Equitable Access to Gene Therapy: A Call to Action for the American Society of Gene and Cell Therapy
Authors: Kenneth Cornetta, Kirtika Patel, Christopher Mwaniki Wanjiku, Naftali Busakhala
Journal: Molecular Therapy (2018)

A long-standing ethical concern with gene therapy is that it will further advantage the already advantaged. The fear is that genetic engineering will be utilized by those with means to improve intellect, physical abilities, and longevity, thereby furthering social inequality. While the current focus of gene therapy is on therapeutic applications, the field remains at risk of becoming a prime example of health care inequity. The impact of social standing has long influenced medical care. Access concerns were raised when Glybera, the first gene therapy approved in Europe, was priced at €1 million.1Ylä-Herttuala S. Glybera's second act: the curtain rises on the high cost of therapy.Mol. Ther. 2015; 23: 217-218Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar The chimeric antigen receptor (CAR)-T cell therapy Kymyriah has been priced at $475,000,2Kolata, G. (2017). New gene-therapy treatments will carry whopping price tags. The New York Times, September 11, 2017. https://www.nytimes.com/2017/09/11/health/cost-gene-therapy-drugs.html.Google Scholar and the Biogen product for spinomuscular atrophy was priced at $750,000 for the first year of therapy and $375,000 each year after.3Friedmann T. Progress toward human gene therapy.Science. 1989; 244: 1275-1281Crossref PubMed Scopus (358) Google Scholar The high price tag for novel pharmaceuticals is not limited to gene therapy. Even for those with insurance, the out-of-pocket costs for cancer therapy have highlighted the large number of US citizens that are underinsured. The significant financial burden has been associated with psychological distress and non-compliance.4Zafar S.Y. Peppercorn J.M. Schrag D. Taylor D.H. Goetzinger A.M. Zhong X. Abernethy A.P. The financial toxicity of cancer treatment: a pilot study assessing out-of-pocket expenses and the insured cancer patient's experience.Oncologist. 2013; 18: 381-390Crossref PubMed Scopus (655) Google Scholar In 2013, Ubel et al.5Ubel P.A. Abernethy A.P. Zafar S.Y. Full disclosure--out-of-pocket costs as side effects.N. Engl. J. Med. 2013; 369: 1484-1486Crossref PubMed Scopus (218) Google Scholar highlighted the challenges for metastatic colon cancer patients on Medicare; the addition of Bevacizumab to first-line chemotherapy increased the cost to approximately $44,000 for a 10-month course, resulting in an estimated $8,800 out-of-pocket co-pay. The out-of-pocket costs for immunotherapy can be even greater.6Carrera P.M. Kantarjian H.M. Blinder V.S. The financial burden and distress of patients with cancer: Understanding and stepping-up action on the financial toxicity of cancer treatment.CA Cancer J. Clin. 2018; 68: 153-165Crossref PubMed Scopus (383) Google Scholar This led Khera7Khera N. Reporting and grading financial toxicity.J. Clin. Oncol. 2014; 32: 3337-3338Crossref PubMed Scopus (56) Google Scholar to propose a financial toxicity grading criteria. An example of a grade 1 impact would be reduced expenses on leisure activities or use of a charity organization to supplement income or medical payments. Grade 4 activities include medical bankruptcy, selling one's home to pay off medical treatments, or discontinuing treatment due to financial considerations. While patients in high-income countries (HICs) may find access to gene therapy challenging, the outlook for access for individuals in low and middle income countries (LMICs) can only be described as bleak. Even for clinical trials, opportunities to participate in research has historically been limited.8Hanna E. Rémuzat C. Auquier P. Toumi M. Gene therapies development: slow progress and promising prospect.J. Mark. Access Health Policy. 2017; 5: 1265293Crossref PubMed Google Scholar The database ClinicalTrials.gov (accessed in September of 2018) provides information on recruiting or near-recruiting trials and can be searched by geographic location. Of the 179 recruiting or not-yet-recruiting trials found using the search term "gene therapy," only 2 trials are open in Africa, 3 in South America, and 1 in South East Asia. When we look at the 179 gene therapy trials by disease targets, 81% have been identified as global health priorities for LMICs, of which 41% match to the search term cancer, 14% to HIV, 4% to sickle cell disease, 3% to thalassemia, 8% to hemophilia, and 11% to immunodeficiency (not HIV related). All of these diseases are relatively uncommon in HICs or the outcome is much worse in LMICs. Cancer is adding to the communicable disease burden and is seen as the next major health threat for many LMICs.9Ferlay J. Soerjomataram I. Dikshit R. Eser S. Mathers C. Rebelo M. Parkin D.M. Forman D. Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.Int. J. Cancer. 2015; 136: E359-E386Crossref PubMed Scopus (21334) Google Scholar It has been recognized that a global effort will be needed for cancer control and treatment in LMICs.10de Souza J.A. Hunt B. Asirwa F.C. Adebamowo C. Lopes G. Global Health Equity: Cancer Care Outcome Disparities in High-, Middle-, and Low-Income Countries.J. Clin. Oncol. 2016; 34: 6-13Crossref PubMed Scopus (107) Google Scholar There are no open gene therapy trials in Africa or South East Asia. In South American there is an open trial for melanoma in Argentina, a country which is classified as a HIC. For sickle cell disease, it is estimated that 75.5% of the 312,000 infants born with this disease live in sub-Saharan Africa.11Piel F.B. Patil A.P. Howes R.E. Nyangiri O.A. Gething P.W. Dewi M. Temperley W.H. Williams T.N. Weatherall D.J. Hay S.I. Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates.Lancet. 2013; 381: 142-151Abstract Full Text Full Text PDF PubMed Scopus (642) Google Scholar From a clinical needs perspective, it is estimated that mortality ranges from 50%–90% for African children, but, in HICs, early deaths are rare and the majority of patients live into adulthood.12Grosse S.D. Odame I. Atrash H.K. Amendah D.D. Piel F.B. Williams T.N. Sickle cell disease in Africa: a neglected cause of early childhood mortality.Am. J. Prev. Med. 2011; 41: S398-S405Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar Currently there are no open gene therapy trials for sickle cell disease in Africa. Thalassemia is a disease with a high disease burden, with the vast majority of patients residing in resource poor countries within Southeast Asia and Africa.13Weatherall D.J. The inherited diseases of hemoglobin are an emerging global health burden.Blood. 2010; 115: 4331-4336Crossref PubMed Scopus (572) Google Scholar Of the 13 treatment sites listed on ClinicaTrials.gov as recruiting or near recruitment, there is only one site in Thailand and none in Africa, India, or South and Central America. The World Federation of Hemophilia has advocated for "Treatment for All" due to the high morbidity and mortality of bleeding disorders outside HICs.14Skinner M.W. Haemophilia: provision of factors and novel therapies: World Federation of Hemophilia goals and achievements.Br. J. Haematol. 2011; 154: 704-714Crossref PubMed Scopus (28) Google Scholar Gene therapy has the potential to revolutionize the treatment of hemophilia,15Iorio A. Skinner M.W. Clearfield E. Messner D. Pierce G.F. Witkop M. Tunis S. coreHEM panelCore outcome set for gene therapy in haemophilia: Results of the coreHEM multistakeholder project.Haemophilia. 2018; 24: e167-e172Crossref PubMed Scopus (57) Google Scholar and the ability to replace factor VIII or IX infusions with long-term disease correction will be particularly impactful in LMICs. Biomarin is conducting two phase III clinical trials in hemophilia A at 65 sites, with two sites in South America (Brazil) and one in Africa (South Africa). Both countries are listed as upper-middle income economies by the World Bank. The other 12 trials have no sites in LMICs. Immunodeficiencies have proven to be ideal candidates for gene therapy, with one approved product (Strimvelis) and a number of additional products likely to achieve licensure in the next few years. The outlook for these diseases in LMICs is bleak due to lack of newborn screening and access to curative allogeneic transplantation.16Etzioni A. World Primary Immunodeficiency Week: a call for newborn screening.Eur. J. Immunol. 2014; 44: 925-926Crossref PubMed Scopus (3) Google Scholar Given the limitations of donor availability and screening in LMICs, gene therapy may be the optimal treatment option for children with these diseases. There are no open trials in LMICs. The Ethics Committee of the American Society of Gene and Cell Therapy (ASGCT) highlighted the challenges of gene therapy pricing at the 2018 Annual Meeting, but additional opportunities to address health care equity exist. ASGCT can continue to work with patient advocacy groups and policy makers to insist that access to gene therapy be distributed fairly to all those in need. Promoting access in LMICs will require additional efforts by ASGCT. Fostering research in LMICs will be important in gaining acceptance of gene therapy. The recent paper by Arbuthnot et al.17Arbuthnot P. Maepa M.B. Ely A. Pepper M.S. The state of gene therapy research in Africa, its significance and implications for the future.Gene Ther. 2017; 24: 581-589Crossref PubMed Scopus (8) Google Scholar reviews the challenges to gene therapy research and clinical implementation in Africa. Grants for LMIC researchers to spend time with mentors in the US may help to foster gene therapy research. Opportunities for women in science is also needed.18Okeke I.N. Babalola C.P. Byarugaba D.K. Djimde A. Osoniyi O.R. Broadening Participation in the Sciences within and from Africa: Purpose, Challenges, and Prospects.CBE Life Sci. Educ. 2017; 16: 16Crossref Scopus (37) Google Scholar The current ASGCT travel grant program for our annual meeting may be insufficient for those traveling from LMICs and should be reviewed. Continuing to provide online access to ASGCT journals at no cost is also an important service. Outreach programs for clinicians will also be important to help build the clinical infrastructure required to implement gene therapy. While these may prove helpful, an important first step is obtaining feedback from LMIC scientists and clinicians on their views and needs. While ASGCT is small, the diverse clinical interests of our members suggest opportunities to collaborate with other societies in providing joint educational efforts. The American Society of Clinical Oncology, the American Society of Hematology, and other societies have active global health outreach program and present opportunities for jointly sponsored programs. Equitable access to gene therapy in HICs is challenging. Delivering clinical care and conducting clinical trials in LMICs faces a different set of logistical and ethical challenges, including national support for science and improved legal infrastructure around clinical research. For LMICs, some might see the hurdles to implementing gene therapy as too high and therefore not worth pursuing. We must remember this argument was made about HIV treatment, and those critics have been proven wrong. Similar arguments have been made regarding cancer therapy, but there is a growing list of cancer centers in resource-poor areas. Global partnerships are key to the success of these efforts. The ASGCT mission is "to advance knowledge, awareness, and education leading to the discovery and clinical application of genetic and cellular therapies to alleviate human disease." By considering how we promote these objectives in HICs and LMICs, ASGCT has the opportunity to be a catalyst for ensuring gene therapy improves health care on a global scale.