Roscigno: diagnostics need a push up

4 Nov 2010

TropIKA.net team

Source: TropIKA.net

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Dr Georgio Roscigno.

Technology already installed throughout the US mail system to detect anthrax in the post could soon be deployed for tuberculosis diagnosis.

The development of an automated molecular test, called Xpert MTB/RIF, was reported in the New England Journal of Medicine [1] in September. The test can detect TB – and also the presence of resistance to one TB drug, rifampicin – in 90 minutes. It was trialled in five sites – from Lima, Peru to Mumbai, India and South Africa – by the Foundation for Innovative New Diagnostics (FIND), a product development partnership dedicated to developing diagnostic technologies for low-income countries.

Georgio Roscigno, who helped create FIND and has run it since launch in 2003, says the new test is the greatest advancement in FIND’s TB portfolio to date. (FIND also works on malaria and sleeping sickness diagnosis.)

The gold standard of TB diagnosis (culturing TB in a Petri dish) is over a century old and can take weeks to produce results. So, whilst it is accurate, patients must travel great distances to reach health centres where they can be tested and they often fail to return to collect their results.

The most popular alternative in developing countries is the sputum smear test, which is much quicker but notoriously inaccurate. Often it indicates that a patient does not have TB (i.e. is smear negative) when in fact he or she does have the disease and needs treatment. As a result, people with TB often return home untreated and spread the disease further.

FIND’s new test will mean that patients are not forced to return to clinics weeks later for results and that they will be more likely to be treated for TB, if they have it, says Roscigno. It can pick up 75% of people who would have been reported as smear-negative cases but actually have the disease. Such misdiagnosis is particularly common in HIV patients, who have weakened immune systems and produce fewer numbers of TB bacteria in the sputum, making their presence harder to detect. “This has tremendous implications in highly endemic HIV areas,” he says.

Roscigno has tried to steer the organization towards important milestones in recent years. He wants more successes in diagnosis further down in the public health system. “We have been thinking more about technology platforms for different levels of the health system and are getting extremely near to the community health workers, where you can screen large populations of patients,” he says.

Technology for the front line of care

Today the most advanced, accurate and fast technologies – such as polymerase chain reaction (PCR) – are often limited to cities where there is supply chain infrastructure, diagnostic expertise, equipment and electricity. And some of FIND’s past successes in TB have been focussed on tools that could be used in such better-equipped laboratories: for example, a PCR-based line-probe assay that helps to identify multi-drug resistance is now being introduced to regional labs in 27 countries across the world.

Roscigno says Xpert represents the first molecular technology that can be used at district and sub-district level in developing countries, because it automates many PCR processes and so does not require as much specialized training to use. Other technologies, such as the loop-mediated isothermal amplification technology platform (LAMP), which goes into trials in October, could be employed at even lower levels of health care, including isolated rural health centres with very basic facilities.

Another key change in FIND’s strategy has been to create kits that can be used to diagnose more than one disease. That is why, as well as TB diagnosis, both LAMP technology and Xpert might, in theory, be developed to assess viral load for HIV. Screening for human papiloma virus (HPV) or detecting Chagas disease or leishmaniasis are other possibilities. FIND has been working with Murdoch and Obihiro Universities, as well as research institutes in endemic countries, to develop LAMP-based tests for human African trypanosomiasis (sleeping sickness) diagnosis and with the Hospital for Tropical Diseases in London (HTDL) to investigate the possibility of a LAMP test for malaria. “We wanted to make sure we didn’t develop push any technology that is serving any one disease,” Roscigno says. In addition, he plans to expand to include non-communicable diseases such as diabetes.

In addition to developing technologies, Roscigno has ensured that FIND works on implementation too. It devises strategies to disseminate the technologies once they are proven and to strengthen the laboratories where they will be used. It also conducts implementation research to check that tools can be successfully incorporated at scale into the public health system, and assess how they are used once on the market. It has embarked on a project with WHO to rank the performance of malaria rapid diagnostic tests (RDT), in an effort to help countries buy the most accurate tests.

A change of focus

Roscigno’s priorities are now developing single platforms for multiple diseases and access strategies to get them to where they are needed. This is surely a world away from much of his career, which focused solely on developing tools for single diseases.

Working for Merrell Dow Pharmaceuticals, which later became Hoechst Marion Rouelle then Aventis (and today is Sanofi Aventis), Roscigno was in charge of clinical research of the tuberculosis drug rifapentine, as well as the development of fixed-dose combinations of TB drugs that made treatment of the disease more effective.

He also worked on eflornthine (difluoromethylornithine or DFMO), or, a compound that is able to interrupt cellular replication by activating an enzyme crucial for cellular duplication. He became involved in trials and registration of DFMO as a treatment for sleeping sickness in several countries. The trials were supported by the Special Programme for Research and Training in Tropical Diseases (TDR).

At the end of the nineties, Roscigno was asked to start up one of the first product development partnerships, the Global Alliance for TB Drug Development. He was asked to join – he thinks – because there were so few available candidates working in TB drug development at the time.

Ironically, the Alliance’s remit was to create a portfolio of TB drugs in the absence of any meaningful R&D by the industry to which Roscigno belonged at the time. He was director of anti-infectives in Paris and says the entire market was shrinking at the time, even in developed world. He believes that Aventis would have been willing to work on existing classes of drug, but not new molecules that could reduce treatment times and tackle multi-drug-resistant TB). “There was a failure and weak interest in completely new compounds that we thought were absolutely needed to reduce the time for treatment to two or three months,” he says.

Making the leap out of industry after 19 years, Roscigno started the Alliance as a one-man-band, setting up its offices in New York and Brussels. He established its scientific advisory committee and set about creating what is now an extensive portfolio of molecules.

After two years as acting chief of the TB Alliance, by which time the organization looked pretty well-established and well-funded, Roscigno started looking at diagnostics. It had emerged as a remarkably underserved area and – under the guidance of Peter Small at the Bill & Melinda Gates Foundation – Roscigno started work on establishing FIND, a new product development partnership dedicated to diagnostics. FIND was launched over a year later at the World Health Assembly in 2003 (TDR provided expertise in diagnostic resources, under the then-director Carlos Morel.)

Perhaps Roscigno’s focus on specific diseases is unsurprising. Born to an Italian father and a half-Italian-half-Ethiopian mother in today’s Eritrean capital Asmara, Roscigno’s says his links with Ethiopia extend several generations. His grandmother, mother, wife and eldest daughter were all born in Ethiopia. “I am Ethio-Italian but have a close emotional and real connection with Ethiopia,” he says. And his first job as a doctor, after studying in Europe, was home in Eritrea. His work for the next five years also took him to Algeria, Sudan and Zaire (today known as Democratic Republic of Congo). Infectious diseases were part and parcel of his work in these countries, he says.

Roscigno does not regret leaving medicine for the private sector (he was recruited to Merrell as medical director for Africa), because he felt as if he was working on diseases specific to the region – tuberculosis and sleeping sickness. Indeed industry armed him with skills that have proved vital to his work with public–private product development partnerships (PDPs).

Although he admits he could probably have left industry a few years sooner, he says that, “Everything I learned is paying me back every day in the work we do here at FIND. The focus, the sense of urgency, accountability comes from quite a very strong experience from that side.” Certainly, his experience of working in industry helps in the negotiations with the large number of companies that developed technologies such as the line-probe assay, Xpert and LAMP. (He had already managed to negotiate a deal with Chiron/Pathogenesis to buy a TB drug candidate, PA824 while at the Global Alliance. PA824 is now one of the alliance’s most promising molecules)

Back at FIND in Geneva, Roscigno admits that diagnostics still have a long, long way to go. Initial reactions to Xpert are that it may be too expensive, even if used in large volumes. [See TropIKA.net article.]

Rapid diagnostic tests for TB, which are simple to use and could be deployed on a large scale by community health workers, are a long way off too, despite Roscigno’s assertion that FIND is getting further into the public health system.

About two years ago, the organization had to face a tough reality – that creating accurate rapid diagnostic tools using existing knowledge had been extremely unsuccessful to date. Existing tests have not been accurate enough to use with any degree of confidence in the field.

FIND, as a result, has since been forced to go back to the drawing board. That means venturing for the first time, into basic research to find new antibodies and antigens that might be used to create a new generation of rapid diagnostic tools. With partners including the Public Health Research Institute, New Jersey Medical School, FIND has now identified completely new proteins that must now be whittled down to the most effective predictors of disease [2].

To compound the problems, the money available for research into diagnostics is tiny, especially compared with drugs and vaccine research. How FIND expects to fund basic research, technology development and implementation, as well as to broaden out to non-communicable disease diagnostics is unclear.

The foray into multiple platforms, multiple diseases and new basic research techniques, is informing Roscigno’s work on the Global Report on R&D into infectious diseases of poverty, initiated by the Special Programme for Research and Training in Tropical Diseases (TDR). Co-author of a chapter on innovation, he says that many of techniques – he calls them technological platforms – could be harnessed for the development of new drugs, vaccines and diagnostics by middle-income, emerging and low-income countries. With more systematic and proactive approaches, these countries could address more research questions and, eventually, generate their own tools, he says.

“Biotechnology platforms can spin off in different directions,” he explains. “So you might identify biomarkers that have good capacity for the identification of new proteins with immunogenicity, the capacity to become translated into a new test to detect TB or there may be a protein that could fit more into vaccine discovery,” he says.

Different countries – including those where the diseases are endemic – could then share out the products of this initial research between them, so each can focus on developing different tools. “That single platform might one day be used for the translation of new ideas of research into products that are specifically aligned to the priorities of those developing and middle-income countries,” he says.

About Georgio Roscigno

Born: Asmara, Eritrea. 8th December, 1947. Married, two children.

Education:

Università Cattolica del Sacro Cuore Facolta’ di Medicina e Chirurgia, Rome, Italy. 1965–1972.
Certificate in Tropical Epidemiology, Institute of Tropical Medicine, Amsterdam, Netherlands. 1983.
Certificate in Clinical Trials, London, UK. 1984.
Diploma in Tropical Medicine and Health, New York Medical College, New York, USA. 1988.

Career:

FIND (Foundation for Innovative New Diagnostics): Chief Executive Officer, Geneva, Switzerland. 2003 – present.
Global Alliance for TB Drug Development: Acting Chief Executive Officer; Senior Advisor; Director of Strategic Development, Brussels (Belgium) and New York (USA). 2000–2002.
Aventis International: Medical Director Anti-infectives, Paris, France. 1998–2000
Hoechst Marion Roussel: Global Rifamycin Development Director, Addis Ababa, Ethiopia – Milan, Italy 1996–1998; Global Medical Development Director, Milan, Italy.1993–1996.
Marion Merrell Dow: Clinical Research Director Europe – Anti-infectives, Winnersh, UK. 1990–1993.
Merrell Dow Research Institute: DFMO (eflornithine) Clinical Research leader; Medical Director for South East Asia; Global Rifamycin Director, Strasbourg, France. 1987–1990.
Dow Lepetit – Merrell Dow: Medical Director Africa; Rifamycin Global Medical Director, Geneva, Switzerland. 1982–1987.
Impresa Sapiem: Health Director, Hassimessaoud, Algeria. 1981.
Ospedale Civile di Arezzo : Medical Intern in the local Hospital, Arezzo, Italy 1979–1982.
Impresa Recchi: Health Director, Kosti, Sudan. 1977–1978.
Impresa Astaldi: Health Director, Kinshasa, Zaire. 1976.
Italian Embassy: Coordinator of Health Activities, Addis Ababa, Ethiopia. 1974–1975.
Ospedale Italiano – Hospitem: Medical Internship and assistant of Medical Director, Asmara, Eritrea. 1972–1974.

References

1. Boehme CC, Nabeta P, Hillemann D, Nicol MP, Shenai S, Krapp F, Allen J, Tahirli R, Blakemore R, Rustomjee R, Milovic A, Jones M, O'Brien SM, Persing DH, Ruesch-Gerdes S, Gotuzzo E, Rodrigues C, Alland D, Perkins MD (2010). Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med; 363(11):1005-1015. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20825313

2. Kunnath-Velayudhan S, Salamon H, Wang HY, Davidow AL, Molina DM, Huynh VT, Cirillo DM, Michel G, Talbot EA, Perkins MD, Felgner PL, Liang X, Gennaro ML (2010). Dynamic antibody responses to the Mycobacterium tuberculosis proteome. Proc Natl Acad Sci USA; 107(33):14703-14708. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20668240