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.

 

 

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