John G Bartlett, MD

Disclosures

October 16, 2003

Editorial Collaboration

Medscape &

Why Some Companies Are Getting Out of Anti-infectives

Steven Projan, PhD,[1] from Wyeth Research, Pearl River, New York, examined the reasons for the decreasing interest by pharmaceutical companies in developing anti-infectives. He highlighted some of the main reasons: that the global market is flat at $24-$26 billion a year, demands are too high at the regulatory body (the US Food and Drug Administration [FDA]), new agents that target resistance have done poorly (eg, synercid and linezolid), and that there is increasing pressure to use less antibiotics.

The Net Present Value (NPV) is an equation used to predict the value of investment. This is shifting from therapy for acute disease toward long-term treatment of chronic disease. For example, the NPV for a musculoskeletal drug is 1150, for a neuroscience drug it is 720, and for a drug for resistant Gram-positive cocci it is 100. Furthermore, with the delta 10% rule that tightens the statistically acceptable margins for equivalence, this NPV is reduced to 35.

The reason for the problem is multifaceted. The FDA has an impossible job. The public demands drugs that are absolutely safe and cheap, and industry needs to worry about cost containment and review length. An example of the frustration is Ketek, the ketolide from Aventis. It had the largest safety trial ever done (24,000 participants), and Europe has 1.5 million treated patients with no serious side effects, but it is still not FDA-approved.

What is needed to remedy this situation is better science, public funding to define mechanisms of resistance and discovery of novel targets, a regulatory climate that allows multiple indications, surrogate end points and phase 3 studies without comparators, "wild cards" (extension of patents) as a means of incentive, a greater sense of urgency for this issue, and guaranteed markets for niche products.

Why Are Others, Including Biotechs, Staying in the Market?

Karen Bush, PhD,[2] from Johnson & Johnson Pharmaceuticals Research and Development, Raritan, New Jersey, examined why other companies are staying in the field. She said a major reason why they remain is out of need. Although there is an emphasis on the role of HIV, tuberculosis, and malaria as the major microbial causes of death, the leading cause is really acute respiratory tract infection. The continuing need is due in large part to resistance. Nearly all major antibiotics have shown the evolution of resistance within 3 years of introduction. Unmet needs now include methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant tuberculosis (MDRTB), fluoroquinolone-resistant Streptococcuspneumoniae, vancomycin-resistant enterococci (VRE), Pseudomonas aeruginosa, and many others. There are also needs based on safety issues (temafloxacin, trovafloxacin, grepafloxacin), patient convenience (amoxicillin every 8 hours vs every 6 hours, ciprofloxacin twice daily vs levofloxacin once daily), drugs that can be given both orally and parenterally (linezolid and fluoroquinolones), and drugs for new diseases (Legionnaire's disease, Helicobacter pylori, Ebola virus, bartonellosis, severe acute respiratory syndrome [SARS], West Nile virus) and for recurring diseases (anthrax, cholera, dengue).

Developmental issues favor this field. Anti-infectives have the highest rate of success in each stage of development -- phases 1, 2, and 3 -- and for FDA licensing. The development process is comparatively fast and efficient; in vitro studies predict activity, courses of treatment in trials are short, and safety and pharmacodynamics are well defined.

The market is good. The top 3 categories in global pharmaceutical markets are cardiovascular drugs ($67 billion per year), CNS drugs ($64 billion per year), and anti-infectives ($45 billion per year). Of the $45 billion in the anti-infectives markets, 62% is for antibacterials, 12% is for HIV, 6% is for other viral infections, 7% is for antifungals, and 13% is for vaccines and immunology. The 4-year compounded growth rate for anti-infectives is strong at 10%. The best markets for anti-infectives are the United States (48%), Europe (22%), and Japan (13%).

Finally, there is the social responsibility to provide new anti-infectives. Dr. Bush reviewed the mission statements on the Web sites of 15 pharmaceutical companies. They all claimed a societal benevolence such as "citizenship," "social responsibility," and "core values."

Richard White, PhD,[3] from Vicuron Pharmaceuticals, Fremont, California, asked if the rules are different for biotech companies. The rationale to pursue this field is based on medical need, the availability of new targets (antimicrobial genomics), the advantage of highly predictive preclinical data, and the availability of highly defined end points. "Big Pharma" is clearly exiting this field due in large part to economics. But biotech companies "spend other peoples' money," have less complicated infrastructure, and generate funding as a part of their lifestyle. Factors that would help foster more biotech research include decreasing the cost of drug development, incentivizing loans, extending proprietary rights, and collaboration with major pharmaceutical companies.

Anti-infectives and the Regulatory Picture

John Powers, MD,[4] from the FDA discussed the role of the regulatory authorities. The growth of anti-infective development has stopped, he said. The number of new antibacterials licensed by the FDA has steadily decreased: 16 in 1983-87, 14 in 1988-92, 10 in 1993-97, and 10 in 1998-2003. The "pipeline" of drugs in development is relatively dry. There are only 5 new antibacterials, 12 anti-HIV drugs, and 5 other antivirals. The reason is largely economical: other drugs have bigger markets; antibiotics are given for short courses; and the current emphasis is on less use.

The FDA recognizes the problem and has several initiatives to deal with it. These include a list of priority pathogens with the following criteria: prevalent (not vancomycin-resistant S aureus -- only 2 cases), cause serious disease, limited treatment options, public health problems (eg, tuberculosis), and clinical correlation between in vitro and in vivo activity (eg, macrolide-resistant S pneumoniae, which seems to respond clinically despite in vitro resistance). To be a priority, it is not necessary to have all features, but there is a need for clinical data. The advantage is that priority review reduces the time from 10 months to 6 months. An example of the use of this mechanism is the approval of levofloxacin for penicillin-resistant S pneumoniae -- a claim approved and based on just 15 cases.

Suggestions made by Dr. Powers to improve development in this area included:

  1. A recognition of the advantages of anti-infective development by pharmaceutical firms -- good preclinical data based on in vitro sensitivities and pharmacodynamics;

  2. The use of data from one study to support claims for another indication (factors such as comparability in severity, drug penetration, etc must be accounted for);

  3. The need for placebo-controlled trials for diseases in which spontaneous cure is likely (eg, otitis, sinusitis, and exacerbations of chronic bronchitis);

  4. The use of surrogate end points (eg, the use of viral load for anti-HIV drugs as a surrogate for clinical end points);

  5. Single studies have pitfalls (eg, data from 5 trials of a new antibiotic for community-acquired pneumonia showed 2 better than the comparator and 2 worse [1 was a tie]);

  6. Use of novel end points (eg, time to recovery for travelers' diarrhea and anti-influenza drugs);

  7. High-quality studies can decrease the quantity; and

  8. Microbiological end points are good, but FDA needs clinical data.

Powers concluded that there are real, high-priority needs, and FDA guidance in this area is forthcoming. There continues to be a need for high-quality data, and the process can be streamlined at the same time that the FDA continues its mission of ensuring efficacy and safety.

Summary

There is no question that new drug development in anti-infectives is decreasing dramatically at the time of escalating need based on bacterial resistance and new high-profile diseases such as SARS, anthrax, smallpox, and West Nile virus. The reason is not mysterious. Other disease categories are simply more attractive economically. The real question concerns the mechanisms necessary to reverse this process. Specifically, we need to find what incentives would be necessary and how we achieve them once they are identified.

References
  1. Projan SJ. What is NPV and why is it killing my research? Program and abstracts of the 43rd Annual ICAAC; September 14-17, 2003; Chicago, Illinois. Abstract 1124.

  2. Bush K. Why are some companies electing to stay in this field? Program and abstracts of the 43rd Annual ICAAC; September 14-17, 2003; Chicago, Illinois. Abstract 1125.

  3. White RJ. Are the rules different for biotech companies? Program and abstracts of the 43rd Annual ICAAC; September 14-17, 2003; Chicago, Illinois. Abstract 1126.

  4. Powers J. Program and abstracts of the 43rd Annual ICAAC; September 14-17, 2003; Chicago, Illinois. Plenary session.

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