Orphans and Incentives Developing Technology to Address Emerging Infections (1997) / Chapter Skim
Currently Skimming:
Workshop Summary
Workshop Summary
Pages 9-46
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 9... ...
, World Bank, and World Health Organization (WHO:realized that accomplishment of that mission would be impossible without collaboration between the public sector and industry. Although the public sector in the United States had historically conducted most of the basic research leading to development of new or improved vaccines, product-oriented R&D was undertaken almost exclusively by vaccine manufacturers and development-stage firms, with only a handful of major commercial vaccine manufacturers having the capacity to scale up and manufacture vaccines on the large scale required for global application.5 The public sector had tended to look at vaccines as a separate series of scientific problems, or as product development problems, or as delivery problems, rawer Han as an "end-to-end," integrated *
|
From page 10... ...
The implications of this prospective cross-sectoral strategy would prove to be far greater than anticipated, rooted as they were in distinct sectoral cultures, divergent incentive structures, and mutual perceptions that augured poorly for authentic collaboration. The public sector had historically denigrated the profit motive, correspondingly mistrusted all industrial motivation, and did not fully understand the real costs and effort involved in developing a vaccine.
|
From page 11... ...
Defining, Creating, and Stabilizing the Market Situation Analysis There is consensus that a most useful and in many ways groundbreaking CVI undertaking was the contracting out, to professional private-sector management consultants, of the task of analyzing the economics of the vaccine industry, thereby providing a fresh evidence base for policy determinations.6 The first situation analysis by Mercer Management Consulting calculated the size of the world vaccine market in 1993, then estimated at around $2 billion annually, and revalued it at almost $3 billion and growing rapidly; the basic pediatric vaccines accounted for one-third of that market. The report also discussed the dynamics of the world vaccine market and examined the role of large-scale purchasin, by donors.7 Overall, the study provided both sectors with a common understanding of economic realities, helped the public sector feel informed and therefore able to work with industry as an equal partner, effected change in public-sector strategies, and modified industry perceptions of market potential.
|
From page 12... ...
A global targeting strategy for sustainable vaccine supply, as defined by Bards A-D, and market segmentation and tiered vaccine prices according to the primary market of international suppliers, direct procurement, local production and the UNICEF market.
|
From page 13... ...
and, eventually, pneumococcal conjugate vaccines they have worked together to find ways to make procurement processes more flexible and to explore with industry ways to create value other than price for example, "bundling" vaccine orders, using supply contracts, and extending contracts beyond the typical duration of two years." These approaches and other efforts at true partnership have motivated some vaccine companies to donate vaccines, provide cash grants to special immunization programs and disease surveillance, lower prices, make selected new products available in some preferential fashion, and furnish R&D pipeline information for assessment by WHO/UNICEF advisory groups. Tiered Pricing The backbone of public-sector access to new vaccines is a strong "tiered" pricing system in which the relative ability to finance vaccines is translated into different price levels for different countries.
|
From page 14... ...
The mechanism could conceivably play a role in connection with emerging infections HIV/AIDS may prove to be the most immediate example but the public sector has yet to frame a refined and thoughtful argument to take to the Congress for more reasoned, less stereotypic discussion than has been the case. The task cannot be done by industry alone, because its motives will inevitably be perceived as suspect, particularly when the topic is a "public good" with undertones of entitlement.
|
From page 15... ...
A CVI-sponsored meeting in Brazil in 1995 explored the position previously held by many in the public sector that patent protection was an obstacle to vaccine production in developing countries. At a CVI-sponsored follow-up meeting in Bellagio, Italy, in February 1997, it became clear that protection of and respect for intellectual property are now seen as rational and defensible stimuli for further innovation, a position that has been adopted as a focal activity for the CVI and for the International AIDS Vaccine Initiative (see following discussion)
|
From page 16... ...
This history was contrasted with that of the 1976 swine influenza vaccination program, when what has been called a disaster ensued as a consequence of an agenda that did not adapt to shifts in circumstance.' Despite disparities between many aspects of the two events, they send a similar message: the need for a scientific and technical consensus; an explicit decision in advance as to the market for a successful R&D effort; periodic review and reevaluation that is both broad and meaningful; and, throughout, close consultation between public- and privatesector collaborators. The swine flu affair taught an additional lesson of prospective relevance to emerging infectious disease: Programs to prevent such diseases are essentially insurance policies, entailing some risks almost by definition, rather than subjects for punishment when anticipated dangers fail to materialize.
|
From page 17... ...
.'7 OTHER MODELS The Malaria Vaccine Development Board Malaria is not a formal focus of the CVI but is nonetheless highly relevant to a discussion of the CVI because of the disease burden it generates for children and because of the practical and theoretical challenges it shares with the Initiative. And, of course, malaria is most relevant to Forum concerns about the special challenges of addressing those emerging and reemerging infections that predominantly threaten the developing countries.
|
From page 18... ...
The combination of some or all of these factors, together with failure in earlier commercial development efforts, deeper understanding of the technical challenges involved, and an erratic pattern of support for public-sector malarial research, was what had led to attrition in the relatively few industrial and public-sector R&D efforts that had managed to get under way.20 The IOM committee's primary conclusions were that the dimensions of the problem demanded a commensurate commitment, and that the United States would have to take a leadership role in the search for a malaria vaccine. A secondary conclusion was that the tasks at hand making the international case for support, attracting many more resources from all sectors worldwide, assembling the critical scatterings of intellectual property, performing a competent reassessment of developing world market realities are necessarily multisectoral activities.
|
From page 19... ...
The IAVI and the notion of the Malaria Vaccine Development Board were included in the workshop discussion as possibly informative variations on the CVI approach to solving a "social product" problem. The exploration that led to the establishment of the IAVI in 1996 began in 1993, when HIV vaccine research, stymied by technical difficulties, was at a nadir in comparison with the level of investment in HIV/AIDS therapies.
|
From page 20... ...
AN INDUSTRY PERSPECTIVE ON THE EMERGING INFECTIONS AGENDA * Periodically, the Pharmaceutical Research and Manufacturers of America (PhRMA)
|
From page 21... ...
Although there is understandably some overlap of products, particularly for opportunistic infections occurring in AIDS sufferers and in the general population, the total of the two surveys places the number of clinical research projects currently in process for infectious disease at well over 200. In 1996, industry R&D expenditure on infectious disease of $2 billion was exceeded only by industry R&D expenditures in the categories of cardiovascular disease, cancer, and neurobiological disease.24 Many of these projects are not new anti-infectives but new dosage forms or new indications for established products.
|
From page 22... ...
SOURCE: J Siegfried, Pharmaceutical Research and Manufacturers Association of America, annual survey: New Medicines in Development for AIDS (1996~.
|
From page 23... ...
Fourth, global surveillance for antimicrobial resistance and for emerging infectious disease is progressing. WHO's Division of Emerging and Other Communicable Diseases and Surveillance and Control has made "WHONET" software available to laboratories in its global network for the input of antibiotic resistance data, and PhRMA's contribution in June 1996 helped make possible the extension of WHONET to Africa; the International Federation of Pharmaceutical Manufacturers Associations (IFPMA)
|
From page 24... ...
, yet another agency/industry/academic collaboration, has been charged with answering the following, generic question: Where does drug development time go? The question assumes paramount importance in the context of emerging infections.
|
From page 25... ...
LEGAL AND REGULATORY ISSUES Another area where disincentives to pharmaceutical research and development are said to reside is the legal and regulatory domain. Questions for the Forum have to do with the extent to which any of those disincentives applies to emerging infections, notably in connection with the widening range of threats from antimicrobial resistance and, more positively, whether there are incentives within that domain that could be brought into play.
|
From page 26... ...
There are other legal and regulatory issues that lie beyond this special category of exception that are consequential for emerging infectious diseases. These include the labeling of existing antimicrobials; product availability; international harmonization of pharmaceutical regulations; intellectual property rights; and another category of exception, "orphan drugs." ., Accelerated Approval and Development of Drugs for Serious and Life-Threatening Illnesses Clinical Studies FDA approval of new compounds is often constrained by difficulties inherent in clinical trials.
|
From page 27... ...
Should the studies fail to confirm the validity of the surrogates, the regulations also provide for quick removal of the product from the market, although this is difficult for the agency in practical terms and probably disappointing to industry. Restricted Distribution and the Matter of Antimicrobial Resistance The accelerated approval regulations also carry an option for restricted distribution of a product if there is reason to think that it should be made widely available only after confirmatory studies have been implemented.
|
From page 28... ...
Absent such information, antimicrobials are prescribed presumptively and therefore, in some cases, inappropriately. The availability of rapid, low-cost diagnostics at the point of care would reduce such misapplications and would also serve the urgent needs of the public sector and industry for ongoing data on patterns of disease and the evolution of resistance.
|
From page 29... ...
The budget for WHO's pivotal role in bringing together the different surveillance networks worldwide is $17 million, an amount generally seen as insufficient. The CDC appropriation for FY1997 was $44 million out of the $125 million estimated as needed annually to implement its Emerging Infections Strategy, the first component of which is addressing surveillance and response needs.30 Funding at the state level, even in states that are disposed to support infectious disease programs and that have been designated as CDC emerging infection program (EIP)
|
From page 30... ...
Intellectual Property Rights Revisited In the case of emerging infections, lack of patent protection may be acting as a major disincentive in at least one possibly important respect. Among the hundreds of potential antibiotics left undeveloped on company shelves, some compounds
|
From page 31... ...
If the active ingredient has been previously approved by the FDA and new clinical studies are essential for the approval of the product, then the innovator is protected from ANDA generic competition for a period of 3 years from marketing approval. Two limitations inherent in the act reduce its value as an incentive for companies to pull existing compounds with expired patents off their shelves for application to emerging infections.
|
From page 32... ...
If, for example, there are many products in the R&D pipeline, perhaps an infectious disease equivalent to the Orphan Drug Act might spur those products to market and thus justify further consideration. If, however, the objective is to stimulate research on entirely new classes of products to diagnose and treat infectious disease, an orphan drug clone would be inappropriate and legislatively improbable.
|
From page 33... ...
Overall, public-sector thinking is oriented toward foundation issues: encouraging basic science and its translation into products; understanding and strengthening systems; gathering and disseminating good data; and, throughout, seeking participation by the private sector and developing the contexts that will make that possible. By these accounts, the public sector has not yet developed a list of emerging infectious diseases that might constitute the kind of R&D "menu" that some industry representatives have indicated could be useful.
|
From page 34... ...
Another important lesson for the public sector was reinforced in the conclusions of the CVI/ Rockefeller Bellagio meeting, namely, that the public-sector international organizations still have much to do to fulfill their responsibilities in the public/private partnership, including, importantly but surely not limited toproviding earlier estimates of demand for public health products and fully engaging in well-articulated advocacy for public health needs. An ancillary fundamental was acknowledgment of what are basic disparities between the two sectors in the understandings of risk.
|
From page 35... ...
This has involved tactics such as price tiering and attempts to enhance market exclusivity, all possibly relevant to emerging infectious diseases, some still incompletely resolved, none simple. Authentic Collaboration Particularly difficult was learning to implement collaboration in ways that go beyond rhetoric.
|
From page 36... ...
36 Cd m o ¢ ~ ~ ~ ~ ~ cat o ¢ ~4 a Cal o ._ C)
|
From page 37... ...
Issues for Resolution Other issues arose in the workshop that go beyond vaccines and were identified as being of special, even profound relevance to emerging infectious diseases, especially when those diseases are likely to be commercial orphans. In their majority, these are areas of tension concerning mechanisms that could stimulate the research that is most directly necessary for addressing emerging infections, but that are somehow problematic.
|
From page 38... ...
Funding Inadequate funding appears to be an issue at every level of infectious disease surveillance, as evidenced in insufficient infrastructure, inability to support recurrent costs, or both. These problems are not exclusive to the developing world; the surveillance capability ofthe United States is similarly threatened..The subject of emerging infectious diseases has commanded interest in the U.S.
|
From page 39... ...
Surrogate Endpoints The identification and use of surrogate endpoints has been critical for developing new products to address the AIDS pandemic and is part of the FDA strategy for accelerated approval of certain product classes. The development of generic categories of endpoints that might be used in connection with a range of infectious disease endpoints is an issue awaiting consideration, as is the development of alternatives to correlates of protection for vaccines against diseases for which clinical trials would be difficult or even impossible, for example, the case of Ebola virus or pathogens used in biowarfare or bioterrorism.
|
From page 40... ...
Furthermore, even though congressional receptivity to utilization of orphan drug legislation for generic public health needs has been limited, prospects for orphan drug designation seem to be more likely when the objective is to spur products already in company pipelines to market. The challenge is then to define what products are needed for what emerging infectious diseases and to seek to make a match with what industry may have in relevant pipelines.
|
From page 41... ...
3. The CVI now defines itself as "a coalition committed to expanding protection against infectious diseases, particularly through the development and introduction of new and improved vaccines" (CVI Secretariat, Conclusions from the CVI/Rockefeller Foundation Bellagio Conference on the Global Supply of New Vaccines, 2-7 February 1997, Geneva, World Health Organization, 1997~.
|
From page 42... ...
The Mercer report did not address at least two issues that are especially relevant to emerging infectious diseases. The first question is whether benefits from economies of scale will apply to new vaccines; for example, increasing lot size for vaccines involving conjugation technology may be more complex and costly than for the current vaccines.
|
From page 43... ...
human papillomavirus, pelvic inflammatory disease, and cytomegalovirus. (Pharmaceutical Research and Manufacturers of America, New Medicines in Development for Infectious Diseases: 1996 Survey, Washington, D.C., 1993.)
|
From page 44... ...
was to restore part of the patent life lost during the regulatory approval process. It allows extension of the patent term to a period equal to the total time taken by the ORPHANS AND INCENTIVES Pharmaceutical Research and Manufacturers Association
|
From page 45... ...
The limitation on population size is based on prevalence, defined as the number of persons in the United States diagnosed as having the disease or condition at the time of the submission of the request for orphan drug designation, in other words, confirmed cases.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.