug-resistant tuberculosis in some countries and if moxifloxacin is currently under clinical development for newly-diagnosed tuberculosis.

- Five target helminths: triclabendazole is registered only for Fasciola hepatica and was thus excluded by Trouiller et al. who considered only intestinal helminths. Cohen et al. were probably unaware that the four other drugs received market authorisation before 1975: levamisole as Solaskil® in 1974 in France [6]; mebendazole as Vermox® in 1974 in the U.S. [7]: pyrantel as Combantrin® in 1973 in France [8]; and niclosamide as Tredemine® in 1964 in France [9].

In addition, five products were included by Trouiller et al. but excluded by Cohen et al. Cohen et al. considered atovaquone + proguanil to have been marketed in 2000, but we found it was approved in France in 1997 [10]. The four other drugs - pyrazinamide, benznidazole, nifurtimox and pentamidine - are considered by Cohen et al. to have been approved prior to 1975. This would reinforce Trouiller et al.’s conclusions, as the number of NCE to have been approved for neglected diseases between 1975 and 1999 would thus be even lower that Trouiller et al.’s total of 16.

In conclusion, Cohen et al.’s findings differ from previous studies, largely due to the application of a broader definition of NCE. Even for malaria, for which an unprecedented number of compounds are now in the pipeline and drugs have been registered in the past few years, novelty has so far been very limited - all recent approvals are variations around an artemisinin derivative and a quinoline antimalarial.

Overall, the conclusion remains that despite more investments in recent years for some diseases, there is still insufficient innovation in general and a considerable need for new drugs for neglected diseases.

1- Cohen J, Dibner MS, Wilson A (2010) Development of and Access to Products for Neglected Diseases. PLoS ONE 5(5): e10610. doi:10.1371/journal.pone.0010610
2- Trouiller P, Torreele E, Olliaro P, White N, Foster S, et al. (2001) Drugs for neglected diseases: a failure of the market and a public health failure. Trop Med Int Health 6(11): 945–51.
3- Sulfadoxine + pyrimethamine :
4- Makanga M, Krudsood S The clinical efficacy of artemeher/lumefantrine (Coartem®). Malaria Journal 2009, 8(suppl I): SS doi: 10.1186/1475-2875-8-S1/S5.
5- Amodiaquine:
6- Levamisole:
7- Mebendazole:
8- Pyrantel:
9- Niclosamide:
10- Atovaquone + proguanil:

Chirac P1, Olliaro P2, von Schoen-Angerer T3, Torreele E4

1 : Public health pharmacist, MSF Campaign for Access to Essential Medicines
2 : UNICEF/UNDP/World Bank/WHO Special Programme on Research & Training in Tropical Diseases (TDR) World Health Organization, Geneva, Switzerland
3 : Director, MSF Campaign for Access to Essential Medicines
4 : Project Director, Access to Essential Medicines Initiative, Open Society Institute

No competing interests declared.

RE: Different methodology and some mistakes

CohenJP replied to PierreChirac on 07 Jul 2010 at 15:23 GMT

Chirac makes some interesting points in his criticism of our paper on progress in neglected disease drug development. We appreciate his critique.

As the title of our paper suggests, our main purpose was to mark progress in drug development, and to make it clear that drug development is a necessary but insufficient condition for improving the situation of those afflicted by neglected diseases.

Trouiller et al. did public health a great service by pointing to the huge problem with respect to the dearth of products (and funding) targeting neglected diseases prior to 1999. Regardless of how one does the counting, the 1975-1999 period was not good for neglected disease product development. Improvement appears to be on the way. And surely, the funding situation has gotten much better. However, thus far, and it may be too early to judge, post 2000 approvals targeting neglected diseases have been disappointing.

Please note, initially when we embarked on marking progress in neglected disease drug development, we did not make a conscious decision to revisit Trouiller's numbers. We simply used his study as a benchmark. Yet, when we found discrepancies, as Chirac also noted (drugs approved prior to 1975 that were included on the 1975-1999 list), we decided to do a recount. We attempted to follow as closely as we could Trouiller's methodology. One problem we encountered in doing so was that Trouiller's methodology was not always transparent (he reports no dates of approvals nor places of first regulatory approval in the Lancet article), nor consistent (Trouiller, and Chirac in his comment, claim not to include fixed dose combinations, yet atovaquone/proguanil is included; moreover, artemether/lumefantrine was mentioned as a "new drug for malaria").

Finally, we take issue with Chirac's assertion that "antibiotics launched for indications other than for anti-TB" should not be included in our count. The point is not, and never should be, what a drug was initially approved for, or whom the sponsor originally had in mind when it developed the drug. It should be about which approved uses (now) target neglected diseases, when this happened, where, and whether WHO or other agencies view the drug or new indication as part of the neglected disease armamentarium.

No competing interests declared.