The (Unfinished) Conquest of Tuberculosis

World TB Day Thoughts, 2016

One more world TB day.

March 24, 1882 was when Dr Robert Koch announced at the University of Berlin's Institute of Hygiene that he had discovered the cause of tuberculosis (TB), the TB bacillus. In the second half of 19^th century, TB was causing the death of one out of every seven people in the US and Europe. Koch's discovery opened the way to diagnosing TB and led to effective treatment. TB, dubbed as the ‘white plague’, declined substantially in the United States and Europe that by second half of 20^th century sanatoriums were closed and routine screening was abandoned. The discovery of antibiotics led to such optimism that in 1964, S A Waksman wrote the book The Conquest of Tuberculosis.

Sadly, TB still rages in most part of the world, killing one person every 25 seconds. In India, two persons die every three minutes, even today. For most of the world, the conquest of TB is still a dream.

Experts are unanimous about the need of new TB drugs and diagnostics. So where do we stand now?

There has been some progress. Many challenges remain if we have to conquer the disease. 

The Good News

There has been progress in the drug discovery and development for TB. There are two drugs in advanced stages: Bedaquilin (Janssen Pharmaceuticals) and Delamanid (Otsuka Pharmaceuticals). The pipeline of TB drugs also looks promising with about 117 new candidates being reported by G Finder in its Survey as of October 2015.

On the diagnostic front, Xpert of Cephid is an excellent tool to detect drug resistance and where it is deployed, physicians are happy. DNA based diagnostics like Line Probe Assay are available.

The Challenging News

While the progress is significant, the sad news is that these are not translating to reduce the mortality in those parts of the world where it is most wanted, that too among the most vulnerable, poor in the tropics.

The reasons are known. Sadly, solutions are often found wanting.

The difficulty with TB is the absence of an attractive market. That acts as a disincentive. Most of the drugs in the pipeline has received support of public or philanthropic funds at some time, without which they would not have reached the stage where they are now. Some for profit companies have invested their funds as well. Pfizer and Astra Zeneca had developed a drug each. Both closed down their internal programs and have licensed the drugs out for development.

Added to this is the lack of effective diagnostics. Even after a century and a quarter of Koch’s discovery, most hospitals still use the method of sputum smear microscopy discovered by Robert Koch in 1882, to detect TB. It is a good test. But not capable of detecting drug resistance (DR). Thus people with DR get treated on the normal course leading to further complications.

Some of the following issues have already been discussed in this blog earlier. 

1. Both Janssen (for Bedaquilin) and Otsuka (for Delamanid) are seeking marketing approval in limited number of countries and not in all TB affected countries
2. The above drugs have affordability concerns.
3. The diagnostic tools are not widely available and where available it has raised affordability question.
4.  Trials of TB are complex and time consuming. Yet, no urgency is shown by any of the agencies to get trials of the available drugs done at the earliest.
5. The new diagnostics have affordability concerns. 

The Missing Million

It is reported that the Joint Monitoring Mission of the RNTCP has admited that in the last two years, more than a million people living with TB in the country have gone undiagnosed or unreported. This fact has been known and has been called the missing million. Addressing this missing million is a huge challenge.

India has recently approved the use of Bedaquiline for MDR TB treatment. It has been hailed as a wonder drug for TB. While there is no doubt about the efficacy of this new drug, the tags like wonder drug could only help to bring in complacency back into the system. Take a note at the caution that WHO has added in its guidelines for the use of Bedaquiline:

Bedaquiline has been reported to disturb the function of the heart and liver in particular. Interactions with other drugs, especially lopinavir and efavirenz (used in the treatment of HIV), ketoconazole, as well as other drugs used in the treatment of MDR-TB (eg moxifloxacin, clofazimine) may be expected. More deaths were reported among patients taking bedaquiline during the studies carried out to investigate the drug, although it is not clear whether this was due to the drug. For all these reasons, it is important that patients are closely monitored and that adverse events are systematically reported (“active pharmacovigilance”), particularly those that are serious and life-threatening…

There is no room for complacency. TB needs new drugs. 

The Development Bottleneck

Globally, it is sad to note that even in the background of the robust pipeline that has been built up over the past two decades has seen little progress in the drug development front. There are 117 new compounds on the pipeline. The public funds have promoted research but not development, it is now time to shift our focus from discovery to development front. If concerted efforts are made several new drugs can be got to the market in a decade’s time. But that requires determination and concerted action which, unfortunately, is absent as of now.

The IP Bottleneck

It is difficult to believe that patents do play a role in limiting the development of new TB drugs. But even that is happening. The reason is that all drugs in pipeline are under patents. So no one other than the patentee/licensee could develop the drugs. And it is left to the will of the patentee/licensee to develop at their pace for the markets which they want.

The need of new TB drugs is global, a clear and present requirement. Therefore, is it inappropriate to leave it to some companies to develop and market the drugs in markets of its choice and leave the patients in other countries to their fate.
If we really have to conquer TB, the world has to give a real push at the development front. The business as usual approach of leaving everything to the market has not worked and will not work in future too. Someone will have to take the yoke on her shoulders and get the drugs through the development phase through a real push.

Needed : A New Innovation Policy in Market Failure Cases

 The post-industrial society has an IP based innovation policy as the primary mechanism to foster innovation, which is driven by markets. This is clearly not working for neglected diseases. In market failure situations like TB, the world does not know how to innovate affordable products accessible to all. We need to innovate the way we innovate in market failure cases.