Developing World Bioethics ISSN 1471-8731 (print); 1471-8847 (online) Volume 16 Number 1 2016 pp 45–54

doi:10.1111/dewb.12084

ANYTHING TO STAY ALIVE: THE CHALLENGES OF A CAMPAIGN FOR AN EXPERIMENTAL DRUG NATHAN GEFFEN

Keywords ethics, South Africa, treatment, developing world bioethics, HIV/AIDS, informed consent, MSF

ABSTRACT Drug-resistant tuberculosis (TB) has a high mortality rate. Most medicines used to treat it are poorly tested and have terrible side effects. Activists have campaigned for patients with drug-resistant TB to have access to experimental drugs, particularly one called bedaquiline, before these have been approved by regulatory authorities such as the Food and Drug Administration (FDA) in the United States (US) and the Medicines Control Council (MCC) in South Africa. Some activists have also campaigned for bedaquiline to be approved by regulatory authorities before testing of the drug is completed. These campaigns raise ethical concerns about whether patients should be offered experimental, unapproved, medicines for the treatment of life-threatening illnesses, and if authorities should approve drugs for life-threatening illnesses when vital questions about safety and efficacy remain outstanding.

INTRODUCTION Since 2009, activists have campaigned for access to experimental medicines, such as bedaquiline and delamanid, to treat drug-resistant TB before these medicines have been approved by regulatory authorities. They have also campaigned, successfully, for bedaquiline to be approved by regulatory authorities before clinical trials for the drug have been completed. Current medicines for treating drug-resistant TB have limited evidence of safety and efficacy. They have serious, sometimes fatal, side-effects, and treatment typically takes two years with poor outcomes. Campaigns for access to experimental TB drugs have been motivated by this question: ‘If you were diagnosed with drug-resistant TB, with its high mortality rate and long and difficult treatment with poorly tested drugs, would you want the choice to use experimental drugs that have had promising results in early clinical trials?’ Ethical concerns have arisen during the course of these campaigns, especially when as the FDA considered approval of bedaquiline, a serious safety concern arose. Some of these are: Should patients be offered experimental, unapproved, medicines for the treatment of life-threatening illnesses, and, if so, when?

Should regulatory authorities approve drugs for lifethreatening illnesses when vital questions about safety and efficacy remain outstanding and, if so, under what conditions? This article describes the history of the campaign for pre-approval access to bedaquiline, with emphasis on the South African side of the story. The views, sometimes differing, among activists about the ethical concerns that arose are also discussed. This article does not offer comprehensive answers to these ethical concerns. Instead, it presents the details of a practical case study that can be used to explore the ethics of access to experimental medicines for life-threatening diseases.

BACKGROUND TB is estimated to have caused 1.3 million deaths globally in 2013.1 It is the largest recorded cause of death in South Africa for 2010 to 2012, the latest period for which data is 1

C.J.L. Murray, K.F. Ortblad, C. Guinovart, S.S. Lim, T.M. Wolock, D.A. Roberts, et al. Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014 Sep 13; 384(9947): 1005–1070.

Address for correspondence: Nathan Geffen, Room 4.29, Centre for Social Science Research, Leslie Social Science Building, University of Cape Town, Cape Town, Western Cape 7700, South Africa. Email: [email protected]. © 2015 John Wiley & Sons Ltd

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available.2 Because people with HIV are more prone to becoming ill with TB, the TB epidemic has been exacerbated over the last two decades by the HIV epidemic. At least 60% of South African TB patients are also infected with HIV.3 Drug-susceptible TB is a treatable disease with good outcomes, especially for otherwise healthy people who adhere to their regimens and are treated in facilities that do not have drug stockouts.4 Standard treatment is a six month course consisting of four drugs taken for two months then two drugs taken for four months.5 Multi-drug resistant (MDR) TB is defined as resistance to two important TB antibiotics, isoniazid and rifampicin, and is treated with a different drug regimen.6 Extensive or Extremely drug resistant (XDR) TB is defined as MDR-TB plus resistance to two further classes of drugs (any fluoroquinolone and one or more of three injectable drugs: amikacin, kanamycin, or capreomycin).7 The prognosis for a drug-resistant TB diagnosis is poor.8 Treatment is long, up to 24 months.9 In South Africa, after two years of treatment less than 40% of MDR-TB and 20% of XDR-TB patients are successfully treated, meaning a patient has completed treatment and, according to culture tests, has had no actively replicating TB for at least a month.10 The evidence base for regimens used to treat drug-resistant TB is poor, and the drugs

2 Statistics South Africa. Mortality and causes of death in South Africa, 2012: Findings from death notification. Pretoria: Statistics South Africa; 2014 Sep. 3 K. Weyer. Case study: South Africa. Bull World Health Organ. 2007 May; 85(5): 325–420. 4 N. Massyn, C. Day, N. Peer, A. Padarath, P. Barron & R. English. District Health Barometer 2013/14. Health Systems Trust; 2014. Available at: http://www.hst.org.za/publications/district-healthbarometer-201314 [Accessed 14 April 2015]. 5 World Health Organization. Guidelines for treatment of tuberculosis. World Health Organization; 2010. Available at: http:// www.who.int/tb/publications/2010/9789241547833/en/ [Accessed 14 April 2015]; Department of Health. National Tuberculosis Management Guidelines 2014. Department of Health; 2014. Available at: http:// www.sahivsoc.org/upload/documents/NTCP_Adult_TB%20Guidelines %2027.5.2014.pdf [Accessed 14 April 2015]. 6 Centers for Disease Control and Prevention (CDC). Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs–worldwide, 2000–2004. MMWR Morb Mortal Wkly Rep. 2006 Mar 24; 55(11): 301–305. 7 G.B. Migliori, R. Centis, L. D’Ambrosio, A. Spanevello, E. Borroni, D.M. Cirillo, et al. Totally Drug-Resistant and Extremely DrugResistant Tuberculosis: The Same Disease? Clin Infect Dis. 2012 Jan 5; 54(9): 1379–1380; A. Matteelli, A. Roggi & A.C. Carvalho. Extensively drug-resistant tuberculosis: epidemiology and management. Clin Epidemiol. 2014; 6: 111–118. 8 N. Ndjeka, F. Conradie, J. Hughes, S. Moyo, N. Bantubani & H. Ferreira. Access to Bedaquiline and interim outcomes for patients with DR-TB within the National Bedaquiline Clinical Access Programme in South Africa. 4th South African TB Conference; 2014; Durban. 9 World Health Organization, op. cit., p. 62. 10 Ndjeka et al. op. cit.; World Health Organization, op. cit., p. 58.

composing these regimens cause a high rate of severe side effects including ototoxicity (ear poisoning) and psychosis.11 Moreover drug-resistant TB appears to be rising in South Africa with over 11,329 recorded cases in 2013, of which over 10,719 were MDR-TB and 610 were XDR-TB.12 In South Africa TB treatment is managed in the public health system, and is free to patients; the state pays for medicines. What medicines patients have access to is primarily dependent on what is provided for in the National Department of Health’s treatment guidelines. The price of medicines per patient for the full course of treatment of drug-susceptible TB is low, less than R480 (approximately US$40) as of November 2014.13 By contrast, the WHO states that MDR-TB drugs can cost up to US$5,000 per patient and that XDR-TB treatment is ‘far more expensive.14 The risk of death after a drug-resistant diagnosis is high. In 2013, the mortality rate of recorded MDR-TB cases in South Africa was about 18%. The defaulter rate is approximately the same and many defaulters would likely have died too. For XDR-TB the situation is bleaker, with more than half of recorded cases dying within two years of follow-up.15 Before the advent of TB treatment, mortality for those sick with the disease was high even amongst the wealthiest patients who could check into sanatoria.16 The mortality rate dropped dramatically from the 1940s to the 1960s when numerous clinical trials of new TB agents, led by the British MRC, were conducted, eventually leading to the current standardised six-month course of treatment.17 TB has been gradually eliminated as a major public health threat in wealthier countries, with occasional outbreaks, such as in New York City in the late 1980s and early 90s. This has not only been a result of effective

11 T. Törün, G. Güngör, I˙. Özmen, Y. Bölükbas¸ı, E. Maden, B. Bıçakçı, et al. Side effects associated with the treatment of multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2005 Dec 1; 9(12): 1373–1377; D. Knoetze. You see yourself vanishing and you think: I’m going to die. Available at: http://groundup.org.za/article/the_need_for_medicines _for_drug_resistant_tb_2475 [Accessed 14 April 2015]. 12 Ndjeka et al. op. cit. 13 Medprax. Private Sector Single Exit Medicine Prices. 2014. Available at: http://www.tac.org.za/community/node/2021 [Accessed 14 April 2015]. 14 World Health Organization. Drug-resistant tuberculosis now at record levels. WHO. 2010. Available at: http://www.who.int/ mediacentre/news/releases/2010/drug_resistant_tb_20100318/en/ [Accessed 14 April 2015]. 15 Ndjeka et al. op. cit. 16 O.R. McCarthy. The key to the sanatoria. J R Soc Med. 2001 Jan 8; 94(8): 413–417. 17 A. Zumla, P. Nahid & S.T. Cole. Advances in the development of new tuberculosis drugs and treatment regimens. Nat Rev Drug Discov. 2013 Apr 30; 12(5): 388–404.

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Accessing Experimental Drugs treatment, but treatment has been a vital contributing factor.18 Since TB has no longer been a major public health problem in wealthy countries, investment in developing new TB drugs has dried up. Until recently no new class of TB drug had been approved by a major regulatory authority in over 40 years.19 Yet worldwide, less than $700m dollars is invested annually in TB research and development (R&D), a fraction of the investment in research and development for AIDS, diabetes, breast cancer and many other diseases. Total private sector investment in TB R&D was less than $100 million in 2013.20 By contrast, in 2013, the US National Institutes of Health (NIH) alone spent over $1 billion on diabetes R&D and nearly $2.9 billion on HIV. It’s TB investment was much less, at $240 million.21 There is little incentive for pharmaceutical companies to develop TB drugs.22 Surowiecki (2014) writes, ‘Diseases that mostly affect poor people in poor countries aren’t a research priority, because it’s unlikely that those markets will ever provide a decent return. So diseases like malaria and tuberculosis, which together kill two million people a year, have received less attention from pharmaceutical companies than high cholesterol.23 This echoes the finding of a World Health Organisation (WHO) report, for which pharmaceutical companies were interviewed.24 So with the recent escalation in drug-resistant TB in several poor countries, treatment options have been 18 O.R. McCarthy. op. cit.; J.P. Cegielski, D.P. Chin, M.A. Espinal, T.R. Frieden, R.R. Cruz, E.A. Talbot, et al. The global tuberculosis situation: Progress and problems in the 20th century, prospects for the 21st century. Infect Dis Clin North Am. 2002 Mar; 16(1): 1–58; W.F. Paolo & J.D. Nosanchuk. Tuberculosis in New York city: recent lessons and a look ahead. Lancet Infect Dis. 2004 May; 4(5): 287–293; T. Navin, S. McNabb & J.T. Crawford. The Continued Threat of Tuberculosis. Emerg Infect Dis. 2002 Nov; 8(11): 1187. 19 R. Mahajan. Bedaquiline: First FDA-approved tuberculosis drug in 40 years. Int J Appl Basic Med Res. 2013; 3(1): 1–2. 20 L.A. Gillum, C. Gouveia, E.R. Dorsey, M. Pletcher, C.D. Mathers, C.E. McCulloch, et al. NIH Disease Funding Levels and Burden of Disease. PLoS ONE. 2011 Feb 24; 6(2). Available at: http:// www.ncbi.nlm.nih.gov/pmc/articles/PMC3044706/ [Accessed 14 April 2015]; M. Frick. 2014 Report on Tuberculosis Research Funding Trends, 2005–2013. Treatment Action Group; 2014. Available at: http://www.treatmentactiongroup.org/tbrd2014 [Accessed 14 April 2015]. 21 NIH. NIH Categorical Spending. 2014 Feb. Available at: http:// report.nih.gov/categorical_spending.aspx [Accessed 14 April 2015]. 22 C. Harper. Tuberculosis, a neglected opportunity? Nat Med. 2007 Mar; 13(3): 309–312. 23 J. Surowiecki. The Economics of Ebola Drugs. The New Yorker. 2014. Available at: http://www.newyorker.com/magazine/2014/08/25/ ebolanomics [Accessed 14 April 2015]. 24 D. Chang Blanc & P. Nunn. Incentives and disincentives for new anti-tuberculosis drug development. World Health Organization; 1999. Available at: http://www.who.int/tdr/publications/documents/ incentives-disincentives-anti-tuberculosis.pdf [Accessed 14 April 2015].

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limited. Public investment is also small, because there is pressure on large public research institutions such as the NIH to prioritise spending according to national burdens of mortality and morbidity.25 For a number of years, organisations such as the Treatment Action Group (TAG) in the United States and the Treatment Action Campaign (TAC) in South Africa have been calling for increased investment in TB drugs. They have had limited success.

BEDAQUILINE AND THE CALL FOR PRE-APPROVAL ACCESS On 22 July 2009 AIDS activists from TAG, TAC and the European AIDS Treatment Group (EATG), as well as a representative of Stop TB Partnership, met in Cape Town with representatives of a pharmaceutical company, Tibotec, a subsidiary of Johnson & Johnson. The activists asked the company to allow ‘compassionate access’ to an experimental drug for the treatment of drug-resistant TB called TMC207.26 At that time, it had become clear that drug-resistant TB was an emerging epidemic of concern to South Africa and other countries. At a meeting organised by TAG and the Stop TB Partnership on 1 December 2009 in Cancun, Mexico, two days before the World Lung Conference that was held in the same city, activists, including one from TAC, began publicly calling for patients with drug-resistant TB to be able to access TMC207. This means that patients would be able to use the drug before clinical trials were finished and before regulatory authorities such as the FDA and MCC had approved it. This is called pre-approval access.27 TAG, TAC, EATG, a UK organisation called HIV i-Base and an organisation since formed called the Global TB Community Advisory Board took the campaign forward. Subsequently so did Medecins Sans Frontieres (MSF) and the Southern African HIV Clinicians Society.28 In South Africa, drugs may only be brought to market once registered (i.e. approved) by the MCC. The logistics of pre-approval access are not well-defined, but in practice it typically means that a doctor would inform a patient about an unregistered drug. If the patient agrees 25

Gillum et al. op. cit. N. Geffen. Meeting with Tibotec regarding compassionate care access to TMC207. 2009. [Email] 27 Stop TB Partnership, Treatment Action Group. Agenda for Addressing Critical Challenges in TB/HIV Research and Program Implementation. 2009. 28 Treatment Action Campaign, Treatment Action Group, HIV i-Base, Global TB Community Advisory Board, Southern African HIV Clinicians Society, Medecins Sans Frontieres. The case for pre-approval access to bedaquiline. 2012. Available at: http://www.tbonline.info/ posts/2012/11/24/case-pre-approval-access-bedaquiline/ [Accessed 14 April 2015]. 26

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to take it, then an application under section 21 of the Medicines and Related Substances Control Amendment Act is made to the MCC for that particular patient.29 The MCC may then approve the application. The drug is then obtained from a pharmaceutical company and dispensed to the patient. It is a time-consuming and inconvenient process, but it is a procedure that has been used frequently with medicines for HIV and AIDS-related illnesses by both MSF and TAC. TMC207 was later given a scientific name, bedaquiline. Another experimental drug that emerged at about the same time was OPC-6783, since given the scientific name delamanid, developed by a Japanese company Otsuka. Pre-approval access is also being called for by activists to this drug.30 This article confines discussion to bedaquiline. The process for testing new drugs so that they receive regulatory approval goes through several stages. At each stage, a drug must perform well to proceed to the next stage. Laboratory testing is done, followed by animal tests, then human trials. Human testing starts with a small phase I trial in healthy individuals, in which safety and dosage is established. This is followed by a larger phase II trial primarily concerned with determining safety, efficacy and dosage in people with the disease being targeted, and finally a large phase III trial to determine safety and efficacy. In some phase II and all phase III trials there is a control arm that receives the current standard of care plus (usually) a placebo, and an intervention arm that receives the current standard of care plus the test drug. Participants are randomly assigned to the two arms. Ideally participants and health workers are blinded as to who is in which arm.31 The impetus for the campaign for pre-approval access to bedaquiline was the poor state of treatment for drugresistant TB. The WHO rates the evidence base for its recommendations. All five of its recommendations for the construction of a regimen for the treatment of MDR-TB are rated ‘very low quality evidence’.32 The evidence base for all drugs used in the treatment of MDR-TB is poor, with the exception of pyrazinamide a medicine used to 29

South African Government. Medicines and Related Substances Control Act, 1965 (Act No. 101 of 1965). 1965. Available at: http:// www.acts.co.za/medicines-and-related-substances-control-act-1965/ [Accessed 14 April 2015]. 30 Global TB CAB. Open letter to Otsuka: continued concerns about delamanid’s accessibility. http://www.tbonline.info/posts/2014/3/ 19/open-letter-otsuka-continued-concerns-about-delama/ [Accessed 2 May 2015]. 31 How are drugs tested. Accord Clinical Research. Available at: http://www.accordclinical.com/clinical-study/how-are-drugs-tested/ [Accessed 14 April 2015]. 32 World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. World Health Organization; 2011. Available at: http://whqlibdoc.who.int/publications/2011/ 9789241501583_eng.pdf [Accessed 14 April 2015].

treat drug-susceptible TB, that in any case has high levels of resistance to it amongst MDR-TB patients. In 2012 the Global TB Community Advisory Board published an article titled The Case for Pre-Approval Access to Bedaquiline. It described how poor the evidence base was for drugs recommended by the WHO and used in South Africa to treat multi-drug-resistant TB. Since this article was published, the evidence base has improved only slightly.33 By comparison the evidence base for bedaquiline was promising. In a Phase II clinical trial of 44 people, a greater proportion of those on the bedaquiline arm had no detectable active TB in their sputum by day 56.34 A further motivating factor for the call for preapproval access was that there were precedents with AIDS drugs (antiretrovirals) such as AZT, lamivudine, didanosine and stavudine. Tens of thousands of people with HIV used these drugs before regulatory approval in what were known as expanded access programmes (which is effectively pre-approval access). For the most part these programmes benefited patients.35 The programmes have however been controversial because of occurrences of fatal or debilitating drug side-effects, especially for the high doses at which AZT and stavudine were originally prescribed. Moreover, while the aforementioned drugs were eventually approved for the treatment of HIV, it has not always worked out this well. For example, patients with HIV also received expanded access to adefovir, but this drug was not approved for HIV following clinical trials (it has however been approved for the treatment of hepatitis B).36 Now that HIV has become a chronic manageable disease, with a multitude of effective and reasonably safe treatment regimen options, some researchers have voiced concerns about future expanded access programmes for HIV.37 However, the situation with drug-resistant TB is

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A. Jindani, T.S. Harrison, A.J. Nunn, P.P.J. Phillips, G.J. Churchyard, S. Charalambous, et al. High-dose rifapentine with moxifloxacin for pulmonary tuberculosis. N Engl J Med. 2014 Oct 23; 371(17): 1599–1608. 34 A.H. Diacon, A. Pym, M. Grobusch, R. Patientia, R. Rustomjee, L. Page-Shipp, et al. The Diarylquinoline TMC207 for MultidrugResistant Tuberculosis. N Engl J Med. 2009 Jun 4; 360(23): 2397– 2405. 35 V. Amorosa & P. Tebas. Is It Time to Rethink the Expanded-Access Programs for HIV Infection? J Infect Dis. 2007 Jan 10; 196(7): 974–977; T. Creagh-Kirk, P. Doi, E. Andrews, S. Nusinoff-Lehrman, H. Tilson, D. Hoth, et al. Survival experience among patients with AIDS receiving zidovudine. Follow-up of patients in a compassionate plea program. JAMA. 1988 Nov 25; 260(20): 3009–3015. 36 L. Highleyman. Preveon expanded access program broadened. BETA Bull Exp Treat AIDS Publ San Franc AIDS Found. 1998 Jul; 3; Clinical and Research Information on Drug-Induced Liver Injury. Adefovir. Adefovir. Available at: http://livertox.nih.gov/Adefovir.htm [Accessed 14 April 2015]. 37 Amarosa et al. op. cit.

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Accessing Experimental Drugs closer to the situation for patients with HIV infection in the early 1990s before it had become the manageable disease it is today. Pre-approval (or expanded) access for HIV drugs has been largely confined to patients in wealthy regions such as North America and Europe. Patients in African countries including South Africa seldom obtain access to antiretrovirals before they are approved by at least one major regulatory authority, unless they are participating in a controlled clinical trial. A further reason for the pre-approval access campaign was the slow pace at which Tibotec and other companies testing new TB drugs were moving. TMC207 is first mentioned in medical literature and patent filings circa 2003/ 4.38 As of the time of writing, it still has not been through a phase III trial. Yet TMC278 (now known by its scientific name ripilvirine), an antiretroviral – and a comparatively unimportant one in the antiretroviral arsenal – has been through the full gamut of clinical trials and was approved by the FDA in May 2011.39 Tibotec prefixes its experimental compounds with ‘TMC’ and suffixes it with a number. Since 207 comes before 278, TMC278 was presumably discovered or catalogued by Tibotec after TMC207. A search of US patent filings of these medicines confirms this; the patent application for TMC207 was filed more than a year after TMC207.40 This is an example of how much slower TB drug development is than antiretrovirals. Personal communication with Tibotec staff involved in the bedaquiline clinical trials also revealed that the drug was not a priority for the company.

HOW THE CAMPAIGN WAS CONDUCTED

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subsequently Janssen Pharmaceuticals, another Johnson & Johnson company that assumed responsibility for bedaquiline.41 It also included several meetings between activists and the pharmaceutical company. The TAC ran workshops for its membership explaining what bedaquiline was and why pre-approval access was being called for. The TAC and MSF also tried to get the South African Department of Health and MCC to allow preapproval access. It is important to note that advocacy for pre-approval access also emphasised caution. Activists pointed out, in public correspondence and particularly in training workshops, that there were risks, the most important of these being: •

Safety had not been established. Patients who took this drug needed to be told of the risks so that they could make an informed decision in consultation with their clinician. • The manufacturer was concerned by the possibility of resistance to the drug developing before it was approved by regulatory authorities. Nevertheless, on balance activists argued that the benefits for getting pre-approval access outweighed the risks.42 Although several European countries allowed preapproval access to bedaquiline, at least up until September 2012, the MCC was reluctant to do so.43 MSF had attempted several times to get pre-approval access for specific patients, but the MCC had refused.44 Over the next two years the MCC softened its stance and allowed some pre-approval access. Perhaps this was in part due to criticism of its initial refusal coupled with increased media coverage of the campaign, especially

The campaign for pre-approval access involved writing public letters to regulatory authorities and Tibotec, and 41

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DECRANE LFB c/o J-CSA, GUILLEMONT JEG johnson&jonhson pharma, F.C. Odds, H.J.J. Poignet, G.J.F.E. Van, M.G. Venet, et al. Quinoline derivatives and their use as mycobacterial inhibitors. EP1527050 A1, 2005. Available at: http://www.google.com/ patents/EP1527050A1 [Accessed 14 April 2015]. 39 H. Azijn, I. Tirry, J. Vingerhoets, M.-P. de Béthune, G. Kraus, K. Boven, et al. TMC278, a Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI), Active against Wild-Type and NNRTI-Resistant HIV-1. Antimicrob Agents Chemother. 2010 Jan 2; 54(2): 718–727; E. Cox. NDA Approval (letter from FDA to Tibotec approving rilpivirine). 2011. Available at: http://www.accessdata .fda.gov/drugsatfda_docs/appletter/2011/202022s000ltr.pdf [Accessed 14 April 2015]. 40 P. Stoffels. 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2pyrimidinyl]-amino]-benzonitrile with nucleoside and/or nucleotide reverse transcriptase inhibitors; prevention of HIV transmission; pharmacokinetic profile allowing once daily dosing. US20080200435 A1, 2008. Available at: http://www.google.com/patents/US20080 200435 [Accessed 14 April 2015].

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Treatment Action Campaign. Open letters by AIDS and TB organisations calling for access to a new TB drug and a new TB diagnostic. 2010. Available at: http://www.tac.org.za/community/node/2962 [Accessed 14 April 2015]; G. Van Cutsem. Open letter to the Medicines Control Council of South Africa regarding compassionate use of bedaquiline for drug-resistant tuberculosis in South Africa. 2012. Available at: http://www.tbonline.info/posts/print/open-letter-medicinescontrol-council-south-africa/ [Accessed 14 April 2015]; Treatment Action Campaign. TAC puts pressure on Janssen finalize development of TB drug bedaquili. 2013. Available at: http://www.thepharmaletter .com/article/tac-puts-pressure-on-janssen-finalize-development-of-tbdrug-bedaquiline [Accessed 14 April 2015]. 42 Treatment Action Campaign. op. cit. 43 Stop TB Partnership. FAQs regarding procurement of Bedaquiline (BDQ) through the Global Drug Facility (GDF). 2014. Available at: http://www.stoptb.org/assets/documents/gdf/drugsupply/ FAQonprocurementofbedaquilinethroughGDFFINALVERSION 300414.pdf [Accessed 14 April 2015]. 44 A. Thom. MCC says no to TB drug access. 2012. Available at: http://www.health-e.org.za/2012/09/27/mcc-says-no-to-tb-drug-access/ [Accessed 14 April 2015].

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when health workers who contracted drug-resistant TB spoke of their experiences.45

TAC AND THE CAMPAIGN AGAINST UNTESTED MEDICINES The TAC has been credited with changing government policy on HIV treatment and prevention. In 2001 and 2002 the organisation successfully sued the government, compelling it to implement a mother-to-child transmission prevention programme. In 2003 it ran a volatile civil disobedience campaign which culminated in the South African government agreeing to roll out antiretroviral treatment starting in 2004.46 Today well over two million people in South Africa are on antiretroviral treatment and life-expectancy, which had been in decline for several years, is now increasing again.47 A key TAC campaign was against quackery. During the 2000s President Mbeki via the late former health minister, Manto Tshabalala-Msimang, promoted several alternative treatments for AIDS. Tshabalala-Msimang took no steps to prevent a vitamin salesman by the name of Matthias Rath carrying out an unlawful experiment on people with HIV. This culminated in the TAC taking her and Rath to court in a high-profile case which the TAC won in 2008.48 So by calling for pre-approval access to bedaquiline the organisation superficially appeared to be acting inconsistently. It had campaigned against the promotion of untested medicines, yet it was now calling for preapproval access to a medicine with limited data supporting its use. However on closer examination TAC’s position was not inconsistent. The demand for preapproval access was predicated on patients being given an informed choice, in which they would be aware that testing of bedaquiline was incomplete, and that there were unknown risks associated with taking the drug.

Critically, in contrast to treating HIV, the standard of treatment for drug-resistant TB has a poor evidence base. The TAC was therefore not suggesting that patients take an untested alternative drug instead of a proven regimen, but a partially tested drug as part of an otherwise poorly tested regimen for patients with severe morbidity and a high risk of mortality. Activists were confident the campaign had a sound scientific and ethical basis. However this confidence was dented by subsequent events.

ACCELERATED APPROVAL AND BEDAQUILINE’S SAFETY CONCERN In 2012, in addition to pre-approval access, the TAG in the United States had advocated for bedaquiline to receive accelerated approval by the FDA. Accelerated approval allows a drug to be approved before it has been properly tested because of compelling need. But while understandable, there are risks involved for both patients and scientific drug development. Interestingly TAC activists did not make a corresponding call for accelerated approval for bedaquiline from the MCC, but neither have they publicly opposed accelerated approval. As Goldacre explains, accelerated approval usually is granted on the basis that the pharmaceutical company will do a post-approval clinical trial (typically phase III).49 Unfortunately pharmaceutical companies sometimes renege on this commitment and the FDA does not withdraw approval, often because it is faced with pressure from patient groups. Goldacre particularly singles out questionable cancer drugs. He writes: ‘The General Accounting Office is the investigative audit branch of the US Congress. In 2009, it examined the FDA’s failure to chase these kinds of post-approval studies, and its findings were damning: between 1992 and 2008, ninety drugs had been given accelerated approval on the basis of surrogate endpoints alone, with the drug companies making a commitment to conduct 144 trials in total. As of 2009, one of every three of those trials was still outstanding. No drug has ever been taken off the market because its manufacturer had failed to hand over outstanding trial data.50

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A. Barton. FDA panel finds new type of TB drug effective, raising hopes for treatment of drug-resistant strains. Science Speaks: HIV & TB News. Available at: http://sciencespeaksblog.org [Accessed 14 April 2015]; L.L. Gonzalez. Doctor turns patient after contracting XDR-TB. Available at: http://www.health-e.org.za/2014/03/24/doctorturns-patient-contracting-xdr-tb/ [Accessed 14 April 2015]. 46 N. Geffen. Debunking Delusions: The Inside Story of the Treatment Action Campaign. 1 edition. Auckland Park, South Africa: Jacana Media; 2010. p. 63. 47 UNAIDS. Access to antiretroviral therapy in Africa: Status report on progress towards the 2015 targets. UNAIDS; 2013. Available at: http://www.unaids.org/sites/default/files/media_asset/20131219_ AccessARTAfricaStatusReportProgresstowards2015Targets_en_0.pdf [Accessed 14 April 2015]; D. Bradshaw, R. Dorrington & R. Laubscher. Rapid Mortality Surveillance Report 2014. Burden of Disease Research Unit, Medical Research Council; 2014 Feb. Available at: http:// www.mrc.ac.za/bod/RapidMortality2011.pdf [Accessed 14 April 2015]. 48 Geffen. op cit. pp. 149–172.

Bedaquiline came before the FDA for consideration at about the same time as activists published The case for pre-approval access to bedaquiline. A document was released as part of the FDA hearings with the results of a 49

B. Goldacre. Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients. Reprint edition. New York: Faber & Faber; 2013. p. 140. 50 Ibid.

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Accessing Experimental Drugs phase II bedaquiline safety trial.51 In this trial, 79 patients were randomised to take bedaquiline and standard background therapy versus 81 on placebo and standard background therapy. Patients on the bedaquiline arm had significantly faster time to having no active TB in their sputum, a promising result. However there was also a serious setback. Ten people died on the bedaquiline arm versus two on placebo and this was statistically significant.52 Underlying the call for pre-approval access was the view that access to this drug would likely save lives. Now in a clinical trial, the opposite had occurred; the drug was associated with higher mortality (the trial was not designed to detect a mortality benefit in either direction). There are caveats however: • This appears to be a low mortality rate for a drugresistant cohort. In practice drug-resistant patients are likely to be sicker than this cohort and the benefit of becoming sputum TB negative quicker might be more important in an operational setting. • Nine of the ten deaths in the bedaquiline arm occurred after patients had stopped taking bedaquiline (median time to death was 49.1 weeks after the last bedaquiline dose), but the drug does have a long half-life (meaning it stays in the body for months after patients stop taking it) and it also causes a side-effect called QT prolongation which might be associated with cardiac arrest.53 • The only cause of death that was repeated was TB, of whom five patients in the bedaquiline arm died, and one in the placebo arm.54

this split, this was sufficient for the FDA to approve bedaquiline (branded as Sirturo by Janssen) on 28 December 2012 and it became the first new class of TB drug to be approved in the US in more than 40 years, and the first drug approved specifically to treat MDR-TB.57 The approval however required Janssen to run a phase III trial that ‘should bring further clarity to the observed mortality finding for bedaquiline.58 The FDA warned, ‘If postmarketing studies/clinical trials fail to verify clinical benefit or are not conducted with due diligence, we may . . . withdraw this approval.59 The FDA decision has been controversial. One activist group in the US, Public Citizen, in anticipation of the FDA’s decision, called on the institution not to approve bedaquiline. It even suggested that continuing to test the drug in a phase III trial would be unethical.60 Correspondence between TB activists in the Global TB Community Advisory Board (which includes TAG and TAC members) shows they are cognisant of the concerns raised by Goldacre in Bad Pharma. Pressure has been put on Janssen to proceed with a phase III trial.61 The process is slow however: the trial, known as STREAM II, is only expected to proceed in early 2015, to complete in 2021, and for a report of its results to be presented to the FDA in 2022.62 Another phase III trial, called NExT has been proposed by Keertan Dheda of the University of Cape Town.63 It will compare a completely new regimen, including bedaquiline and another drug relatively new to TB treatment, linezolid, against the current standard of 57

The researchers write, ‘No deaths were considered to be related to the study drug by an investigator who was unaware of the group assignments, nor was there any association between the deaths and bedaquiline plasma concentrations’ or QT prolongation.55 The FDA Advisory Panel in late 2012 voted 18-0 that bedaquiline was effective, i.e. that it had been shown to reduce TB bacteria in the body. But it voted 11 for versus 7 against on the issue of bedaquiline’s safety.56 Despite 51

Janssen Pharmaceuticals. TMC207 (bedaquiline) Treatment of Patients with MDR-TB. Janssen Pharmaceuticals; 2012. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/Committees MeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/ UCM329260.pdf [Accessed 14 April 2015]; A.H. Diacon, A. Pym, M.P. Grobusch, J.M. de los Rios, E. Gotuzzo, I. Vasilyeva, et al. Multidrugresistant tuberculosis and culture conversion with bedaquiline. N Engl J Med. 2014 Aug 21; 371(8): 723–732. 52 Janssen Pharmaceuticals. op. cit. p. 5; Diacon et al. op. cit. 53 Diacon et al. op. cit. 54 Ibid. 55 Ibid. p. 730. 56 M.E. Tucker. FDA Approves Bedaquiline for Resistant TB Treatment. 2012. Available at: http://www.medscape.com/viewarticle/776901 [Accessed 14 April 2015].

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Food and Drug Administration. FDA approves first drug to treat multi-drug resistant tuberculosis. 2012. Available at: http://www.fda .gov/NewsEvents/Newsroom/PressAnnouncements/ucm333695.htm [Accessed 14 April 2015]. 58 E. Cox & K. Laessig. FDA Approval of Bedaquiline – The Benefit– Risk Balance for Drug-Resistant Tuberculosis. N Engl J Med. 2014 Aug 20; 371(8): 689–691. 59 E.M. Cox. Accelerated Approval. 2012. Available at: http://www .accessdata.fda.gov/drugsatfda_docs/appletter/2012/204384Orig1s 000ltr.pdf [Accessed 14 April 2015]. 60 Public Citizen. Public Citizen Urges FDA to Reject Accelerated Approval for Possibly Dangerous Anti-TB Drug Bedaquiline. 2012. Available at: http://www.citizen.org/pressroom/pressroomredirect.cfm? ID=3786 [Accessed 14 April 2015]. 61 AIDS Treatment Activists Coalition, Community Research Advisors Group, European AIDS Treatment Group, Global TB Community Advisory Board. Concerns regarding STREAM stage II trial design for bedaquiline approval. 2014. Available at: http://www.tbonline .info/media/uploads/documents/letter_to_regulators_re_stream_design _from_community_%281%29_%282%29.pdf [Accessed 14 April 2015]; M. Frick. Fool’s Errand: The Sloppy Science of the MDR-TB STREAM Trial. Available at: http://www.treatmentactiongroup.org/ tagline/2014/spring/fool%E2%80%99s-errand-sloppy-science-mdr-tbstream-trial [Accessed 14 April 2015]. 62 E.M. Cox. op. cit. p. 2. 63 K. Dheda & A. Goolam-Mahomed. Evaluating a new treatment regimen for patients with multidrug-resistant TB (MDR-TB) – a prospective open-label randomised controlled trial. 2014.

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care regimen for MDR-TB in South Africa. If approved it might produce results on bedaquiline’s safety and efficacy before STREAM II. The safety and efficacy of bedaquiline for children is still unknown, although Janssen has begun clinical trials to determine this.64 Bedaquiline’s safety in pregnant women has also not yet been established.65 Following FDA approval, the WHO issued what it called ‘interim guidance on the use of bedaquiline to treat MDR-TB.66 The drug was also approved for treating drug-resistant TB by the European Medicines Agency (EMA) in the European Union in March 2014. This was also conditional on further studies being conducted.67 Little progress was made on pre-approval access in South Africa. By the time the MCC approved the drug in October 2014, 151 people in the country had benefited from what Jannsen called its treatment access programme. The company estimates that 3,000 patients will benefit from bedaquiline in its ‘first year of availability’ in South Africa and another 6,000 in the second.68 Given the concerns about bedaquiline’s safety, the MCC’s decision to register (i.e. approve) bedaquiline before the completion of a phase III clinical trial, came as a surprise to TAC activists. It is not clear what prompted this decision after the reluctance shown through until at least September 2012 to even grant pre-approval access. Possibly, the MCC, whose deliberations are not in the public domain, determined that registration would be less cumbersome than considering hundreds of individual pre-approval requests. Besides regulatory approval status, access to a drug is also determined by its price. As of September 2014, the prices of a six-month course (the length of time the drug is currently taken in clinical trials) of bedaquiline were $30,000, $3,000 and $900 in high-, middle- and low-

64

R. Prasad. Clinical trials on child-friendly bedaquiline MDR-TB drug for children initiated. 2013. Available at: http://www .thehindu.com/sci-tech/health/medicine-and-research/clinical-trials-onchildfriendly-bedaquiline-mdrtb-drug-for-children-initiated/ article5459156.ece [Accessed 14 April 2015]. 65 Food and Drug Administration. Bedaquiline package label. Food and Drug Administration; 2012. Available at: http://www.accessdata .fda.gov/drugsatfda_docs/label/2012/204384s000lbl.pdf [Accessed 14 April 2015]. 66 World Health Organization. WHO interim guidance on the use of bedaquiline to treat MDR-TB. WHO. 2013. Available at: http://www .who.int/mediacentre/news/notes/2013/bedaquiline_mdr_tb_20130613/ en/ [Accessed 14 April 2015]. 67 European Medicines Agency. Sirturo: EPAR summary for the public. European Medicines Agency; 2014. Available at: http://www .ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/ 002614/human_med_001730.jsp&mid=WC0b01ac058001d124 [Accessed 14 April 2015]. 68 L. Garrido. SIRTURO® (bedaquiline), A Novel Treatment for Multidrug-Resistant Tuberculosis, to be Made Available to Patients in South Africa. 2014.

income countries respectively. An open letter by activists to Janssen has called for these prices to be reduced.69

DISCUSSION: QUESTIONS RAISED BY THE CAMPAIGN FOR ACCESS TO BEDAQUILINE The campaign for pre-approval access to bedaquiline, as well as the successful call by TAG for accelerated approval, raises important questions. At the time of writing it remains unknown if the benefits of bedaquiline outweigh the risks for patients with drug-resistant TB. Was the call for pre-approval access justified? In general, should patients with life-threatening illnesses be offered access to drugs that are still in preapproval testing? Darrow et al. (2015) summarise the arguments for and against pre-approval access (they use the term expanded access). In favour they state, ‘patients should have a right to mitigate extreme suffering and to enhance selfpreservation. This logic holds that as rational actors, patients are presumed to be capable of making wellinformed treatment decisions in consultation with their physicians. According to this argument, not only can patients with serious or life-threatening conditions accurately identify promising experimental drugs, but they should also be entitled to utilize their own risk–benefit thresholds in deciding whether to consume such products. Advocates of expanded access argue that deference to the assumed capacity of patients to thereby make appropriate treatment decisions should be greatest when the stakes are highest (i.e., when death is likely or certain).70 Summarising the arguments against pre-approval access they state, ‘the odds of an experimental therapy working in many expanded-access settings are extremely small – the probability of clinically meaningful benefit from early-stage experimental trials may be less than 10% . . . and informational asymmetries can lead to patient vulnerability. By definition, data on experimental drugs are very limited, and patients generally do not have access to all the information that does exist, because some of it is proprietary. Moreover, most patients do not have the training or experience to evaluate the combined pharmacologic, clinical, and statistical information on experimental therapies that is available to them. Risk comprehension among the general public is low, is not 69

Treatment Action Group and others. Open letter: Reducing the price of bedaquiline. 2014. Available at: http://www.tbonline.info/ media/uploads/documents/bedaquiline_pricing_letter_2014_sept_10 _compressed_.pdf [Accessed 14 April 2015]. 70 J.J. Darrow, A. Sarpatwari, J. Avorn & A.S. Kesselheim. Practical, Legal, and Ethical Issues in Expanded Access to Investigational Drugs. N Engl J Med. 2015 Jan 15; 372(3): 279–286. p. 283.

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Accessing Experimental Drugs strongly correlated with self-perceived ability to understand risk, and may be more impaired in sicker patients. Skeptics of expanded access caution that the risk of treatment-selection decisions that could exacerbate suffering or hasten death justifies greater – not reduced – paternalism for patients with serious or life-threatening conditions.’ A principle of the campaign for bedaquiline access is that patients should be given an informed choice. It is unknown if the benefits of the drug outweigh its risks, but given the high morbidity and mortality associated with drug-resistant TB, patients, after having the current state of scientific knowledge explained to them, should be able to decide in consultation with their clinicians whether they are willing to take this risk. This campaign insists that patients – as Darrow et al. put it – are ‘capable of making well-informed treatment decisions in consultation with their physicians’. Four characteristics of the campaign facilitate informed choice: First, while ‘most patients do not have the training or experience to evaluate’ the risks and benefits of bedaquiline by themselves, a competent and dedicated clinician can help patients reach an informed decision. Clinicians who have favoured pre-approval access to bedaquiline in South Africa would for the most part be at the forefront of public sector TB treatment programmes, be well informed of the drug’s known risks and benefits, and involved or associated with organisations such as MSF or the Southern African HIV Clinicians Society both of which have an ethos of promoting patient literacy and autonomy. Second, an organisation such as the TAC provides patient education and many of its members are current or future drug-resistant TB patients, or people likely to be in contact with current or future drug-resistant TB patients. This provides opportunities for more patients to make informed decisions that adequately assess risks and benefits. Third, Darrow et al. present their arguments in the context of the debate about ‘right-to-try’ laws in some US states that allow patients to circumvent the FDA in order to access experimental drugs. But the campaign for preapproval access to bedaquiline was predicated on regulatory authority involvement. For example, in South Africa pre-approval access to bedaquiline would only have been available to specific patients via authorisation from the MCC. In contrast to ‘right-to-try’ the entire pre-approval process takes place within a system designed to protect patients and public health, and none of the activist organisations involved in the bedaquiline pre-approval campaign would have it otherwise. Fourth, the campaign does not depend on patients identifying ‘promising experimental drugs’ as noted by Darrow et al. Identifying the drugs has already been done by highly informed patient advocacy groups working in

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conjunction with scientists and clinicians. There is not as much leeway given to patients in the call for pre-approval access to bedaquiline as is given to patients in US ‘rightto-try’ laws. The presence of these characteristics does not guarantee that all patients who receive pre-approval access to experimental drugs for TB can and will make informed decisions, but they increase the likelihood of this for many. For current drugs still being tested, such as delamanid, as well as for future drugs to treat drug-resistant TB, the principle that patients in consultation with their clinicians can make an informed choice provides a sound ethical basis for running pre-approval access campaigns. The higher mortality in the phase II trial of bedaquiline changes the risk-benefit calculation that patients and clinicians would have to make in deciding whether or not to take the drug, but not the principle. Also, some patients, for a multitude of reasons, might not be able to make an informed choice. What the treating clinician should do in such situations is an important ethical question but beyond the scope of this discussion. A further concern about pre-approval access is raised by Okie (2006). She writes that accepting the existence of a right of terminally-ill patients to access drugs in early clinical trials ‘would fundamentally challenge the government’s system for evaluating drugs.71 In the context in which she was writing, a court decision in the US allowed patients to access such drugs without FDA approval (with a similar effect to ‘right-to-try’). Again, this is less of a concern for the kind of pre-approval access called for in the bedaquiline campaign, which is contingent upon regulatory authority approval. Indeed, Okie points outs that the FDA could already approve compassionate use of a drug for which some evidence of efficacy exists; it is this kind of access that is sought in the bedaquiline preapproval access campaign. The situation is more complex with accelerated or fasttracked approval. When a regulatory authority approves a medicine for the treatment of a disease, it is effectively saying that expert consensus is that the medicine is sufficiently safe and effective to treat that disease. Generally, neither clinicians nor patients can be expected to secondguess this authoritative stamp of approval. It would be impractical and unnecessarily stressful if every patient was expected to go through a complex decision-making process about every drug in his or her prescribed regimen. Regulatory authorities and official treatment guidelines alleviate the patient and clinician of this burden. TAG was favourably disposed to bedaquiline being approved before a phase III trial was completed, but this was not a position that TAC ever promoted. Email 71

S. Okie. Access before Approval – A Right to Take Experimental Drugs? N Engl J Med. 2006 Aug 3; 355(5): 437–440. p. 437.

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correspondence shows that TAC members were concerned about bedaquiline being approved when there were unanswered questions about its effect on mortality. TAC has not campaigned for accelerated approval of bedaquiline. Yet the evidence base for bedaquiline’s efficacy exceeds that of most other already approved drug-resistant TB medicines. The risk-benefit profile of the drug is in a grey area. As the FDA’s deliberations show, experts are divided on whether the drug is safe or not. TAG’s support of accelerated approval versus TAC’s reticence reflects differences in how people interpret complex and incomplete evidence. Drugs are usually approved in the US long before South Africa. The history of HIV activism in the US has a longer history too than it does in South Africa. TAG’s members, some of whom such as Mark Harrington, the organisation’s director, have been at the forefront of the struggle for antiretrovirals in the US for decades. They have had much more experience with drug development and preapproval access than the TAC members who led the bedaquiline pre-approval access campaign in South Africa. This extensive experience possibly gave TAG members, who have impressive technical knowledge of clinical trial processes, greater confidence to estimate that the mortality result on the phase II trial of bedaquiline was a fluke, and therefore continue to advocate for the drug’s approval by the FDA in advance of the completion of clinical trials. Marcus Low, who works for the TAC, is actively involved in the Global TB Community Advisory Board and has also been involved in the campaign for preapproval access to bedaquiline, raises an important point about accelerated approval, ‘To what extent is the poor evidence base for bedaquiline and other new drugs negatively affected by accelerated approval? Accelerated approval removes industry urgency for further research.’ (personal communication).

However, in the case of TB drugs industry urgency does not generally exist pre- or post-approval. It will be up to activists, patients and clinicians to pressure drug companies into carrying out additional vital studies, and completing the phase III study of bedaquiline in particular. The high mortality of drug-resistant TB, incomplete and contested data as well as slow drug development poses difficult questions for activists about the ethics of campaigning for access to experimental medicines. Understanding and debating these ethics can provide guidance to activists both for new TB drugs and experimental medicines for other high-mortality illnesses.

Conflicts of Interest Nathan Geffen was a board member of the TAC, and one of the original members of the Global TB Community Advisory Board for much of the period described in this paper. He received funding in 2014 for his PhD research, of which this paper might form part, from the CSSR (R45,000) and the South African Centre for Epidemiological Modelling and Analysis (R100,000).

Acknowledgements Thank you to Nicoli Nattrass, Alex Welte, Marcus Low, Jeremy Seekings and Tom Yates for advice on drafts of this paper. Technical information from Erica Lessem and Mark Harrington of TAG has been invaluable.

Biography Nathan Geffen is the editor of GroundUp and a researcher with the AIDS and Society Research Unit (ASRU) at the Centre for Social Science Research, University of Cape Town in South Africa. His current research areas are the science of AIDS treatment and the modelling of the AIDS epidemic and treatment interventions.

© 2015 John Wiley & Sons Ltd