[Ip-health] Neglected Diseases Product Development recount disputed in PLoS ONE

Mike Gretes mike.gretes at gmail.com
Fri Jul 2 15:41:55 PDT 2010


 Several weeks ago a
paper<http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010610>*
was published challenging the number of drugs developed for Neglected
Diseases (1975-1999) published by Trouiller et al. in
2002<http://www3.interscience.wiley.com/journal/118999340/abstract>**.
 A recent comment <http://ow.ly/26usP>*** by Chirac et al. (including two of
the 2002 paper's authors) disputes the new numbers and is copied, for
interest, below.

* - http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010610
** - http://www3.interscience.wiley.com/journal/118999340/abstract
*** - http://ow.ly/26usP

Above all, whether 32 or 16 ND drugs were developed 1975-1999 (vs. far
greater than 1000 for non-NDs), the key message must be to redouble our
efforts to improve available and effective ND health technologies, including
drugs.  Let us continue do all we can to make the present era the turning
point for ND R&D.

Best,

mg

-- 
Mike Gretes, PhD (Biochemistry)
Medicines for Neglected Diseases (MeND) Workshop
Boston 10-11 Sept. 2010
http://MeND2010.mindthehealthgap.org
http://twitter.com/mindthehealth_
+1.415.230.0514

[Comment follows -mg]

Sir,

Cohen et al. [1] 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.


REFERENCES
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 : http://afssaps-prd.afssap...
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: http://www.ncbi.nlm.nih.g...
6- Levamisole: http://afssaps-prd.afssap...
7- Mebendazole: http://www.accessdata.fda...
8- Pyrantel: http://afssaps-prd.afssap...
9- Niclosamide: http://afssaps-prd.afssap...
10- Atovaquone + proguanil: http://afssaps-prd.afssap...

Chirac P (1), Olliaro P (2), von Schoen-Angerer T (3), Torreele E (4)

(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



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