Geneva, Switzerland (Scicasts) — Despite tuberculosis ranking as the leading cause of death from infectious disease globally, only 2% of patients who need the latest TB drugs have been able to access them.

Moreover, prices for some of the most efficient drugs on the market could feasibly be reduced up to 98%.

These are among the conclusions of the latest report from Médecins Sans Frontières, “TB Drugs Under the Microscope, 4th Edition”, in which MSF experts analyzed the factors affecting patients’ access to new treatment regimens and the barriers for effective drug development.

The experts found that although the prices for individual TB drugs have been decreasing over the last several years, the costs of many combined treatment regimens remain too high to efficiently scale up these treatments in countries with the highest TB rates.

Combined medication regimens are especially important in cases of Multiple Drug Resistant TB, which require two years of continuous treatment and still have only 50% success rate.

The price for combined treatment courses for Drug Resistant TB, as was found in the report, ranged from $1,023 to $4,646 (USD) for the lowest-priced options, while the full price of preferred treatment courses for DR-TB is about $1,800-$4,600.

However, the MSF experts believe that the total price for a combined treatment course for TB should be no more than $500, which would be possible if the prices were based on production costs plus profit margins.

Why so high?

Upon publication of the report, MSF stressed the urgent need to increase people’s access to these more effective treatments, and called on the pharma companies, Janssen and Otsuka, who own the latest TB drugs (bedaquiline and delamanid) to lower the prices and therefore make the drugs more accessible.

Dr. Grania Brigden, TB Advisor for the MSF Access Campaign, said: “We desperately need treatment that is easier for people to tolerate, that cures more people, and that is more available and affordable, otherwise it’s just deadly business as usual.”

“It is important to keep in mind,” responds Marc Destito, Communications Director of the Global TB Program at Otsuka, in an interview to Scicasts, “that $1,700 cited in the report is the mutually agreed upon price for delamanid between Otsuka and the GDF. The community specifically asked us for a single price instead of a tiered model.

“$1,700 is a sustainable price for 6 months of treatment, which already represents a 95% reduction from the publicly listed price for delamanid in Europe. This price applies to countries that are eligible for the global fund financing through the GDF.”

At the moment, over 100 low- and middle-income countries are eligible to acquire the TB treatments through the GDF. Delamanid is currently in use in nearly 40 low- and middle-income countries.

"Our pricing is based on a careful calculation and analysis of the manufacturing costs in order to make this a sustainable project," says Mr. Destito.

He notes that delamanid is a rather expensive product to manufacture: “For instance, it has to be supplied in a special blister packaging, to ensure the compound stability considering the climate of those countries where the drug will primarily be used.”

However, he says, Otsuka is currently working to bring down the production costs and they expect to be able to reduce the price of delamanid over the next several years.

Mr. Destito also reminded that Otsuka had provided the MSF with a donation of 400 courses of delamanid to incite the MSF ‘endTB’ project.

“MSF is also eligible to purchase additional supplies of delamanid through the Global Drug Facility at the concessional price,” says Mr. Destito. “We are expecting an order to be placed by the MSF soon but have not received it yet.”

Janssen Pharmaceutica, currently the only manufacturer and patent owner of bedaquiline, in response to the Scicasts enquiry said that the company “recognizes there is a critical unmet need for new MDR-TB treatment options and are working with health authorities around the world to make bedaquiline available to eligible patients with MDR-TB”.

Harriet Mooney, Associate Communications & Public Affairs Manager at Janssen, said that the company has developed “a comprehensive access and affordability model to fulfill their responsibility to patients with MDR-TB through five key elements” that include

  • prioritized registration efforts by high disease burden;
  • access partnerships and research collaborations to improve access and advance new drug regimens;
  • support of appropriate use in collaboration with international and national TB programs;
  • sustained R&D to determine appropriate pediatric dosing and formulations and to evaluate simpler treatment regimens;
  • and differentiated pricing model to reflect the balance between value & innovation, and affordability & appropriate use.

Bedaquiline and delamanid have both been approved in the UK for treatment of MDR-TB and are available through the NHS. Delamanid is being marketed in the UK as Deltyba®; bedaquiline is sold under the trade name Sirturo®.

Ms. Mooney also stressed out that under the Donation Program, signed in December 2014, Janssen will contribute an estimated $30M USD, which will provide 30,000 courses of bedaquiline to patients at no cost, for use in more than 100 countries worldwide.

However, MSF point out in their report that some of the countries in need, such as South Africa, would still not be eligible for the Program.

“MSF maintains that medical product donation programs are not a solution to access challenges and present a number of complications for sustainable access to essential medicines,” write the experts.

The origins of the crisis

Initially, the price of every new drug reaching the market would also contain part of its R&D costs and clinical trials expenses. But in reality, when less than 10% of all newly discovered drugs gain regulatory approval and the costs of bringing a single new drug to market was estimated at £1.2 billion in 2014, the money spent on failed substances would have to be recovered through higher pricing of successful drugs.

Each case is further complicated by the lack of transparency in clinical trials reporting by companies trying to protect themselves from competition as well as rigid patenting rules, allowing monopoly on the few drugs that reach the market.

The high risk of investing in drug development in the current climate discourages contributions from private sector; the recent reports show that private sector investment in TB R&D since 2011 has fallen by a third. Since 2012, several pharmaceutical giants – Pfizer, AstraZeneca, Novartis and Vertex – have terminated all their R&D programs for new TB drugs and closed down the facilities.

Although the demand for new TB drugs remains high, the profit gains from developing TB treatments do not seem lucrative enough to drive up the products supply.

Only eight new anti-TB chemical compounds are now going through clinical development, according to data from the Working Group on New TB Drugs.

In addition, while companies focus their efforts on developing single substances, a successful TB treatment course requires a combination of several drugs. This, in turn, would require multiple drug combinations testing and successful collaboration with open knowledge exchange between companies, which is nearly impossible to achieve in the current market environment, argue the MSF experts.

Potential alternatives

Despite the solemnity of the TB drug development crisis, tuberculosis is far from being the only disease for which the current market model fails to provide timely and efficient treatments.

Rapidly rising bacterial resistance to antibiotics and emerging infectious diseases, such as the recent Ebola epidemic, indicate that “on-demand” approach may not be able to ensure that we have efficient drugs when we need them most.

“Both AMR and emerging infectious diseases, specifically Ebola, have recently been elevated to the level of public health concerns affecting global security,” write a group of researchers and policy makers in their essay in PLOS Medicine.

“All these areas have identifiable prevention and management strategies that can and should be scaled up. However, an additional consistent thread that runs throughout all these global health concerns is the deficit in innovation of new tools in relation to the identified needs.”

The looming issue, facing developing countries in particular, had already been recognized in 2008, when the participants from 190 countries convened at the 61st World Health Assembly in Geneva.

The resolution adopted at the Assembly assigned an intergovernmental working group “to draw up a global strategy and plan of action in order <…> to secure, inter alia, an enhanced and sustainable basis for needs-driven, essential health research and development relevant to diseases that disproportionately affect developing countries.”

Since then, the Consultative Expert Working Group on Research and Development (CEWG) considered over 100 various proposals and eventually offered to ‘de-link’ the final drug prices from R&D costs and encourage international open-source collaboration to accelerate drug development.

As a means to achieve this, CEWG suggested establishing a global pooled R&D fund (or several funds), which would distribute the money among pharmaceutical companies developing high-priority drugs.

Each fund would be formed through voluntary contributions from a number of private and public agencies; the initial suggestion by CEWG to establish a treaty including mandatory financial contributions from WHO member states did not seem to receive widespread support.

“Many commercial R&D programs are already being funded by the taxpayers money, such as the NIH or MRC grants,” says Dr. Grania Brigden from MSF. “We can take the existing system further and ensure that global efforts are coordinated.”

A similar framework for antibiotics R&D was proposed in a recent report by Jim O’Neill and the AMR Review team:

  • Change how antibiotic developers are rewarded; for instance, award a lump sum of money to the company upon reaching a particular product development stage (milestone payments)
  • Establish a global AMR Innovation fund (proposed sum $2 billion)
  • Create centralized public platforms for clinical trials and ensure open sharing of information between companies at the early stages of R&D.

For tuberculosis, the members of Médecins Sans Frontières - Access Campaign, the WHO Global TB Programme and a number of other international organizations are now developing another model:

The 3P Project

The name stands for “Push, Pool, Pull” and, echoing the antibiotics R&D pipeline, the project coordinators propose to ‘push’ the TB R&D funding, ‘pull’ R&D through financial rewards and ‘pool’ the obtained intellectual property into a database for common use.

In other words, the TB drug development pipeline would look like this:

Image: MSF Access Campaign

  • Funding to finance R&D activities will be pushed upfront (e.g. from a common fund through grants from public sector combined with private investments).
  • The funding to incentivize R&D activities will also be pulled through promising financial rewards on the achievement of certain R&D objectives (milestones).
  • Meanwhile, pulling of intellectual property (IP) and data will ensure open collaborative research through the fair licensing for competitive production of the final products.

The last point will become particularly important for testing promising drug combinations, say the MSF experts, allowing new drugs to reach the market within years, instead of decades, as it currently takes.

Dr. Brigden says that the Project will be ready for a full-scale launch within the next 18 months.

Ms. Mooney said that Janssen is “not currently involved in the 3P Project but welcomes all initiatives that can increase the availability of new treatment options for MDR-TB.”

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