The CF Buyers’ Club and Just Treatment have been working with the Dutch medicines expert, Wilbert Bannenberg, to help understand how the safety of the generic supply of ivacaftor-lumacaftor (Orkambi®) we have identified in Argentina is ensured. Wilbert is a medical doctor with a public health degree, and has 35 years of experience in strengthening pharmaceutical systems in low and middle-income countries. He trained African drug regulators between 1986 and 1995, and has evaluated several national medicines regulatory authorities over the last 10 years. He was the coordinator of the South African Drug Action Program on behalf of the World Health Organization from 1997 to 2002. He also works with NGOs like WEMOS and Health Action International and is currently the chair of the Pharmaceutical Accountability Foundation in the Netherlands.

Here Dr Bannenberg writes about his involvement in the project and the steps taken to ensure the quality of the generic product.

Parents and patients might wonder: how can drug companies in Argentina make generic copies of Orkambi® (a fixed dose combination of ivacaftor and lumacaftor – sold by Gador as Lucaftor®) and Kaydeco® (ivacaftor – sold by Gador as Ivacar®), whereas companies in UK or EU cannot? The reason is simple: the original manufacturer, Vertex, does not have a granted patent for Orkambi® in Argentina, so generic companies can produce the raw materials and the medicine without a licence from the patent holder or the government. Gador produces the raw materials in its own active pharmaceutical ingredient (API) manufacturing plant near Buenos Aires.

Dr Bannenberg meeting with Gador representatives in Argentina earlier this year

During a recent business trip to the Argentinian capital I met with Gador and asked them questions about their Cystic Fibrosis products, and their ability to supply them to patients outside Argentina.

Gador have registered their generic CF products – known as Lucaftor® – with ANMAT, the Argentinian Medicines Regulatory Authority, similar to the MHRA in the UK. ANMAT has a good reputation: for example, they are the only Latin American member of the renowned Pharmaceutical Inspection Co-operation Scheme (PIC/S), and have been a member since 2008.

As the medicine is new for patients in Argentina, ANMAT insisted on a pharmacovigilance risk safety plan to monitor potential adverse drug reactions. Some 120 Argentinian patients use Lucaftor®. Gador conduct the tests to ensure patients have the correct genotype of cystic fibrosis for free. Patients also need a medical prescription and appropriate medical insurance. These patients are responding well to the treatment – mirroring the response to the Vertex product.

Currently, Gador only has the adult version, which can be given to children over the age of 12. A paediatric version is in the process of being approved and is expected to be available by September. Children of 2-12 years can now however use the ivacaftor tablets which are also available from Gador.

There are three critical questions to answer when determining whether to trust the quality of the product:

Firstly, is the manufacturing plant of satisfactory standard, and has it been assessed by a stringent regulatory authority?

ANMAT inspectors have inspected both Gador’s API and finished dosage manufacturing plants and have allocated them the required “Good Manufacturing Practices” status. In terms of PIC/S this means that other PIC/S members will trust the local inspection and will not normally want to repeat such as inspection. Gador states that their API plant has also been inspected by other medicines agencies including, TGA (Australia), FDA (USA), AFFSAPS (France) and Mercosur (South American) countries. The FDA website lists three inspection visits to Gador between 2011 and 2018.

Secondly, has the specific product been approved (registered), and the official information published?

This is true for both Lucaftor® (ivacaftor-lumacaftor) and Ivacar® (ivacaftor): professional information and the package insert are available from both the Gador and ANMAT websites. The product cannot be registered in the UK, as current European data exclusivity rules prevent registering Gador’s version in the EU. But the MHRA does allow patients or their parents to import non-UK-registered medicines for personal use, provided the patient has a valid prescription, and takes the medication under regular supervision of a physician.

Gador is exporting the product (or planning to do so after local registration) to Paraguay, Colombia, Ecuador, Peru and Dominican Republic. In Brazil, Chile and Mexico, Vertex has obtained patents for Orkambi®, so Gador cannot sell its product there unless those governments issue compulsory licenses or after a successful patent challenge.

Third question: can Lucaftor can be used as an effective alternative to the original Orkambi®?

The majority of medicines used in modern healthcare systems are generic medicines. The best methodology to secure regulatory approval of generic versions of original medicines it to undertake a so-called bio-equivalence study. This test involves a group of volunteers taking the generic, and then switching them to the brand (or vice-versa). If the amount of active substances in the blood is similar for both products within some limits (80-125%), then the regulatory authority considers the products bio-equivalent. Gador offered me an insight in their regulatory dossiers, subject to a confidentiality agreement. I can thus confirm that I have seen the 127-page report of the bio-equivalence study of Gador’s Lucaftor® against Vertex’ Orkambi® confirming that these products are bio-equivalent.

I am also aware that the CF Buyers Club conducted independent ‘in vitro’ tests of the final product tablets in the lab of a leading London university, which confirmed that the quantity of API in the Gador product matches the quantity of API in the Vertex product.

From the bio-equivalence and lab tests, the GMP status of the factory and the regulatory status of Lucaftor® in Argentina I am confident that the product can be safely used by CF patients in Argentina as well as the UK (or elsewhere).

Dr Wilbert Bannenberg wrote this blog in his personal capacity. He has no conflict of interest to declare.