Off-Label Use of Drugs and Access to Medicines for All: A Thailand Example

Several years ago an Indonesian girl named Widya posted a message on my blog. She asked where she could obtain the drug Sorafenib for her father, who was terminally ill with liver cancer. Her family had already spent a significant sum on her father’s healthcare and could not afford further treatment. I forwarded the message to a pharmaceutical executive in Jakarta, who responded that Sorafenib was available in Indonesia but a month’s dosage would cost around $4,500 (the average monthly salary in Jakarta is about $1,180). “I hope the patient has health insurance coverage, otherwise the family will have to pay out of pocket,” he said.

Widya’s plight highlights one of the most important reasons to implement universal health coverage (UHC): to reduce out of pocket spending and ensure everyone access to quality healthcare without incurring crippling financial hardship. Drug expenditure typically places the largest burden on the people who can least afford healthcare. A considerable share—up to 68 percent—of out of pocket health costs in resource-limited countries is for medication. The rapid increase of the burden of non-communicable diseases (NCDs) has posed further challenges to accessing healthcare in in low- and middle-income countries, where the high price of promising anti-NCD medication can deter people from seeking care or impoverish families and health systems. Not surprisingly, the UHC target included in goal three of the UN Sustainable Development Goals (SDGs) emphasizes “access to safe, effective, quality, and affordable essential medicines and vaccines for all.”

Inclusion of off-label drugs in the UHC benefit package, as shown in the use of bevacizumab in Thailand, serves as an example of how to offer high-cost NCD treatment in a safe and effective way. As a result of rapid population aging, thousands of elderly persons in Thailand suffer from age-related visual impairment, especially macular degeneration (AMD) and diabetic macular edema (DME). Absent timely and effective treatment, these eye diseases often result in blindness. Injection of ranibizumab (Lucentis)—an FDA-approved anti-vascular endothelial growth factor (anti-VEGF) manufactured by Genentech—has shown to stop, even reverse vision loss in most patients with AMD and DME. With a price tag of $1,733 per dose, however, Lucentis is hardly affordable to people with limited or no health insurance coverage.

Since 2005, another drug manufactured by the same company, bevacizumab (Avastin) has been applied by eye doctors as a highly effective but far cheaper alternative to Lucentis. A study published in the British Journal of Ophthalmology in May 2007 found that while Lucentis is about fifty times more expensive than Avastin, the former needed to be two and a half times more effective to justify the additional cost. Unlike Lucentis, Avastin is FDA-approved only for treatment of colon and other cancers, but not for macular degeneration, which means that Avastin can only be prescribed as an off-label (“unlicensed”) treatment for AMD or DME.

Off-label drug use potentially can improve affordable access to innovative medicines largely because of its flexibility. While a pharmaceutical company is prohibited from advertising a drug for any unapproved purposes, physicians are free to use it for any purposes that in their professional judgement are considered safe and effective. This practice can be adopted by almost any country in the world: in the United States, for example, off-label use of drugs is very common in cancer treatment. Older, generic medications (which tend to be less expensive) are most commonly prescribed for off-label use when they have found new uses not formally approved. They are cheaper also because the developer has not yet invested considerable resources seeking its official approval.

In 2011, at the request of the subcommittee of the National List of Essential Medicines (NLEM), the Thai Ministry of Public Health’s Health Intervention and Technology Assessment Program (HITAP) conducted a systematic study of the clinical efficacy and effectiveness of both Avastin and Lucentis for the treatment of AMD and DME. The study found that the efficiency of Avastin was not significantly different from Lucentis, although the safety of Avastin for treating macular disease is inconclusive. Based on the study, the sub-committee negotiated with the pharmaceutical company, which offered to halve the price of Lucentis. Finding the reduced price would still not fundamentally solve the affordability problem, the sub-committee listed Avastin in the NLEM for AMD and DME, making Thailand the first country to officially endorse Avastin for macular treatment.

Since November 2012, all Thai patients eligible for treatment of AMD and DME have been able to get Avastin nearly free. NLEM constitutes the minimum reimbursement list for all major health insurance schemes, including Civil Servant Medical Benefit Scheme, Social Security Scheme and Universal Coverage Scheme (UCS). Under UCS, which covers everyone regardless of socio-economic status and is used by three quarters of the country’s population, a patient pays only thirty baht ($0.8) to the hospital he or she was referred to receive eye injections of Avastin.

For fear that the wide use of Avastin may negatively affect the marketing of Lucentis, the pharmaceutical company opposed the government’s endorsement of Avastin’s off-label use. In April 2012, Novartis (the other developer of Lucentis) actually challenged the use of Avastin as an alternative to the licensed Lucentis in England and Wales. This concern did not affect the use of Avastin for off-label treatment in Thailand because the original market for Lucentis was kept intact in that country: wealthy people still pay out of pocket for Lucentis and government employees are still able to receive Lucentis for free under the Civil Servant Medical Benefit Scheme. Those two customer segments have remained loyal to Lucentis due to the belief that it is safer and more effective than Avastin. Furthermore, in making the decision of including Avastin in the NLEM, the sub-committee engaged multiple stakeholders including ophthalmologists, academicians, Thai FDA and the pharmaceutical industry. According to Dr. Paisan Ruamviboonsuk, President of the Royal College of Ophthalmologists of Thailand, the government’s alliance with ophthalmologists increased its leverage vis-à-vis pharmaceutical firms in the off-label use of Avastin.

The story of Avastin is dramatically different in China, where at least 10 percent of patients with eye diseases suffer from AMD. Until September 2010, Avastin had been used as an off-label treatment for AMD in more than thirty hospitals where more than one thousand patients had reportedly received the injections. But the hospitals could only use the drug “secretly” because no regulation exists on off-label drug use of medications. Until the end of the month, when Avastin was officially launched in mainland China, the drug had been considered legally “fake.”  Any drug not marketed via legal channels is categorically considered counterfeit by Chinese law. Unfortunately, right before the Chinese hospitals could use the drug legally, adverse reactions were reported among sixty-one patients receiving the injection of Avastin at the Shanghai No. 1 People’s Hospital. The local regulatory body rushed to announce that it was caused by a “fake” version of Avastin, even though it was very likely caused by contamination in repackaging of the drug. By punishing those who marketed and used the drug, the government sent a signal that off-label use of drugs in China was a crime. Unlike their Thai counterparts, the Chinese Medical Doctor Association, which represents two million medical practitioners nationwide, played no active part in the decision making process. As a result, few Chinese hospitals have continued the off-label use of the drug ever since, and a large number of the AMD patients have lost access to affordable and effective treatment.

That said, off-label drug use is certainly not the only means to access high-cost drugs. Access can be increased significantly if off-label use is combined with multiple interventions implemented by different stakeholders, such as compulsory licensing, negotiating prices with pharmaceutical firms and engaging in pooled procurement, expanding patient assistance programs and voluntarily lowering drug price by pharmaceutical firms. No matter what measures are adopted, the decision-making should be an evidence-based process participated in by multiple stakeholders and supported by health technology assessment (HTA), which takes into account human rights, cost-effectiveness, safety, and intellectual property rights.