New drugs are often used not only for one disease (first approved indication) but also for other diseases (supplemental indications). But a study published by The BMJ finds that less than half of approved first indications for new drugs in the US and Europe between 2011 and 2020 add substantial therapeutic value over existing treatments. Only about a third of supplemental approvals add substantial therapeutic value compared with first approvals.
The researchers argue that when first or supplemental indications do not offer added benefit over existing treatments, this information should be clearly communicated to patients and reflected in the price of the drugs.
Previous study findings on the value of new drugs were unclear. To address this, researchers examined all new drugs approved for more than one indication in the US and Europe between 2011 and 2020, and assessed the therapeutic value of supplemental indications compared with first indications.
Using publicly available data, they identified 124 first and 335 supplemental indications approved by the US Food and Drug Administration (FDA) and 88 first and 215 supplemental indications approved by the European Medicines Agency (EMA).
In the US, 48% of drugs had one supplemental indication, 20% had two, 14% had three, and 18% had four or more. In Europe, 48% of drugs had one supplemental indication, 23% had two, 13% had three, and 17% had four or more. Most (58%) of indications approved by the FDA and EMA were for treatment of cancer.
Therapeutic ratings from French and German health technology assessment (HTA) bodies were available for 107 (86%) first and 179 (53%) supplemental indications in the US and for 87 (99%) first and 184 (86%) supplemental indications in Europe.
Among FDA-approved indications with available ratings, 41% (44 of 107) had high therapeutic value ratings for first, compared with 34% (61 of 179) for supplemental indications. In Europe, 47% (41 of 87) of first and 36% (67 of 184) of supplemental indications had high therapeutic value ratings.
Among FDA approvals, when the sample was restricted to the first three approved indications, second indication approvals were 36% less likely to have a high value rating and third indication approvals were 45% less likely when compared to the first indication approval. Similar findings were observed for Europe.
These are observational findings and the researchers acknowledge that therapeutic value ratings were not available for all indications, particularly indications approved in the US but not in Europe. Furthermore, the methods and value assessment system can be influenced by country specific factors and assumptions.
However, they point out that they focused on the highest rating provided by one of the two HTA bodies and did sensitivity analyses with the value scores of each authority separately, which confirmed the initial results.
As such, they conclude: “Fewer than half of approved first indications in the US and Europe were rated as having high therapeutic value, and the proportion of approved supplemental indications rated as having high therapeutic value was substantially lower than for approved first indications.”
“When indications do not offer added therapeutic benefit over other available treatments, that information should be clearly communicated to patients and reflected in the price of the drugs.”
The fact that new does not necessarily mean better needs to be clearly communicated to both patients and clinicians, agrees Beate Wieseler at the German Institute for Quality and Efficiency in Health Care, in a linked editorial.
“The system’s current performance does not meet the expectations of patients and the public, clinicians, or policy makers,” she writes. “Having experienced the potential of a coordinated drug development effort during the covid-19 pandemic, we should seek to align current legislation on drug development more closely with defined public health goals.”
A new joint health supplement has been launched in South Africa by iNOVA Pharmaceuticals which supports healthy joints and helps reduce the symptoms of osteoarthritis such as joint pain and stiffness1. Unlike other osteoarthritis supplements on the market, POSTEON™ has been shown to start working in as little as five days1.
According to scientifically based research, the ingredients in Posteon™ may help reduce the symptoms of osteoarthritis such as joint pain and stiffness, as well as improving range of motion and mobility1.
Boswellia serrata gum resin extract has traditionally been used to relieve symptoms of osteoarthritis. Taken once a day, Posteon™ contains 100mg of 3-O-Acetyl-11-keto-beta- boswellic acid (AKBA), the most active compound of Boswellia extract which is an inhibitor of 5-lipoxygenase (5-LOX). This is a key enzyme in the biosynthesis of leukotrienes from arachidonic acid in the cellular inflammatory cascade1.
It also contains 300mg of Avocado soy unsaponifiables (ASU), a dietary supplement consisting of one-third avocado oil and two-thirds soybean oil. Studies have found that ASU can reduce the production/action of various joint inflammatory substances which can prevent the destruction of joint cartilage and also help in its repair1.
Osteoarthritis is the most common form of arthritis2 and affects between 55.1% and as many as 82.7% of adults aged over 65 years in South Africa3. Globally, the prevalence of osteoarthritis is increasing, and is expected to continue to escalate4.
POSTEON™, which is now available at leading pharmacies, may reduce these symptoms1 which can significantly impact day-to-day functioning2.
Usenbo, A et al. Prevalence of Arthritis in Africa: A Systematic Review and Meta-Analysis. A Systematic Review of Arthritis Prevalence in Africa (2015) at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4524637/ (website accessed on 4 May 2023).
Osteoarthritis Research Society International (OARSI) Osteoarthritis: A Serious Disease, Submitted to the U.S. Food and Drug Administration (2016) at https://oarsi.org/oarsi-white-paper-oa-serious-disease (website accessed on 4 May 2023).
DISCLAIMER: This editorial has been commissioned and brought to you by iNova Pharmaceuticals.
Content in this editorial is for general information only and is not intended to provide medical or other professional advice. For more information on your medical condition and treatment options, speak to your healthcare professional.
The Passing of the National Health Insurance Bill on 12 June 2023 by parliament has many stakeholders in the healthcare industry concerned as to what the implications are. The reality is that there is a long and challenging process ahead, and the NHI Bill has many years to go before all of its provisions could be implemented.
Putting all the challenges and debate aside, Jacqui Nel, business unit head of healthcare at Aon South Africa, highlights the salient points that are at the heart of the matter. “First and foremost, I would like to affirm that the private healthcare sector needs to focus all its efforts on objectively collaborating with all parties concerned to achieve a stronger and affordable healthcare solution for all South Africans. The concept and ideals of providing universal health coverage should not be in dispute.”
“The overarching principle of the NHI bill is to provide universal health coverage and social solidarity, providing all citizens with access to the same essential health care benefits, regardless of their financial means,” she adds.
However, the road to successfully implementing NHI is a long and costly one, with many experts saying it can take up to 15 years to achieve, if not more. Purely from a legislative point of view, there are no less than 11 pieces of legislation that will need to be amended to align with NHI objectives, and this is an onerous process.
This includes:
National Health Act
Mental Health Care Act
Occupational Diseases in Mines and Works Act
Health Professions Act
Traditional Health Practitioners Act
Allied Health Professions Act
Dental Technicians Act
Medical Schemes Act
Medicines and Related Substances Act
Nursing Act
And various Provincial Health Acts.
The first of many court cases are already making headlines. “On the constitutional front, one of the 11 pieces of legislation requiring amendment is the National Health Act, which governs the ‘Certificate-of-Need’ (CoN), a piece of legislation that would dictate to private sector doctors where they are permitted to practice and what services they may provide. This ‘CON’ is essential to government to control doctors under the NHI plans and is being challenged by trade union Solidarity and six other parties,” says Nel.
About the NHI Bill
The NHI Bill lays out the duties and functions of the NHI Fund, which are primarily to strategically purchase health care services based on the principles of social solidarity. All permanent residents and citizens will be eligible as beneficiaries of the “Fund” as it is referred to; and temporary residents and foreigners will have access to emergency medical treatment and access to other health services as determined through a mandatory travel insurance.
“The Bill states that eligible beneficiaries will be able to access health services through registering as a user of the “Fund”. Each member will have a number that is unique to them and their dependents. The Fund will then reimburse health care providers directly for services rendered, provided they have met the accreditation requirements. It is envisaged that comprehensive health services benefits must be made available and these services will be determined by the Benefits Advisory Committee,” explains Nel.
The Bill also refers to the establishment of the ‘Board of the Fund’, and the remuneration and reimbursement of the members of the Board which will be determined by the Minister of Health in consultation with the Minister of Finance. “There are various other functions of the fund for which further administrative departments will need to be set up to address planning, benefits design, price determination, accreditation, purchasing and contracting, payments, procurements, performance monitoring and a risk and fraud prevention unit,” says Nel.
However, there are major points of concern that remain and will need to be addressed to facilitate any implementation of the NHI into South African society, which include:
Ministerial powers, good governance and accountability.
Role of the different spheres of government.
Role of medical schemes.
Tax implications for taxpayers, both from an employee and employer perspective.
NHI funding models – increased taxes?
Health financing expertise.
Training of healthcare providers – consequence management.
Service delivery at state facilities and healthcare facilities.
Infringement on the right of choice.
Lack of detail around major parts of the NHI Bill.
In summary, this Bill is the roadmap to NHI, but many other pieces of legislation will have to be amended, and a crucial element is currently still missing which is the cost of NHI and what the basket of services will include. “To enable the NHI will require an appropriation bill from National Treasury to detail how the NHI is going to be funded. However, detail on this has been slim, while government’s finances are heavily constrained and look likely to worsen in the future with various global and local factors coming into play,” says Nel.
“We fully expect that there are going to be significant challenges to the many technical and restrictive provisions contained within the NHI Bill, and these challenges may well alter its entire substance, and there is also the prospect of political shifts that could have a material impact on health policy going forward. We simply do not see any material shifts to the private healthcare sector anytime soon,” Nel explains.
What is certain is that the Bill in its current shape and format is unlikely to remain as it is today. “While the NHI Bill raises serious concerns, there is no disputing the need for structural change. There will be much debate and negotiation in the years ahead in unpacking the strengths and weaknesses of current public and private healthcare systems, and we look forward to a rational and workable solution to the achievement of better healthcare and to assist in a workable solution for all South Africans,” Nel concludes.
On Tuesday, June 13, South Africa’s National Assembly approved the National Health Insurance (NHI) Bill, signing this new law into effect in the face of strong expert objections. The CEO of Discovery Health, Dr Ryan Noach, said that at the moment there is “no need to panic” over NHI, although overwhelming negativity was a major concern. . This was reflected in Quicknews polls results, with 98% of respondents expressing skepticism over NHI implementation.
Speaking in an interview with Newzroom Afrika, he responded to comments that the implementation of the NHI would devastate the private healthcare sector, which he said “sounds like a panicky reaction”.
While he did not say that NHI implementation would be without consequences, the chief executive of the country’s largest private medical scheme reminded viewers that, even with NHI as promulgated now, there was still a long way to go before there was any impact on private healthcare schemes or systems.
Health Minister Dr Joe Phaahla hailed the Bill: “This is one of the most revolutionary pieces of legislation presented to this house since the dawn of our democracy in 1994.” Briefing the media, he was bullish on existing issues of corruption and mis management in healthcare, saying “Those issues must be dealt with.” He pointed to a number of “good examples” of institutions.
But serious questions about the impact, implementation and feasibility of the extraordinarily expensive and far-reaching Bill have yet to be answered.
The impact of Section 33
Dr Noach noted that one important point regarding the Bill is Section 33, which “talks about the full implementation of NHI before any impact on medical schemes.” Essentially, the NHI would have to be fully in place before the healthcare and health insurance sectors would be affected.
He added that the Department of Health’s expected that NHI would take some 10 to 15 years to fully implement after its promulgation. Speaking with the experience of a scheme that provides for 4 million people, he said that it is already a huge amount of work, and the task of catering to the entire population of South Africa would be even greater.
Dr Noach notes that as for the necessary financing bill for the NHI, it is nowhere to be seen. Little said about it by the Treasury, which has only noted that it is “nascent”. As the population contributes GDP of 8.5% to healthcare, the assumption seems to be that this 8.5% would simply be redirected into a NHI scheme, which is not likely to happen.
Medical funds are contributed from medical schemes after tax, are well-protected by schemes, and as trust funds they essentially belong to the members. By law no-one can take away access to those funds: it would be like taking away people’s pension funds.
No parallel with any other country’s public health scheme
This singular NHI fund would essentially be a monopoly, and there were also no other examples of this to be found anywhere in the world. Even with the UK’s NHS, 12% of the population opts for private medical insurance. No other countries exclude by law the participation of private insurance and private funders. The annual spend would be R500bn to R700bn, and the NHI would disburse this to about 100 000 healthcare providers – assuming that the healthcare market would remain in its present form, which would likely suffer.
The biggest short term risk of the Bill would be the emigration of skilled healthcare professionals from a very negative sentiment emerging among in that grouping.
Meanwhile, those working in the public sector are battling under corruption and a lack resources while those in the private sector are extremely concerned. According to a Quicknews poll which ran for the month of June, 97.78% of the 90 respondents agreed with the South African Medical Association’s objections to the Bill.
In early 2022, a Quicknews poll had found that 81% of respondents had either considered emigrating due to the NHI Bill or were actively planning to do so.
Dr Noach says that “we are doing everything we can to calm the health professionals, partner them and work with them and reassure them, because we do believe that the outcome here could be optimistic.” A version of NHI would be welcomed.
As for the eventual fate of medical aid scheme under Section 33, once the Minister determines that NHI is fully implemented (and it is unclear how that would be determined), only those services not covered by NHI would be covered by medical aid schemes – though there is no indication at this stage of what would be covered.
An alternative approach to NHI
Before this can even be implemented, the government needs to find R200 billion to fix the public healthcare system, something which Dr Noach applauds as a priority.
He described an alternative NHI, with policy reform one in both private and public healthcare to create a “multi-funded environment”, something which Discovery’s actuarial work had found to be a better fiscal option. The NHI has many favourable qualities, which are smart and feasible, he continued.
The current monopolistic approach to NHI would create a single pot of money which would be the largest fund in the country by far – with its attendant risks.
Notes: Updated to reflect latest Quicknews poll results and to include Dr Joe Phaahla’s comments on the Bill.
June Bellamy’s 83-year-old mother got COVID in March 2022 and was in intensive care for two weeks. She was diagnosed with heart disease. When she was discharged, she was put on oxygen and prescribed medication, including blood-thinning tablets containing rivaroxaban.
During a visit to the doctor earlier this month, Bellamy and her mother were shown a list of different medications containing rivaroxaban. But when they tried to obtain the generic version at the dispensary, which is about 40% cheaper, the supervisor said that because of an ongoing court case they were not allowed to supply it anymore.
“We’ve had to buy the expensive one,” says Johannesburg resident Bellamy, who has been unemployed since 2017. It costs her R1100 a month and she also has to buy other medications. She says her mother is on a basic medical aid plan and the medication is not covered.
“While I’m financially decimated, I’m trying to do what I can,” said Bellamy.
One year and counting
There are a number of court cases dealing with the issue. One of these is between Bayer and Clicks and was heard in the court of the commissioner of patents in Gauteng. The details are complicated and we explain them below. But what is clear is that in April 2022 Judge Colleen Collis reserved judgment in this urgent matter about the sale of blood-thinning tablets. More than a year later, she has failed to hand down her ruling.
In urgent matters judgment is expected almost immediately. It is astonishing for a judge to take a year over any judgment, let alone an urgent one. The judicial norms and standards state that judgments, in non-urgent matters, should be handed down within three months of being reserved.
GroundUp previously reported that the last available list of late judgments on the judiciary’s website is 31 December 2021. The judiciary has stonewalled our requests for an updated list.
We asked for comment from Chief Justice Raymond Zondo and Judge Collis but received no response.
What the case is about
The case deals with the extension of Bayer’s patent on rivaroxaban from December 2020 to January 2026.
In 2000, Bayer obtained a patent on rivaroxaban. Patents are granted for 20 years and so the patent was to expire in December 2020.
The patent-holder of a medicine, in this case Bayer, has exclusive control over it. No other pharmaceutical company may sell the medicine in South Africa during the patent period, at least not without Bayer’s permission. Effectively a patent holder has a monopoly. The point of patents is to create an incentive for pharmaceutical companies to develop new medicines.
In 2007 Bayer obtained a patent for rivaroxaban to be dosed once daily (the original patent was silent on dosing). This extended the patent to 19 January 2026. This kind of patent extension is widely criticised by health activists and is called evergreening.
After the initial patent expired in December 2020, two pharmaceutical companies, Austell and Dr Reddy’s, launched generic versions of rivaroxaban. To cut a long story short, there followed a series of court actions which resulted in Austell and Dr Reddy’s being interdicted from selling their versions of rivaroxaban in South Africa. But the interdicts did not yet stop the big three pharmacy groups, Dis-Chem, Alpha Pharm and Clicks, selling the stock they had of both generic products.
Dis-Chem and Alpha Pharm reached a settlement with Bayer in respect of Dr Reddy’s product, Rivaxored, but Clicks did not. Bayer applied to the court of the commissioner of patents to interdict Clicks from selling rivaroxaban and obtained an urgent interim interdict in March 2022. Shortly after that, in April 2022, the main (and still urgent) hearing for this application took place and Judge Collis reserved judgment. That is where matters stand, over a year later.
As of 13 May, OpenUp’s medicine price website gives the price of a pack of 42 Xarelto (Bayer’s rivaroxaban product) 15mg tablets as R1532. Austell’s equivalent product, Rezalto, is R931.26. Dr Reddy’s product, Rivaxored, is a little higher priced than Rezalto (at 15mg) but considerably lower than Bayer. There’s also iXarola, Bayer’s “authorised generic”, which they brought to market just before the expiry of the 2000 patent. It’s priced at R1285. (These prices exclude the dispensing fee.)
The timeline below contains more detail.
Timeline
2000: Bayer gets patent for rivaroxaban (expires December 2020).
2007: Bayer gets patent for dosing rivaroxaban once daily instead of twice daily (effectively means that the patent expires on 19 January 2026).
2020, December: Initial patent expires.
2021, January: Austell launches its generic version of rivaroxaban, called Rezalto.
2021, April 1: Dr Reddy’s launches its generic version of rivaroxaban, called Rivaxored.
2021, May: Bayer obtains urgent interdicts that stop Austell from selling Rezalto.
2021, December: Bayer obtains interim interdict against Dr Reddy’s, but the interdict does not extend to stopping pharmacies from selling the stock they already had of Dr Reddy’s generic pills.
2022, January: Bayer then launches another urgent application to interdict three pharmacy groups from selling Dr Reddy’s generic pills still in stock. Dis-Chem and Alpha Pharm reach a settlement with Bayer. But Clicks refuses to settle and opposes Bayer’s application.
2022, March 15: Bayer obtains an urgent interim interdict against Clicks at the court of the commissioner of patents in Gauteng, pending a main hearing which takes place at the same court in April.
2022, April: The urgent interdict application between Bayer and Clicks is heard by Judge Colleen Collis in the court of the commissioner of patents in Gauteng. Collis reserves judgment.
2023, May: Judgment has still not been handed down by Judge Collis.
In the US, drug approval needs “substantial evidence” of effectiveness – but an investigation by The BMJ into the recent approval of the antibiotic Recarbrio from Merck suggests that these standards are being bypassed.
Recarbrio is a combination therapy made up of a new beta-lactamase inhibitor (relebactam) and a decades old Merck antibiotic (imipenem-cilastatin) to treat complicated infections. It costs $4000–$15 000 for a course, compared with a couple of hundred dollars for the generic version of Merck’s old antibiotic.
Peter Doshi, senior editor at The BMJ, describes how US Food and Drug Administration (FDA) scientists had serious doubts about its highly expensive Recarbrio but the agency approved it anyway.
Did the FDA break its own rules in approving this antibiotic, and what does this case tell us about problems within the agency, he asks?
In its FDA application, Merck submitted results from two clinical trials comparing Recarbrio with imipenem in adults with complicated urinary tract infections and in patients with complex intra-abdominal infections.
But FDA reviewers noted that Merck had studied the wrong patient population to evaluate the added benefits of the new drug, and said the trial for urinary tract infections showed that Recarbrio was as much as 21% less effective than the older, cheaper imipenem.
The FDA concluded that “these studies are not considered adequate and well-controlled.” And of a third clinical study, the FDA called it a “very small,” “difficult to interpret” “descriptive trial with no pre-specified plans for hypothesis testing.”
Yet despite all three clinical studies not providing substantial evidence of effectiveness, FDA approved Recarbrio.
“Instead of basing its decision on the clinical trials in Merck’s application, FDA’s determination of Recarbrio’s efficacy was justified on past evidence that imipenem was effective, plus – to justify the new relebactam component – in vitro (lab) studies and animal models of infection rather than evidence from human trials as required by law,” writes Doshi.
Others are concerned that Recarbrio’s approval essentially amounts to a return to a way of regulating medicines that the FDA abandoned a half century ago prior to the agency’s “substantial evidence” standard.
Doshi explains that, under specific circumstances, the Director of the Center for Drug Evaluation and Research (CDER) can waive in whole or in part the FDA’s “adequate and well-controlled studies” approval criteria. But the FDA told The BMJ ”there was no center director memo in the file” for Recarbrio.
And when The BMJ contacted Janet Woodcock, CDER Director at the time, and now the FDA’s Principal Deputy Commissioner, she said she was not aware that clinical studies showed Recarbrio did not provide substantial evidence of effectiveness.
Woodcock was also unable to confirm that approvals of new drugs require at least one clinical study of the drug itself that demonstrates substantial evidence – evidence lacking in the case of Recarbrio.
A spokesperson for CDER told The BMJ that FDA “applied regulatory flexibility” in approving Recarbrio.
It is unclear whether this regulatory flexibility enabled FDA to conclude Recarbrio had met the legal “substantial evidence” standard without “adequate and well-controlled investigations” of Recarbrio, says Doshi. FDA declined to answer the question, saying “We have no additional information to provide.”
The decline of science at the FDA has become unmanageable, argues David Ross, associate clinical professor of medicine at George Washington University, School of Medicine and Health Sciences, and former FDA medical reviewer, in a linked commentary.
He describes Recarbrio’s approval as “shocking” and says while much of the blame must go to the FDA’s reliance on industry paid user fees for around two-thirds of its annual drugs budget, “the corruption of the FDA’s scientific culture remains the primary culprit driving the deterioration of safety and effectiveness standards.”
To address this “dismal situation” he suggests tapering the FDA’s dependence on user fees and improving public access to the information received by the FDA, its reasoning, and its decisions.
“The Recarbrio approval is a sentinel event, warning of a return to an era when drug effectiveness was an afterthought,” argues Ross. “Although the FDA crowed about this approval, it would have been better advised to remember that “for a successful technology, reality must take precedence over public relations, for nature cannot be fooled,” he concludes.
A survey of military and paid civilian pilots has revealed that they may avoid seeking medical advice out of fear of losing certification to fly. Two-thirds of military and paid civilian pilots answered “yes” to at least one of four survey questions on reluctance to seek formal medical advice about health problems, reported William R. Hoffman, MD, who presented a poster at the American Academy of Neurology annual meeting.
Hoffman, a US Air Force employee, noted that both civilian and military pilots can be grounded if they have certain medical symptoms or diagnoses, with a range of negative repercussions for the pilot. As a result, pilots are disinclined to be truthful about their health if their employers or officials might find out.
In a previous survey of pilots led by Hoffman, more than three-quarters reported that they “felt worried about seeking medical care due to concern for their career or hobby.” The new survey probed this reluctance, with respondents asked whether they agreed or disagreed with the following:
Sought informal medical advice for fear of certificate loss
Flew despite experiencing a new symptom (physical or psychological) that warranted evaluation
Did not disclose prescription medication use
Misrepresented or withheld information on a written healthcare questionnaire for fear of certificate loss
Respondents to the web-based survey included 2383 nonprofessional civilian pilots, 1097 paid civilian pilots, and 261 military pilots.
Just over half of the unpaid civilian pilots denied ever hiding any of the four types of information. But that was true for only 33.6% of the paid civilian pilots and 32.2% of the military pilots.
Fortunately, among all respondents, only 6.8% said they had not disclosed prescription drug use as required, and just 16.8% acknowledged that they had kept new symptoms secret. But 45.7% acknowledged seeking informal advice in place of seeing a professional, and 26.8% said they had withheld or overtly misrepresented information on written forms. A few (2.2%) admitted to all four types of avoidance.
Female pilots reported slightly more avoidance of disclosure (62.0% of all female respondents vs 55.4% of men; P not reported). Younger pilots were also less open, especially those aged 25–40 (69.1% vs 40.7% in those older than 60). Union membership and active-duty military status were linked to high rates of avoidance (70.1% and 75.8%, respectively, vs 51.8% among non-unionised civilian and military reservist pilots).
Hoffman suggested that neurologists recognise that pilots may be shy about revealing their true health condition. “This might be mitigated through developing rapport with the pilot, asking questions about concerns related to their flying status, and clear communication about documentation and clinic course.”
Additionally, he recommended, “it is good technique to order only the necessary tests for all patients, to include pilots to avoid false positives.”
Despite this, medical professionals have an obligation to communicate a pilot’s health concerns to those responsible for evaluating fitness to fly.
Patients-turned-social-media-influencers routinely offer prescription drug advice to their followers and often have close ties with pharmaceutical companies, according to new research the Journal of Medical Internet Research – though they often have good intentions.
In recent weeks, social media has pushed the diabetes drug Ozempic as a weight loss drug, while patients who need the medication to manage their disease have faced global shortages. Those taking it “off-label” to slim down have experienced surprising side-effects, including violent diarrhoea and extreme facial thinning.
The study by University of Colorado Boulder provides some of the first insights into the burgeoning, loosely regulated world of so-called “patient influencers”.
“The bottom line here is that patient influencers act as a form of interactive direct-to-consumer (DTC) advertising, sharing their knowledge and experiences on pharmaceutical drugs with communities of followers in which they wield great influence,” said author Erin Willis, an associate professor of advertising, public relations and media design. “This raises ethical questions that need more investigation.”
A new kind of advertising
Controversial from its start in the 1980s, and still only available in the United States and New Zealand, DTC advertising enables drug companies to target consumers directly, rather than exclusively through physicians. About half of the people who ask their doctor about a drug after seeing a TV ad get it.
With trust in pharmaceutical companies and traditional media declining, drug makers are now turning to real patients as messengers, with companies like Health Union connecting them for partnerships.
Willis conducted interviews with 26 influencers with a range of conditions, including lupus, HIV and chronic migraines. Eighteen of the 26 collaborated with a pharmaceutical company in some way.
Most had between 1000 and 40 000 followers. Such “micro influencers” tend to be less expensive for advertisers to work with than celebrities, and research has shown they have the most influence on purchasing behaviours, said Willis.
Some interviewees posted company press releases directly. Others read studies about drugs and translated results for followers. Some were paid to post content for drug companies.
“Health literacy and digital literacy are both concerningly low in this country,” said Willis, noting that consumers often fail to recognise the difference between a sponsored ad and an altruistic personal post. “The fact that patients with no medical training are broadly sharing drug information should alarm us.”
Good intentions
On the positive side, Willis was heartened by the reasons participants become influencers. Almost all said they were drawn to their roles by a sense that the answers they sought as patients, didn’t exist in other channels.
“I spent a lot of time looking for diabetes information that related to me – an African American woman from the South,” reported one study participant. “I didn’t see what I needed, so I created it.”
Others were motivated by a wish to destigmatise disability in certain communities.
“There’s still not a lot of talk about Latinos and HIV,” said another participant. “When there was information, it wasn’t culturally appropriate.”
Five said they never share information about drugs, stating that they believed it was “borderline unethical.”
Others said they would only post about drugs they personally had been prescribed and taken and always encouraged followers to consult with their doctor. They all said they generally strived to behave ethically.
“It’s comforting that the people we interviewed generally want to stay abreast of the science and be a credible source,” said Willis. “But I also know that doctors go to medical school for a reason.”
Concerns abound
Several influencers reported that followers frequently private message them to get detailed information about dosage and side effects.
“In an online community, there are other people there to say, ‘That’s not true or that’s not what I experienced.'” Willis said. “But with social media, a lot of the conversation happens privately.”
Willis also worries that influencers may stress the upsides of medications without fully disclosing the side-effects. For instance, she references a famously controversial 2015 post by celebrity influencer Kim Kardashian, singing the praises of a “#morningsickness” drug called Diclegis to her tens of millions of followers on Instagram.
The Food and Drug Administration swiftly flagged the post for omitting the drug’s long list of risks, required Kardashian to remove the post and dinged the drug maker with a warning letter. The Federal Trade Commission (FTC) now requires influencers to disclose whether they are paid via hashtags, such as #ad or #sponcon, and the Food and Drug Administration has rules on what can be said on social posts. But those rules are open to interpretation, and videos, disappearing content and direct messaging can be tough to track.
Willis acknowledged that her sample was a small one and that because many of her interviewees were referred to her by Health Union, they likely skew to the responsible side. In future studies, she intends to include broader sample sizes, explore how influencers impact treatment decisions and investigate compensation for and regulations around patient influencers.
Analysts predict the influencer marketing industry as a whole will be valued at $21.1 billion in 2023.
As patient influencers increasingly find their place in it, Willis contends that regulators should work harder to keep up with all the new platforms.
“This is happening, with or without regulation, and people should be aware of it,” Willis said.
Cystic fibrosis (CF), which is caused by a faulty gene inherited from one’s parents, is a debilitating disease requiring difficult and time-consuming treatment and resulting in premature death. CF causes mucus in the body to thicken, with often disastrous consequences in organs such as the lungs and pancreas, and triggers a range of symptoms in people living with the condition, including chronic coughing, wheezing, and malnutrition. Ongoing treatment of symptoms often requires children with CF to miss school and can make it difficult for adults with CF to hold steady employment.
Yet, a new class of medicines introduced over the past decade called CFTR modulator therapies offers new hope to people living with CF – dramatically reducing CF’s symptoms and allowing people with CF to live longer healthier, and more productive lives.
These new treatments, whose research and development benefited from significant public and philanthropic financing, have been hailed as a “miracle” for people with CF. As antiretrovirals did for HIV, the introduction of CFTR modulator therapies is transforming cystic fibrosis from a progressive, life-threatening illness into a chronic, manageable condition. CFTR modulator therapies are so effective because they address the underlying cause of cystic fibrosis symptoms – a malfunctioning protein made by the CFTR gene.
But, more than a decade after the introduction of the first CFTR modulator therapy to treat CF in the United States, no CFTR modulator therapies are yet registered in South Africa and only a fraction of patients who need this therapy have access to it, and that is only after jumping through some extraordinary hoops. As a result, the only way for the vast majority of people to manage CF in South Africa is to aggressively prevent and treat its symptoms using older therapies. This is no small task for patients and their families, as it can require time-consuming, daily physical therapy to loosen mucus in the lungs and weeks-long hospital stays to treat infections. In severe cases, treating cystic fibrosis can even require a lung transplant.
Without access to CFTR modulator therapies, people with CF in South Africa continue to die prematurely. The average age of death of people with CF in South Africa was 27.5 in 2020. People in the global North live almost twice as long. The life expectancy of people living with cystic fibrosis in the United States is now 50 and is expected to lengthen as a result of newly introduced treatments.
Why can’t people in South Africa access CFTR modulator therapies?
As a person living with cystic fibrosis, or the parent of a child with cystic fibrosis, it can be unbearable to know there is a medicine that could allow you to breathe easier, keep you or your child out of hospital, and even prevent the need for a lung-transplant or premature death, but that you can’t have it, largely due to decisions taken by one company.
As recently detailed in the New York Times, one company holds a monopoly on the manufacture and sale of CFTR modulator therapies and is choosing not to make new CF treatments available to people in the developing world through the normal channels. Vertex, the company that holds monopoly patents on all available CFTR modulator therapies, is – for the most part – not registering or marketing its CFTR modulator therapies in developing countries. Registration is typically required before a drug can be marketed in a country.
While Vertex does offer some compassionate use and donation access programmes in select developing countries, Vertex Save Us, a global coalitional of advocates seeking affordable and universal access to CFTR modulator therapies, says these efforts reach only a small minority of patients that could benefit from the treatments and are restricted to countries with which Vertex believes it can secure a reimbursement deal.
Some activists suggest that the neglect of patients in developing countries is part of a strategy to squeeze the highest possible prices for CFTR modulator therapies from health systems in wealthy countries, with which Vertex has been locked in extended negotiations. Offering lower prices to developing countries for its CF medicines could provide ammunition to wealthy countries in demanding lower prices.
“This is a really fundamental and really simple example of how unfettered profit-driven business practices basically sacrifice the lives of people, particularly those of people who happen to live in low- and middle-income countries,” says Diarmaid McDonald, medicine access advocate and Director of the UK-based advocacy group, Just Treatment.
Vertex charges over R5 million ($322 000) annually for its most effective CFTR therapy, Trikafta (which must be taken as a life-long treatment) in the United States. But researchers in the United Kingdom have shown that the medicine can be manufactured and profitably marketed at a fraction of that cost.
Does Vertex plan to register its products in South Africa?
In response to queries from Spotlight regarding whether Vertex plans to register its drugs in South Africa and what the timeline for doing this is, the company indicated that they did not plan to register their medicines but would supply them via Section 21 authorisations – a mechanism allowing for importation of unregistered medicines into the country.
“As seen in other rare disease areas, bringing medicines to patients in South Africa is challenging as the reimbursement system and willingness to invest do not support a viable path to sustainable access. Analyses show that most novel, high-value medicines targeting disease areas comparable to and including CF are not on the Prescribed Minimum Benefits (PBM) list. There is therefore no obligation for funders to reimburse the costs of these medicines even after a lengthy regulatory registration process,” said Vertex’s Director of International Communications Daria Munsel.
“Given this, we believe that sustainable access could be achieved through ‘Section 21’ (on a named patient basis), which provides the fastest and most efficient route to access for rare disease medicines in South Africa,” Munsel added. “As part of this effort, we are currently in discussions with relevant stakeholders in the private insurance system to ensure sustainable access is available to eligible CF patients in South Africa.”
However, Munsel declined to identify the local company with which Vertex has signed an agreement for distributing its medicines, saying, “We can confirm that we have recently signed a distribution contract with a local distribution partner for our CF medicine in South Africa. Given that reimbursement conversations are still ongoing, it is inappropriate for us to name other parties for the moment.”
For now, the lack of transparency about the local distributor effectively blocks the use of Section 21 authorisations for importing Vertex’s medicines into South Africa, as patients and clinicians must supply details of local distributors in their applications to the South African Health Products Regulatory Authority (SAHPRA) for authorisation to import unregistered drugs.
Vertex did not respond to a question from Spotlight regarding what price it would charge patients in South Africa able to secure Section 21 authorisations to import their medicines.
Landmark court case seeks to challenge Vertex’s monopoly in South Africa
Vertex has secured a global monopoly over CFTR modulator therapies by aggressively pursuing patents related to the class of drugs around the world. These patents prevent other companies from manufacturing and marketing CFTR modulator therapies and give Vertex wide latitude in setting prices.
Between 2007 and 2016, Vertex filed six patents in South Africa related to the CFTR modulator therapies, Kalydeco and Trikafta. While Vertex received marketing approval to sell Kalydeco and Trikafta to treat CF in the United States in 2012 and 2019, respectively – it has still not applied for registration of either product in South Africa.
What this means is that despite Vertex’s failure to take steps to register or market its medicines in South Africa years after doing so in the US, patents granted to Vertex in South Africa block any other companies from supplying the medicines to CF patients in the country.
“The bottom line is that people are dying, they need to be able to access affordable treatments,” says Kelly du Plessis, founder of Rare Diseases South Africa. “If Vertex isn’t going to be able to come to the party in South Africa, then fine. We respect their choice, but then move out the way and allow someone else to do it. You can’t maintain the market and hold it ransom, but also not do anything from your perspective to help.”
According to Fatima Hassan, director of the Health Justice Initiative, “You can’t have a system where you file your patents, [but then] you refuse to bring a product to market or you have it at such an excessive price in the country with the highest inequality in the world, but then you don’t allow any generic manufacturers to come in at a lower price.”
Cheri Nel, a woman living with cystic fibrosis in South Africa, and the Cystic Fibrosis Association have now gone to court to challenge Vertex’s monopoly. On 7 February 2023, Nel’s lawyers submitted a Notice of Motion to the Court of the Commissioner of Patents (within the High Court) requesting that the court grants a compulsory license to override Vertex’s patents on Kalydeco and Trikafta.
Nel and the Cystic Fibrosis Association are seeking a compulsory license on the grounds that the patents held by Vertex are being abused. Nel’s lawyers argue that by failing to register or supply their CF medicines in South Africa, make them available in South Africa at reasonable prices, or license other companies to supply the medicines, Vertex is abusing its patents. They further argue that Vertex’s actions are violating the Constitutional rights of people with cystic fibrosis in South Africa, including the right to health care.
If granted, a compulsory license in South Africa would effectively override Vertex’s monopoly and allow the importation of generic cystic fibrosis medicines into South Africa, as well as their manufacturing in the country.
The legal action taken in South Africa is being pursued simultaneously with broader global efforts, led by Vertex Save Us, to overcome Vertex’s monopoly on CFTR modulator therapies and ensure universal access for all people who can benefit from these treatments.
“South Africa is the only country where papers have been launched with courts to start a legal process to try and secure a compulsory license, although the process is playing out in other countries following the most logical, legal routes set out in their national law,” explains McDonald.
“Requests of the government to issue compulsory licenses [have been made] in both Ukraine and in Brazil. And in India, it’s a petition of the government requesting that they revoke the patent under the terms of the Indian patent law,” says McDonald.
Any precedent for granting compulsory license on a medicine in South Africa?
If Nel and the Cystic Fibrosis Association’s pursuit of a compulsory license on the cystic fibrosis medicines is ultimately successful, then the issuing of a compulsory license order will be the first time this type of license is granted in the country on a pharmaceutical product. While South Africa has not issued a compulsory license on a medicine, the Treatment Action Campaign (TAC) has previously used competition law to overcome patents impeding access to affordable antiretroviral medicines in South Africa.
TAC cases at the Competition Commission and the threat of ‘compulsory licensing’ resulting from these cases led several multinational companies to grant voluntary licenses that enabled manufacturing and marketing of generic ARVs in the country. Generic competition resulted in massive price decreases for ARVs and has been critical to South Africa’s success in building the world’s largest public sector HIV treatment programme.
While South Africa’s courts have not issued a compulsory license on a medicine, its own challenges in securing access to affordable HIV medicines contributed to the affirmation and strengthening of the rights of countries to issue compulsory licenses to address health challenges within international trade law in the early 2000s. Both developing and developed countries have subsequently used compulsory licensing to improve access to critical health tools under patent including for HIV, cancer, and more recently, COVID-19.
The Fix the Patent Laws coalition, a coalition of over forty patient groups in South Africa, has long called on government to amend South Africa’s patent laws to improve the usability of compulsory licensing provisions to address health challenges in the country. The landmark court case of Nel vs Vertex will provide important insight into the ongoing need for these reforms in the country.
Who can benefit from Kalydeco and Trikafta
While cystic fibrosis is caused by a defect of the CFTR gene, over a thousand different types of mutations can occur in the gene that causes CF. People with CF must inherit a mutated gene from each parent in order to develop CF illness. The type of gene mutations that each person with cystic fibrosis inherits from their parents determines their eligibility for different CFTR modulator therapies.
Vertex, which has a monopoly over the entire class of CFTR modulator therapies available for CF, currently markets six medicines made up of different combinations of active ingredients that seek to correct the faulty CFTR protein (produced by the CFTR gene).
Kalydeco, made with the active ingredient ivacaftor, was the first CFTR modulator therapy approved to treat CF, yet it is only effective in treating five percent of people living with CF. Trikafta, which was approved in the U.S. in 2019 and combines three active ingredients – elexacaftor, tezacaftor and ivacaftor – is effective in treating 90 percent of people living with cystic fibrosis.
How many people in South Africa could benefit from Trikafta?
The recently established South African Cystic Fibrosis Registry has compiled health and demographic data for 525 people diagnosed with cystic fibrosis in the country. According to 2020 registry data, 450 patients (85.7%) would benefit from currently available CFTR modulator treatments. Dr Marco Zampoli, paediatric pulmonologist at the University of Cape Town, estimates that around 35 patients are currently sourcing generic CFTR modulators in their personal capacity from overseas (see more below on how a small group of patients in the country are accessing treatment from Argentina).
While the registry counts 525 patients diagnosed with CF in South Africa, the true number of people born with CF in the country is likely far higher. Zampoli estimates (using population and genetic data) that between two and three thousand babies could have been born with cystic fibrosis in South Africa since 1999.
“We think a lot of them are probably dying from a very young age without being diagnosed with cystic fibrosis as it looks similar to other common things like malnutrition, TB, and HIV,” says Zampoli.
While improving CF detection and diagnosis can save lives and will also increase the number of known patients in the country that could benefit from currently available CFTR modulator therapies, many of the new patients identified from better detection efforts would be unable to benefit from existing treatments. This is because black Africans are less likely than people of Caucasian descent to have the mutations that are responsive to currently available treatment.
Zampoli, however, notes that research is underway that will likely deliver new treatments that benefit patients who are ineligible for currently available drugs and adds “we’re going to be facing the same issues [of unaffordability] down the line… when we do eventually license a drug that will target their specific genes.”
How do a few people in South Africa get access to CFTR modulators?
While the South African government is not currently in negotiations with Vertex, price negotiations with health systems in wealthy countries have often dragged on for years, as price remained a sticking point.
People living with severe cystic fibrosis, however, do not have years to wait as their disease advances, placing them at risk of severe complications and death. Some have joined together to start a CF Buyers Club. The Buyer’s Club supports CF patients from around the world in buying generic versions of CFTR modulators from Argentina.
Argentina has taken steps to set strict criteria for granting patents and limit the granting of patents on certain types of claims related to pharmaceutical products. As a result, Vertex has not been granted patents on its CFTR modulator treatments in Argentina, and two Argentinian pharmaceutical companies, Gador and Tuteur, are legally manufacturing generic versions of these medicines.
While the Argentinian companies producing these medicines are unwilling to export them to South Africa for fear of facing patent infringement challenges from Vertex, Argentinian pharmacies will supply medicines to CF patients from South Africa visiting Argentina.
“You need to have a doctor’s script and you need to have a Section 21 authorisation,” explains Belinda Nell, a South African advocate working to facilitate access to CF medicines in South Africa. “You’ve got to fly to Argentina in your personal capacity or have a family representative go there and collect [the medicines] and then fly back.”
South Africans holding Section 21 authorisations from SAHPRA can legally travel with up to six months’ medicine supply on them.
While the CF Buyers Club provides an important access pathway enabling some people in South Africa to access life-saving CFTR modulator therapies, this pathway is not a feasible mechanism to ensure access to the CF medicines for all patients that could benefit from them.
The cost of generic CF medicines from Argentina is a fraction of the prices charged by Vertex. They are, however, still prohibitively high for most people living in South Africa. The annual cost of generic Trikafta from Argentina is almost R1 million ($60 000) [other CFTR modulator therapies (tezacaftor/ivacaftor and lumacaftor/ivacaftor) can be bought from Argentina for around R245 000 ($15 000) annually]. The medicine costs, combined with the costs of biannual travel to Argentina, are simply unaffordable for most.
How can a CL further reduce prices?
As seen with other classes of drugs, such as antiretroviral medicines for HIV, and antiviral medicines for Hepatitis C, the introduction of generic competition is expected to substantially reduce the cost of CF medicines.
If compulsory licenses are granted in the countries that they are being sought by Vertex Save Us, or if Vertex buckles under the pressure for expanded and affordable access to CF medicines and grants voluntary licenses allowing other companies to produce generics, then prices are expected to fall.
An analysis of the costs of production of CF medicines produced by health economists shows that generic Trikafta can be manufactured and sold with a 10 percent profit margin for around R93 000 ($5700) per patient per year – 2% of what is charged for the medicine by Vertex in the United States. While supplying medicines at this price would remain a stretch for South Africa’s public health sector, the introduction of new CF medicines must be considered within the context of potential cost savings arising from reduced hospitalisation periods and fewer transplants.
“The ripple effects of an effective CL campaign and petition in South Africa would be felt globally,” says McDonald. “First of all, I think we would see increased interest from generic suppliers… that could help to… drive down prices… this would [also] show the rest of the world that… accepting the unquestioned, monopoly power of Vertex is not necessary – you can put the lives of your citizens over the profits of that drug company.”
Note:The Fix the Patent Laws coalition and the TAC are mentioned in this article. Tomlinson worked at the TAC until 2012 and was a member of the Fix the Patent Laws steering committee until 2019. SECTION27 has also applied to be admitted as amici curiae to the case. Spotlight is published by SECTION27 and the TAC, but is editorially independent – an independence that the editors guard jealously. Spotlight is a member of the South African Press Council.
Bempedoic acid, a new cholesterol-lowering drug, has the potential to be an effective substitute for patients who can’t tolerate statins. Bempedoic acid is an ATP citrate lyase inhibitor that reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events. Its effects on cardiovascular outcomes were uncertain, so researchers used a double-blind, randomised, placebo-controlled trial to determine outcomes on a variety of cardiovascular measures in statins-intolerant patients.
The study, published in the New England Journal of Medicine, recruited patients aged 18–85 years at increased cardiovascular risk and unable or unwilling to take statins due to adverse effects. Patients were first tested with placebo over a 4-week run-in period, and were not randomised if they experience unacceptable adverse effects or if adherence was less than 80%. The 13 970 patients who successfully completed run-in were randomised to receive bempedoic acid 180mg orally per day or matching placebo.
The mean LDL cholesterol level at baseline was 139.0mg/dL in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2mg/dL; the observed difference in the percent reductions was 21.1 percentage points in favour of bempedoic acid.
Compared to placebo, risk of fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause after significantly were lower by 13%, after a median of 40.6 months of follow-up. The risk of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction was 15% lower with bempedoic acid than with placebo, and the risks of fatal or nonfatal myocardial infarction and coronary revascularisation were 23% lower and 19% lower, respectively.
The researchers noted that the LDL-cholesterol lowering effects were similar in magnitude and predicted reduction in cardiovascular risks to that observed with statins. In addition, bempedoic acid did not increase glycated haemoglobin levels or the incidence of new-onset diabetes, unlike statins. Due to the demonstrated benefits, those taking placebo were offered the chance to transition to taking bempedoic acid.
A trial limitation was that it only included patients with statins intolerance, and who therefore had higher LDL cholesterol levels at baseline.
