E-DRUG: MSF rapid response BMJ: US incentive scheme for neglected diseases: a good idea gone wrong?
--------------------------------------------------------------------------------------------------------------------
http://www.bmj.com/content/349/bmj.g4665/rapid-responses
[Rapid responses are electronic letters to the editor. They enable our
users to debate issues raised in articles published on bmj.com.]
31 July 2014
Jennifer Reid, Researcher; Julien Potet; Katy Athersuch; Maisy Grovestock;
Judit Rius Sanjuan (Medecins Sans Frontieres- Access Campaign)
Re: US incentive scheme for neglected diseases: a good idea gone wrong?
As a medical humanitarian organisation that has been working to diagnose
and treat people suffering from neglected diseases for almost 30 years
(1), Medecins Sans Frontieres (MSF) understands only too well that the
dearth of research & development (R&D) for new tools to treat these
diseases is directly attributable to a lack of funding and effective
incentives. These diseases affect some of the poorest and most
marginalised populations in the world. The imbalance between their medical
needs and the availability of suitable medical tools is too often fatal.
In spite of representing more than 10% of the global disease burden, over
the past decade, less than 3.8% of new drugs approved across the world
were indicated for neglected diseases (2). This represents very little
progress from the previous decade, especially as it relates to new
chemical entities for neglected diseases.
Innovative incentive mechanisms for R&D, including pull mechanisms such
as the US FDA Priority Review Voucher (PRV), are crucial to spurring
innovation in areas lacking the conventional market pull of revenue
derived from high product prices and high-volume sales.
However, the FDA's award of a PRV to Knight Therapeutics for a product
that Knight neither developed nor manufactures - and which is not easily
procured at affordable prices - highlights the shortfalls of the PRV
mechanism as currently designed. The PRV's effectiveness as an incentive
for neglected diseases is limited by its failure to ensure it rewards
genuine innovation, a lack of obligations to guarantee affordability and
patient access to treatments, and administrative restrictions that limit
its potential value to innovators and therefore its effectiveness. MSF is
urging the US Congress to amend the PRV legislation to ensure that these
shortfalls are fixed and the PRV can fulfil its role in stimulating
meaningful investments in neglected disease R&D.
Amendments to the PRV legislation are vital to ensuring it delivers
benefits to neglected patients, yet even if fixed, the PRV mechanism alone
is not enough to address unmet medical needs in the area of neglected
diseases. Additional funding, as well as incentives that promote research
collaboration and efficiencies, 'de-link' the costs of R&D from the price
of the end product, and ensure access and the affordability of treatments,
should be prioritised. For example, the 3P Project (3), developed by MSF
in collaboration with other organisations, would employ an open
collaborative R&D framework and a combination of push, pull and pool
mechanisms to promote the timely development of more effective treatments
for drug-resistant tuberculosis (DR-TB).
MSF calls on the US Congress to amend the PRV mechanism to close loopholes
and ensure that benefits reach patients suffering from neglected diseases,
and to consider additional mechanisms to incentivise R&D for neglected
diseases that ensure all patients needing treatment are able to access the
resulting products.
(1) An overview of the current innovation and access challenges MSF faces
for NTDs: http://www.msfaccess.org/our-work/neglected-diseases
(2) Pedrique, et al. 'The drug and vaccine landscape for neglected
diseases (2000â11): a systematic assessment'. Lancet (2013):
http://www.thelancet.com/journals/langlo/article/PIIS2214-109X(13)70078-0/fulltext
(3) 'PUSH, PULL, POOL: Accelerating Innovation and Access to Medicines for
Tuberculosis',
http://www.msfaccess.org/our-work/driving-medical-innovation/article/2157
Competing interests: No competing interests
The BMJ article: COPIED AS "FAIR USE"
US incentive scheme for neglected diseases: a good idea gone wrong?
BMJ 2014; 349 doi: http://dx.doi.org/10.1136/bmj.g4665 (Published 21 July 2014)
Cite this as: BMJ 2014;349:g4665
by Peter Doshi, associate editor, The BMJ (pdoshi@bmj.com)
The US priority review voucher scheme was intended to encourage drug
companies to invest in treatments for neglected diseases. But nearly seven
years on, as Peter Doshi reports, there is little demonstrated innovation
and evidence that the benefits are not going where they were intended
Bill Gates believes or at least believed that government led market
incentives could solve the fundamental conundrum in developing drugs for
neglected diseases. For-profit companies see little economic justification
to invest in treating diseases that affect the poor, but 'creative
capitalism' as Gates put it, could lure companies into solving some of
the world;'s most pressing problems by bringing to market new treatments
for endemic tropical diseases.
At the 2008 World Economic Forum in Davos, Gates highlighted a new US Food
and Drug Administration (FDA) law that rewards sponsors of drugs for
tropical diseases with a voucher that entitles the bearer to a 'priority
review' of another new drug application. 'If you develop a new drug for
malaria your profitable, say, cholesterol lowering drug could go on the
market up to a year earlier,' Gates explained. And under the law, the
voucher can be sold. 'This priority review could be worth hundreds of
millions of dollars.'
Gates was not the only one to be excited about the idea. Originally
proposed by Duke University economist David Ridley and colleagues in the
health policy journal Health Affairs,1 the concept was quickly championed
by a republican senator from Kansas who, along with two democrat senators,
successfully introduced the priority review voucher program into US law.
The vouchers are fully transferable between companies and might be worth
around $300m (£175m; â¬220m).
Who is benefiting?
But more than six years later, has this promising concept flopped? Ridley
does not think so. 'Drug development takes many years (7+) so the impact
of the voucher is not immediate' He points to companies that have taken
up the charge: 'NanoViricides was focused on HIV and flu before learning
about the voucher, and now they're developing a drug for dengue.'
Nevertheless, the FDA has awarded just three priority reviews vouchers
since the law was introduced in 2007: for combination
artemether-lumefantrine (Coartem) for malaria, bedaquiline for multidrug
resistant tuberculosis, and, most recently, for miltefosine to treat
leishmaniasis.
But far from spurring research into new treatments for neglected diseases,
two of the three drugs were developed and registered outside the US well
before the voucher system was established, meaning that, at least in these
cases, the scheme did little to encourage the development of new drugs for
neglected diseases.
Miltefosine, for example, has been around for decades. Originally
identified as an anticancer compound in the 1980s, the drug came to be
used for treating leishmaniasis. Visceral leishmaniasis, the most serious
of the three presentations of the disease, kills around 59â000 people a
year, making it the 'world's second biggest parasitic killer after
malaria,â according to the World Health Organization.2 Miltefosine is
included in WHO' essential medicines list.
Since 2004, miltefosine has been marketed for the treatment of
leishmaniasis in Germany (home of its original manufacturer) and India
(where most cases of visceral leishmaniasis occur).3 4 Before its 2014
approval in the US, miltefosine was also registered in several countries
in South America.5 Licensing and rights to the drug passed through
numerous hands over the years: from AstaMedica to Zentaris (which later
became AEterna Zentaris). Then in 2008, AEterna Zentaris sold the drug to
Paladin, a small Canadian company that was purchased by Endo International
for $1.6bn in late 2013.
Miltefosine, however, did not come along for the ride to Endo. By this
point Paladin's new drug application to the FDA was well under way and it
was expecting approval of miltefosine along with a priority review
voucher. Paladin's chief executive, Jonathan Goodman, put a separate price
tag on miltefosine, which the company had acquired for $C9m, ($8.5m; £5m;
â¬6.3m) and the expected voucher of more than $100m. Endo refused to pay
and so Goodman's new company, Knight Therapeutics, retained the drug. In
March 2014, the FDA approved miltefosine, making Knight Therapeutics the
fourth company to be awarded a priority review voucher.
Following the miltefosine money
But did the voucher go to the right party? Was it right that a drug
co-developed with public money and already licensed in key countries
should attract such lucrative incentives? The international medical aid
organisation Medecins Sans Frontieres (MSF) thinks not.
âThe PRV [priority review voucher] for miltefosine is not rewarding true
innovators,â says Julien Potet, a policy adviser at MSF. âPaladin/Knight's
efforts have been strictly on regulatory affairs, and we argue that
Paladin/Knight should not be rewarded for some preclinical and clinical
risks that they did not take.â
MSF points out that not only was miltefosine developed well before the
voucher program was conceived but neither Paladin (which currently
manufactures and markets miltefosine) nor Knight Therapeutics (which holds
the licensing rights) even underwrote the drug's research and development.
Instead, they note that the clinical trials were funded by a mixture of
public and private sources.
Miltefosine has been celebrated as a success story of public-private
partnerships.6 Its development and ultimate registration as a drug to
treat leishmaniasis was the product of a near decade-long partnership
between industry (first Asta Medica, then Zentaris) and Unicef, the United
Nations Development Programme, World Bank, and WHO's Special Programme for
Research and Training in Tropical Diseases (TDR). TDR brought knowledge of
disease control programs, field experience, and contacts to help build
capacity to run the trials as well as money. Industry brought expertise in
drug development and money. Together, the partnership resulted in the
first oral, single drug treatment for leishmaniasis.4 While miltefosine's
activity against Leishmania was known early on, without interest from TDR,
the drug would arguably have remained as just a cancer treatment. TDR's
involvement in the development of miltefosine achieved the same goal as
the FDA's priority review voucher - bringing to market treatments for
neglected tropical parasitic diseases.
Pricing
One of the goals of this public-private venture was to ensure miltefosine
was an affordable drug. But it is unclear that this goal has been
achieved. According to MSF, Paladin charges â¬2636 ($3570; £2080) for an
adult treatment course (â¬842 for children). It also offers substantially
reduced prices (â¬45-â¬55 for an adult course) for bulk orders of at least
3500 courses. This, however, presents a problem for MSF.
'It may be possible for a large and highly endemic country like India to
reach this quantity, but it is nearly impossible for smaller organisations
to reach this quantity. Recently MSF and DNDi [Drugs for Neglected
Diseases initiative] had to buy a whole batch together, although this
quantity actually exceeded our needs. We are now seeking to donate the
drugs that we have bought in excess to third parties. It would be a shame
if these drugs expired unused on our shelves,' explains Potet.
But Goodman was unsympathetic. He said that MSF 'needs to weigh the
benefits of the discount against the risk of over-supply.'
Reforming the priority review voucher system
Today, Knight Therapeutics is a company with a single product
(miltefosine), two employees, $255m in cash, and a priority review
voucher. While at Paladin, Goodman bought miltefosine for $9m CAD, which
included clinical trial data. FDA approval cost another $10m. And now,
Knight hopes to sell the voucher for âa ton of money.
For MSF, Knight's story shows how the priority voucher scheme is a good
idea gone wrong. While it strongly agrees with the need for mechanisms to
speed development of new treatments for neglected diseases, it questions
the wisdom of the law, which allows companies like Knight Therapeutics to
singly reap the benefits of the voucher despite the significant public
investment in miltefosine's development.
Goodman, however, defends the history. âI find it ironic that MSF would
take issue with the PRV program as it is specifically designed to help the
same people that MSF is passionately trying to help by encouraging the
development of innovative, new therapeutics for neglected tropical
diseases.â He highlighted the investments his company made: 'Paladin spent
years and millions of dollars improving the dossier to obtain FDA approval
on March 19, 2014. Better lucky than smart'
A spokesman for the Bill and Melinda Gates Foundation said that although
the program has not yet delivered on its original promise, 'it's clearly a
step in the right direction' He pointed to some theoretical benefits from
the law other than novel drugs. 'If we do get new formulations, if we do
get new manufacturers . . . I think we would see those as benefits as
well'.
Despite his optimism about the priority review voucher, Goodman
acknowledges that the program is -so far at least- a failed policy that has
not shown real advances in the treatment of tropical diseases. But for
Goodman, this is because the value of the voucher is still unclear and
'just theoretical.' Of the three vouchers issued, none has been sold. And
only Novartis has used its voucher - for an application the FDA ultimately
did not approve. Goodman speculates that this financial uncertainty is
what has deterred smaller drug companies from developing drugs for
tropical diseases. âUntil you can demonstrate that the voucher actually
has some sort of value, where's the incentive for companies to go out and
now specialize in finding treatments for these diseases' asks Jeffrey
Kadanoff, chief financial officer of Knight Therapeutics. (Smaller
companies would have no capacity to use the voucher themselves, so would
want to sell it to another company with a blockbuster in the pipeline.)
'It's going to sound self serving, but if we do our job well and get a big
price tag for this voucher, we will be doing humanity great service. And
our shareholders' Goodman says.
In 2010, Duke University's Ridley urged Europeans to adopt a similar
priority voucher system.7 But even Ridley would like to see some changes
in the law. While 'it's not entirely bad to reward good deeds,' he told
The BMJ, favor some changes, including precluding award to drugs
approved outside the US several years ago.
Such a change would have kept Knight from its voucher.
NOTES:
Cite this as: BMJ 2014;349:g4665
Footnotes
Competing interests: I have read and understood BMJ policy on declaration
of interests and have no relevant interests to declare
Provenance and peer review: Commissioned; not externally peer reviewed.
References
âµRidley DB, Grabowski HG, Moe JL. Developing drugs for developing
countries. Health Aff2006;25:313-24.Abstract/FREE Full Text
âµTDR. Bangladesh beats a deadly scourge, 19 May 2014.
www.who.int/tdr/news/2014/deadly_scourge/en/.
âµÃterna Zentaris receives regulatory approval for Impavido® in Germany.
Press release, 6 December 2004. www.aezsinc.com/en/page.php?p=60&q=103.
âµTDR. Visceral leishmaniasis elimination. Draft business plan for JCB.
2007. www.who.int/tdr/publications/documents/bl10-business-plan.pdf?ua=1.
âµShamsuddin H. FDA medical review of application number 204684Orig1s000
IMPAVIDO (miltefosine). 2014.
www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204684Orig1s000MedR.pdf.
âµBryceson ADM. Preface. Trans R Soc Trop Med Hyg
2006;100(suppl):S1-S3.FREE Full Text
âµRidley DB, Sánchez AC. Introduction of European priority review vouchers
to encourage development of new medicines for neglected diseases.
Lancet2010;376:922-7. CrossRefMedlineWeb of Science
Michelle French <Michelle.French@newyork.msf.org>