CERN Gives a Quantum Push to Open Science

In the biggest push towards Open Science so far, CERN launched its Open Data Portal with 300 terabyte dump of experimental data from real collision events of the Large Hadron Collider (LHC) openly available to all.

Through its Open Data Portal CERN has made available the experimental data in analysable form from the collision data of the first LHC run in 2010. Not just the data, CERN has made available the analytical tools too. The open source software to read and analyse the data together with the corresponding documentation in open access accompanies the data. CERN says that this data is meant for students and citizen scientists and expects that ‘these data will be of high value for the research community, and also be used for education purposes’.

Remember, we are dealing with data at the frontiers of complex scientific research. In an article CERN cautions that the complexity of this data from real collision events should not be underplayed. Those who access the data will have to put in time and effort to understand the data, the learning tools and the techniques to interpret the data.

Sharing of Real Experimental Data

Sharing of real experimental data has always been a highly debated issue. When should the data be shared? How will the credit be attributed to the data? How will access be regulated or should it be regulated at all? These questions had dampened the enthusiasm of well-meaning scientists and institutions that wanted to share data. To all these questions that troubled researchers for long, CERN has given an illustration of how experimental data can be shared, archived and preserved for long.

The Open Data Portal assigns digital object identifiers (DOIs) to the data sets and code, making them citable objects in the normal scientific communications, and offers the data openly for anyone to download since they are published under a Creative Commons license.

Another area of concern among researchers in sharing raw data was how to cite the data. LHC has addressed this concern with a clear data access policy for those who access the data. This contains its publication policy for those who analyse and publish papers by accessing the data. It requires a suitable acknowledgement and disclaimer to be included (in this case LHCb experimental data): 

“acknowledgement that the data was collected by LHCb, and disclaimer that no responsibility for the results is taken by the collaboration.

A suitable disclaimer is: This paper is based on data obtained by the LHCb experiment, but is analyzed independently, and has not been reviewed by the LHCb collaboration.”

This is second of such initiatives this year. Earlier this year, scientists from the Laser Interferometer Gravitational-Wave Observatory (LIGO) released data from the first confirmed measurement of gravitational waves and even included source code documenting the analysis step-by-step.

Pioneering Open Science

The LHC experiments at CERN are what one considers to be at the frontiers of research. It is heartening to see CERN adopting Open Science as a matter of conviction. Here is an excerpt from an article On the Road to Open Science written by Tim Smith who leads the collaboration and information services at CERN.

Science is predicated on the concept that the hypotheses that we propose to explain the phenomena that we observe can be tested through repeatable experiment. We should share sufficient details of our observations and conclusions for independent scrutiny, reproduction and verification. In this data-intensive age we have somewhat fallen short of this ideal since we have continued to “share” through publication processes which had no place for data, certainly not large volumes of it, nor the code that was needed to interpret it. Hence Open Science is striving to rebalance the processes and reintroduce data and code as first-class research objects to be shared, scrutinized and reused.

Even for Schools

The CERN Open Data Portal also provides real experiment data (event datasets from the ALICE,ATLAS, CMS and LHCb collaborations) specifically prepared for educational purposes for even high school students. These resources are accompanied by visualisation tools. Apparently over ten thousand high-school students are accessing, using and learning from this data every year. This data is meant for the international masterclasses in particle physics. For educational purposes the complex primary data has to be processed in a manner understandable as simple applications. CERN has developed many such applications and made them available online. In addition, it has invited, those who would like to build similar applications.

A Great Opportunity for India

This is indeed a golden opportunity for researchers and students in India. Indian researchers have been major collaborators in the CERN experiment. But these have been from specialised institutes. India has, at the same time, a large number of institutions teaching and doing research in physics and mathematics, with teachers and students of excellent calibre, but bogged down by outdated syllabus. They have now the ability to access and work on the live data from one of the most complex of the experiments ever carried out in physics. The teachers in these institutions who want to break away from the traditional mould has now tools that can excite brilliant minds to understand how complex problems in physics are addressed. School teachers have an excellent opportunity to ignite the interest of students in Physics.

Physics is seeing exciting times in leading Open Science movement. Indian researchers in physics and in other science disciplines should take an active part in this Open Science movement.

 

Outcome Switching

Make my Trials!

A hot topic that is now being discussed in the scientific research is 'outcome switching'.  In layman’s language outcome switching means the authors of a study did not report something they set about to find they set out initially but included additional outcome without disclosing the result of the original findings, with no explanation for the change. The field is so new that there is no Wikipedia entry on this, yet!

The most discussed case in outcome switching is that of a clinical trial named ‘Study 329’. That study was sponsored by GlaxoSmithKline (GSK) on antidepressant paroxetine with tradename Paxil. The result that was published in 2001, claimed the demonstrated that the drug was well tolerated and effective as an antidepressant for kids. This way in which the result of this study has been published demonstrates what outcome switching is about. 

Study 329 of GSK set out to monitor the efficacy of Paxil as an antidepressant on eight specific parameters. On all these parameters the research showed that it had no significant impact; the drug was no better than the placebo sugar pill. The researchers then came up with additional 19 new measures. Just 4 of the 19 new parameters showed result. In the paper that was published the researchers presented the results on these four only without discussing the other components as if the study was set out to measure the impact of these four parameters only. So even though the pre-decided parameters showed negative outcomes these were not discussed in the publication and few additional parameters that suited the study got reported.

The above is not a rare incident. The Economist reported about a study published in BMC Medicine in 2015 which found that 31% of the clinical trials did not stick to their original parameters. The problem is beginning to receive academic attention. University of Oxford, has launched the COMPareProject. The  project aims to systematically check every trial published in the top five medical journals - the New England Journal of Medicine, the Journal of the American Medical Association, The Lancet, the Annals of Internal Medicine and British Medical Journal (BMJ). The finding so far are revealing. COMPare team has so far studied 67 trials (information in their site as on 3^rd April). They found 9 trials conducted as per original protocol questions. In other cases, they found that 300 outcomes were not reported and 357 new outcomes were added.

GSK’s study 329 was initiated in 1992 and got completed in 1998. 

Fortunately, there has been changes in the regulatory processes after this. All trials have to be registered before they begin and the specified outcomes have to be published on website clinicaltrial.gov or similar national sites.

The website, retractionwatch carries an interview with Ben Goldcare the project leader of COMPare. He explains that not all changes in the outcomes of clinical trials are for nefarious reasons. What is of concern according to him is that when every time outcomes are switched, that creates a culture of permissiveness that lets other people do the same to tweak the trial’s conclusions.

The motivation for outcome switching can be many. Could it be mere survivorship bias? Survivorship bias is the logical error of concentrating on the people or things that "survived" some process and inadvertently overlooking those that did not because of their lack of visibility. This can lead to false conclusions in several different ways. But in clinical trials this can be very costly. But the evidence above weighs otherwise.

But the price may have been paid by patients. GSK's Paxil has been prescribed to millions of children and young adults. By early 2000s its sale was nearly US$ 2 billion a year!

You may read more about it in the Vox article or in the aptly titled article in The Economist - For My Next Trick. 

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.

Ending TB Epidemic – An Unreachable Milestone in Sustainable Development Goals?

Is it possible to end the epidemic of TB in the next 14 years as contemplated in the Sustainable Development Goals? Simple answer is a straight no!

The world is justifiably happy that the Millennium Development Goals (MDG)on TB of arresting and reversing the TB mortality trend has been achieved.  TB mortality has fallen 47% since 1990. This reduction by half is a significant achievement made possible by the enthusiastic implementation of DOTS and WHO and national governments deserve credit.

The Goal 3 of the Sustainable Development Goals (SDG) calls to end the epidemics of AIDS, tuberculosis, malaria and neglected tropical diseases by 2030 and combat hepatitis, water-borne diseases and other communicable diseases.

Achieving SDG targets will require management of the complex drug resistance (DR) problem in TB, particularly in high incidence countries like India.  

Why is it tough

The Global Tuberculosis Report 2015, reported 6 million cases of TB globally in 2014. It is estimated that around 3,00,000 had multi drug- resistant (MDR TB) while only 1,23,000 were detected. 1,90,000 people died of MDR TB. Globally, only 50% of MDR cases get successfully treated. More than half of the global DR TB cases are in India, China and Russian Federation.

As per WHO estimates, the cost per patient treated for drug-susceptible TB in 2014 ranged from US$ 100−500 in most countries. This is mostly met by public health system through DOTS, supported by Global Fund. The cost per patient treated for MDRTB was typically US$ 5000-10,000. The MDR TB costs almost 10 times and does impact national TB budgets significantly. If the large number of undetected MDR TB cases come up for treatment, even at the current costs there will be a significant burden on national TB control budgets. There are limitations on the reach of public facilities and many patients avail private care which is paid out of pocket. That is why there are serious concerns about the cost of new TB drugs.

Experts are unanimous that new drugs are needed to manage drug resistance.

Happily, there are new drugs are on the horizon. FDA has approved Janssen Pharmaceutical’s Bedaquiline (tradename Sirturo), based on Phase IIb results. Its Phase III trials are ongoing. Similarly, Otsuka Pharmaceutical’s Delamanid has also been approved by EMA based on Phase IIb results; its Phase III trials are still ongoing. TB Alliance is testing PA 824 in combination with other drugs. There are other candidates like, Sutezolid, a drug developed by Pfizer, now licensed to Sequella and AZD 5840 of Astra Zenecca.

Concerns

Yet, there are serious concerns of affordability and accessibility of the new drugs. This is due to the particular nature of TB. TB has earned the sobriquet ‘poor man’s disease’, and is prevalent in the less fortunate neighborhoods in the tropics.

The Cost of the New Drugs

Janssen has priced the Sirturo (Bedaquiline) at $ 30,000 in US for the course of treatment. Delamanid of Otsuka is marketed in EU under the tradename Deltyba in Europe and is priced at around US $ 30,000 (Delamanid costs £1,045.83 in UK and €1,500 in Germany, for a course).

The new standard of price seems to be USD 30,000. Janssen is offering the drug at a discounted price of $ 3000 in middle income countries and $ 900 in low income countries.

Even with the discounted price of $ 3000, if we add this price to the WHO’s lower estimate of the current cost of $ 5000, a course of MDR TB treatment with the addition of new drugs could cost around $ 8000. So the MDR TB regimen is likely to cost around Rs 5,00,000 or more in India.

This likely cost of MDR TB regimen would be beyond the means of a large number of TB patients. A comparison could be with the Income Tax payment threshold amount in India. India has a threshold limit of Rs 2,00,000 (~$3000) above which all are required to pay income tax and file returns. As per news reports, only 35 million tax payers (3.5 crore) have income above this limite and pay Income tax, which is just 3% of Indian population. Even in this bracket, the majority of the tax payers fall in the category of Rs 2,50,000 to Rs 5,00,000 bracket

As per the last census, the average household size in India is 4.8. Most of these households may have only one breadwinner. That adds to the financial strains of healthcare. The healthcare costs in India is largely borne by the patients with about 70% out of pocket expense (as compared to less than 30% in developed world). With most of the affected population being poor, the way the new drugs are being priced, MDR TB treatment will be priced out of reach of most of the affected population in the most affected countries.

Affordability is only one part. There is also a more serious concern of access to the new drugs.

Accessibility Issues

Both Bedaquiline and Sirturo are available only to patients in US and Europe, that too in limited numbers. It is reported that by March 2015, only around 1000 patients have received Bedaquiline. The results of the Phase III trials approved in 2013 is yet awaited; an indication of the length and complexity of TB clinical trials. Even if the trials are successful, Janssen has registered the drug only in 21 countries. Otsuka has moved for registration only in Europe, Japan and South Korea. WHO has issued guidelines on the use of Bedaquiline and Delamanid, but the limited access keeps the drugs away from the patients in a large number of countries.  

There is little progress in the case of Sutezolid, which remained dormant in the hands of Pfizer for a long time before Sequalla got the license. Sequalla has not yet announced any plans for trials in the developing world.

On their own the pharmaceutical companies are not interested in venturing into the developing world, as markets TB drugs are not attractive enough.

Affordable Diagnostics

DR TB cannot be tackled detecting it at the earliest. This requires better diagnostics tools that detect resistance which enables the physicians to prescribe the right therapy. The new diagnostics like Xpert are expensive and require frequent purchase of costly cartridges. What is required is an affordable high quality diagnostic tool.  

Concerted Steps Needed

The above background points to the need of concerted action by health policy makers to get new drugs for TB to the patients in the high burden countries. There has to be a global effort to push the clinical trials of all drugs in pipeline in the developing world where the disease is predominant. Conduct of clinical trials will require access to funds and facilities to conduct complex TB trials. The regulatory authorities in high burden countries will have to be equipped to take up registration of new TB drugs on priority. WHO and global civil society and patient groups will have to push for such measures. Unless such steps are taken WHO’s issuance of guidelines for Bedaquiline and Delamanid would only be of academic interest and useless for a majority of the afflicted. A promising candidate which is progressing in trials is PA 824 of TB Alliance which is undergoing trials in combination with other drugs. In line with its mandate TB Alliance is likely to make the drug affordable and accessible.

No such new initiatives are visible, at least in India which harbours one fourth of global TB burden. We seem to be content with the slow progress of DOTS. 

At the rate, we are going, the SDG goals are unlikely to be met, as the deadline is just 14 years away. Without globally coordinated measures to make affordable new drugs available we will still be grappling with the TB epidemic in 2030 and, Goal 3 of SDG will remain elusive for most nations.

The twinning of hope and the despair on the TB drug-discovery horizon reminds one of Charles Dickens:

It was the best of times, it was the worst of times, it was the age of wisdom, it was the age of foolishness, it was the epoch of belief, it was the epoch of incredulity, it was the season of Light, it was the season of Darkness, it was the spring of hope, it was the winter of despair, we had everything before us, we had nothing before us, we were all going direct to Heaven, we were all going direct the other way - in short, the period was so far like the present period…