Special Lecture
Experience in translational research for acute ischemic stroke
2022 Volume 8 Pages 9-12
Details
2022 Volume 8 Pages 9-12
Translational research (TR) refers to a series of research processes from basic research in academia to the application of new drugs and medical technologies in clinical practice. Compared to conventional basic research, in which the goal is the publication of papers, TR involves a long period of research and many hurdles, including many failures. Therefore, perseverance is required to overcome these hurdles. In addition, it is difficult for a researcher to complete a project alone; thus, it is necessary to appeal to and work closely with many collaborators. It is also important to have a mission to help others through research. In this paper, I outline the points for successful TR, including those from basic research to non-clinical studies, related to obtaining intellectual property rights, and regarding industry-academia collaborations.
Even a paper with academic value will not lead to a cure. Therefore, it is the responsibility of the researchers publishing their results to aim for practical applications, a process called “translational research” (TR). We have developed three seeds of drug discovery for acute ischemic stroke for eventual clinical applications (an anti-vascular endothelial growth factor (VEGF) antibody in combination with tissue plasminogen activator [tPA]1), progranurlin2), and oxygen-glucose deprivation (OGD)-treated microglia and peripheral blood mononuclear cell therapy3,4)). However, drug discovery requires overcoming many hurdles, and many seeds of drug discovery fail to cross the “death valley.” In this paper, I introduce five points necessary for overcoming the “death valley,” based on our experiences.
The realization of drug discovery is a long road; the process of which requires some understanding. Before starting research to develop a therapeutic drug, it is necessary to thoroughly consider if there is a need for the drug, what the indications will be, and how the drug will differ from existing drugs. The next step is to investigate prior research on therapeutic candidates and the existence of intellectual property. For the latter, the patent information platform J-PlatPat (https://www.j-platpat.inpit.go.jp/) is useful. If there are no problems, the type of drug should also be examined. Specifically, consider whether to focus on small molecules, peptides, or antibodies. At this time, the presence or absence of inhibitors or activators used in basic research, side effects, and the possibility of drug repositioning of existing drugs should be considered.
Next, we move on to basic research, in which in vitro/in vivo experimental systems are the optimal method to evaluate efficacy. Ideally, experiments using animal models should be decided based on the design of the final clinical trial. After confirming the efficacy of a candidate drug in basic research, more rigorous non-clinical studies (pharmacodynamic, pharmacokinetic, and toxicity studies) are conducted. In clinical pharmacology, absorption, distribution, metabolism, excretion, half-life time, dosage, frequency of administration, and route of administration are examined. In my experience, the accuracy and rigor of data obtained in university laboratories are insufficient at this stage; thus, it is necessary to take advantage of the expertise of pharmaceutical companies with more experience. Finally, health economic issues, namely, pharmacoeconomics, must be considered. In other words, consider the relationship between development costs, product prices, and cost-effectiveness.
In addition, the quality of animal experiments should match the level of human clinical trials by selecting models that are similar to patients’ conditions, with the understanding that “rodents are not small humans.” A recent paper examined why drugs that are effective in animal studies are ineffective in human clinical trials5); the authors statistically compared the study design, publication bias, power, and true report probability (TRP) of 50 phase III clinical trials for acute ischemic stroke in early phase clinical trials and animal studies of each drug. The results suggest that the causes of this disparity were differences in study design (treatment timing, primary endpoints, and evaluation methods), publication bias, and low power (Table 1). In other words, in animal studies, the middle cerebral artery is occluded, therapeutic intervention is performed shortly after ischemia, and evaluation is performed in the acute phase by infarct volume. There is not only a large barrier between animal experiments and clinical trials, but also between animal experiments, early clinical trials, and phase III trials. Therefore, an ideal animal study should include a large sample size , randomization, blinding, use of animals with comorbidities, a delay in the timing of therapeutic intervention to match that in clinical trials, and evaluation of functional impairment rather than infarct size. To reduce publication bias, papers with negative results should also be submitted. While it is not easy to find a drug that works under these conditions, only such a drug can be expected to have a high success rate in clinical trials.
Differences between animal studies, early phase clinical trials, and phase III clinical trials5)
| Animal experiments | Early-phase clinical trials | Phase III clinical trials | |
|---|---|---|---|
| Number of studies | 209 | 75 | 50 |
| Success rate | 69% | 32% | 6% |
| Sample size (of animals, etc.) | Few | Many | Significantly more |
| Co-morbid disease | None to rare | Existence (at the present moment) | Existence (at the present moment) |
| Intervention timing | Fast | Slow | Slow |
| (>3 hours mainly) | (>12 hours mainly) | (>3–12 hours mainly) | |
| Randomized and blinded | Few | Many | Most common |
| Primary endpoints | Infarct size | Functional prognosis | Functional prognosis |
| Publication bias | Existence (at the present moment) | Existence (at the present moment) | None |
The difficulty mentioned above is the large sampling of individuals. There is a limit as to what can be done in a single laboratory; thus, protocols for drugs that have been effective in a small number of cases should be standardized and animal experiments should be conducted through multicenter studies. It is also necessary for journals to more frequently publish manuscripts reporting results from negative studies.
Securing intellectual property rights is essential for the realization of drug discovery. In academia, it is difficult to conduct clinical trials and apply for regulatory approval alone; thus, joint research with pharmaceutical companies is necessary. Therefore, patent applications are needed to develop industry-university collaborations.
First, it is necessary to understand the requirements for filing a patent application: the invention must be industrially applicable, novel, inventive, not previously applied for, and not contrary to public morals. Particular attention must be paid to “novelty.” If the research results are made “publicly known” by disclosing information about the invention at conferences or in papers, the invention loses its novelty and cannot be patented, except in cases where it is possible to apply for an “exception to loss of novelty” under Article 30 of the Japanese Patent Law. Therefore, it is important not to make the research results public knowledge before filing a patent application.
Deciding if and when to file a patent application is difficult and I recommend first consulting with the intellectual property department of your university. Since medical doctors are not accustomed to writing patent specifications, it is common to ask a patent attorney’s office to do so. It is important to choose a firm that is familiar with your invention and to communicate the contents of the invention to the patent attorney in an easily understood manner so the claims and patent scope can be thoroughly discussed.
There are some difficult hurdles in obtaining patent rights. First, patenting poses a dilemma for graduate students’ education. If a graduate student presents a paper at an academic conference before filing a patent application, the seed becomes public knowledge and the patent cannot be granted. Therefore, until the patent application is completed, graduate students will not be able to present at conferences, which may lower their motivation.
Second, obtaining a patent is costly. Drugs that will become international products require international patents; thus, patent applications must be filed in multiple countries. In my experience, only applying in Japan and the US is insufficient, which bio-venture capitalists and pharmaceutical companies consider a problem. In general, national applications, international applications based on the Patent Cooperation Treaty, and transition to patent countries are filed, in this order. Each of these procedures is costly; in particular, translation fees and payments to foreign patent attorneys and patent offices are expensive, and securing financial resources is a serious problem. Specifically, support from the Japan Science and Technology Agency (JST), venture capital, drug discovery ventures, and pharmaceutical companies should be considered; however, obtaining such support is not easy.
Third, application patents are a higher hurdle for drug discovery compared to substance patents; thus, the goal is to obtain a substance patent, if possible. A substance patent in drug discovery refers to a patent obtained for a newly created drug, while an application patent refers to that obtained when an existing drug is found to be useful for a new disease that differs from its original indication. In the case of drug discovery using an application patent, the intention of the owner of the substance patent (generally, a pharmaceutical company) is a decisive factor in the subsequent development. While joint development is pursued in some cases, in many others, the patent does not match the company’s policy and the patent is rejected without the company showing interest.
The final outlet for drug discovery, that is, the partner of an industry-university collaboration, is usually a pharmaceutical company. However, it is difficult to find pharmaceutical companies for joint development. One way is to use “open innovation.” This is an attempt by pharmaceutical companies to create innovative new drugs by incorporating the drug discovery seeds and technologies of outside academics and bio-ventures. If a pharmaceutical company’s drug discovery goals and its research theme match, an industry-university collaboration is likely. Such information can be obtained from the “List of research recruitment activities of pharmaceutical companies” website (https://japantechnologygroup.jp/pharmaneeds/#recruitment). In addition, the opportunities for matching, as shown in Table 2, allow active participation. Even if a match is not made, it is beneficial for obtaining advice.
Opportunities for matching with pharmaceutical companies
| (1) DSANJ |
| The Japan Pharmaceutical Manufacturers Association and the Osaka Chamber of Commerce and Industry are sponsored by the Japan Agency for Medical Research and Development. Information will be provided in advance and interviews will be conducted with interested companies. |
| (2) BioJapan |
| Organized by the BioJapan Organizing Committee. Posters and materials will be displayed at booths and visitors can exchange business cards and meet pharmaceutical company representatives. |
| (3) BIO tech |
| Organized by Reed Exhibitions Japan, Ltd. |
| (4) New technology briefing. |
| Sponsored by the Japan Science and Technology Agency (JST). |
| (5) Drug discovery seed consultation meetings |
| Organized by medU-net (Medical University Industry-Academia Network Council). |
After obtaining a patent, a university-launched venture is started or an industry-academia collaboration is formed with a pharmaceutical company, with the goal of reaching clinical trials. It is important to recognize the difference in thinking between conventional research that aims to publish papers and industry-university collaborations that aim for clinical applications and practical uses. For example, pharmaceutical companies conduct rigorous research and development by setting goals and using Gantt charts to track progress towards achieving them, while academic researchers are not accustomed to this type of research planning. In addition, the availability of research time is uncertain due to clinical and educational commitments, making it difficult to follow a Gantt chart and keep the collaborative research on track. In such cases, it is necessary to compromise and hold regular face-to-face research meetings to ensure the success of bridge research.
The priorities in industry-academia collaboration are not necessarily academic values but can be summarized as the needs, approach, benefits, and competition (NABC) that are important in innovation.6) The NABC can be replaced by the following four questions. Needs: Is the drug really necessary? Approach: Is the methodology correctly used in this study? Benefit: Does the drug provide a benefit? Competition: Can the drug beat the competition? These questions should be considered during the design stage of basic research rather than after the basic research is performed.
In summary, achieving therapeutic innovation requires an understanding of the ecosystem and the process of therapeutic drug development. In addition, I have learned that, in TR, it is important to have a passion to contribute to the world and corresponding persistence. If you work hard, you will meet supportive people. Although TR is a series of hurdles, the many people you encounter in the process are also a great joy in retrospect.
Disclosures: Takayoshi Shimohata is an academic advisor to ShimoJani LLC, a drug discovery venture.
