Fighting Drug-Resistant TB Was Costly. Here’s How That’s Changed
19 September 2024
Nearly universal access to bedaquiline was only secured in 2023 following yearslong effort involving behind-the-scenes negotiations and public challenges by activists and survivors of multidrug-resistant tuberculosis.
It was while she was in a clinic in Cape Town, South Africa, enduring the complicated, agonizing treatment for extremely drug-resistant tuberculosis, that Phumeza Tisile began to question why “there weren’t better medications that had less side effects.”
In 2010, soon after her initial diagnosis with multidrug-resistant TB, or MDR-TB, Tisile had received a painful injection of the drug Kanamycin. It had caused her to go deaf essentially overnight, but did not stop the disease’s progression. She had not even been told that hearing loss was a potential side effect.
It was after she was finally cured, more than three years after starting treatment, that Tisile became aware that the drug company, Johnson & Johnson, had actually just developed a safer treatment with fewer risks. The treatment, bedaquiline, had only gained approval from the U.S. Food and Drug Administration, or FDA, in 2012. Had it been available to her it would have prevented her hearing loss and cut her daily pill count from 25 to fewer than 10.
She also came to understand the tangle of complications that made the treatment inaccessible to people across South Africa and in other parts of the world. This initially included regulatory and licensing procedures that stalled domestic adoption in some countries, but also the patchwork of intellectual property protections that activists accused the drug’s developer, Johnson & Johnson, of using to keep the price too high for some nations to access.
Ultimately, nearly universal access to bedaquiline was secured in 2023 following behind-the-scenes negotiations between international organizations and J&J officials, but also public challenges by activists and survivors, including Tisile, who would help block J&J’s effort to extend its patent protection.
“It didn’t make sense to me why they would make this drug and keep it out of reach of people who need it,” she said.
Advocates and policymakers are now looking to these efforts for strategies they can replicate in their attempts to make other groundbreaking treatments more widely available. That includes taking early steps to monitor companies as they file patent claims, but also thinking about partnerships that might facilitate quicker access even while patents are in place.
Early efforts
Bedaquiline was a revelation, the first novel TB drug in nearly five decades. Compared to the previously existing options, it is a vastly more effective and tolerable treatment for MDR-TB, a disease that affected an estimated 410,000 people in 2022.
The treatment was first discovered around 2002 by researchers at Janssen, a subsidiary of J&J, and received accelerated approval from FDA in 2012 without the Phase 3 trial results that are typically required. That it advanced so fast was thanks to what researchers have estimated was at least $455 million in public investments in the drug’s development and a priority voucher review by FDA.
Its approval by a U.S. regulator did not guarantee global access, as individual country regulators also have to approve the treatment. And many were reluctant given the lack of Phase 3 data. It does set up disparities, though, as survivors like Tisile hear about a superior treatment that they don’t have access to often until years later when their countries’ regulators approve the use of the medicine.
J&J had introduced tiered pricing as it rolled out bedaquiline, but activists protested that it was still too expensive for low- and middle-income countries that were willing to use it. Under pressure, the U.S. Agency for International Development and J&J started a donation program for bedaquiline in 2015, with support from the Global Drug Facility, which administered the medicine. The unique institution, housed within the Stop TB Partnership, takes on the responsibility of storing, bundling, and distributing treatment so that drug companies don’t have to, ultimately improving the efficiency of the system. Over the course of four years, GDF distributed 105,000 free courses of bedaquiline.
“To ensure patients all over the world can access the medicines they need, we need to be as innovative in our approaches to access as we are in the scientific discovery and development of medicines and vaccines themselves,” James Anderson, executive director of global health at the International Federation of Pharmaceutical Manufacturers Association, told Devex. “Companies are working with healthcare systems and governments to put in place new approaches, including tiered and differential pricing as well as value-based healthcare approaches and managed entry agreements.”
The program did not satisfy activists, though, who chafed at the idea of national TB programs growing dependent on donations that could easily disappear. They wanted the drug company to invest its resources in getting the drug registered in more countries and setting up a pricing and licensing strategy that would allow for more sustainable access to the product. They welcomed the end of the donation program in 2019.
As the end of the program approached, J&J agreed to sell a six-month course through GDF for $400 to the countries that had been eligible for the donations. But activists countered that the price was still too high for many countries, particularly with new World Health Organization guidance set to expand demand for bedaquiline.
Following an initial, compressed update to its MDR-TB treatment guidelines in 2018, WHO released detailed recommendations that made bedaquiline the centerpiece of future treatment efforts. The donation program actually played a role in the new guidance, offering additional evidence of the treatment’s effectiveness. This spurred more countries across the global south to revise their treatment policies in line with the new recommendations.
In acknowledgement of the growing demand, J&J did take steps to ensure the treatment remained accessible.
“Another company would have said, the donation’s over, lucky us that we get to sell it and capitalize on the new recommendations,” said Brenda Waning, who runs GDF. “J&J actually gave us additional quantities through the donation, even though they knew they’d be able to sell it.”
Once they returned to selling the treatment, J&J also negotiated with GDF to reduce the cost of a course of treatment from more than $400 to a volume-based price of between $238 to $306 for the full course of treatment, she told Devex.
“By the time countries had to buy it in 2020, they had the new lower price,” Waning said. She described the company as “a good partner.”
But the global health experts were growing frustrated at having to negotiate with only one player and they believed the price was still coming down too slowly. They wanted the patent lifted and the monopoly on control over access to bedaquiline lifted.
“Everything felt as if it’s coming too late,” Jayasree Iyer, CEO of the Access to Medicine Foundation, told Devex. “From the global health community point of view, you’re stuck with one drug that is in the hands of one company, whatever you try to do.”
J&J, of course, has a different view.
“Today, three of every four multidrug-resistant tuberculosis patients on treatment are receiving a bedaquiline-containing regimen, and more than 864,000 courses have been shipped to more than 160 countries,” a J&J spokesperson wrote to Devex in an email. “We’re proud to have played a leading role in the collaborative efforts that enabled this broad access to bedaquiline.”
Evergreening
Some activists remained wary of the company, and not just because of ongoing concerns about pricing. They were tracking J&J’s patent applications for bedaquiline, noting that the pharmaceutical giant had filed intellectual property claims on the essential compound that is the basis of the treatment. In most places in the world, those claims were set to expire in 2023.
Patents on pharmaceuticals are usually 20 years, but drug companies argue that they don’t actually get to enjoy the full period of exclusivity because some of the time is eaten away in waiting for regulatory approval or other delays in getting the product to market. That is one of the reasons they might look to extend the patent, a process known as evergreening. In general, they argue it is within their rights to claim the intellectual property protections they can in an effort to recoup their investments and incentivize future innovation.
In the case of bedaquiline, J&J had filed additional patent claims, including in India, where it submitted a claim in 2009 to protect the formulation of the treatment.
Priyam Lizmary Cherian, a lawyer with a background in intellectual property, said she believes these evergreening claims are attempting to stretch the boundaries of what is patentable.
“There is a lack of an inventive step,” she said, which is one of the things a patent is meant to reward. “We’re showing that all of this already existed in the field of this particular science and technology,” like introducing a standard delivery method to a new drug and then trying to claim an additional patent. There is nothing new there, she argued.
She said the claims also fail to show how changes to formulations or to how the drug is dispensed enhance efficacy, which would be another justification for an additional patent protection.
In this instance, the claims would have extended J&J’s monopoly on production and distribution of the treatment for as much as four more years.
J&J’s attempt to do this in India was particularly galling to activists, because the country is home to a massive generic pharmaceutical industry. By producing cheaply and at scale, the generic manufacturers are able to sell drugs affordably, while spurring other manufacturers to try to match their prices. It is why the country has become known as the “pharmacy of the world.”
But a patent extension there might have delayed the start of generic manufacturing at a moment when global demand for bedaquiline was growing because of the WHO recommendations.
A group of lawyers, led by Leena Menghaney of Médecins Sans Frontières’ Access Campaign, decided to file an opposition to try and convince the Indian Patent Office to reject the additional application. That would pave the way for generic production when the original patent expired in 2023.
Menghaney recruited Tisile and Nandita Venkatesan, an Indian MDR-TB survivor who also lost her hearing to the now-outmoded, harsh treatment, to be the face of the opposition claim.
Tisile, whose hearing loss was later reversed thanks to cochlear implants, had experienced her illness as a period of terrible stigma, “reading in people’s faces that they blamed you for having TB.” She saw the patent opposition as an opportunity for “the people who are actually affected by the disease to use their power to change it.”
They filed the paperwork in 2019, arguing that the attempt to claim a patent on the formulation of the treatment did not meet the necessary standard for enhanced efficacy.
“I was very convinced that [J&J] didn’t deserve the patent,” said Cherian, who would ultimately argue the case. “If they got the patent, it would have been totally unreasonable, and I would lose my faith in the system.”
It would take four years for India’s patent office to issue a ruling.
In that period, activists from around the world, in an act of solidarity, filed their own oppositions to patent claims in their countries. That included in Thailand, even though “we don’t have many people with MDR-TB,” said Thai activist Chalermsak Kittitrakul. “But we wanted to make an impact globally that this kind of patent is not acceptable.”
It proved a significant amount of work, but the Thai activists ultimately filed four patent oppositions in 2020. They have convinced intellectual property officials to reject two of J&J’s claims so far and are still waiting for decisions on the other two.
“It helps civil society to work in tandem,” Cherian said. “And we can also use orders from other countries in our jurisdictions,” adding to the pressure on the Indian patent authorities to decide in their favor.
While Cherian is grateful that countries offer opportunities to challenge patent claims, she noted that it requires a concerted effort to track filings, to organize the paperwork and to be available for hearings and arguments — all of which can be time consuming and expensive.
The March 2023 ruling in India striking down J&J’s patent application took activists around the world by surprise. But Menghaney said the decision by the authorities to release the decision around World TB Day 2023 sent a clear signal: “There was a message that India was giving out that we will not grant you this patent irrespective of how much pressure you put on us.”
Within months, J&J agreed not to enforce any secondary patents on bedaquiline in 134 low- and middle-income countries. The company said it was taking this step to address underdiagnosis of MDR-TB.
“Underdiagnosis of people living with TB remains the most significant barrier to ending TB, which is why we have invested in numerous community-centered initiatives aimed at helping people seek care,” the J&J spokesperson wrote. “Continued collaboration is needed to build on these efforts, save lives and end TB once and for all.”
Speeding access
The decision by the Indian patent authorities had immediate implications for GDF, where officials had already been working with generic manufacturers through the monthslong process of reverse engineering the formula for bedaquiline, so they would be prepared to start production and compete with J&J as soon as the patent lifted in July 2023.
“If India had granted the patent extensions, then that would have shut off those suppliers, unless J&J agreed to do something,” like issuing voluntary licenses that would have allowed them to continue production, Waning said.
Instead, GDF was able to issue a tender within days of the patent lifting and secure offers from three companies. J&J actually came in with the lowest bid, charging $130 for the six-month treatment, according to Waning. Lupin, a generic manufacturer, was next at $194 but eventually decreased its price to $159.
GDF now has a license from J&J to provide generics in nearly all low- and middle-income countries. And its leaders are still at work on negotiating the price of bedaquiline down further, although Waning cautioned that will take time.
For Cherian, the lesson of the fight to gain affordable access to bedaquiline is one of “people with different expertise working together.” The effort brought together patients and activists from around the world, but also policymakers and mediators willing to work directly with the drug companies. “It wasn’t a solo effort, is what I really understand from the bedaquiline story,” she said.
By Andrew Green
Source: Devex
