The need for expanded access to experimental medicines for drug-resistant TB
Nathan Geffen, TAC
Currently treatment outcomes for multi-drug-resistant (MDR) and extensively drug-resistant (XDR) TB are poor. Neel Gandhi presented data at IAS2009 showing 69% one-year mortality for MDR TB and 82% mortality for XDR TB in Tugela Ferry. Over time, mortality for MDR TB had declined from 87% to 45% but there was no significant decline in mortality for XDR TB. At the same conference, Max ODonnell presented data showing that of 72 patients treated for XDR TB in a Durban hospital, less than half were alive and in care at six months. [1, 2, 3]
Several new drugs are being developed for TB. 
The furthest along in the pipeline for the treatment of drug-resistant TB is Tibotecs TMC207. A small phase IIa trial (n=43) published in the New England Journal of Medicine last year showed quicker time to sputum-negative conversion with TMC207. [5, 6] Further data is expected to be presented at the World Lung Conference in Berlin later this year.
OPC-67683 produced by Otsuka is also in a phase II drug trial. No human trial data has yet been published for this compound, but it has been reported at a conference to have succeeded in phase I safety, tolerability and pharmacokinetic testing as well as a 7-day early bactericidal study. 
Both these compounds are novel in their class. TMC207 is a diarylquinoline and OPC-67683 is a nitroimidazole. They are both therefore expected to be active against current strains of drug-resistant TB.
The need for expanded access to new TB drugs has been the subject of discussions at two meetings, at a satellite conference organised by the Treatment Action Group during the World Lung Conference in Mexico in December 2009 and more recently at Open Forum 4, hosted by TB Alliance in Ethiopia. At the latter there was a panel discussion on expanded access. One of the panel speakers, Brian Woodfall of Tibotec, indicated that the company is prepared to expand access to TMC207. 
There are compelling reasons to expand access to TMC207 and even OPC-67683 before they receive regulatory approval:
- Patients with MDR-TB or XDR-TB might reasonably believe that the risk of not taking these drugs outweighs the risk of taking them, given the extremely high mortality and prolonged treatment periods for these conditions. It is arguably unethical to deny patients access to these drugs when they are at high risk of death or need to get back to work or their lifes activities.
- Health workers are at especially high risk of contracting MDR and XDR TB. ODonnell presented data at IAS2009 showing that in the general Kwazulu-Natal population: the rate of MDR TB was 11/100,000. But in health workers it was 59 per 100,000 people (OR: 5.5; 95%CI; 4.76.5). For XDR TB the rate was 1/100,000 in the general population versus 4/100,000 in health workers (OR: 3.89 95%CI: 2.0-71).  People who risk contracting a fatal illness by doing their essential work should surely be entitled to extraordinary measures to save their lives if they become ill. Also, health systems are overstretched. Saving the lives of nurses with drug-resistant TB will help reduce the loss of skills as well as the loss of confidence of other health workers.
- There is a precedent for expanded access. In the late 1980s and throughout most of the 1990s, community pressure led to expanded access programmes (EAPs) to new antiretrovirals for HIV-positive people who required urgent access to treatment. Over 100,000 people in the US are estimated to have benefited from EAPs. More than 35,000 people (22,000 in the US) accessed ddI from 1989 to 1991 prior to registration. People with drug-resistant TB today have just an urgent need. 
The cautions for EAPs are well known:
- The limited data both for efficacy and safety. Although EAPs are usually only launched when approval is guaranteed, there are exceptions (for example the adefovir EAP enrolled 9,000 people for whom toxicity overweight efficacy and adefovir was never approved as an antiretroviral.
- Maintaining consistent drug supplies is another legitimate concern. With TB medication, non-adherence has a greater potential public health impact than with HIV.
- Resistance if the new compound is not sufficiently supported by other active drugs. Adding a single drug to failing regimens essentially puts patients on functional monotherapy.
- Unknown interactions between the new compound and other TB of HIV drugs.
- A potential impact on ongoing registrational trials (for people who may be maintained on a placebo when the EAP would provide definite access. For ARV EAPs the research concerns we met by careful definition of entry criteria and trial design.
None of these concerns are greater than the need for expanded access in this example. Given the high fatality rate with TB, we will know with greater confidence by the end of 2010 whether the risks associated with TMC207 outweigh the benefits. Adherence is as big an issue post-registration as it is pre-registration. The risk of monotherapy can be reduced in time once the pipeline becomes more robust and people with XDR TB can be given regimens with multiple experimental drugs (eg both TMC207 and OPC-67683).
Even people with XDR TB are not necessarily resistant to every drug in their regimen and so will not necessarily be placed on monotherapy with the addition of a new drug. As for interactions, trials are underway for TMC207 in patients taking ARVs. Also, therapeutic drug monitoring could aid the administration of drugs in some expanded access sites. Placebo patients can be recruited from the healthier end of the MDR TB spectrum and should expect to be placed on the intervention drug immediately after the placebo period if the drug performs well.
EAPs can provide additional safety and operational data on the new drugs while ensuring that they are not used as a cheaper replacement for randomised clinical data. Only sites with capacity to ensure a reliable drug supply, adequate resistance testing and high probability of patient adherence should be able to participate. Sites run by organisations like MMdcins Sans Frontiers and Partners in Health should qualify.
Drug trials are unfortunately not an adequate way to expand access, at least not in their current form. Including healthy subjects for phase I trials and placebo patients, a search on clinicaltrials.gov in August 2010 reveals that there are just over 900 places presently being recruited for OPC-67683 and TMC207. But there were already nearly 30,000 notified cases of MDR-TB in 2007. 
Instead, either the drug companies responsible for the drugs or a respectable international NGO, such as TB Alliance, needs to administer expanded access. This will involve negotiating with regulatory authorities in multiple countries. These regulatory authorities also need to be flexible and co-operate with expanded access programmes. This mechanism should be set up by January 2011 ideally with published site and patient qualification criteria and a procedure for applying for the drugs.
Expanded access is necessary but not ideal. There would be fewer people needing expanded access if drugs moved through the pipeline quicker. The new TB drugs are taking extraordinarily long to reach the point where regulatory authorities can approve them. TMC207 was discovered in 2003. It is not expected to receive regulatory approval anywhere before 2012. Compare this with HIV drugs such as AZT. Its anti-AIDS effect was discovered in 1984 and it was registered three years later. 
Also compare current development times with the development times of the original TB drugs. The very first TB drug, streptomycin, moved from discovery in 1943 to successful completion of controlled clinical trial in 1947, so that many patients, including George Orwell, were using the drug by 1948. [12, 13] As the above mortality rates show, patients in the 1940s with TB were probably no worse off than current patients with drug-resistant TB.
While increasingly complex regulatory requirements are part of the problem, the main cause of the long time taken to bring new TB drugs to market is political will. Patients with MDR-TB today are for the most part poor and politically marginalised in contrast to TB patients of the 1940s in Europe and people with HIV in the 1980s in the United States. Pharmaceutical companies, including Tibotec and Otsuka, public entities such as the NIH and the governments of high drug-resistant TB burden countries like South Africa, China, India and Russia need to put up more R&D money for TB drugs and
diagnostics. We cannot simply depend on the Gates Foundation, which is by far the biggest contributor to the approximately $500m spent on TB R&D in 2008. 
Just as we have a Global Fund to Fight AIDS, TB and Malaria, perhaps we need an international fund to drive TB drugs and diagnostics research.
- Gandhi N et al. High Early Mortality among HIV-infected Patients with Extensively Drug-resistant or Multidrug-resistant TB in Rural
South Africa. Poster abstract 784. http://www.retroconference.org/2009/Abstracts/36299.htm
- ODonnell M. et al. Improved Survival for Patients with Extensively Drug-resistant TB and HIV in South Africa. 16th CROI 2009. Poster abstract 785. http://www.retroconference.org/2009/Abstracts/34552.htm
- Geffen N. HIV and TB from CROI. HTB South April 2009. https://i-base.info/htb-south/589/
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