The plan to revive medicines regulation in South Africa

By Catherine Tomlinson

The South African Health Products Regulatory Authority (SAHPRA) is responsible for the regulation of medicines in South Africa to ensure that medicines marketed in the country are safe, effective and of good quality. In addition, SAHPRA is responsible for the regulation of medical devices, clinical trials and radiation-emitting devices.

SAHPRA replaced South Africa’s previous medicine regulatory authority, the Medicines Control Council (MCC), in February 2018 with the objective of creating an effective regulator that is responsive and publicly accountable and able to make timeous regulatory decisions. However, SAHPRA inherited many historical challenges that plagued the MCC, including slow regulatory decision times, an extensive backlog of pending regulatory applications, and a culture of non-transparency and resistance to public accountability. Since its formation, SAHPRA has developed a range of plans to overcome these challenges, which were outlined in its recent 2019/2020 annual performance plan.

Inherited challenges

At its establishment, SAHPRA inherited a massive backlog of around 16 000 medicine regulatory applications from the MCC. These include applications for “new registrations, variations, duplicates, clones, multiple doses and different dosage forms”.

While 50% of backlogged applications were submitted in the past five years, the backlogged applications date all the way back to 1992 and include applications for high priority public health products, including medicines for HIV, tuberculosis, cancer and diabetes.

The University of Western Cape’s Henry Leng and colleagues have highlighted the adoption of policies to promote generic access as key drivers of the accumulated backlog. In the early 2000s, South Africa adopted policies to fast-track the registration of medicines of high public health priority and to promote generic access. The adoption of these policies led to a large influx of applications for the registration of multiple generic versions of high priority products.

In general, the registration and availability of multiple generic versions of individual medicines is critical to improving medicine access, because competition between generic suppliers drives down prices and improves affordability. Research conducted by the United States’ medicines regulatory authority, the Food and Drug Administration, has shown that it generally takes the introduction of multiple generic products to bring down prices, as the first generic companies to enter the market tend to price their products close to the prices offered by originator companies.

While broad generic competition plays an important role in enabling medicine access, the introduction of policies to promote generic access in South Africa contributed to a regulatory backlog, as they were not coupled with an expansion of capacity at the regulator to process the influx of applications. At the same time, South Africa has struggled with “frivolous” regulatory filings by companies that fail to market their products after receiving registration. In a review of eight priority medicines, Leng et al. found that only 54% of registered generic medicines were actually marketed in the country following registration. Leng et al. suggested that the comparatively low cost of filing for registration in South Africa may encourage filings by companies without serious intentions to market their products, and cautioned that time and resources spent by the regulatory authority on fast-track approval of unmarketed products for which there are already existing alternatives, delays the registration of new products for which there is no equivalent in the country, or existing competition.

Inadequate capacity

SAHPRA has indicated that even without the large inherited backlog, the regulatory authority does not currently have the capacity to timeously process new applications. Evidence shows that while SAHPRA receives an average of 4 700 new applications annually, it is only able to process around 2 550 applications per year. With inadequate capacity to process backlogged and new applications, timelines for registration of medicines in South Africa are typically extremely long.

Research conducted by Keyter et al. demonstrated that the median time for approval of new chemical entities by the MCC was 1 161, 1 678, and 1 422 calendar days in 2015, 2016 and 2017, respectively. Keyter et al. further demonstrated that the median time for approval of fast track applications was 1 218, 921, and 609 calendar days in 2015, 2016 and 2017, respectively – far slower than the regulatory authority’s target for approval of fast-track applications in 250 days.

Slow regulatory decision times in South Africa have serious public health consequences, as they impede access to important and life-saving medicines, as well as cheaper generic versions of medicines, long after they are available on the global market. Recognising this challenge, SAHPRA has set a target to reduce regulatory decision times to 275 working days for new chemical entities and 180 days for registration of generic products. SAHPRA has also set a target to clear the regulatory backlog in two years.

The recently released annual performance plan outlines SAHPRA’s plans to “re-engineer” the regulatory authority to achieve its targets. Its plans include (among other interventions) the strengthening of its human resource capacity, the introduction of a new fees model and the digitisation of key processes.

SAHPRA’s strategy to address the medicine regulatory backlog

SAHPRA has set a target to clear the regulatory backlog in two years – but notes that, at current capacity with no new applications, clearing the backlog will take up to eight years. SAHPRA’s annual performance plan clarifies that the regulator has developed a costed strategy to clear the backlog and has secured ring-fenced funding for the backlog clearance strategy from the government, development partners and donors.

SAHPRA’s strategy to reduce the backlog involves three key elements, including reducing the number of backlogged applications to remove applications that are no longer relevant, prioritising the remaining applications for review according to public health needs and risk, and implementing new regulatory pathways to reduce regulatory decision times.

Given that the regulatory backlog dates back to 1992, it is expected that some applications may no longer be of commercial interest to applicants or of public health relevance. SAHPRA will seek to remove applications that are no longer relevant through requiring applicants who submitted applications in 2013 or earlier to indicate that they would still like their applications to undergo review through a survey template and requiring all applicants to update their applications to meet current requirements. SAHPRA has already begun to implement this and noted in a May 2019 communication that 3 000 applications in the backlog have already been deemed to be withdrawn. Moving forward, SAHPRA has indicated that it will prioritise the remaining backlogged applications for review according to public health risk and need. Public health need will be based on the government’s priority therapeutic areas and unmet medical need, and public health risk will be based on the complexity and type of application and “level of prior scrutiny by recognised regulators”.

In addition to reducing the number of applications and prioritising applications for review according to public health need and risk, SAHPRA has committed to implementing “new evaluation models” to clear the backlog, as well as to facilitate timeous registration of new applications. This strategy will involve the implementation of so-called reliance pathways to facilitate greater collaboration and information sharing with other regulatory authorities.

Reliance pathways provide mechanisms for collaboration across global regulatory agencies, and with the World Health Organisation, by creating pathways that allow regulators to access and use data and reports, and rely on other evaluator decisions, in domestic regulatory decision making. Reliance pathways provide important mechanisms to reduce times to regulatory decision making when capacity challenges impede timeous local decision making. Medicine regulators in both developing and developed countries struggle to manage their workloads and make timeous regulatory decisions due to increasing application volumes, and the need to monitor the compliance of foreign producers to good manufacturing practices (GMP).

Historically, South Africa’s medicine regulators (the MCC and SAHPRA) have not utilised reliance pathways – despite arrangements and collaborations in place with other regulatory bodies to facilitate their use – and selected instead to conduct full scientific reviews of quality, efficacy and safety data for all regulatory applications. However, SAHPRA has now committed to operationalising these pathways to address the backlog and reduce regulatory decision times for new applications. SAHPRA has further indicated that it will formalise processes to facilitate the use of several different reliance pathway models, including full review, abridged review, verified review, recognition and notification – each requiring different levels of local review and evaluation.

Implementation of the “abridged review” model, for example, would allow SAHPRA to rely on regulatory data and evaluations from other agencies (such as the European Medicines Agency), while requiring local review and evaluation of domestic contextual issues – such as the interaction of the medicine under review with HIV treatment.

Building SAHPRA’s human capacity

A further challenge faced at SAHPRA is its limited human resource capacity to effectively fulfil its mandate. According to information provided to Spotlight by SAHPRA’s CEO Portia Nkambule in November 2018, SAHPRA then had 178 full-time employees and around a similar number of external evaluators supporting regulatory activities. SAHPRA is seeking to significantly increase its staff capacity to around 450 full-time staff over the next five years and has already initiated a hiring drive, advertising more than 100 new posts in May 2019. SAHPRA has further indicated that staff members were recently transferred from the National Department of Health’s Pharmaceutical Trade and Product Regulation programme to SAHPRA under a section 197 transfer agreement and, according to SAHPRA’s annual performance plan, the transferred staff will support core programmes responsible for medicines evaluation and registration and authorisation management.

While SAHPRA is seeking to strengthen staff capacity in all of its programmes, the 100 recently advertised posts included 17 new posts for medicines regulation and 19 posts for the backlog clearance project. A key goal of SAHPRA is to build its internal capacity to fulfil its medicines regulatory functions, unlike the MCC which relied heavily on external evaluators. SAHPRA’s annual performance plan explains that its reliance on a “dwindling” number of external evaluators creates difficulties in managing and optimising regulatory decision times due to the lack of contractual performance agreements with external evaluators. The annual performance plan clarifies that while SAHPRA hopes to absorb some external evaluators as internal staff, it will also seek to build its internal capacity through upskilling existing staff and recruiting new staff – but notes challenges in attracting and recruiting new internal evaluators.

SAHPRA did not respond to requests for more information on the difficulties it is facing in recruiting new internal evaluators. However, recruiting challenges faced by SAHPRA may include challenges identified by regulatory authorities in other jurisdictions – such as shortages of required skills in the domestic labour market and difficulties in competing with higher salaries offered by the industry.

Opportunities and challenges for public engagement

SAHPRA has taken significant and commendable steps since its establishment in February 2018 in outlining reform plans and processes to improve its functioning to effectively fulfil its mandate. In addition to the adoption and initiation of a strategy to address the regulatory backlog and its efforts to build its staffing capacity, SAHPRA has developed plans to digitise key processes and implement a new fees model (among other interventions). These steps have been taken despite significant challenges faced by the new regulatory agency in its first year of operations, including staff protests and the closure of its offices in the Civitas building due to unsafe working conditions.

While SAHPRA should be commended for its important work to date, responsiveness to the public and accountability remains a challenge despite the regulators commitments to improving and demonstrating transparency and accountability. Health NGOs in South Africa continue to express frustration due to the non-responsiveness of the regulator following requests for information and engagement. Additionally, despite questions Spotlight sent SAHPRA for this article, no responses were received.

In December 2018, SAHPRA CEO Nkambule noted that the regulatory authority was seeking to create a culture of transparency and that in the current transitional phase it would prioritise the implementation of a formal communications strategy and systems. SAHPRA’s annual performance plan notes that a communications strategy has been drafted and has been approved to be implemented during 2019. The plan further adds that through implementing the communications strategy, SAHPRA will endeavour to (among other goals) “develop mechanisms to allow all stakeholders to communicate easily with the regulator including being able to lodge queries and complaints”.

Beyond the implementation of a communications strategy, the Minister of Health should introduce legislative reforms to require greater transparency and accountability from SAHPRA. Vawda and Gray recently undertook a review of secrecy provisions contained in section 34 of the Medicines and Related Substances Act No 101 of 1965 and concluded that section 34 “violates the right to access to information in section 32 of the Constitution of SA”. They added that section 34 “appears to grant the MCC/SAHPRA unfettered authority to refuse access to information, except on limited grounds, based on its sole discretion”. Vawda and Gray recommended the amendment of section 34 to accommodate the right to access to information and added that the regulatory reform processes underway “provides an opportunity to redress a serious anomaly in our regulatory framework, and to align it with our constitutional paradigm, in order to reflect greater openness, transparency and accountability in our public institutions”.

As SAHPRA moves forward with the development and implementation of plans to re-engineer the authority, there is significant scope for civil society to monitor developments to demand meaningful transparency and accountability from the regulator (including necessary regulatory reforms) and ensure that the development and implementation of reforms serve the public interest.

 

 

 

A healthcare system in crisis: The long road ahead

A healthcare system in crisis: The long road ahead
A Speech by Sibongile Tshabalala, TAC National Chairperson, 11 June 2019, SA AIDS Conference Opening Plenary, Durban

Greetings comrades!

I would like to take this moment to acknowledge the Deputy President, DD Mabuza; the Health Minister, Dr. Zweli Mkhize; the Premier of KwaZulu Natal, Sihle Zikalala; MECs for health; the organisers of the SA AIDS Conference; the media; delegates; and importantly, people living with HIV who managed to make it to the conference. We also acknowledge those who could not make it as a result of many factors such as the high cost of conference fees and  the need to work in order to feed their families, amongst others.

Comrades, the ninth SA AIDS Conference occurs during a critical juncture in South Africa’s history.

We meet at a time when AIDS denialism is beginning to recede in the nation’s collective psyche.

A time where South Africa has the world’s largest HIV treatment programme.

And let me pause here to acknowledge the tremendous work of former Minister of Health Dr. Aaron Motsoaledi in building the HIV treatment programme.

But we also meet at a time where corruption is rampant.

While the disgraceful details of state capture are being exposed in commissions of inquiry – much corruption in our provincial departments of health goes unreported and unprosecuted.

Comrades, we are being trampled down into the dirt by the co-epidemics of corruption and mismanagement.

These are the co-epidemics behind the Life Esidimeni tragedy, behind the disgraceful cancer crisis here in KZN, and the looting of the HIV Conditional Grant to pay Buthelezi EMS in the NorthWest.

Honourable Deputy President and Minister of Health, if you have any doubts of the scale of the crisis, I urge you to study the reports of the Office of Health Standards Compliance.

Let me focus on one symptom of these co-epidemics. Stockouts.

Comrades and friends, as some of you know, the Treatment Action Campaign turned 20 in December last year. As one of the foremost social movements in the country, we have been monitoring drug availability in health facilities for much of those two decades.

According to PEPFAR data, in 2018, around 750 thousand people were initiated on treatment but only around 400 thousand additional patients were retained by the last quarter of the year.

What happened to the other 350 thousand people?

Through our ongoing monitoring campaign, which recently focused on the Free State and Gauteng provinces, PLHIV sector members found that many facilities still undergo drug shortages, or worse, stockouts.

As part of the Stop Stockouts Project, 673 facilities were monitored by members of the PLHIV sector and other comrades within the past two months. We found that of the health care facilities monitored, 109 facilities in the two provinces had drug stockouts of Dumiva, a key antiretroviral. 106 overall did not have injectable contraceptives. When our publication Spotlight travelled to the Northern Cape, they found many facilities with no stock of basic medical supplies such as bandages, plasters and intravenous drips.

It is heartbreaking that as we stand here today in 2019, some of the same issues from a decade ago still plague us.

We cannot run away from the fact that the health system that you are inheriting, Honorable Minister, is one that is in dire need of resuscitation.

Often we have stockouts simply because our healthcare system is in such a terrible state that medicines pile up in depots while clinic shelves are empty.

When the problem is with the supplier, it takes months for the news to filter through to clinics and for the department to provide advice on alternatives – as has just been the case.

Honourable Minister, patients are being turned away. Patients are being told to go pay R900 for Dumiva at private clinics.

Stockouts is one thing. But there are also long queues, often demoralized healthcare workers, a lack of confidentiality. These are all symptoms of the mediocrity and dysfunction in our healthcare system.

We do not accept this.

We do not accept that the price we have to pay for accessing healthcare services is to give up our dignity.

So what do we ask?

We as the Treatment Action Campaign, the PLHIV sector and public health care users call for the urgent prioritization of health care through an access to healthcare ‘bailout’ starting with the  during the October budget review.  In real terms our health budgets have been falling while the need for healthcare services has grown. In simple terms, we need money so that we can employ more healthcare workers.

We urge government to root out corruption in our provincial healthcare systems and to ensure only appropriately qualified persons are appointed in these departments. We will hold you responsible if the co-epidemics of corruption and mismanagement are not dealt with.

We urge the new national and provincial administrations to prioritise the welcome back campaign, in order to trace people who are missing and link them back to care and treatment.

Our HIV response is already beginning to unravel.

In order to get it back on track, we have to transform our healthcare system into a place that affirms human dignity rather that degrades it.

Comrades, Deputy President, Minister, Premier, MECs, we are not anti-government.

But please understand that we are a membership-based organizations andour responsibility is to our members and to the poor.

We are guided by this responsibility and by the Constitution of South Africa and the right to access healthcare and the right to dignity.

We will work with government in instances where it is in the best interest of our members and of the poor to do so.

But we will also hold you accountable to the highest standards.

Our lives, our dignity, is not negotiable.

Amandla!

I thank you!

Why SA’s medicines regulator should consider affordability

By Tendai Mafuma and Nomatter Ndebele

Before any medicine can be sold in South Africa, it has to be approved by the South African Health Products Regulatory Authority (SAHPRA), who certify that the medicine is safe, of good quality and is effective. Unless the medicine has gone through these processes, it cannot be on the shelves for sale. In exceptional circumstances, SAHPRA may permit access to unregistered medicines. This exception is permitted by section 21 of the Medicines and Related Substances Act, 101 of 1965 through a process that is commonly referred to as “a section 21 application”.

Section 21 applications are typically used to access an unregistered medicine in circumstances where there is no version of that medicine that has been registered in South Africa. An example of this could be where registration of the medicine is pending but there is a need to urgently access that medicine in order to save lives. This was the case during the height of the HIV/AIDS pandemic, when organisations such as the Treatment Action Campaign used section 21 applications to get access to fluconazole for the treatment of HIV-related opportunistic infections. This provision may also often be relied on where a patient has sufficiently justified why they cannot use the registered product, for example if a patient can show that the unregistered alternative is not only superior in terms of safety and quality standards but will also have superior therapeutic effect on their health.

One of the questions that comes up regularly is whether the fact that a registered medicine is excessively priced is sufficient justification for seeking section 21 access to an unregistered alternative. Over the past decade, individual patients have sought access to unregistered medicines on the basis that the alternatives registered in South Africa are excessively priced, and therefore inaccessible. SAHPRA has routinely declined authorisation of the applications on the basis that cost is not a factor to be considered. Put simply, according to SAHPRA, if there is a registered medicine in South Africa, that would be effective for the diagnosed condition, you cannot request access to an unregistered alternative solely on the basis that you cannot afford the registered medicine. This means that if patients cannot somehow find money for the registered treatment, they will not access any treatment.

People with chronic health conditions such as cancer are particularly affected by this. We use cancer as an example because due to the astronomical costs of cancer medicines, very few patients are able to gather the money required for new cancer medicines.

Take for instance Hayley Stols who was diagnosed with stage 4 malignant metastatic myeloma. Her oncologist recommended treatment with Opdivo, a drug that was not registered in South Africa. At the time, there was a registered drug, Pembrolizumab which would have cost R1,8 million per year. Opdivo, on the other hand, would have cost R770 000 per year if purchased from the Netherlands. Whichever option Hayley chose, it would have had to be self-funded as neither medicine was covered by her medical aid scheme. It is difficult to imagine anyone in South Africa who has R1,8 million per year for one course of treatment. R770 000 is still a lot of money, but it is significantly less than R1,8 million.

Hayley made two section 21 applications to SAHPRA to request permission to access Opdivo. In both applications, she clearly stated that the reason for this request was that Opdivo was more affordable. Both applications were rejected.

There are a few exceptional cases where SAHPRA has approved section 21 applications on the basis of cost, for example applications by MSF for access to the TB medicine linezolid, but the fact is most of these applications are rejected. Patient advocacy groups have been trying to engage SAHPRA on this issue with little success.

In the past, SAHPRA has argued that the law does not empower it to make decisions based on cost and that its only mandate is to consider the “safety, quality, and therapeutic efficacy” of medications. This, in our view cannot be the only consideration.

Firstly, the Constitution doesn’t only guarantee the right to access to health care services, it also requires the State to take reasonable measures, within available resources, to achieve progressive realisation of the right. It also places an obligation on organs of state such as SAHPRA, to respect, protect, promote and fulfil fundamental rights. Moreover, the Constitution states that legislation must be given an interpretation that promotes the spirit, purport and objects of the Bill of Rights. This means that laws must be interpreted in a manner that will allow the enjoyment of rights to the fullest possible extent. As an organ of state responsible for ensuring that consumers have access to safe, quality and effective medicines, SAHPRA’s interpretation of the law should not be one that effectively hinders access to healthcare.

It also means that SAHPRA must develop and implement policies that do not undermine access to medicines. At the most basic level, access to medicines refers to the ability of all persons to receive the medicines necessary for the treatment of any condition affecting them. It entails physical, informational and economic access (i.e. affordability). This interpretation of access to medicines has been laid out by the courts. If SAHPRA does not concern itself with practical concerns about whether patients can afford medicines, that is tantamount to a failure of its duty to respect, protect, promote and fulfil the constitutional right to have access to medicines.

Considering affordability does not mean that SAHPRA must turn a blind eye to considerations of safety, quality and efficacy. Neither will it open the flood gates of section 21 applications as patients seek access to unregistered medicines even where the price difference is marginal. Rather, it requires an acknowledgement that there can be no access if the medicines are priced excessively and beyond the means of those who need them.

SAHPRA recently published a guideline aimed at ensuring that section 21 applications are received, processed effectively and consistently, and decided timeously. Despite SAHPRA already having dealt with several section 21 applications based solely on cost, the guideline makes no mention of how the entity intends to resolve such applications. Given the constitutional obligations, we think that it is about time SAHPRA begins to concern itself with matters of affordability of medicines. Failing to do so would be a failure to ensure access to medicines and a violation of the right to access health care services.

ARV stockouts putting lives at risk, says SSP

By Anso Thom and Marcus Low

LATEST NEWS! Updated circular on Lamivudine can be seen here

Stockouts of several critical medicines have been reported at healthcare facilities in five provinces, according to a statement from the Stop Stockouts Project (SSP). This includes stockouts of the antiretroviral (ARV) combination of Abacavir and Lamivudine and of various oral and injectable contraceptives. The Abacavir and Lamivudine combination is prescribed in the public sector to tens of thousands of patients who have become resistant to first line ARVs.

Following up on initial reports from users of the public healthcare system, Treatment Action Campaign (TAC) members are currently visiting healthcare facilities in the Free State and Gauteng to assess the situation. They are reporting stockouts of ARVs, paracetamol, flu medication, contraceptives, some antibiotics and HIV test kits. The TAC, together with various other civil society organisations, is a member of the SSP.

National Department of Health Director-General Precious Matsoso said they had sent technical teams to work with the TAC in an effort to identify affected facilities and patients. She said a circular was being prepared and will be sent to doctors with guidance on how to switch patients to alternative drugs.

The SSP says that several stockouts have been unresolved since the second half of 2018 and “the situation has now escalated into a crisis”.

They warned that scores of lives are at risk.

SSP’s Kopano Klaas said they had received stockout reports of second-line ARVs from the Free State, Gauteng, Mpumalanga, Limpopo and KwaZulu-Natal.

A list of stockouts supplied by the Treatment Action Campaign in the Free State reveals that since March there has been stockouts of the Abacavir/Lamivudine combination in at least 15 health facilities.

In the Mangaung Metro district it includes Mafane, Thaba-Nchu, Freedom Square, Bloemspruit and Gabriel Dichabe.

In the Lejweleputswa district the TAC reported stockouts at Rheederspark, Bophelong, Tshepong, Welkom, Leratong, Phomolong, Boithusong and Welkom.

In the Thabo Mofutsanyane districts stockouts were reported at Intabzwe and Qholaqhwe. The stockouts at Qholaghwe were understood to be mainly due to a break-in at the clinic.

Information from a TAC visit to Gabriel Dichabe Clinic in Bloemfontein suggests that there has been a breakdown between the provincial depot, the pharmacy, the clinic and patients. In cases where the clinic does not have stock, patients are given scripts so that they can purchase medicines at private pharmacies. The Medicines Price Registry lists a price of R921 for a month’s supply of the Abacavir and Lamivudine combination – likely out of reach for most public sector patients.

SSP also said that there had been repeated stockouts of injectables and oral contraceptives. Klaas said according to their information only one company was contracted to supply the oral contraceptive and because they were given very short notice they have been unable to keep up with the demand. Klaas also claimed that alternative companies were not interested in supplying the contraceptives as they were paid late or not at all.

The only alternative, an implantable device, is ineffective in women on ARV regimens containing Efavirenz, contained in most first line combinations provided in the public healthcare system.

“The SSP reports in to District, Provincial and National Departments of Health staff on a daily basis, but they seem to know as much or as little as we do. Surely someone needs to account to the scores of patients, who are travelling long distances to collect their medication, having to take a day off work to do so, only to be turned away when they get there?” Klaas said.

Deputy Director General in the NDOH Dr Anban Pillay said that there was a shortage of  Lamivudine globally and that the pharmaceutical company Mylan was unable to supply full order quantities.

He said they had secured a section 21 approval so that they can get stock from another source. Pillay advised facilities to manage the shortage by providing lesser quantities than usual for each patient.

On the contraceptives, Pillay said there should be no stockout but a shortage of the injectable nuristerate. “This is due to the only supplier Bayer being unable to produce sufficient quantities relative to demand. SA is one of a few countries using nuristerate,” he said.

Note: Spotlight is published by SECTION27 and the TAC – both of which are members of the SSP. Spotlight is editorially independent and a member of the Press Council.

Regulatory barriers to life-saving and affordable HCV medicines can be overcome

Hepatitis C (HCV) is a viral infection of the liver that is transmitted through blood. HCV can be spread through blood transfusions, organ donations, needle stick injuries, injecting drug use and other blood exposures. The vast majority of people with untreated HCV will develop chronic hepatitis C infection, which can lead to serious and life-threatening liver conditions including liver damage, cirrhosis and cancer. The prevalence of HCV in South Africa is unknown due to inadequate screening. While prevalence in the overall population is believed to be low (under 1%), screening initiatives have indicated higher prevalence in certain populations. For example, a recent screening initiative in Cape Town showed an HCV prevalence of 3.4% in HIV-positive men and 5.6% in HIV-positive men who have sex with men. This was confirmed in another study. In addition, a viraemic prevalence of 50% has been demonstrated in people who inject drugs (PWID).

Until relatively recently, the gold standard of HCV treatment globally consisted of the medicines pegylated interferon and ribavirin. This regimen required patients to withstand lengthy treatment with difficult side effects and inadequate cure rates. The introduction of a new generation of direct-acting antivirals (DAAs) from 2013 onwards has been heralded as a “game-changer” for HCV. The new drugs which can be taken orally, have significantly shorter treatment lengths (generally 12 weeks), fewer side effects and cure rates of over 95%.

While new generation DAAs provide significant and game-changing benefits to patients, the high costs charged for patented DAAs has been a considerable barrier to their use and scale-up globally. However, patents should not be a barrier to use in South Africa, where voluntary licenses allow for generic versions of key DAAs to be marketed. Bilateral licenses between the pharmaceutical company Gilead and generic companies allow for the use of generic sofosbuvir on its own and in combination with ledipasvir or velpatasvir. Medicine Patent Pool (MPP) licenses also allow for use of generic daclatasvir and glecaprevir/pibrentasvir. (All of these are considered important DAAs for the treatment of HCV – which typically requires two or more DAAs).

Yet, despite the fact that there are licenses in place allowing for generic sale and use in the country, no generic versions of these new generation DAAs have so far been registered in South Africa. The lack of registered products has required patients and doctors to use alternative pathways to access these life-saving treatments in the country.

Groote Schuur hepatologists Professor Mark Sonderup and Professor Wendy Spearman have previously described the difficult journey faced by one of their patients in accessing affordable DAAs in South Africa. The patient described as a businessman in the import and export business learnt about the life-saving benefits of HCV DAAs sofosbuvir and daclatasvir and started exploring options to import the unregistered medicines in South Africa. However, he soon learnt that the pharmaceutical companies holding patents on sofosbuvir and daclatasvir were charging astronomical prices for the drugs. Unable to afford the cost of patented drugs, the South African businessman flew to China and bought sofosbuvir and daclatasvir’s active pharmaceutical ingredients, which he dispersed into empty capsules for his personal use. He later contacted Sonderup and Spearman to inform them of what he had done in the hope that it could help other patients. Sonderup and his colleagues advised the patient that they could not engage in any activities that contravened South Africa’s laws to bring unregistered products into the country and highlighted the potential dangers of developing one’s own drugs from active pharmaceutical ingredients, including the inability of the patient to ensure that what he bought was not mixed with toxic chemicals, or that it was properly formulated to ensure that it is safe and effective.

On testing the patient, Sonderup and Spearman found that while the patient’s attempt at self-treatment initially lowered his HCV viral load, it did not cure his disease. Together the clinicians and patient explored ways to legally import quality approved sofosbuvir and daclatasvir into the country. Their efforts opened up an important pathway for people living in South Africa to access new, life-saving HCV drugs. The clinicians found that while patented medicines remained unaffordable to the vast majority of people living in the country, generic HCV medicines had started entering the global market at substantially reduced prices – due to a combination of strategies to overcome patent barriers in the global South, including patent oppositions and challenges, voluntary and compulsory licensing.

Using Section 21 authorisations granted by the South African Health Products Regulatory Authority (SAHPRA), Sonderup and his colleagues began legally importing unregistered generic DAAs to South Africa for HCV treatment in patients. Section 21 authorisations refers to section 21 of South Africa’s Medicines Act, a section that contains provisions that provide for the importation of medicines that are not registered in South Africa. To date, more than 200 patients have been treated with DAAs imported with Section 21 authorisations.

Generic products that have been imported into the country using this regulatory pathway include generic sofosbuvir, sofosbuvir/ledipasvir, sofosbuvir/velpatasvir and daclatasvir. However, the pending registrations of Gilead’s patented sofosbuvir, sofosbuvir/ledipasvir and sofosbuvir/velpatasvir threatens to extinguish this important access pathway for sofosbuvir and sofosbuvir combination products. This is because Section 21 importation is often not allowed once there is a registered product on the market in South Africa, even if the product is unaffordable.

Something similar to this recently happened in South Africa following the registration of the patented cancer medicine lenalidomide, which is used to treat multiple myeloma. Prior to the 2016 registration of the pharmaceutical company Celgene’s patented lenalidomide in South Africa, multiple myeloma patients were able to access generic lenalidomide from India at around R4,000 per month (including importation costs) through Section 21 authorisations. After the registration of the patented product these authorisations were refused, leaving patients to pay over R70,000 per month for the same treatment they previously imported for a fraction of the price. With pro-bono legal support, the Cancer Alliance has been able to assist previously treated patients in challenging the refusal of their Section 21 re-authorisations to access further generic lenalidomide treatment. However no new patients have been authorised, so all new patients must now pay the exorbitant prices for the registered patented product – or forgo this treatment.

Similarly to the lenalidomide case, the pending local registration of patented sofosbuvir products threatens to end Section 21 authorisation for use of generic sofosbuvir products in the country. The exorbitant prices likely to be charged by patent holders will block treatment access for most new patients that could benefit from this treatment. Yet, unlike for lenalidomide, there are voluntary licenses in place that allow for the sale and use of generic sofosbuvir products in South Africa as soon as they receive registration by SAHPRA. Unfortunately, experience shows that SAHPRA registrations are often extremely slow – and regulatory delays could thus interrupt access to generic sofosbuvir products in the country for years after the registration of patented products.

SAHPRA has however committed to clearing the backlog of applications that contributes to regulatory delays. In order to do this, the regulatory body will need to employ new strategies to speed up medicine regulation including through use of so-called “reliance pathways” that allow for SAHPRA to better utilise and rely on resources and decision making of other stringent regulatory authorities (such as the US Food and Drug Administration and European Medicines Agency) and the World Health Organization (WHO) in informing domestic decisions.

One of these reliance pathways is the WHO’s collaborative procedures for accelerated registration of medicines that have undergone regulatory review and received prequalification by the WHO. Through the collaborative procedures national medicine regulatory authorities can access regulatory evaluations and related information for medicines that have been prequalified as safe and effective by the WHO. Countries that use this process must commit to reaching national decisions within 90 days of receiving regulatory data from the WHO. This procedure has already been used to register generic sofosbuvir in Botswana, Zambia, Malawi, Zimbabwe, Ukraine and Thailand.

While South Africa has agreed to participate with the WHO’s collaborative procedures for accelerated medicine registration, to date it has not used these procedures to register a single medicine locally. Sofosbuvir offers an important ‘test case’ that South Africa can use to test these procedures as a reliance mechanism to speed up domestic registration of medicines – while simultaneously securing access to life-saving generic sofosbuvir.

Health advocates and the Department of Health should encourage generic companies whose sofosbuvir products have WHO prequalification (Mylan, Hetero and Cipla) to file for domestic registration as soon as Gilead’s sofosbuvir is registered and call on SAHPRA to use WHO collaborative procedures to accelerate rapid domestic registration. This procedure can also be used to secure access to generic sofosbuvir/velpatasvir and sofosbuvir/ledipasvir as soon as generic products under review by the WHO receive prequalification.

In addition to using WHO registration pathways, SAHPRA must develop new pathways for registering generic products when originator products are not yet registered in the country. Originator products may not be registered due to a lack of interest of originator companies in registering and marketing their products in South Africa – or delays by SAHPRA in registering originator applications.

Generic companies that have filed for registration of generic products that do not have a domestically registered originator have previously been told by SAHPRA that they need to provide their own clinical data. SAHPRA’s requirement for generic companies to submit their own clinical data effectively blocks generic companies from entering the market – as it is generally not financially feasible or ethically possible for generic companies to repeat clinical trials for their products. When originator products are registered, generic producers are able to rely on originator’s clinical trial data and must simply demonstrate bioequivalence with the originator product for registration – meaning that the two products are the same for all intents and purposes.

Previous experiences with SAHPRA have disincentivised generic producers of HCV DAAs from seeking registration in the country when originator products are not registered. To overcome this challenge, SAHPRA must create regulatory pathways for generic companies to enter the market when originator products are unregistered. Again, SAHPRA could utilise “reliance pathways” to access unredacted regulatory data and assessments from other stringent regulatory authorities with which it is aligned and has confidentiality agreements that have already registered relevant originators. Registration of generic daclatasvir could provide an important test case for use of this reliance pathway – despite licenses in place allowing for generic daclatasvir sale in South Africa since 2015, the originator producer Bristol-Myers Squibb has not filed for registration or indicated that it will seek domestic registration in South Africa.

While Section 21 authorisations currently provide an important access pathway to generic daclatasvir and sofosbuvir products in South Africa, the cumbersome nature of these procedures prevents broad access for all patients that could benefit from these medicines. However, despite their limitations, Section 21 procedures (which are currently under review) remain vital to securing access to unregistered products and should be expanded to explicitly allow for importation of unregistered generic products when the costs of registered originator products are prohibitive. There is precedent for this reform, as SAHPRA (when under the banner of the MCC) has previously authorised the importation of unregistered generic fluconazole and linezolid, used to treat HIV and TB respectively, on affordability grounds when patented products registered in the country were unaffordable. Section 21 approvals may also be used to allow for bulk importation of stock on other public health grounds, such as to address shortages of registered products.

As South Africa moves to adopt a viral hepatitis treatment policy, the registration of generic versions of key medicines (including sofosbuvir, sofosbuvir combination products and daclatasvir) will be critical to enabling an effective HCV response in the country. Regulatory barriers and delays have prevented the registration of affordable generic versions of key HCV medicines to date – and important access pathways secured through Section 21 authorisations are under threat. Through employing new reliance pathways, SAHPRA can begin to register key generic products. Health advocates and the Department of Health have an important role to play in highlighting the need for and encouraging SAHPRA to urgently use these pathways.

 

 

Donor shift threatens adherence clubs in the Free State

Mosamaria’s Connie Motsoeng addressing an adherence club at Pelonomi Hospital in Bloemfontein Photo by Khothatso Mokone

A shift in donor funding for HIV has endangered the continued existence of successful and effective antiretroviral adherence clubs in the Free State.

The Mosamaria project, an NGO-run adherence club project based in Mangaung, has in the last five years reached 25 000 people through 21 health facilities and achieved a 98% patient retention rate. The clubs operated on a R4 million a year budget, which translates into about R161 per patient, per year.

These gains are in danger of being reversed as donor support from the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) shifts to other programmes.

Right to Care (a large national NGO), which for five years has been a primary recipient of money from the GFATM, has been distributing funds to Mosamaria. The GFATM distributes funds to a series of so-called primary recipients in South Africa, who then distribute it to specific projects.  Right to Care is no longer a principal recipient of GFATM funds and none of the new primary recipients will be stepping in to fund the Mosamaria Project. The key reason for this appears to be that South Africa’s country coordination mechanism (CCM – a committee that submits funding applications on behalf of the country) decided last year that no further application to the GFATM to support community adherence clubs would be undertaken. The CCM is administered by the South African National AIDS Council (SANAC).

Mosamaria’s funding for adherence clubs came to an end on 30 March 2019.

As a result, the Mosamaria project is in the process of being shifted to the Free State health department, a risky move in a province with a poor track record when it comes to health and more especially HIV.

That adherence clubs are part of the solution to South Africa’s HIV epidemic is now widely accepted. The clubs have been a model of successful HIV management since they were first piloted by MSF (Medicins Sans Frontieres) in Khayalitsha in the Western Cape in 2007. By filtering stable HIV positive patients into the clubs it helped patients receive their medicines on a fixed schedule and helped them save time by avoiding regular long hospital or clinic queues. Peer support is also a key part of adherence clubs.

As a result of successful pilot projects, adherence clubs as a model was adopted, along with CCMDD (Centralised Chronic Medicine Dispensing and Distribution) and Fast Lane dispensary services as part of the National Department of Health’s ARV adherence policy.

What clients say

Patients’ adherence club logbooks Photo by Khothatso Mokone

Bloemfontein local Margaret Baratang is one of the Mosamaria patients at Pelonomi Hospital in Bloemfontein. On the morning of her last club meeting with the Mosamaria team, Baratang was angry and deeply anxious.

“These people [Mosamaria facilitators] treat us nicely. I’ve been coming to the club for three years. Every time I’m here 30 minutes then I can go. Now if we must go back to the hospital queue and we will have to wait for two or three hours, I’m telling you,” she says.

She talks as she shuffles up the rows of seats. The queue moves fast. In her hand is her club booklet. It’s covered in decorative wrapping paper. Most of the patients have done the same – they are a support group after all. The foil wraps, the prints of flowers and butterflies represent their care and respect for a club model that’s come to represent service and significance in their lives.

Others in the queue with Baratang include a man who works as a driver. He’s juggling car keys and says he is irritated. His HIV status is his private business and the club model respected this he says, by allowing him to arrive every second month, have a basic medical screening, receive his medicines and still arrive at work on time. Now he will have to explain to his employer and colleagues why he has to take a whole morning off every second month to be at the hospital.

Another patient, Boitumelo Mokeane, launched a petition to the Free State MEC for Health. In representing “concerned people living with HIV”, she said in her petition that patients deserve access to quality healthcare. She raised fears that the Mosamaria facilitators’ expertise would be lost and that CHWs would not be able to cope. Over time Mokeane also said people would default because collecting medicines would become too much of a hassle.

“We don’t want the situation where we have to start from scratch in adjusting with new people and new systems,” she says.

Mosamaria workers host one of their final adherence club meetings. Photo by Khothatso Mokone.

CHWs assigned to take over

With the absorption of the project into the Free State Department of Health, community healthcare workers (CHWs) have been assigned to take over the running of the clubs. Mosamaria facilitators spent the last few weeks while they were still employed, training the CHWs. It was a scramble against time as the Free State’s Chief Director of district health service and health programmes only sent out an internal memo on 6 February. It was a memo to the three affected districts of Fezile Dabi, Mangaung Metro and Xhariep to identify two CHWs per facility to be trained to run adherence clubs. It was also only in February that the Department met with NGOs for a “transitioning meeting”. This was less than two months before Mosamaria was scheduled to wrap up its operations.

Thapelo Mabule, Mosamaria’s outgoing programme manager for the adherence clubs, says often CHWs didn’t show up for training sessions in those weeks.

“CHWs are being paid a stipend by the department of health, not salaries so maybe they don’t care enough to come for training. The clubs as we know them will collapse the minute we hand them over,” he says.

His seems a realistic assessment, because without the structure, that includes salaried facilitators trained in record keeping, monitoring and evaluation and managing patient loads and communicating with the pharmacy for filling pre-packing scripts, the club model has a slim chance of succeeding.

Free State Department of Health spokesperson Mondli Mvambi however, is confident there will be few disruptions. He says: “The transitioning of Mosamaria will not negatively influence the patients as the clubs will continue using the principles outlined in the National Adherence Guideline Standard Operating Procedure. When the project was started the Free State Department of Health was aware that funding was only for a limited period of time, hence the province has worked on a transitioning plan for when funding comes to an end.”

He adds that in addition to the two CHWs assigned to each club, each facility will have a nurse and an operational manager for continued implementation of the clubs and other differentiated care interventions.

“Patients trusted us”

Mosamaria’s Connie Motsoeng Photo by Khothatso Mokone

For Connie Motsoeng, a Mosamaria club facilitator, walking away is tough. She says: “We are losing something that we love. Patients trusted us and now we worry that they will suffer without properly run clubs.”

She’s also worried because she has a baby on the way – her second child. She’s one of 39 facilitators and administrators who are now jobless as their posts were funded through Right to Care funding.

According to Mabule, communication with Right to Care has been minimal. Mosamaria were notified that their funding would be discontinued in mid-October last year and they had a close-out meeting with Right to Care in Johannesburg, but not much else has been communicated.

According to Right to Care discussions with Mosamaria were initiated in October 2018 to indicate that the funding will come to an end in March 2019. “Representation to the CCM were undertaken to indicate that adherence clubs will require continued support.  The Department of Health indicated that transition plans would be made,” Right to Care said in response to questions from Spotlight. Going forward, Right to Care will provide adherence club services in Ehlanzeni and Thabo Mofutsanyane districts in the Free State with support from the United States government.

By the beginning of December Mosamaria fired off hopeful funding proposals to new Global Fund South African principal recipients and also notified the provincial department of health of the situation.

Trudie Harrison, a Mosamaria co-ordinator, says one local principal recipient didn’t respond, another told them to wait till February to submit proposals. A month after that they were told HIV adherence clubs would not be funded.

“Five months is not enough time to close out a project like this. We did assume that one of the other local principal recipients would continue funding the clubs because they have proven to work so well.

“We are a small organisation but instead of being in the field, we end up spending more time writing proposals, stuck in meetings and following up with would-be funders,” says Harrison.

She adds: “International donors do not consult sufficiently, if at all, with the people who are actually implementing programmes in communities. We just get told by principal recipients ‘the Global Fund has decided …’ without any reasons why this has happened.

Government’s responsibility

Lynne Wilkinson, a differentiated service delivery consultant with the International AIDS Society, says closing out plans need to be properly and effectively managed so there is seamless transfer and patients are not put at risk or under any anxiety over the future of their care.

Wilkinson, who was involved with MSF’s first clubs launched in the Western Cape (that now are run by the Western Cape Department of Health), says it remains government’s responsibility to ensure that adherence club models are not compromised, even as outside funders’ priorities shift.

“The national adherence policy guidelines are in place to ensure that stable patients can access their medication as easily as possible throughout the cycle of lifelong treatment,” Wilkinson says.

She adds too that it’s adherence clubs that have over time proven to be the cheapest most effective model of keeping patients on treatment. She says: “The government’s target is to get another two million people on ARV treatment by 2020, it means we need to use every resource we have. So when an organisation like Mosamaria has successfully built up clubs that have proven to be successful and cost effective, they should be supported and funded, not allowed to fall away.”

South African National Aids Council (SANAC) CEO Dr Sandile Buthelezi drives home the point that donor funding is finite. He says: “Principal recipients [like Right to Care] are aware that their funding is for three years. It is therefore imperative that sustainability plans and transition plans are part and parcel of the application, and the Oversight Committee of the Country Co-ordinating Mechanism ensures that these plans are followed and implemented. In addition, the main reason for the Department of Health to always be part of principal recipients is to ensure that this transition takes place.”

He says SANAC, through its Resource Mobilisation Committee, will canvas for more domestic and donor funding to ensure that ARV adherence is implemented and that South Africa continues to wean itself off foreign donor funding.

Stockout of Depo-Testosterone is life threatening

A months’-long national shortage of an affordable masculinising hormone has not just adversely affected the health of a number of transgender men but has revealed worrying levels of disregard for the general well-being of a sector of the population already carrying an unusually heavy load of discrimination, stigma and even violence. KARIN SCHIMKE reports.

Depo-Testosterone, an affordable injectable hormone used by cisgender men with testosterone deficiencies, transgender men undergoing gender affirming treatment and non-binary people, has been out of stock in South Africa for more than three months. The shortage has been described as life-threatening.

“When we say life-threatening, we are referring to the fact that suicidality among transgender people is extremely high,” says psychologist and transgender man Elliott Kotze. “Gender dysphoria is extremely unsettling to live with and hormones are the key to translating your body so that others can read it the way it really is. We’re pretty frantic and desperate. This is an emergency for us, but no one except we seem to see it that way.”

GenderDynamiX health advocacy officer Linda Zakiyya Chamane explains that because the medication is chronic, physical manifestations of ceasing to take it are immediately felt, and all these pose not only serious physical health risks, but also have an impact on the mental health.

Lwazi Mbokazi, from KwaZulu-Natal, says he recently phoned his pharmacy to get an update on a restock of T, as the hormone is generally called. “They couldn’t give me date because they are having issues with their supplier. The mentioned middle of March. Nobody has given us a valid reason behind the supplier complications and, we weren’t forewarned in the first place, which is unethical.”

Mbokazi, like many of the trans men Spotlight spoke to, has helplessly had to watch his health decline.

“I’ve been off testosterone for nearly two months now and I have been experiencing severe depressive episodes that make it difficult for me to perform simple task, because of the fatigue and moodiness caused by low T levels. I haven’t been able to sleep much, and I wake up with anxiety every morning, because my hormones are all over the place. But I am relieved that my menses haven’t returned.”

It became clear to users of the injectable Depo-testosterone by February that it was difficult to have their prescriptions filled, though some report that their difficulties began in November last year.

Communication from the suppliers, Pfizer, around the reasons for the stock-out has been terse. It has emerged that a letter was sent by a junior brand manager at Pfizer Laboratories to health care professionals on 3 December 2018, stating that “we continue to experience an out-of-stock situation of Depo-Testosterone 100mg INJ 10ml […] We wish to assure to assure you that every effort is being made to resolve this situation as quickly as possible. We apologise for the inconvenience that this situation may cause you, your customers and/or patients.”

It appears that this message didn’t filter through until the stock-out became evident to users early in February, at which point Pfizer said in a short statement that stocks would be replenished by the end of that month. Two weeks later, as trans men around the country scrabbled around desperately trying to find stock, Pfizer released another short statement, saying that the interruption was out of their control.

Charmaine Motloung, the communications and media manager, said in a statement: “Pfizer recognizes the importance of the consistent availability of Depo-Testosterone … and actively worked with the Regulatory Authority to minimize the impact of the shortage on our customers and patients.”

Portia Nkambule, acting chief executive officer of the South African Health Products Regulatory Authority (SAHPRA), responded to a media query about whether the stock-out was the result of a hold-up in the issuing of permits, saying that “the issuing of permit by SAHPRA was sub-optimal between November 2018 and January 2019. This was partly caused by the migration of SAHPRA office to new premises.”

SAHPRA has recently undergone restructuring. It used to be known as the Medicines Control Council.

She said the internal matter of permit issuing had been resolved in February.

Transgender activist, author and general practitioner Dr Anastacia Tomson said not having the permits issued might be valid as an excuse for a period of time but bringing drugs into a country was an operation that had hold-ups all along the way, from lead times, to shipping, to customs to import duties.

“Drug companies know that they can expect delays along the way and there are usually reserves and surplus. You don’t start ordering a widely used drug when the last stock runs out. This problem must have been coming for a while and one cannot help but think that poor planning is an issue here.”

Depo-Testosterone is used by transgender men as a chronic medication, but it is also used by cisgender men with testosterone deficiencies. Demand for hormones is growing exponentially as more and more trans people come out. Canada and France recently experience hormone stock-outs, and Italy is currently also experiencing one. Last year, the feminizing hormone Premarin was unavailable to trans women in South Africa for several months.

“The amounts world-wide don’t seem adequate, especially if you consider how many people who need it don’t even have access to the hormones for a variety of reasons,” says Dr Tomson.

The stock-out, which has caused enormous distress, was widely discussed on social media, with users asking for tips on who might still have stock. Cisgender men who had extra vials of the hormone were offering their supplies to desperate transgender men.

Some people, like Germaine Gabriel de Larch, decided to try black-market hormones, because the only other masculinising hormone available, Nebido, is expensive in comparison to Depo-Testosterone.

“I had to go on to a black-market testosterone as it is the only one I can afford. I have been experiencing exhaustion, nausea, severe light-headedness and dissociation. These symptoms became too unbearable after just two shots and I stopped taking that testosterone a week ago,” they said.

“I’m feeling desperate in medical terms as I struggle with mental health issues. Keeping my body hormonally balanced is essential for my mental health. I also worry about the physical effects of low testosterone, which include exhaustion, insomnia and reduced bone mass. Then there are the symptoms which worry me in terms of my gender dysphoria: loss of muscle mass, redistribution of fat to hips and thighs, and the worst, the return of my period, all things that make me extremely uncomfortable and affect my mental health.

“Once you’ve experienced the relief of the masculinising effects of testosterone and the relief and sense of confidence that that brings, the thought of the loss of these effects is terrifying. Emotionally, I’m feeling despondent, overwhelmed and anxious.”

The stock-out, with its own particular set of frustrations about the lack of communication and the fall-out for individual physical and mental health, has thrown a stark light on much larger issues facing — by some estimations — around one in 200 of our fellow citizens.

De Larch says. “I’m feeling despondent, anxious and let-down by a system that is supposed to provide us with the human right of access to healthcare. The lack of response to this healthcare crisis points to a lack of concern and a lack of awareness of the magnitude of this issue for the trans, non-binary and intersex community.

“What needs to change is the medical and healthcare sectors being more serious about providing healthcare to these minority communities, and being more understanding of how this stockout and the larger apathy towards the concerns of the trans community needs to be analysed in order to cater to the health issues of trans people.

“This lack of understanding and apathy is based on the misapprehension that trans healthcare is elective, rather than a chronic healthcare condition.”

Mbokazi says: “The way the relevant parties have failed to immediately act to resolve the issues around the stock-out has made me realise that trans healthcare isn’t taken seriously in this country. Or anywhere else for that matter. I don’t know if it’s because of underlying transphobia, but the healthcare system doesn’t have any preventative policies or measures in place that could compensate trans people during emergencies like this.”

System-wide neglect of the transgender population

The recent stock-out of a hormone used in gender-affirming treatment for transgender men following soon on the heels of a stock-out last year of the primary hormone used by transgender woman, has revealed a system-wide neglect of a large sector of the South African population. KARIN SCHIMKE reports.

Transgender men, who require testosterone as a chronic medication for gender-affirming treatment, were caught unawares by a stock-out of Depo-Testosterone earlier this year. No one seemed to know, or be prepared to fully communicate, the reasons for the stock-out, when the problem would be resolved properly, and whether it would reoccur.

The shortage of the hormone is described as life-threatening. The transgender population has a high incidence of suicide and the changes wrought by the sudden cessation of treatment has dire effects, not just on the men’s transitioning bodies and their endocrine systems, but on their mental health.

Seth Deacon, a transgender man, said that, as is often the case, the transgender community had been left to seek their own solutions to their unique problems. Information and support are shared on social media.

Psychologist Elliott Kotze, a transgender man, said that some of the problems in the healthcare system, both private and public, was that gender affirming treatment and surgeries were classified elective and cosmetic treatments, rather than life-saving care.

Deacon said transitioning was difficult and financially taxing in numerous ways.

“I grew up in the public health system. I’m lucky enough now to have a good job and private medical aid. But even people like me don’t get the level of care they need, because medical aids don’t pay. Transgender people come from all walks of life and being able to access to healthcare should not be reserved for the privileged few.”

There are currently only three public hospitals that provide care for the transgender community: Steve Biko, in Pretoria, Chris Hani Baragwanath in Johannesburg and Groote Schuur in Cape Town. Last year, due to training done by, among others, GenderDynamiX, Nelson Mandela Hospital in Mthatha did its first gender reassignment surgery.

People who do not live in those provinces, cannot access care from those hospitals’ special units, and those who live in the provinces and do want the surgery, have to add their names to lists so long, they’ll be lucky if they have their surgeries done within 25 years.

Not everyone opts for surgery, but even just getting the correct hormones or any other support services, is extremely hard, including for those people who lives in metropoles.

GenderDynamiX health advocacy officer Linda Zakiyya Chamane says transgender people in rural areas have almost zero hope of getting any support at all for their needs.

Dr Anastacia Tomson said: “Transgender populations are neglected by a number of areas in society, but especially or very prominently by the health care system. This group of people has very specific needs — not complicated needs, just specific needs — and those are underserved.

“We know that the healthcare system is failing all kinds of marginalised groups of people. We know that it is failing women, children, people who are HIV-positive and LGBTQI+ people. And we definitely know that amongst the latter group, it is possibly the most seriously failing transgender and intersex people. And those problems run deep [provide link here to what the failings are ].”

Deacon said: “There are NGO’s and individual doctors in the public and private sectors who are sympathetic and helpful and provide support, but not enough of them. It occurred to me, as I was chatting to friends online, that it is important for us to advocate for ourselves.

“Very little is ever achieved without a mass movement of people — and I use ‘mass’ in inverted commas when it comes to the transgender community for various reasons, not least of which is that to be openly transgender is hard. People are genuinely afraid to come out. We have this one issue now, the stock-out of Depo-Testosterone, but there are lots of issues.

“So, what if we all got together? We have lots of problems, but we also have lots of skills, contacts and resources, and our numbers together in themselves are worth something.”

Transgender people and their allies — including parents, medical practitioners and representatives of NGO’s — met and formed #Unite4TransRights in February.

The group, endorsed by NGO heavyweights such as Treatment Action Campaign, SECTION27, Be True 2 Me, Triangle Project and GenderDynamiX, sent out a statement to the media outlining their demands.

They called not only for a clearer response from Pfizer, who supplies Depo-Testosterone, about the stock-out and the planned remedies, but also the National Department of Health to respond to the crisis “and put pressure on Pfizer to uphold their commitment to provide healthcare to its clients” and to “ensure that gender affirming hormones can be accessed at all primary healthcare facilities, including in rural areas”.

The statement also asked for national and international LGBTQI+ human rights organisations to show solidarity, and a revision of healthcare policies for transgender, non-binary and intersex communities.

On 19 March, the Psychological Society of South Africa (PSYSSA) had a Western Cape launch of its Practice Guidelines For Psychology Professionals Working With Sexually and Gender-Diverse People which was printed last year.

The only other guide for health professionals that exists is The Adult Trans Gender Patient: A Guide for General Practice: Hormone Transition Therapy, published by GenderDynamiX. That guide is out of date, however, and Dr Tomson, along with Dr Elma de Vries, who compiled the first guide, is currently updating it.

There are no national Department of Health endorsed standard treatment protocols or guidelines, said Kotze.

Dr Tomson said: “We are having these conversations amongst ourselves, but we need mainstream society to have this conversation. We need people to understand what the difficulties are and how easily they’re fixed.

How many people are transgender, non-binary or intersex and in need of treatment?

This is almost impossible to say, even internationally, because of stigma and a real threat to people’s safety if they come out. But, said Dr Tomson, overseas figures indicated that transgender people generally made up about 0,5% of the population.

“That means, that if you have a room of 200 people, there’s at least one trans person in that room,” she said.

“Transgender identity is a normal variant of human development. There have been trans people for millennia. We are not going away. We have always been here, we will always be here. We are not broken, we are not defective. Some of us want access to medication and we should have it.”

Analysis: How a cutting edge medicine made it to SA’s new ARV tender

South Africa’s recently awarded antiretroviral (ARV) tender, worth around R14-billion over three years, heralds the introduction of a much-anticipated new medicine called dolutegravir into the public healthcare system from July 2019. For a cutting-edge HIV drug to reach the public sector so quickly, and at such a low price, is unprecedented.

Dolutegravir is in a relatively new class of antiretrovirals called integrase inhibitors. There is much excitement about dolutegravir given that it suppresses HIV very quickly and effectively, has few side effects, and HIV does not easily become resistant to it.  It is set to replace efavirenz in the standard first-line treatment combination given to people living with HIV in the public sector in South Africa. There will however still be efavirenz in the system for TB patients, for the very small number of people who cannot tolerate dolutegravir, and for women who want to have a baby – given that dolutegravir’s safety during pregnancy is still under review. Dolutegravir was first registered by the United States Food and Drug Administration in 2013.

The part of the new tender for the three-drug combination containing dolutegravir, lamivudine and tenofovir was split relatively equally between eight different companies. The lowest price for the drug combination was R75.13 (US$5.42) per person per month from Macleods Pharmaceuticals SA and the highest was R98.61 from Adcock Ingram Healthcare. According to our calculations, the average price is R86.54 (US$6.26) per person per month. Of the eight versions of the new three-drug combination available in the private sector in South Africa, the cheapest is priced at R616 per month – more than seven times the average public sector price.

The price of the old efavirenz-based combination has also come down substantially in the new tender, with the lowest being R85.10 from Mylan and the highest being R97.51 from Cipla Medpro SA. We calculated the average price for this combination at around R91.50 – R5 (or around 6%) more than the average price for the dolutegravir-based combination. It seems the low prices of the dolutegravir-based combination exerted downward pressure on the price of the efavirenz-based combination – which used to be priced over R100.

For a cutting-edge new HIV drug such as dolutegravir to be priced this low, is very unusual, if not unprecedented. Raltegravir, a drug from the same class as dolutegravir and launched a few years earlier, is still priced at around R1 200 (around US$86) in the private sector and R537 (US$38.72) on the new public sector tender for a month’s supply (without the two companion drugs).

The license that enabled generic dolutegravir

Dolutegravir did not follow the normal trajectory we associate with new drugs. While the pharmaceutical company ViiV Healthcare owned the patent, they did not insist on being the only producer of dolutegravir on the market. In April 2014, through the Geneva-based Medicines Patent Pool (MPP), they negotiated an agreement that allowed multiple generic companies to produce and market the medicine in exchange for royalties. This agreement is called a voluntary license, since ViiV voluntarily agreed to it, as opposed to a compulsory license, where a company is forced by government, or by a court, to license generic companies.

ViiV’s decision to voluntarily license dolutegravir to the MPP was something of a sliding doors moment. Had ViiV instead chosen to hold on to their market exclusivity, a years-long battle would likely have followed with activists trying to negotiate better prices or urging their governments to make use of compulsory licenses to force the price down. Had we gone down that route, chances are ViiV would still be the sole provider of dolutegravir (the main patent only expires in 2026), and the price would still be far beyond the South African government’s ability to pay for it at scale, as still is the case with raltegravir.

Voluntary licenses like the Viiv-MPP license typically exclude wealthy countries such as the United States, since that is where ViiV makes most of their money. The original license however also excluded less wealthy countries such as Morocco  and Ukraine – something for which both entities were criticised.

Not just competition

Either way, the MPP license provided for generic competition to start very early on, thereby setting the stage for much lower prices.

It wasn’t just competition though that brought down the price. In September 2017 the Bill and Melinda Gates Foundation and the Clinton Health Access Initiative together with a long list of allies including the South African government, negotiated an agreement with generic manufacturers Mylan and Aurobindo that they will produce the dolutegravir-based three-drug combination at under US$75 per person per year (around R86.50 per person per month at time of writing). Having these two large companies committed to this price meant that other generic manufacturers would have to price at least similarly if they wanted to compete. It seems likely that this agreement accelerated price reductions that may otherwise. have only occurred later on. The fact that the average price in the new tender is very close to the Gates ceiling price suggests that the agreement had the intended impact.

At current exchange rates Aurobindo’s R87.28 per person per month tender price works out to US$75.41 per year – just over the US$75 ceiling, although this is likely the result of currency fluctuations rather than Aurobindo breeching the agreement. At R78.78 per month (US$68.13 per year) , Mylan’s South African tender price  came in well below the ceiling price set in the Gates agreement.

Apart from the MPP license, the Gates agreement, and various generic manufacturers coming on board, a number of other things had to go right for dolutegravir to come to the public sector in South Africa. The South African Health Products Regulatory Authority (the body that last year replaced the old Medicines Control Council) was surprisingly quick to approve generic drug combinations containing dolutegravir. While SAHPRA has well-publicised backlogs, and money is set aside in the budget specifically for dealing with these backlogs, the fact that there are now eight dolutegravir-based combination products on the market in South Africa indicates that the institution has at least done a reasonable job in registering these high priority medicines. The first dolutegravir, lamivudine, tenofovir generic to be approved by the United States Food and Drug Administration was approved in 2017, less than two years ago.

The push to fast-track the registration of these medicines hints at another easily over-looked part of the story of dolutegravir in South Africa. Since Dr Aaron Motsoaledi became Minister of Health, South Africa has generally been very fast to update HIV and tuberculosis treatment guidelines and introduce new medicines in response to new evidence. This, combined with government’s knack for negotiating reasonable HIV and TB medicines prices, has meant that people living with HIV or TB in South Africa have generally had access to the same, or better, treatments than those available to people in much wealthier countries. When you stop to think about it, it is an incredible reversal from the peak of state-sponsored AIDS denialism at the beginning of the century.

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Dolutegravir- why new does not automatically mean better

By Tom Boyles

As has been previously reported by Spotlight, a new and exciting anti-retroviral, dolutegravir, is soon to become widely available in South Africa. Whilst its very real advantages have been extensively reported, the potential disadvantages have received relatively little attention.

In the past when new HIV drugs have become available, the advantages have clearly outweighed the disadvantages for the vast majority of people. For example, when tenofovir became available to replace D4T (stavudine), the choice to switch was straightforward for most patients; similarly when the current first line drugs became available in a fixed dose combination (FDC). In both cases there were clear advantages and very few disadvantages for most patients so they quite rightly demanded the new drugs. Now that the dolutegravir roll-out is on the horizon, we see an impatience to access the drug. However, it’s important to realise that it might not be right for everyone and that new does not necessarily mean better. For patients to make informed choices, they need to know how the advantages of dolutegravir may or may not apply to them and weigh these against the potential disadvantages.

One issue with dolutegravir that has received considerable attention is the possible risk of serious birth defects if women conceive while taking the drug, details can be found here. This issue will not be discussed further here, other than to say that hopefully all women will be offered correct and up to date information as well as access to contraception so that they can make empowered decisions.

 

Six reasons to be cautious of dolutegravir

  • Potential risk of serious birth defects. See above.
  • Potential for insomnia. The commonest side effect of dolutegravir is insomnia, whilst this may be mitigated by taking treatment in the morning and may wane over time, it has led to some patients stopping the drug. Efavirenz has similar side effects when people first take it but many patients are now stable on efavirenz and free of this distressing side effect.
  • Potential for weight gain. It has not been widely reported, but early studies have suggested that dolutegravir might lead to weight gain in some patients. For example, a 2017 study found that virally suppressed patients who switched from an efavirenz-based regimen to dolutegravir (or a similar drug) gained around 3kg after taking it for 18 months. The effect was greatest for dolutegravir compared to other similar drugs. Another 2017 study found that among 462 patients who were virally suppressed and changed to dolutegravir, the average weight gain was also around 3 kg after only 9 months of treatment and was greater for women than men. While these are relatively small studies it is clear that one potential effect of switching from efavirenz to dolutegravir might be weight gain, which is associated with serious non-AIDS events, impacts body image, and can be a barrier to ARV adherence.
  • Skin and liver reactions. Almost all drugs used to treat HIV have been known to cause skin rashes or problems with the liver, and dolutegravir is no different. There is no suggestion that dolutegravir causes these problems more commonly than drugs such as efavirenz or lopinavir/ritonavir (tradename Aluvia). However, patients who are side-effect free on their current drugs do run a small risk of developing skin or liver problems if they change to dolutegravir.
  • Drug interactions. Dolutegravir rarely causes interactions with other drugs but it can be the ‘victim’ of drug interactions. Notably, it is necessary to double the dose when it is taken with rifampicin, the most important drug for treating TB.
  • Potential for the unknown. Possibly the most serious reason to be cautious about dolutegravir is the potential for as yet unknown side effects. History is littered with examples of drugs that were introduced with fanfare after successful trials, only to later be withdrawn from the market due to side effects that only became apparent when the drug was used by large numbers of patients and for a longer duration. This review lists 462 such examples from 1950 to 2013.

In conclusion

There are several clear advantages to dolutegravir, notably its tolerability and high barrier to resistance and few would argue against its use in patients in whom this is most relevant. For example, patients who are newly diagnosed with HIV, returning to care after a period of treatment interruption and therefore at risk of drug resistance, those suffering side effects on their current regimen e.g. lopinavir/ritonavir, or those taking complex multi-tablet regimens. I would certainly advise patients to choose dolutegravir under any of those circumstances.

However, the vast majority of patients in South Africa who will be offered dolutegravir, possibly over 2 million, are currently virally suppressed and side effect-free on an efavirenz based FDC. For those patients the balance of advantages and disadvantages is less clear cut. The fact that dolutegravir is well tolerated and is a potent suppressor of viral load are of limited relevance to patients who are already side effect free and virally suppressed. However, those taking dolutegravir for the first time run the risk of developing new side effects, be they rashes, liver problems, insomnia, weight gain, or some new unknown side effect. They will also need to take dolutegravir twice a day if they need rifampicin for TB treatment.

For these reasons, patients who are already virally suppressed and side effect free on the current first line FDC may have more to lose than to gain by switching to dolutegravir. A more sensible option may be to stick with their current regimen for now and see what side effects are seen in others before considering a switch. Hopefully, such patients will be counselled that in this case new does not necessarily mean better and they are empowered to make their own decisions on this important issue.

Dr Tom Boyles is a Senior Research Clinician at the Wits Reproductive Health and HIV Institute.