Compassionate and optimum use of new tuberculosis drugs

Bedaquiline (Janssen Pharmaceuticals, Titusville, NJ, USA) and delamanid (Otsuka, Osaka, Japan) are two drugs recently approved for the treatment of drug-resistant tuberculosis.¹ Timely access to both drugs has been problematic, especially for combination use. We report a patient with the most resistant strain of tuberculosis documented in the USA whose inability to access combination bedaquiline and delamanid compromised his care and created a public health risk.

The patient is a man aged 39 years, diagnosed with tuberculosis on Dec 23, 2013. Sputum smears and cultures were positive for Mycobacterium tuberculosis. Chest CT showed extensive bilateral disease. The patient was treated with a series of regimens but he had sputum persistently positive for M tuberculosis, progression of disease on chest CT, and many susceptibility tests showed resistance to isoniazid, rifampicin, pyrazinamide, ethambutol, kanamycin, capreomycin, ofloxacin, moxifloxacin, ethionamide, para-aminosalicylic acid (PAS), and clofazimine. The patient's definitive regimen included bedaquiline, clofazimine, amikacin, doripenem–co-amoxiclav, linezolid, PAS, and cycloserine, but the effectiveness of most of these drugs was questionable. He also developed severe peripheral neuropathy resulting in the linezolid dose being lowered to 300 mg daily.

Delamanid is not registered in the USA, and requests to access delamanid through Otsuka's restricted compassionate use programme were denied. Otsuka's policy is to withhold delamanid from patients who have received bedaquiline in the past 6 months because of concerns over additive cardiac toxic effects. Plans for intensive cardiac monitoring were developed for this patient, but Otsuka continued to deny access to delamanid. Because of his weak treatment regimen, the patient underwent left pneumonectomy, leaving him oxygen-dependent and with severe neuropathy, both of which have left him permanently disabled.

Otsuka indicated they would reconsider providing delamanid 6 months after bedaquiline was removed from the regimen. Removing bedaquiline would have left the patient with inadequate medical therapy. Given the serious toxicity and efficacy risks of this patient's definitive regimen, the patient and treating physicians determined the potential benefits of adding delamanid outweighed the theoretical risks of co-administration with bedaquiline. They indicated a willingness to sign a consent form explicitly stating they accepted these risks, but access was still denied.

Withholding delamanid also created the significant public health risk of ongoing transmission of this strain of tuberculosis. The transmission implications of untreated tuberculosis feature prominently in USA tuberculosis control guidelines² and recent data from South Africa show that most cases of highly resistant tuberculosis are due to primary transmission.³ The public health effect of highly resistant strains of tuberculosis should merit special consideration in access decisions. Such considerations seemed absent from Otsuka's decision to withhold delamanid.

This case emphasises the urgent need for access to combinations of new drugs for patients who have few options to treat their highly resistant tuberculosis. Because results from planned clinical trials of new drug combinations will not be available for 2–3 years, alternative access mechanisms need to be urgently established.

We declare no competing interests.

By Caitlin Reed, Leona Mason, Helen Cox, Barbara Seaworth, Erica Lessem, Jennifer Furinemail

References

1. Zumla, A, Gillespie, S, Hoelscher, M et al. New antituberculosis drugs, regimens, and adjunct therapies: needs, advances, and future prospects. Lancet Infect Dis. 2014; 14: 327–340
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2. Centers for Disease Control and Prevention. Tuberculosis control laws and policy: a handbook for legal and public health practitioners. http://www.cdc.gov/tb/programs/TBLawPolicyHandbook.pdf; 2009. (accessed April 28, 2014).
3. Shah NS, Brust JC, Mathema B, et al. Majority of XDR TB cases are due to transmission in a high-HIV-prevalence setting. 2015 Conference on retroviruses and opportunistic infections; Seattle, WA; Feb 23–24, 2015. Abstract 92.

ERS/WHO TB Consilium reply

Caitlin Reed and colleagues' description of a severe case of extensively drug-resistant tuberculosis emphasises the emerging issue of access to newly developed second-line drugs for difficult-to-treat or even untreatable tuberculosis cases^{1, 2} from the perspective of both affected patients and health-care providers.

As the authors correctly point out, the potential benefits of accessing effective treatment go beyond the individual, and extend to public health because of the risk of transmission of a potentially lethal strain. Our understanding is that the reason for denial of delamanid to a patient already treated with bedaquiline was based on existing policies on the rational use of new drugs.^{3, 4} Recent WHO guidance stated that there are no data on the simultaneous use of bedaquiline and delamanid in the same patient and that until such data become available, no recommendation on their joint administration is possible. However, the policy guidance, although accounting for the potential additive cardiac toxic effects, and aimed at minimising harms to those treated within a public health perspective, did not forbid the combined use of the two drugs in individual cases.

We recall that when a similar discussion took place about allowing procurement of second-line antituberculosis drugs at discounted prices via the Green Light Committee in the context of the risk of increasing the prevalence of drug resistance, important organisations were against it. Once again, we need to balance the patient's right to access a new, potentially life-saving drug against the risk of unknown, potentially life-threatening, adverse events, which might severely affect its future use.

Similar cases,² although sporadic, will probably appear again in the future. In our opinion, since the rational use of new drugs (aimed at protecting both the patient and the drug) is an internationally agreed milestone, the simultaneous use of delamanid and bedaquiline might be considered if several conditions are met: an effective treatment cannot be designed by using only one new drug in addition to the optimised background regimen, the clinical centre is qualified, informed consent and pharmacovigilance are in place, and new drug use is supported by expert opinion (panel).

Panel

Proposed conditions for simultaneous use of delamanid and bedaquiline

An effective treatment cannot be designed by adding only one new drug to the optimised background regimen

If the patient is given one or two drugs that are likely to be effective, the addition of only a single new drug will not bring the number of drugs likely to be effective up to the minimum of four, as recommended by WHO guidelines; in this situation, the addition of both bedaquiline and delamanid might be considered.

The clinical centre is qualified

The clinical reference centre should be highly qualified in terms of clinical expertise on extensively drug-resistant tuberculosis management, number of cases managed, and laboratory services; the eligibility criteria for these centres should comply with national regulations, and, ideally, with international ones yet to be developed.

Informed consent

The patient should give informed consent, as recommended by WHO, separately for delamanid4 and bedaquiline.

Pharmacovigilance

A pharmacovigilance system must be in place—to be seen as both a guarantee for the patient and an additional source of information complementing clinical trials.

Expert opinion on rational use of drugs

The use of the new drugs is considered rational and appropriate by an independent and qualified organisation such as the ERS/WHO TB Consilium;⁵ this step is already an essential component of Otsuka's delamanid compassionate use programme.⁵

Clinical trials on the combined use of delamanid and bedaquiline are planned by the US Food and Drug Administration, but results will not be available for the next 2–3 years. We hope that the planning and implementation of such trials will be seen as a priority research issue because evidence in this field is desperately needed. We also hope that the public debate will create an environment where the delamanid compassionate programme could make the drug available for future patients who also need bedaquiline, provided that essential requirements for co-administration are met, without posing a risk to the commercialisation and the future availability of the drug.

We were contacted by Otsuka to respond to the Correspondence by Caitlin Reed and colleagues; however, the views expressed here are solely ours and do not reflect those of any company or organisation. We are not qualified to comment on Otsuka's policy on delamanid licensing procedures. We declare no competing interests.

By Alberto Matteelli, Lia D'Ambrosio, Rosella Centis, Marina Tadolini, Giovanni Battista Miglioriemail

References

1. Migliori, GB, Sotgiu, G, Gandhi, NR et al. Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis. Eur Respir J. 2013; 42: 169–179
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2. Migliori, GB, De Iaco, G, Besozzi, G, Centis, R, and Cirillo, DM. First tuberculosis cases in Italy resistant to all tested drugs. Euro Surveill. 2007; 12: E070517.1
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3. Migliori, GB, Lienhardt, C, Weyer, K, van der Werf, MJ, Blasi, F, and Raviglione, MC. Ensuring rational introduction and responsible use of new TB tools: outcome of an ERS multisector consultation. Eur Respir J. 2014; 44: 1412–141
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4. WHO. The use of delamanid in the treatment of multidrug-resistant tuberculosis—interim policy guidance. World Health Organization, Geneva; 2014
5. Esposito, S, D'Ambrosio, L, Tadolini, M et al. ERS/WHO Tuberculosis Consilium assistance with extensively drug-resistant tuberculosis management in a child: case study of compassionate delamanid use. Eur Respir J. 2014; 44: 811–815
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Source: The Lancet Infectious Diseases (here and here)