The Second International China BioPharmaceutical Symposium:
Executive Summary of Session Presentations
All of the over 150 participants in this second International China BioPharmaceutical Symposium (ICBPS-2), are to be commended for their highest degree of professionalism as demonstrated by their presentations and their attention to details of their fellow presenters. Please see the Notes that follow the final session, Session VI.
Session 1: ICBPS-2 Overview and General Vaccine Development
Chair: Dr. David Robinson, Vice President and Chief Biologist, Battelle Memorial Institute, US
Co-chair: Professor Shen Xinliang, Director National Vaccine and Serum Institute, China
This session provided an overview of current regulatory initiatives with insights into how several countries are approaching compliance with current and predicted regulatory activities.
The “globalization” of the world economy and the rapid spread of biological technologies have produced both an opportunity and a problem for products developed, manufactured, tested and marketed under strict regulatory requirements. These products include drugs and biological products. Many companies would like to manufacture their products or the active pharmaceutical ingredients external to the country of licensure or to expand the market for their products into additional countries which require compliance with the local laws and regulations.
Unfortunately, there is no conformity of these among the countries of the world other than in the European Union (EU). The World Health Organization (WHO) has developed a series of guidelines for individual products that are intended to be incorporated into the legal structures of the individual states. Not all states have adopted these guidelines; and in those states that have, the implementation of the guidelines varies from state to state. While this generally provides assurances of purity, safety, potency and efficacy, it does not provide a uniform path to product licensure in multiple countries.
A specific example is what has come to be known as the “animal rule” in the United States (US). This rule provides for the licensure of products for which human clinical trials would be impossible or unethical. While this rule has been implemented in the US, it has not been adopted by any other country. This leaves the manufacturer with an unknown mechanism to expand the market for drugs and biologics intended to prevent or treat serious diseases that do not naturally occur at predictable incidences in known populations. The US is in the process of stationing employees of the Food and Drug Administration (USFDA) to foreign countries and areas such as China, India, Japan, Latin America, Europe and the Middle East. While this is an interesting strategy to increase the quality of products imported into the US, it does not promise to harmonize the manufacturing procedures and testing necessary for broader licensure.
A companion problem has been the cost of biotherapeutics. The extensive and expensive R&D required to develop candidate products, the number of these products that fail in testing prior to licensure, and the regulatory requirements for sophisticated facilities and equipment and highly skilled personnel all serve to increase the cost of an individual dose. To expand the ability of developing countries to access the vaccines and biotherapeutics, mechanisms should be made available to share the risk and cost of developing, producing and testing such products.
Considering the variation in the strategies of different countries to provide these vital components of the public health armamentarium, this problem will probably have to be resolved by meetings at the WHO or other multinational NGO.
China has launched an aggressive program with multiple platforms to develop vaccines for drug resistant tuberculosis and other diseases endemic to China, along with additional general procedures for the development and production of future biopharmaceuticals. This extensive multiyear program promises to increase both the quality and availability of vaccines for the Chinese population.
Session II: Quality Control and Regulation
Chair: Prof. Wang Junzhi, Deputy Director National Institute for the Control of Pharmaceutical and Biological Products (NICPBP), China
Co-Chair: Dr. Ivana Knezevic, WHO, Geneva, Switzerland
Summary details are to be supplied (TBS). As an overview, Session II included five very interesting presentations: an in-depth look at European Union regulatory affairs for medicinal product registration; a presentation on a quality control study of a pandemic influenza vaccine; a preclinical safety assessment of vaccines; a presentation on intellectual property (IP) and biotechnology in the P. R. China; and a presentation on safety considerations in the approval of pharmceuticals/biopharmaceuticals
Session III: Vaccines and Biopharmaceutical R & D
Chair: Prof. Filiz Hincal, Haceteppe University, Ankara, Turkey
Co-Chair: Dr. Xiaomi Tong, Emergent Biosolutions, Rockville, Maryland USA
Quality control studies conducted at the 3rd division of viral vaccine of NICPBP on the biological and genetic stability, standardization and validation of pandemic influenza vaccine, which is produced by using a virus strain derived for the first time by a reverse-genetic technique, were presented. Quality control was also assessed by the evaluation of immune response, by both HI and micro-neutralization tests, on sera samples taken from the volunteers in pandemic influenza vaccine clinical trials.
Researchers of Chongqing Biopharmaceuticals Engineering Technology Research Center developed an oral recombinant Helicobacter pylori vaccine as a new class of the national biological product. Phase I, II and III clinical trials have been completed with more than 5500 volunteers with satisfactory safety and immunogenecity. The antigen-specificity antibody positive rate was over 85%, the protection rate was 72%. The vaccine is now under the process of approval of SFDA.
Development of a Japanese encephalitis live-attenuated vaccine by NICPBP is produced by using an attenuated encephalitis virus strain (SA14-14-2), was described. Safety and immunogenecity evaluation were done on almost 600,000 children ages of 1-15 years. Total reaction rate was 6.5/10,000 and there was no report of severe reaction after immunization. Efficacy was 99.3-100%, and after 5 years of one dose of vaccination the protection rate was still 96%.
The study presented by the research group of Guangxi Center for Disease Control and Prevention described the clinical trial conducted on about 10,000 volunteers to verify the safety and immunogenecity of a local Haemophilus influenza type b (Hib) vaccine. No serious adverse reaction was found in this trial, and their data showed the safety of vaccine that could induce satisfactory specific antibody response.
Research interests, strategies and activities of Battell's Health and Life Science were presented, and recent initiatives on the development of cutting-edge technology and biomarkers were also discussed.
Session IV: Vaccines and Biopharmaceutical R & D
Chair: Dr. Peter Leitner, President MaxWell USA, LLC
Co-Chair: Prof. Lou Jue-Ren, Shanghai Institute of Biological Products, China
Session IV covered a wide range of issues concerning both elemental and applied research on a variety of transmissible diseases.
One presentation focused the prevention of TB by the use of a recombinant Vaccinia Virus. The results reportedly displayed a 30% protective rate but offered no protection for those already infected. Nor did it offer any assistance for patients with compromised immune systems. Efforts are underway to boost the effectiveness of this approach, which currently performs best with younger children rather than older patients.
Another presentation focused on bird flu (H5N1) by reporting on known human cases. Both the US CDC and China (State) CDC are exploring all known strains (China has 3-4 domestic strains) to focus on vaccine development to prevent pandemic outbreaks, but it is up to the World Health Organization to develop standards for preclinical and clinical studies. It was pointed out that no natural human antibodies against H5N1 exist. Currently the Vietnam strain has a better antibody effect but an annual booster injection is needed to maintain protection. An interesting caveat was offered by one Chinese presenter “Our research can not be compared with Western research as we publish very quickly and share our findings.” Another experience described using serum taken from a patient to inject into a second patient. This second patient was saved as a result.
Another very interesting presentation on findings of H5N1 studies raised the following issues: what kinds of serotypes should be used? Antibodies transmitted to children via mothers need further study as no data exist. A review of data will focus on vaccinations of mothers and whether or not these afforded any protection to the child.
Our final presentation was also very interesting. It offered an insight into the development of transgenic vegetables as a delivery vehicle for an edible hepatitis B vaccine. It was pointed out that traditional vaccine delivery does not help gastro, respiratory and genital tracts interlinked via mucosa. It was argued that oral delivery may be very effective in high-level antibody production and holds great promise for a variety of applications to include: HIV/AIDS and the pox virus - as well.
Session V: Vaccine/Biotechnology Development
Chair: Dr. Jerome Donlon, Chief Science Advisor, BARDA/DHHS, USA
Co-Chair: Mr. Liu Jianzhong, Sanofi Pasteur, China
This Session included a variety of topics related to the development of vaccines and therapeutics.
A presentation on the sequencing of the whole genome of a vaccine strain virus emphasized the importance of this critical information in the analysis of the epidemiology of disease outbreaks and the development of appropriate vaccines.
Vaccine effectiveness can be optimized by using relevant epitope targets, adjuvant formulations or delivery techniques. The use of intradermal micro needle delivery of a current seasonal influenza vaccine was presented. The results of clinical studies showed that the intradermal delivery of the vaccine provided an adequate and robust immune response, comparable to that of an intramuscular injection. Of specific interest was the result in the elderly (age 60 or older) population. The intradermal micro needle system gave some transient local reactions and no systemic reactions.
The issue of passive immunization or therapy using selected monoclonal antibodies was discussed. A system for the selection of human monoclonal antibodies was briefly presented. This system was applied to selecting monoclonal antibodies active in neutralizing the PA and LT toxins of bacillus anthracis. Animal studies indicated that a combination of the monoclonal antibodies was more effective than the use of either alone.
The critical issue of biosecurity-biosafety-bioethics as it applies to laboratories and researchers working with highly pathogenic organisms or dangerous chemicals was comprehensively presented and discussed. Strategies to identify and manage potential risks were presented. It was generally agreed that a culture of responsibility, a common sense approach, an emphasis on ethical practices was needed to provide assurances to the general public that containment and appropriate research procedures will minimize the risks of these agents to the general public.
Finally, in recognition that many effective drugs have been developed from herbal or plant extracts, there was a presentation of the analysis and animal studies to evaluate the action of an extract of adintum cappilus. This extract has antihistaminic, hypoglycemic and diuretic effects. Ongoing studies will further identify the specific components in the extract responsible for each of the observed effects.
Session VI: Biopharm Development
Chair: Dr. Barbara Price, President Applied Science and Analysis, Inc., US
Co-Chair: Prof. Cao Cheng, Academy of Military Medical Science, China
Two of the four presentations were about bacteriophages. A detailed description of the work done in the Republic of Georgia, with an emphasis on the use of phages against methicillin-resistant S. aureus (MRSA), was presented. Bacteriophages have been used for over 70 years, but efforts in their use waned with the successes of antibiotics, such as penicillin and the myosins. Bacteriophages are specific against bacteria, but cocktails of phages can be used instead of some broad-spectrum antibiotics. The Eliava Institute of Bacteriophage, Microbiology & Virology has been a leader in research in bacteriophages. Monoclonal phages represent another more directed and specific phage. Another presentation included a case study of a patient with a long-standing MRSA infection who was successfully treated with phages.
A presentation on safety issues in biosimilars introduced the concept and difficulties in determining the effectiveness and safety of biologically produced pharmaceuticals, biopharmaceuticals, that are similar to others that are already approved. Biopharmaceuticals include a wide-range of products such as recombinant proteins, monoclonal antibodies, blood products, immunologicals, such as sera and vaccines, allergens, and advanced technology products such as gene and cell therapy products. Generally, patents protect small molecule pharmaceuticals after they are developed and tested. After the protective patents have expired, these small molecule pharmaceuticals are usually produced in generic versions. However, manufacturers of biopharmaceuticals do not patent the biological compound itself, but rather the production process. If other biological systems are used to produce similar biological products, these are not necessarily the same as the original biopharmaceutical, but may be very similar in how they work. For example is a vaccine produced from E.coli the same as that from a chicken? And what about producing the biological outside of cells? How can the safety and efficacy of each biological system and process be evaluated? The European Union, WHO, and European Agency for the Evaluation of Medicinal Products (EMEA) have been working to establish a legal framework and guidelines for biopharmaceuticals and biologicals. These guidelines require comparisons and data demonstrating that a biosimilar and the original or first generation biopharmaceutical be produced to the same analytical standards and that they can treat the same condition and use the same set of receptors, or other system to show comparability. Nonclinical data from an abbreviated programme of in vitro and in vivo tests prior to clinical studies are required, usually with at least one toxicokinetic study. Finally clinical testing establishes clinical equivalence, safety, and immunogenicity and is augmented by a pharmacovigilance plan, which monitors use for several years.
The last speaker described the use of acellular production of vaccines. In many countries, and in China, regular vaccines for DPT, rabies, measels and other diseases are under-produced or lot releases are slow because of quality control issues. To overcome these problems, the speaker described five-ton reactors, using acellular cultures and that are fully automated for control, which have been used to make vaccines for DPT, Japanese encephaltis, measels, rabies, HIV, HPV, chicken pox and herpes zoaster. As a result, the incidence of childhood diseases have increased. These acellular cultures can be adapted more quickly than classical vaccine cultures to changes in virus types, such as occured with the change in rabies types seen across China.
Note 1:
Dr. Peter Leitner summed up his Session IV with the following very appropriate footnote: “The most encouraging aspect of these, and many of the other findings offered, is the richness of the variety in approaches, methodologies, and commitment to the scientific method that are rooted in the cultural background of the many participants. The dedication of the researchers from academia, as well as the public and private sectors, and the demonstrable quality of their efforts is the single greatest evidence as to why individual national science cultures should assiduously avoid being homogenized into a single universal approach to science. Approaching common problems from a variety of unique vectors greatly accelerates the arrival of solutions for the overall benefit of mankind.
International bodies such as the World Health Organization and the International Standards Organization need to evolve rules, procedures, and guidance whereby dissimilar approaches may be encouraged and their results harmonized and disseminated. As suggested by one of the speakers, perhaps an international Code of Ethics may be promulgated that recognizes the value of differing approaches to research, trials, and the acceptability of findings therefrom.”
Note 2:
While at ICBPS-2, ASA received several very laudatory comments on how professional this symposium had turned out for all. We had participants from every corner of China and from Australia, Georgia, Indonesia, Iraq, Japan, Netherlands, Russia, Saudi Arabia, Spain, Switzerland, Turkey and the USA.
On behalf of all ICBPS-2 participants we would like to thank the following for their tireless efforts to make this second meeting a success:
Symposium Chairs: Prof. Sang Guo-Wei, President Chinese Pharmaceutical Association (CPA), and Dr. David Robinson, Vice President and Chief Biologist, Battelle Memorial Institute,
Symposium Co-Chairs: Prof. Shen Xinliang, China National Biotech Group (CNBG) and Dr. Barbara Price, President Applied Science and Analysis (ASA), USA.
Symposium Organizers and Sponsors: The ICBPS-2 was developed, organized and sponsored by the CPA and Battelle Memorial Institute. The CNBG was the primary sponsor with Sanofi Pasteur, Roche, GE Healthcare and ASA as sponsors and co-sponsors. A very special thanks to the CNBG for their sponsorship of the ICBPS-2 Symposium Dinner at the fabulous Summer Palace in Beijing.
And a special thanks to Ms Shaoli Li, Vice President and General Secretary CPA for her unfailing support for the ICBPS and all of us as we prepared for the ICBPS-2.
And this writer’s special thanks to his fellow Symposium Co-Organizers: Mr. Liu Chunguang, CPA International Affairs Department with the assistance of Ms Ge Junhua and the CPA staff who were literally working 24 hours a day in covering the multitude of symposium details that all ‘demanded’ immediate attention. And to Mr. Mason Soule of Battelle Memorial Institute who tenaciously worked behind the scenes to help identify candidates for participation, sources for sponsorship, information of highest interest to the ICBPS-2 candidates and who greatly assisted in symposium organization and execution. A well done to all. And a Special Well Done to Ms Florence Ma, the special consultant in China for Battelle Memorial Institute. “Flo” always managed the most difficult challenges with aplomb.
And lastly A Well Done to Battelle Memorial Institute’s Mr. Stephen Kelly, President, National Security Global Businesss and Dr. David Robinson, Vice President and Chief Biologist Battelle. If they and Battelle did not believe in the importance of the ICBPS to world health and the professional community, we would not be providing a summary of this very important meeting because it would not have happened. Battelle does this - they make it happen.