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Successful integration of biomarkers (hFR) into mainstream medicine

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Successful integration of biomarkers (hFR) into mainstream medicine

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Content SUCCESSFUL INTEGRATION OF BIOMARKERS (hFR) INTO MAINSTREAM MEDICINE by Alexander Braham ___________________________________________ A Thesis Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCE (Biochemistry and Molecular Biology) 2014 SPRING 1 ACKNOWLEDGEMENT I wish to thank various people for their contribution to the completion of my thesis because without their guidance, help and support, I would never have accomplished such a milestone. First and foremost, I would like to offer the most heartfelt gratitude to my advisor, Dr. Zoltan Tokes, whose patience is beyond measure. His encouragement and attitude to never give up on me, kept me moving forward through the various stages of my program and this thesis. I would also like to thank Dr. Peter Danenberg, who provided the guidance and direction needed in assisting me with the creation of my thesis topic and seeing it through to its completion. A very special thank you to my entire committee, Dr. Zoltan Tokes, Dr. Peter Danenberg and Dr. Peter Laird who were willing to take time out of their busy schedules to review and offer direction and suggestions for my thesis. Their help was invaluable through the final stages and I owe them more just my appreciation and admiration. Finally, I wish to thank my family and friends for their love and support through this tumultuous and arduous process. They were always there offering encouragement and support, with nothing but their best wishes and confidence that I would finally complete my Masters degree. 2 TABLE OF CONTENTS ACKNOWLEDGEMENT……………………………………………………………….1 LIST OF FIGURES……………………………………………………………………...4 ABSTRACT………………………………………………………………………………5 I. Biomarkers…………………………………………………………………………...6 1. The Functionality of the Biomarkers….....…………..……………………………8 2. Protein Expression…………………………..…………..…….............................10 3. hFR as an Indicator.…......……………………..…………...................................11 4. The advantages of using Biomarkers for the monitoring of the efficacy of Chemotherapy……………………........................................................................15 5. The disadvantages of using Biomarkers for the monitoring of the efficacy of Chemotherapy………............................................................................................16 6. Biomarkers as part of the Standard of Care….………..………………................17 II. The Feasibility of Biomarkers (hFR)…...……...………………………………….18 III. Licensing and Patenting Biomarkers….………………………………………….20 IV. Marketing…………………………………………………………………………..22 1. Advantages in Marketing Biomarkers…...……………………………………....22 2. Target Market…………………….....…………………………………………....26 3. How to Market Biomarkers…...…………………………………………………28 V. Financing…………………………………………………………………………...29 1. Start-up Financing………………………………………………………………..30 2. Continuous Financing……………………………………………………………31 a. Milestones/Metrics……….…………………………………………………...32 3 3. Private Financing………………………………………………………………...33 a. The advantages of private financing………………………….……………....34 b. The disadvantages of private financing………………………………..……...35 4. Public Financing…………………………………………………………………36 a. The advantages of public financing………………………..…………….........36 b. The disadvantages of public financing……………………………..…............38 VI. Market Potential…………………………………………………………………...40 1. Testing the Biomarker (Phase I, Phase II & Phase III)…………………………..40 2. Profitability…………………………….………………………………………...42 a. Selling to Individuals……………..…………………..…………………….…42 b. Selling to Laboratories……………………………………….……………….43 3. 3, 5 & 10 Year predictions/valuation of Biomarkers…………………………….43 VII. From Lab  to Clinics (Doctors)  to Business (Putting it all together)….....45 1. Advance current technology……………………………………………………..46 2. Search for new Biomarkers………………………………………………………48 VIII. Conclusion…….………………………………………………………………….49 IX. References..………………………………………………………………………..50 4 LIST OF FIGURES Figure 1. Deaths: Preliminary Data for 2010………………………………………….6 Figure 2. DNA Methylation……………………………………………………………..9 Figure 3. Enzyme-linked immunosorbent assay (ELISA)…………………………...10 Figure 4. Folic Acid Structure………………………………………………………...11 Figure 5. Folate Receptor expression in selected solid tumors……………………...12 Figure 6. FOLR1 Receptor-Mediated Endocytosis…………………………………..12 Figure 7. Microfiltration versus Immunoblotting Assay in the detection of hFR…14 Figure 8. Start-up Financing Cycle…………………………………………………...30 Figure 9. Summary of the PMA Process..…………………………………………….41 5 ABSTRACT The second largest killer in the United States, cancer, has led biotechnology and pharmaceutical companies to focus on treatments to cure or mitigate the risk of cancer. Biomarkers have emerged as a method for diagnosing and predicting the prognosis of cancer. Biomarkers are biological molecules that may be used to determine the normal versus abnormal processes of a condition or disease. In particular, Human Folate Receptor (hFR) is a membrane-bound glycoprotein that has the potential of being a cancer indicator, as over expression of hFR has been seen in tumor cells. Biomarkers could be utilized in addition to the standard of care as they can be used to predict the efficacy of chemotherapy, as well as the likelihood of failure, which would allow for the selection of an alternative treatment. The feasibility of biomarkers will face some adverse reaction, due to this new technique being introduced to the science industry and due to lack of data and evidence. In addition, there is also the hurdle of the standard phase III testing, which could experience its own troubles due to participation from the subjects. Once identified as a cancer indicator, this paper aims to discuss the viable options as a proprietor from conception to completion on the process of protecting oneself and starting a business with the biomarker hFR. The objective is to educate the proprietor on the marketing options, in addition to the finance options and where the industry may be headed in the future. 6 I. Biomarkers Cancer is the second largest killer in the United States, behind diseases of the heart, based on the statistical findings of the Center for Disease Control (CDC). Results published by the CDC indicate that little has changed with regard to the number one and number two killers in the United States from 2009 to 2010. Figure 1 The above referenced statistics have led biotechnology and pharmaceutical companies to focus on treatments to cure or mitigate the risk of cancer. Therefore, the emergence of biomarkers has become more prevalent as a method for diagnosing and predicting the prognosis of cancer. Scientists and doctors are unsure of the exact causes of cancer, but they do believe the underlying sources include, “physical carcinogens, such as ultraviolet and ionizing 7 radiation; chemical carcinogens, such as asbestos, components of tobacco smoke, aflatoxin (a food contaminant) and arsenic (a drinking water contaminant); and biological carcinogens, such as infections from certain viruses, bacteria or parasites” (1). Treatments are still being researched and tested, but the constant genetic mutations that occur in our cells, due to our expansion of our lifespan, could also be an additional basis for cancer. A combination of environmental factors, a person’s lifestyle and/or genetic variables cause cancer. Though we know of some causes and treatments, detection and successful treatment have become the force behind biomarkers. Biomarkers are biological molecules that may consist of proteins and nucleic acids found in blood, tissues, and genes. Biomarkers may be used to determine the normal versus abnormal processes of a condition or disease. Biomarkers can be used to test how well the body reacts to a treatment or disease by the activity or the level of the biomarker. Biomarkers have been discovered using multiple methods, including determination of DNA, RNA and protein expression, which allow scientists to compare these specific factors in a normal pathway versus an altered disease-causing pathway. Conversely, biomarkers should be heavily scrutinized for their specificity and sensitivity. A biomarker that is limited in its sensitivity could ultimately provide false negatives. Conversely, a biomarker limited in its specificity could provide false positives. These two issues could contribute to the reason that biomarkers never become accepted by mainstream medicine. “To be useful, a biomarker needs to have sensitivity — that is, the likelihood that it detects disease — of at least 90%. The other key quality is specificity — the probability that a positive signal is a true sign of disease and not an error. That, too, should be 90% or more for a biomarker to be of clinical value” (2). 8 Although there are performance metrics, such as the ones suggested by Brower, that could be instituted to ensure accurate outputs, there are no guarantees that the medical community will accept these results as they may hold biomarkers to a higher standard until further data validations are conducted. Biomarkers have the potential to become one of the key elements to a modern diagnosis and prognosis of cancer. Therein lies the major issue with the use of biomarkers. People may become dependent on a biological molecule that takes time and money to research and test to ensure the results are accurate and significant, in order to determine any abnormal pathways that could be harmful to their health. The Pharmaceutical Research and Manufacturers of America reported recently, “their members had spent $38.8 billion on R&D in 2004. This reflects a 12% increase from 2003 where the total budget was $34.5 billion, and this is in concordance with the ~13% annual growth rates expended on biomedical research by both government and industry over the past decade” (3). The time frame in which a biomarker is discovered, tested, and then implemented can take years from conception to completion. The financial investment to research, test, and, if successful, to market a biomarker can cost a company millions of dollars. Additional issues also come to light, such as to whom to market the biomarkers; should it be the doctors, patients, or insurance companies? 1. The Functionality of Biomarkers Research for biomarkers can occur through focus and specialized study or trial and error, but in both instances, the amount of research can be almost insurmountable since biomarkers are specific. Biomarkers can utilize nucleic acids, such as DNA, RNA, 9 or proteins for detection, which means there are multiple ways to test for biomarker expression. One example of a biomarker is DNA methylation. DNA methylation can lead to altered protein expression, and ultimately serve as a biomarker. DNA methylation occurs when a methyl group (-CH 3 ) becomes attached to the 5 position of a cytosine or the 6 position of an adenine. Figure 2 Scientists have discovered that hypermethylation of a gene can cause transcriptional silencing, which may potentially contribute to malignant transformation of cells. “Alterations to the ‘on-off’ switches of genes occur early in the development of prostate cancer and could be used as biomarkers to detect the disease months or even years earlier than current approaches, according to the Mayo Clinic. These biomarkers – known as DNA methylation profiles – also can predict if the cancer is going to recur and if that recurrence will remain localized to the prostate or, instead, spread to other organs” (4). Therefore, not only can the detection of biomarkers determine if the patient has cancer, but it can also uncover how aggressive the cancer has become, if it can be treated, and the likelihood of recurrence. 10 2. Protein Expression Protein expression is one possible method for identifying a biomarker, and thus protein analysis is one approach to test for abnormalities associated with cancer. In order to test for abnormalities, Enzyme-linked immunosorbent assay (ELISA) could be used to analyze proteins. In ELISA, the antigen is immobilized and coupled to the assay plate, and the enzyme conjugate is used to detect the antigen by fluorescence. The enzyme conjugate utilized is an antibody. Figure 3 This method could be used to test normal versus abnormal proteins in the indication of cancer cells by searching for a specific protein. An additional method in protein analysis is protein mass spectrometry, where protein presence is identified by its mass. Whether testing upstream or downstream, there are multiple methods to test using biomarker expressions, either DNA, RNA, or proteins and these are only the options that have been recently discovered. 11 3. hFR as an Indicator “Human Folate Receptor (hFR) is a surface glycoprotein with a high affinity for folic acids and reduced folates. Folates are essential for cell survival. They are required for numerous biochemical processes, including DNA and RNA synthesis and transmethylation reactions (1–4). Internalization of folates by αhFR involves receptor- mediated endocytosis” (5). Jhaveri states that although the relevance of over expression of αhFR in malignant tissues remains unclear, it is possible that elevated levels of αhFR induce cell proliferation, not only by mediating folate uptake, but also by generating other regulatory signals. hFR binds to Folate and Folate derivatives and transports the molecules to the interior of the cell. Figure 4 “The human folate receptors (hFR) are a family of membrane-bound glycoproteins that share biochemical and molecular properties. These proteins mediate the transport of folates/antifolates and are important pharmacologic determinants of antifolate 12 cytotoxicity” (6). hFR has the potential to become a biotechnologically recognized tumor biomarker, since over expression of hFR is seen in tumor cells. Figure 5 Studies have been conducted in which scientists are using the over expression of hFR and its presence on tumor cells as a target for cancer drugs/treatments. Figure 6 13 “Since folate is a component of cell metabolism and DNA synthesis and repair, and rapidly dividing cancer cells have an increased requirement for folate to maintain DNA synthesis an observation supported by the widespread use of antifolates in cancer chemotherapy” (7). One can infer from this observation, that hFR could be utilized as an indicator of cancer, since high levels of hFR indicate a higher frequency of cellular division. Kelemen additionally states that, “Epidemiologic and clinical studies using human tumor specimens are lacking and increasingly needed to understand the role of FRα in tumor etiology, progression, and patient survival” (7). Although it has been observed that elevated levels of hFR are present in tumor cells, more studies are need to determine if this is a precondition and if this discovery can be utilized as a biomarker. In order to test patients with elevated levels of hFR in cancer cells, Basal, et al conducted a study in which Ovarian Cancer patients’ blood was tested. A microfiltration binding assay, the separation of solids from fluids, and immunoblotting, which uses antibodies (MOv18/ZEL) to identify and target proteins among a number of unrelated proteins were conducted. Per Basal, “As shown in Figure 7, using this strategy, 13% and 27% of cases were considered to have elevated levels of FRα in the microfiltration and immunoblotting assays, respectively. Statistical analysis using Fisher’s Exact Test showed that the fraction of cases with elevated levels of FRα, as detected with the immunoblotting assay, was significantly different than the fraction of controls considered positive. In contrast, the fraction of cases detected with the microfiltration assay was not significant, suggesting that the immunoblotting assay may potentially have a better positive predictive value” (8). This exemplifies the concept that by utilizing the immunoblotting assay, one can detect elevated levels of hFR. The over expression of 14 hFR has been shown to be present in elevated levels in tumor cells, therefore, hFR could be utilized as a cancer indicator. Figure 7 Even though, it can be inferred that an over expression of hFR can be utilized as an indicator of cancer, hFR is currently not recognized as a tumor marker by the National Cancer Institution as of 2011. However, there are companies, such as Biocare Medical, utilizing hFR for their in vitro assay in the detection of hFR expression in formalin fixed paraffin embedded tissues (FFPE). Dr. David Tacha of Biocare Medical stated in March 2012 that, “The development of a highly characterized and high affinity folate receptor alpha antibody IHC kit is extremely important; not only for its potential use in the development of targeted therapeutics, and hopefully it could be developed into an independent prognostic marker for various cancers” (9). Although hFR has not been identified as a cancer indicator, companies are beginning to take advantage of the possibilities of hFR for targeted therapies, in addition, to the future thought of it as a biomarker. 15 4. Advantages of using Biomarkers for the Monitoring of the Efficacy of Chemotherapy Chemotherapy is currently one method of what is referred to in medicine as, the standard of care in the treatment of cancer, with radiation being an alternative or utilized in conjunction with chemotherapy. Therefore, there may be benefits to utilizing biomarkers to monitor the efficacy of the prognosis of chemotherapy. Biomarkers can be used to predict the efficacy of chemotherapy, as well as the likelihood of failure, which would allow for the selection of an alternative treatment. “Scientists have found that a protein (p16INK4a) expressed by some cancers is a good predictor of how the cancer will respond to standard chemotherapy for osteosarcoma, the most common bone cancer in children. Knowing whether a patient's tumor has this protein biomarker could help doctors determine if a patient should undergo standard treatment or if a more aggressive or alternative therapy may be more effective” (10). Using biomarkers, such as hFR, as an indicator in predicting the effectiveness of chemotherapy can reduce health care costs by avoiding unsuccessful treatments. Furthermore, an additional advantage of biomarkers is not only in the prediction of chemotherapy, but also in the early detection of cancer. In addition, since biomarkers can be utilized as signals to show patients whether a cancer treatment is working, patients may be more willing to use a drug not thought to be successful in the past for one that is deemed “standard” if they have been shown its proven success. Since the range of biomarkers has yet to be determined, we can currently assume that biomarkers can be utilized in determining if a patient has cancer, then what the best method of treatment for that patient would be. In addition, biomarkers can be utilized for specific drug targeting. Therefore, from a business standpoint, the market 16 share of cancer drugs could dramatically increase once biomarkers have been shown to have a proven success of the drug with other patients. 5. Disadvantages of using Biomarkers for the Monitoring of the Efficacy of Chemotherapy If the use of biomarkers begins to replace the standard of care for various cancers then, most likely, the Federal Drug Administration (FDA) will require validation of the biomarker. The need for additional trials will lead to increased costs and an extended timeline, which is prohibitive to smaller biotechnology companies. Alternatively, this action may force biotechnology firms to create partnerships with pharmaceutical companies, which may benefit both industries. Another disadvantage to utilizing biomarkers, is that they are not considered the “standard of care”, thus, Healthcare/Insurance companies may be unwilling to reimburse patients or doctors for their use. Though they would likely be cost-effective in the future, the initial costs would be high. The industry would have to absorb the high cost associated with testing a new biomarker in patients, as well as receive regulatory clearance for trials using an unapproved product. Also, since biomarkers are not currently FDA-approved, the ethical implications of healthcare/insurance companies paying for a biomarker test comes into question. Finally, only a long record of efficacy will allow a biomarker, such as hFR, to be considered part of the standard of care for cancer patients, as most doctors would not want to risk the health of their patients on developmental data. Patients may also fear discrimination resulting from the genetic 17 testing required to use biomarkers, leading to rejection of the biomarker option in spite of proof of efficacy. 6. Biomarkers as part of the Standard of Care The Standard of Care is mentioned as a barrier to the use of biomarkers as predictors of the efficacy of chemotherapy; however it’s not necessarily a disadvantage for treatment methods in medicine in general. “Finally, the organizational, financial, and size differences among cancer care practices may influence the strategies providers use to implement the standard of care. For example, the economics of collocation and care coordination is affected by the volume of cases” (11). As stated by Adler, the volume of cases and the economics behind the cost-effectiveness make the standard of care a simple streamline process already accepted by insurance companies. The reason most doctors utilize the Standard of Care when treating a patient is because the method has been presumably shown to work successfully, so why alter a good thing? Attempting to convince doctors to use biomarkers in the prognosis of chemotherapy or disease identification will be one of the challenges associated with the implementation of biomarkers. Alternatively, biomarkers could be utilized in conjunction with the standard of care as an additional approach to treating a patient with cancer. In particular, a physician can treat the prognosis of the patient through the streamline process, as well as implement biomarkers into the prognosis to ensure the treatment is working, if not opt to switch to an alternative method. A necessary and helpful strategy for implementation of a particular biomarker is a prospective trial. 18 A prospective trial is a study that follows a specific set of individuals with similar factors in common in order to test an outcome. With regard to biomarkers, a prospective trial would be put into place in order to verify if biomarkers should be used as the current treatment and diagnostic tool versus current the standard of care. However, one has to consider the financial costs, versus the monetary gains that a prospective trial offers. A prospective trial can take years in order to collect sufficient data to draw a statistically significant conclusion. Prospective trials also run the risk of losing patients to follow-up as time passes. Prospective trials are advantageous since the testing factors can be controlled from the start, in contrast to a more cost-effective retrospective trial, in which historical data must be interpreted. In the end, one must conclude that running a successful prospective trial is financially advantageous in order to change the standard of care, since biomarkers have the possibility of saving lives and money in the future. Biomarkers are just an example of the latest in cutting edge medicine as they can determine the diagnosis and prognosis of diseases. While there are many methods for testing the abnormalities associated with various conditions or diseases, biomarkers appear to be a straightforward approach to treatment. However, with new methods and techniques come new challenges, such as financing, marketing and changing the minds of the target market. If researchers can find a way to overcome these challenges by reducing the costs and displaying the advantages of biomarkers, the medical world may more easily accept this new science. II. The Feasibility of Biomarkers (hFR) “Unfortunately, studies of chemopreventive approaches have been hampered by 19 serious feasibility problems; development of cancer as the study end point requires observation of many subjects over a longer period than in standard phase III clinical trials” (12). As discussed earlier, hFR can be used as a cancer indicator; therefore, utilizing hFR as a biomarker to test that chemotherapy is treating the cancer is of vital importance. As pointed out by Lee, the standard phase III would be where it is determined if hFR is a better biomarker or indicator than any other option currently available to the medical industry. The standard phase III process can be problematic when implementing hFR as a viable biomarker, since that process involves following multiple subjects who represent a similar demographic. Issues could arise during the trial, such as subjects moving, dying, or deciding they no longer wish to be a part of the study. The loss of a significant number of participants during a phase III trial, can greatly impact the results and conclusions of the study, and possibly negating positive results because of the decreased sample size. On the other hand, the practical implementation of hFR as a biomarker is possible because of the practicality of microassay techniques that are able to test small biopsy samples, thereby making the process easier on the participants and hopefully maintaining them in the study. In addition, with the continued emergence of scientific technology and biomarker discovery, there is more data readily available to compare samples to create logical conclusions. “Few published putative biomarkers have made it into clinical practice because (a) most biomarker development studies were done on small patient numbers and significance in multivariate analysis was not studied or not confirmed; (b) often studies published are based on a learning set only, without independent validation on a test set; (c) most studies are retrospective and suffer from incomplete data or 20 insufficient data quality; and (d) the tests proposed are often derived from experimental studies with insufficient validation in a clinical setting, taking factors such as tissue preservation, sampling adequacy, and test reproducibility into account” (13). The fact that hFR can be tested using microassays and small biopsy samples provides a counterpoint to Bosman’s opinion, since data suitable datasets could be collected in a prospective study to validate the findings. In conclusion, the feasibility of biomarkers will face some adverse reaction, due to the new techniques being introduced to the science industry, due to lack of data and evidence. In addition, there is also the hurdle of the standard phase III testing, which could experience its own troubles due to participation from the subjects. Yet, with this acknowledgement comes the basis that as more participants are examined, the data validations will be accepted over time. In addition, participants might be more willing to begin to accept the studies since only a small biopsy may be needed in order to confirm the efficacy of hFR as a biomarker. III. Licensing and Patenting Biomarkers As science and technology advance, so does the opportunity for success and financial gain. With the increase of personal success and financial gain comes the opportunity for theft through replication. Technology and science, in addition to other industries have given rise to the notion of intellectual property. “Intellectual property (IP) refers to creations of the mind: inventions, literary and artistic works, and symbols, names, images, and designs used in commerce” (14). With the establishment of intellectual property, comes the opportunity to protect yourself, should you discover a 21 new biomarker. There are two ways to protect yourself as the proprietor, in addition to a monetary advantage should you desire access for others to utilize your discovery. The first method of protection is the patent. A patent on the discovery gives the proprietor the right to bar others from using your invention or discovery commercially for their own personal monetary gains. The second method is licensing. Licensing is the act of giving permission for someone or an establishment to utilize your invention or intellectual property for the licensor’s own personal gain. The proprietor may benefit financially or indirectly from this use. Through the act of licensing, the proprietor has the ability to charge a fee for the use of the biomarker, thereby keeping the rights of the invention and being compensated for the creation. In either instance it is the decision of the proprietor which pathway to follow, or to apply both protection methods of intellectual property. “Intellectual property (IP) is central to incentivizing investment in innovation. It provides market exclusivity for products. It provides additional revenue to a company from out-licensing. And it can sometimes be used as a way of keeping products and/or technologies out of competitors’ hands” (15). In the case of a biomarker discovery, such as hFR, the owner can either control the patent and monopolize the discovery, or give permission for others to utilize the discovery, or do both and maximize their exposure to financial gain and notoriety. In order to decide which method will benefit the rights of the owner more will depend on their ultimate outcome. In both instances, patenting the discovery is recommended, however, whether to allow others the use of the intellectual property or keep it for themselves would depend on what their personal and financial goals are in the future. 22 IV. Marketing 1. Advantages in Marketing Biomarkers Marketing is another piece to the monetary puzzle in implementing a biomarker into the mainstream. There are multiple ways to market a biomarker depending on the end goal, such as financial gain through patents/licensing or ensuring scientific utilization leads to further biomarker discovery through the procedures created. In order to successfully market the product you have to first look at the landscape of viability, in addition to conducting a SWOT (Strengths, Weaknesses, Opportunities and Threats) analysis to determine the best course of action in order to be successful. When analyzing the landscape of the market itself one has to look at those currently in the market and those conducting the purchasing or using the product. From there one can determine what the options are and the best course of implementation. For example, too much competition from other cancer biomarkers may lead to patenting and licensing a product, rather than marketing it to the public. However, if the product hFR is the first to the market and will not be met with competition, the best course would be to market the product directly to doctors, patients and insurance companies. Focusing on marketing the product directly as a viable cancer biomarker would have to be backed up with strong research and development presenting the product as effective. Depending on how the product will be available, will also determine how the product is advertised to the public. The purpose of marketing the biomarker hFR to the public enables the proprietor to directly reach individual patients, due to the availability of information through the Internet. The consumer could request the product from their doctor or insurance company based on the information they have found from reputable 23 online sources. In addition, by marketing and advertising the biomarker through physicians and the insurance company, the patient would have another possibility for the product to be introduced to them, if they haven’t become fully aware of all their medical options. By analyzing the landscape of the market, the proprietor of the biomarker would be able to determine which course would benefit them the most, by scrutinizing the patients, doctors and insurance companies as viable subjects. Strengths The biomarker market is continuing to grow, as cancer indicators are needed in order to determine if the chemotherapy is working or if another strategy of treatment needs to be put into effect. “The global biomarker market is valued at $13.16 billion in 2011 growing at a steady pace of Compound Annual Growth Rate (CAGR) 14.40% to reach $25.79 billion by 2016. The biomarker discovery technology market is the major contributor of this market followed by the application market. Oncology is seen to be the largest indication in terms of revenue but cardiology is the fastest growing indication with a CAGR of 16.24% from 2011 to 2016” (16). With the growth of the prognostic indicator market, the ease with which to market the product will be determined by how quickly one can get the biomarker to the market in addition to the cost of utilizing the product, on top of the acceleration of receiving the results. The faster, more cost effective products that produce the most accurate results are the products that will thrive and survive despite the competition. Furthermore, one of the largest hurdles to overcome in biomarker research/discovery and development comes from the small business perspective. Once the biomarker hFR is viable as an indicator, the medical community will not accept its use without statistically 24 significant results, which are also needed to obtain regulatory approval. Therefore, a prospective trial will be needed for validation. The cost of the prospective trial could run into the low millions, thereby creating a monetary obstacle for a small business. However, if a small business can partner with a large business, it will be able to confirm the validity of the biomarker as an indicator and if the statistical significance of success is less than 5%, proving that this biomarker is hFR specific, the product will not have to be marketed itself as consumers will request the product due to its significant findings and support. Weaknesses On the other hand, weaknesses that the biomarker industry could face are contrary to the biomarker’s strengths. Since biomarkers are specific to a group, then one would only be able to market the biomarker to that group. In addition, biomarker and cancer drugs could become even more scrutinized due to side effects and follow-up studies that become public, even if the biomarker is FDA approved, such as Avastin (breast cancer drug). “Potential adverse effects of Avastin that came under scrutiny along with unfavorable cost benefit analyses might pose challenges to its growth potential and continued widespread use” (17). Since the market potential is so narrow due to the specificity of biomarkers, any adverse publicity would quickly affect the marketing brand of the indicator, thereby diminishing future marketability and monetary gains. Opportunities There are and will be multiple opportunities for the biomarker industry as it continues to grow and proves itself to the medical community. Firstly, hFR produces statistical evidence that it be can utilized as an indicator, the market that it is specific to 25 will accept and desire the product for what it can achieve. Since biomarkers are specific, they can only be utilized for certain patients; therefore, the company can capitalize and monopolize the marketplace for that specific niche. Secondly, if the company that is marketing hFR establishes the use of multiple biomarkers, it has several options. It may choose, not to release the alternative biomarkers to the public, thereby not competing against itself, or it can work in conjunction with their current marketing plan to introduce the new biomarker. Finally, as the medical and scientific communities begin to accept the validity of hFR as an indicator, less funding will be required to market their own product. The company will not necessarily need large financial support in order to advertise if it is the second to the market. Therefore, a company has the ability to compare the value of their product versus a competitors’ or non-competitor’s product (by contradicting/comparing). Threats As with any product that is venturing into the marketplace, the greatest threat one can encounter is to be the second into the market against a product similar in function to one’s own. However, if one produces a better product than what is currently available; then the initial biomarker in the marketplace will be handled by the competitor and their statistically significant findings will aid in overtaking the competition. Furthermore, due to the high cost to patients and consumers of the biomarkers, another threat will be breaking the barriers put into place by the insurance companies. Insurance companies may not take to novice technology in the medical community; however, if they gradually accept biomarkers, they will search for the availability of a generic option. 26 2. Target Market Whether marketing the biomarker to patients, doctors or the insurance companies themselves, validation of their efficacy as a significant disease indicator will have to be demonstrated for it to be accepted by the target market. “Biomarkers are currently being developed to identify patients at risk for diseases and to predict potential treatment responders, adverse event occurrences, and favorable clinical outcomes for many disease states, particularly cancer. In fact biomarkers have already established important applications in the selection of therapies in which the drug targets are also the biomarkers. Biomarker measurements support target validation and proof of target, mechanism, efficacy and they are being developed first in preclinical animal models of disease” (18). Therefore, the proof of the targeting and efficiency with which they produce results would be the focus of the marketing. With all three options as possible marketing landscapes, the proprietor or business would have to decide whom to focus on or if they believe the benefits would mask the costs, the entire landscape would be the best route. For example, if the goal is to market hFR to potential patients, then viable options become advertising via television commercials and social media. By conducting the marketing in this manner, the proprietor will prompt the patient to ask questions to their physician, thereby expanding the brand. If the proprietor can brand the biomarker product effectively, then the customer will associate biomarker indicators with the name of their product and possibly replace the term “biomarker” with the product name itself. “The connection component effectively drives the customers in their purchasing decisions. Therefore ‘what’ and ‘how’ the customers feel about the brand can have a 27 powerful impact on the decision, sometimes superseding the rationality of their buying decisions” (19). The connection component will be derived from the confidence the customer comes to realize from the statistically significant findings of the biomarker, which is why the prospective trial, although costly, can be vital to the businesses growth and success. Furthermore, the proprietor or business can additionally or separately market the biomarkers to the doctors. This can be achieved through the utilization of pharmaceutical representatives. “Studies show that marketing strategies used by pharmaceutical representatives (PRs) such as education, samples, office support, and patient resources can increase brand recognition and influence prescribing” (20). Through the utilization of pharmaceutical representatives, the business can market the biomarkers directly to the marketplace that is most desired. Moreover, the representatives will have the ability to educate the physicians on the new scientific advancement, in addition to presenting them with the statistically significant findings from the prospective trial. This approach to marketing hFR will not only spread the word, but also educate physicians on alternative forms of medicine available to them, which will ultimately aid in the branding of the biomarker. Finally, one of the biggest hurdles in marketing hFR will revolve around educating and marketing to the insurance companies. Insurance companies may be hesitant to adapt new forms of medicine, in addition to dispersing funds for a new technology that is not fully accepted by mainstream medicine. However, if a cost-benefit analysis is conducted and proven to be effective, it might be the first method to overcome this obstacle and demonstrate the usefulness of biomarkers in the treatment of cancer. 28 3. How to Market Biomarkers One can conclude from the above discussion regarding the target market for biomarkers that the process of branding or marketing is expensive, costing upwards a million dollars for a start-up or small business. Therefore, a solution to that monetary hurdle would be to create a partnership with another business. “Drug discovery is difficult, long and expensive. The likelihood of success for any particular project is low, with industry metrics suggesting that around one in 15 projects result in a marketed product. Thus, the risks are higher than with most industries; but the rewards can be great: overall” (21). Partnering with a pharmaceutical company, who represents the same objectives and ambition, without having to relinquish all control and decision-making, would be the ideal situation. An example case would be a pharmaceutical/biotechnological company that has the capital to assist in the marketing of the biomarker for a fee, but allows the proprietor to maintain some decision-making power. This would allow the proprietor to make decisions concerning marketing of the product to the desired clientele, particularly physicians, or the ability to retain all rights to the product without licensing the product to others. This partnership should benefit both parties economically and intellectually, with both parties being given the rights to utilize the biomarker for further research, if inclined. In conclusion, due to the landscape of the market, the costs can be exorbitant, which is why a strategic marketing plan, if enacted properly, can benefit both parties monetarily and ensure financial success. 29 V. Financing Every start-up needs capital or financial funding in order to continue to grow and develop as a business, regardless of the industry. Therefore, finding the seed money (or start-up capital) is vital to success. Financing can come from a multitude of groups depending on the route and monetary goals of the proprietor. For example, financing a biomarker such as hFR, with the intention of marketing, selling and distributing the product domestically or internationally can cost millions just to get started. “Biotech firms attempting to make the transition from early-stage R&D to fully integrated companies with robust pipelines face a daunting financial challenge. Given that the extraordinary costs and time required to bring not one but a series of successful compounds to market cannot be sustained through operational revenues, firms are forced to use a range of external financing sources” (22). Therefore, in discovering the multiple venues to facilitate this process the proprietor needs to be informed of the advantages and disadvantages of each selection before they sign on the dotted line. Possible financing options come in the form of public financing in which the company is established and creates an Initial Public Offering (IPO). While the proprietor may retain some decision- making rights, the shareholders would own the company. On the other hand, the proprietor can choose to finance their venture privately with loans or investments made by private parties, which provides more decision-making power to the proprietor than the public option, but they may have to offer more equity to secure this arrangement. 30 1. Start-up Financing Start-up financing usually begins with small loans from friends and family, and as the company becomes more established, the proprietor moves toward the distribution of larger equity shares and funding in order to grow and develop the business. The early funding/loans are seed capital to get the business off of the ground (see the Start-up Financing Cycle below). If the business is successful and continues to grow, that can lead to a variety of opportunities from acquisitions, mergers, and strategic alliances. An alliance with a pharmaceutical company with similar intentions can ultimately lead to a public offering or continue to be held privately. Figure 8 The start-up funding is the most difficult to obtain, since the product has not been proven to be effective or successful. A cost-benefit analysis would be the best predictor and persuader of investors, however these figures are difficult to obtain. The cost estimate can be in the range of $5-10 million. Since research facilities conduct experiments using 31 multiple machines that are not specific to biomarker discovery, narrowing down the exact dollar amount of start-up cost is inefficient and difficult. Moreover, the financial component is increasing in difficultly within the biotechnology industry, “with higher costs of drug research and longer clinical development timelines. The average drug takes over $1.0 billion and 12 years to go from laboratory to approval. Part of the reason for rising development costs is the high failure rate of product candidates in clinical trials due to increasingly specific molecular targets for unmet diseases—which necessarily increases development risk, complexity of biologic systems with compensating mechanisms, overlapping intellectual property claims, and shifting regulatory requirements” (23). 2. Continuous Financing In addition, since the majority of start-up companies don’t produce any profit for their first few years, investors are weary of providing funding, until they can see the benefits. Given this situation and the financial issues that befall a start-up, investors are hesitant to provide all of the funding upfront without a guarantee in place. In order to meet the demands of investors and alleviate their fears regarding the returns on the investment, the proprietors must develop a way to meet their needs, along with the investors. This leads to creating metrics that requires the proprietor to deliver updates on the business to satisfy the investor and obtain continuous funding. “The financial metrics that entrepreneurs employ at start-up are very different from the metrics that established companies use to monitor their progress toward whatever goals they’ve set. Start-up financial metrics must give entrepreneurs feedback on whether their business model is 32 working and whether it’s the business model the start-up should keep as it grows” (24). Using metrics not only allows the investor to observe the progress of the business, but it also allows the proprietor to consider incorporating some of them into their business models as advisors to ensure continuous growth and a successful venture. a. Milestones/Metrics Metrics come in many different forms such as customer acquisition, size of order and financial versions. For example, revenue growth, profit growth and even expense growth. The view from most people would be that financial metrics are the most important, since they will show the investors the status of the company’s success and whether it can sustain its business plan, in order to develop. “Profitability is the critical driver with the strongest relationship to financial strength. This is intuitively obvious because high profit levels will ultimately drive debt down, increase cash, and result in more capital funding for acquisition of newer plant and equipment” (25). The main rationale and motivation behind investors focusing on profitability is that they expect to see a return on their investment in the time agreed upon. The most accurate way to view this possibility is through inspection of the company’s financial records. As a start-up, another metric to view would be marketing performance of hFR in the industry. This can prove difficult and cumbersome, since marketing success of the business can be difficult to quantify. “Firms need sophisticated marketing systems, both operational and analytical, to pursue differentiation and strategically excellent strategies. In particular, differentiators need to meld customer information, purchasing patterns and the results of marketing research to develop customer knowledge based differentiation 33 ([20] Koo et al., 2007). Appropriate customer-based, measures are needed to see the performance differences” (26). The first goal in establishing marketing metrics would be to identify a method to quantify customer retention, the customer being patients, doctors or insurance companies. Once that method has been established, the proprietor will be able to measure their performance and be able to provide reports to their investor that not only includes financial standing, but also relates to marketing. Once both methods of metrics have been established and implemented, the proprietor and investor will have to decide on how the start-up funding will be segmented. This is an important process in obtaining the necessary funding in order to grow the company, since investors are unlikely to provide the start-up business with a lump sum of financing without viewing progress beforehand. For example, based on the financial metric, the investor could decide to break the funding up into payments based on yearly growth, meaning that once the business grows by a certain percentage, the investor will provide more funding in order to support further expansion. Metrics are vital to a company in many ways, not just in proving to investors that the company is succeeding. Metrics can also exhibit weaknesses in a company’s strategy and can alert them to this issue before it causes more harm and damage, granting them the ability to continuously improve their operations. 3. Private Financing Private financing in its simplest form is investments from an investor’s perspective, but debt from a business’s in the form of loans or equity. When seeking private financing, investors and proprietors can either secure this financing in the form of 34 a loan, in which after a set timeframe the business pays back the loan with interest, or in the form of equity, in which interest is not paid back, but a percentage of the profits are share with the investor. “Private equity broadly includes various types of equity and equity-like capital. Buy-out funds, mezzanine financing, and venture capital are the most commonly known forms of private equity. This capital is traditionally used to re-finance, acquire or farther develop private companies” (27). Moreover, whichever form of private financing the business and investor agree upon, the sole purpose of the funding is to grow the business into the possible potential outlined. a. The Advantages of Private Financing There are many advantages to accepting private financing versus public, such as sole decision-making by the head(s) of the company, quickly saturating the company with more funding for further development or research. In addition, private financing can incentivize management to improve the performance of the business in order to appease the investors. Finally, private financing removes the aspect of shareholder involvement in decisions. This is advantageous because shareholders may not understand the complex science behind hFR or the business’ daily operations, but invested in the company because it seemed lucrative. “Moreover, private equity still benefits from many strategic advantages over public companies in that it is nimble and less bureaucratic” (28). Companies that tend to go the private equity route for financing appear to have more freedom with their investors, as long as they continue to produce profits and provide dividends. If the company structures the initial financing to their advantage, they may 35 even be able to pay-off the initial loans in a short amount of time and become self- sustaining, without the need for future assistance. b. The Disadvantages of Private Financing Although there are many incentives and advantages in seeking private funding in order to develop and grow a start-up company, there are also disadvantages in seeking private funding. One of the most common issues a proprietor may face is obtaining the funding itself, which can ultimately cause the business to leverage itself too much and risk the business just to grow. “’The overwhelming disadvantage of being private equity- owned is the leverage. Often that doesn't matter. But when it does, it really matters," says Mr Evans” (29). While being private provides the business the freedom and discretion to run the business how they see fit, not many investors will be enthusiastic to provide financial stability to a company whose responsibility is to only pay back a loan or provide equity without regulations in place. For example, a company can choose to research a new biomarker while marketing its current biomarker hFR, but as discussed above, this research can cost in the millions of dollars and that is money that might be better served establishing the original biomarker that started the business. In addition, the utilization of loans will require the business to pay back the loans with interest on a strict schedule that may not provide for any leeway and can ultimately jeopardize the business if payments are made late. Finally, decreased regulation is not always a good thing, since complete freedom can lead to decisions that may do more harm than good to the business, such as the example given 36 above, where the business ventures into a new strategy without establishing themselves in the original methodology. 4. Public Financing As discussed above, in private financing, the business is offering equity to a restricted group or person, or the loan is secured from a restricted group or person. On the other end of the spectrum is public financing, in which the business offers equity in the form of stocks and takes out loans in the form of bonds. These offers are made to public investors and are not restricted to a specific group or person. There are many advantages to this form of a financing strategy, but it also comes with intense scrutiny by federal legislation. “Being public has long been identified with issuing equity to public investors. Many features of becoming a public firm by issuing equity, however, are relevant for firms that choose to become public by issuing debt. These features include reporting requirements, observable security prices, improved access to financial markets, dealing with many security holders, etc.” (30). Furthermore, there is intense scrutiny from not just the government, but the many shareholders who believe they have a voice in how the company is being operated and their vocal opinion could cause the desired goals to be altered over time. a. The Advantages of Public Financing There are many advantages to obtaining public financing by offering equity and bonds, the first being availability. There will always be investors looking for bonds, stocks and a business to add to their mutual fund. If investors view a company as having 37 potential growth over time, start-ups can be very attractive. The more established the start-up, the more appealing they become to the investor. “As the firm moves through acquiring different sources of capital, greater experience and an enriched understanding of each source of capital is attained. In addition, more mature firms may have used a larger variety of capital sources than less mature firms and may thereby be more familiar with different types of capital” (31). The difficulty in obtaining capital in order to expand and grow the hFR product will be to prove that the company has become self-sustaining, as it has matured. As a result, various forms of capital can be obtained in its place; therefore, the company will be displayed as successful and established to the public investors. Moreover, if that is possible to achieve, there could be no limits to the amount of capital acquired by the business. In addition, another advantage to achieving public financing as an alternative to private financing is the ability to become established as a publically traded company. By becoming a publically traded company, the company is equated to be more credible and appear more profitable for other investors to either purchase bonds or buy shares of the company, which provides more capital for the business. “Being publicly traded adds to a company’s stature as an institution, which can enhance its competitive position. The IPO process itself generates publicity that may enhance the company’s recognition in the marketplace. As a result, suppliers, vendors and lenders often perceive the company as a better credit risk and customers may perceive it as a better source of products or services. The stature of a public company can also enhance its ability to attract top level executives and employees” (32). This aspect can also create a strategic marketing affect, by 38 introducing the company to the medical society as established and well funded, which will lead investors to consider the business reputable. Finally, as a publically traded company, the business is run by a set legislation where most decisions are made by a board of directors. This ensures the company’s goals remain in-line with what has been committed to their shareholders. “The public trusts the business marketplace to ensure that companies operate ethically, deliver a quality product or service, and employ sound accounting practices. Public companies, in particular, are scrutinized because they are extremely accountable to their stakeholders - and certainly consumers and investors.” (33). Since public companies are scrutinized and accountable to their shareholders, boards have been developed to ensure that a single person is not making the decision that can drastically affect a company. The result is decision making that is consistent with the original desires of the business and its investors. Therefore, even though some decision-making capabilities are removed from the proprietor, the ultimate goals of the business are still intact. b. The Disadvantages of Public Financing There are a few disadvantages to seeking capital, equity or debt as a publically traded company, such as cutting through bureaucratic red tape when decisions need to be made, lengthy proposal requirements, and convincing the company to accept and try a new idea. As discussed above, public companies are heavily scrutinized and therefore, in the wake of Enron, the government has instituted Sarbanes-Oxley (SOX), which requires publically traded companies to document every procedure put into place to ensure nothing illicit is occurring in the business. “However, the challenges faced by businesses 39 of all kinds - especially those endured by public companies required to follow SOX, in particular - add yet another layer to an already difficult environment” (33). This enormous task can require a company to spend more money on overhead to hire an individual, whose sole responsibility is to ensure they comply with government regulations. Finally, not only can this type of regulation cost the company money, but also time, in that employees must first ensure they are in compliance with all regulations before moving forward with any projects or new ideas. Furthermore, as previously mentioned in the public financing section, another drawback to seeking public equity is the lengthy proposal requirements. Since there can be massive amounts of red-tape to cut through in order to move forward with any type of project, a business could lose out in being the first to the market, due to the bureaucracy that a company has to wade through. The purpose of this bureaucracy would be to ensure the company is continuing to pursue the goals outlined to the public, for fear of damaging the company’s reputation and ultimately impacting its success as a publically traded company. Another downfall to seeking public equity to grow the business is the ability to sell new ideas and take the company down another successful, but possibly risky path. Publically traded companies tend to invest conservatively and continue to follow the originally outlined mission statement of the company to avoid alarming stockholders. Moreover, everything the company approves or moves forward with, such as a new project, will be viewed and measured against the company’s success or failure. Therefore, the easiest and safest route for a public company to take would be to stick to their original plans that they were founded upon. 40 VI. Market Potential 1. Testing the Biomarker (Phase I, Phase II & Phase III) Upon completion of a marketing analysis of a product and acquisition of funds, the market potential must be evaluated to ensure that this venture is worth the financial risk. In order to place the product in the market for doctors, patients and insurance companies, the business will have to test hFR in three phases. The purpose of this step is to obtain approval from the Federal Drug Administration, which will allow the biomarker to be safely used in the United States. However, treatments/interventions that require invasive procedures, methods or drugs, require a clinical trial, which can run the course of four phases and cost a company millions. On the other hand, biomarkers, such as hFR, still need to be tested, but comply via a PMA (PreMarket Approval), which may not cost a company as much as a clinical trial, because the biomarker is an in vitro procedure. “Many of the new biomarker products that are being brought to the market have to undergo PMA approval since there is no predicate device available for a standard 510(k) and the fact that many of these are being developed as diagnostic and or prognostic medical devices” (34). Even though hFR is not invasive to an individual; it will be utilized as a diagnostic and prognostic tool, and there will be intense scrutiny because a person’s life can be at risk. 41 Figure 9 The first phase, Phase I, can involve as few as ten participants to as many as one hundred, depending on the design of the trials. The main purpose of Phase I is to test the safety of the biomarker. In Phase II, the business is testing the efficacy of the biomarker, in addition to reporting any side effects that may occur during the course of use. Finally, during Phase III, the sample population has increased, and the intention is to test that the biomarker is safe, efficient, does a better job than other products, and the standard of care in the marketplace, warranting its approval to be the new biomarker of choice. As the phases progress, the sample size expands, which makes it difficult to follow and track the participants and obtain results. Moreover, Phase III is where companies become the least successful in proving that their biomarker/drug is safe and better than other options in the marketplace. “Because of the complexity of cancer biology and because of the gap between where basic research leaves off and clinical development starts, development of a new drug with predictive biomarkers for identifying the patients most or least likely to 42 benefit from the drug is often complex” (35). In addition to the staggering costs going through the three phases needed to bring hFR to the marketplace, the ability to fit a participant into the study becomes another obstacle, which might account for about two- thirds of all studies failing in phase three. 2. Profitability a. Selling to Individuals In addition to discovering the market potential of the biomarker hFR, the proprietor will need to analyze the profitability potential. The best aggregate must be determined before the product can be strategically marketed. Direct selling will most likely become the method of choice to grow the company; however, in this instance it won’t be selling, but direct marketing, since customers will not have the ability to purchase the biomarker directly. “Direct selling is vibrant and successful and it represents a potential new channel for many traditional companies. As it becomes more difficult to continue the expansion of traditional retail, catalog and online selling channels, many companies will look to direct selling as a guerilla marketing and selling channel to fuel growth” (36). Selling or marketing directly to the consumer, whom hFR is specifically designed for, has the advantage of educating the customer/patient before they reach their doctor. This ensures the patient receives the best options for the best care, even if their doctor is unaware of this prognostic tool. In this instance, the customer is already educated about the product, how it works, and whom it can help, cutting out the need for an explanation that might frighten or confuse the patient if presented by their physician. This method of direct marketing or selling of a product can aid the business 43 largely in increasing revenue, through commercials and pamphlets, in addition to seminars that educate patients on their options. b. Selling to Laboratories On the other hand, there can be advantages to direct selling of hFR to the laboratories themselves in order to generate large volume purchases, which possibly assist in growing a company more rapidly. “In other words, a dollar in revenue from a large customer generates more profit than a dollar in revenue from a small customer. Combined with their larger sales volume, this results in a few large customers bringing in the bulk of the profit” (37). The strategy of selling directly to laboratories goes beyond the profitability aspect, since a larger business would be more reputable and could assist in the strategic marketing of the biomarker. In selling to large companies, such as laboratories, a start-up business would gain the benefit of that business’ financial goals being in-line with their own, in that they want to see the product succeed in the marketplace; therefore, partnering aids both companies. 3. 3, 5 & 10 Year Predictions/Valuations of Biomarkers As stated previously, the biomarker industry is growing at an annual growth rate of 14.4%, but will it continue to grow, slow down, slowly disappear or be swallowed by another up and coming technology? Biomarkers are currently the focal point of cancer research and physicians will become more dependent on biomarkers as they are effectively being displayed as useful indicators. “The future of cancer management is expected to be profoundly dependent upon the use of biomarkers that will guide 44 physicians at every step of disease management. Cancer biomarkers can be used for the accurate evaluation and management of the disease in different stages. They can be useful for predicting several outcomes during the course of disease including early detection, outcome prediction and detection of disease recurrence” (38). Therefore, new biomarkers are being discovered and more time and money is being invested into the technology. In addition, with the advancement of technology and the ease of detection and discovery of biomarkers, more will be discovered during the next few years. This explains the valued annual growth rate of 14.4% from MarketResearch.com, since as technology advances, costs decrease, making the accessibility of biomarker testing more readily available for patients. Pair this with financial investments and proper marketing and there is no telling where this industry will be in ten years. “As more potential biomarkers are discovered, the limitations in clinical use of these new markers, in the discovery phase, are reduced and more in the validation of the markers and rapid application to clinical practice. Oncology practice in the next decade will be ruled by cost effectiveness” (38). The industry is predicted to continue to grow, however there are limits to this growth, due to the emergence of this new technology. Firstly, since this a newly emerging industry and technology, there is not enough data to validate the usefulness of biomarkers, however, these limitations will be eliminated through more research undertaken by scientists. Though we know that as technology advances, the cost decreases over time, we still have not proven that with biomarkers, nor with hFR. Therefore, their use remains expensive, thereby making it difficult to sell this product to patients, physicians and especially insurance companies. “There are, however, numerous 45 practical issues and limitations that have to be considered. These include experimental design, biological sample quality and variability, technology platform capability, paucity of good ranking and predictive modeling algorithms, lack of context in disease and drug discovery and development process, limited use of knowledge assembly tools, lack of consideration of global initiatives in biomarkers of disease, company versus public databases, cost-benefit of technologies and ultimately a poor understanding of the potential for reimbursement and/or analysis of value of biomarkers” (39). Moreover, until these limitations are validated or the medical society discovers a method to overcome these issues, the true value of the biomarker will not be determined, but only assumed. VII. From Lab  to Clinics (Doctors)  to Business (Putting it all together) The potential of biomarkers is still a mystery, since no one can predict the future. A proprietor of biomarkers can make future decisions based on the information provided in the previous pages. They can discover a biomarker that can be utilized as an indicator of chemotherapy efficacy, or as an indicator of another important facet of medicine. Their next step would be to decide whether they want to use this new technology solely for themselves and obtain patents or licenses or to allow the technology to be used by others, while still collecting an income for their significant find. In addition, they could use the technology as the backbone for a start-up business, which will most likely require the proprietor to obtain financing of some sort, either public equity or private. Finally, they will use all of this information to decide how they want to market their product and to whom they are going to market their product, in order to maximize their goals and 46 profits. Once the proprietor has established these decisions and moves forward with their plan, they must then decide what their next steps will be. They have the option to advance the current technology and work to reduce the costs, thereby aiding in making their discovery more cost effective and thereby marketable. Moreover, the proprietor has the option to utilize their research to aid them in their search for new biomarkers, which can lead to many findings and business opportunities. 1. Advance current technology Advancing the current technology of biomarker discovery is only a small piece of the big picture regarding the future of biomarkers. The first would be the general concept of advancing the technology to make it more cost-effective for patients and insurance companies to use biomarkers, such as hFR, thereby, streamlining their acceptance into the medical world as a viable patient option. If the tests become economical for an insurance company, then more patients will have access, and the usefulness of the biomarker as an indicator will become part of the mainstream. The second concept behind advancing the current technology would be real-time testing, which would aid patients in multiple ways. By detecting the indicator at an earlier stage, preventative methods could be put in place sooner, thereby reducing the mortality rate of patients. In addition, since no two patients will react the same way to chemotherapeutics or other treatments, individualization allows for more efficient and effective treatment. Doctors will have the ability to make adjustments to the treatment specific to the patient and then modify the prescription as needed based on the indicator’s results. “Individuals at risk for cancer or with cancer would benefit enormously by better 47 methods for determining cancer risk, detecting and localizing cancer at its earliest stage, profiling for therapeutic decision making, and monitoring response to therapy in real time. For some of these applications, we will not know whether a tumor exists or, if so, its anatomical site. Thus, there is a need for biomarkers that can be monitored noninvasively in readily available bodily fluids” (40). Furthermore, the technology itself should be the focus of the progression, as science is constantly evolving. There has not been enough research to validate all of the findings coming out of the biomarker industry; therefore sifting through the data to determine what is valid should be prioritized. Protein research has become the focus of biomarker research since there may be too many mutations at the transcriptional level to determine abnormalities. This has given rise to Proteomics, the study of proteins and their pathways as “proteomics has now gained more attention because by directly analyzing protein expression at the post-translational level, it permits the qualitative and quantitative assessment of a broad-spectrum of proteins that can be related to specific cellular responses (4–6). Proteome analysis provides useful clues to biological processes happening at their level of occurrence, allowing comparison of physiological and pathological states of a cell line or a tissue” (41). It has been estimated that blood contains thousands of proteins and therefore multiple protein pathways, thus the utilization of Mass Spectrometry to separate the proteins is becoming limited because of the associate time and costs. Scientists and researchers must develop a new method or technology to efficiently target a potential biomarker protein. Science will continue to evolve in all niches, not just biomarkers, therefore the need and necessity to sift and sort through the data will also become a primary focus in the advancement of the technology, 48 which will go hand in hand with validating new discoveries. 2. Search for new Biomarkers As previously discussed, one option for the proprietor would be to advance the current technology of their biomarker discovery; however, they may also use their understanding and knowledge of pathways to search for alternative biomarkers. For example, there are currently multiple forms of cancer originating in the breast, pancreas, lungs, and etcetera. A logical use of their knowledge would be to begin working on pathways that affect those forms of cancer. Moreover, the next step toward advancing biomarker technology and basic science would be to discover biomarkers that can be utilized as indicators of abnormalities, but also for use in biomarkers for diagnostic medicine. “Genetic studies will undoubtedly identify variants that could be biomarkers themselves or will point to circulating markers for further exploration. Current technology allows the examination of hundreds of thousands of single-nucleotide polymorphisms (SNPs) in affected and unaffected individuals to search for significant associations with disease” (42). Once a pathway is identified, therapeutic drugs can be administered directly to the specific cancer cells and would not kill healthy cells. This would remove many adverse effects of chemotherapy through the specificity of the drug, since it would target only the tumor cells. The biomarker discovery niche is constantly evolving, as biomarkers have already begun to be utilized in diseases other than cancer, such as cardiac disease. Biomarker sensitivity, accuracy, and ease of use have led to investigations of their ability to differentiate patients in multiple ways, not just prognosis. “In a patient with an 49 established acute MI, a biomarker may be able to assess the likelihood of the following: a therapeutic response (eg, ECG ST-segment elevation indicating need for thrombolysis); the extent of myocardial damage (eg, troponin); the severity of underlying coronary disease (eg, coronary angiography); the degree of left ventricular dysfunction (eg, echocardiography); the risk of future recurrences (eg, exercise stress test); and progression to heart failure (eg, B-type natriuretic peptide [BNP])” (43). Therefore, as Vasan points out, since diseases themselves are complex, the biomarker should be complex and be able to assess the patient in a variety of ways, not just a single specific factor. VIII. Conclusion Biomarkers, such as hFR are significant today because they can be used as disease indicators, lead to the discovery of additional biomarkers, or for faster, more precise diagnosis at Stage 1, rather than Stage 4 of cancer. The discovery of biomarkers themselves will continue to occur; however, being able to validate the effectiveness and efficiency of the biomarkers will continue to be an issue until the more significant findings are presented to show their legitimacy to the medical mainstream. “Biomarkers play an ever-increasing role in today’s drug discovery process and high-throughput molecular profiling technologies have the potential to rapidly accelerate the discovery of highly specific biomarkers for drug safety and efficacy and diagnostic applications” (44). 50 IX. 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Abstract (if available)

Abstract The second largest killer in the United States, cancer, has led biotechnology and pharmaceutical companies to focus on treatments to cure or mitigate the risk of cancer. Biomarkers have emerged as a method for diagnosing and predicting the prognosis of cancer. Biomarkers are biological molecules that may be used to determine the normal versus abnormal processes of a condition or disease. In particular, Human Folate Receptor (hFR) is a membrane‐bound glycoprotein that has the potential of being a cancer indicator, as over expression of hFR has been seen in tumor cells. Biomarkers could be utilized in addition to the standard of care as they can be used to predict the efficacy of chemotherapy, as well as the likelihood of failure, which would allow for the selection of an alternative treatment. The feasibility of biomarkers will face some adverse reaction, due to this new technique being introduced to the science industry and due to lack of data and evidence. In addition, there is also the hurdle of the standard phase III testing, which could experience its own troubles due to participation from the subjects. Once identified as a cancer indicator, this paper aims to discuss the viable options as a proprietor from conception to completion on the process of protecting oneself and starting a business with the biomarker hFR. The objective is to educate the proprietor on the marketing options, in addition to the finance options and where the industry may be headed in the future.

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Asset Metadata

Creator Braham, Alexander (author)

Core Title Successful integration of biomarkers (hFR) into mainstream medicine

School Keck School of Medicine

Degree Master of Science

Degree Program Biochemistry and Molecular Biology

Publication Date 04/30/2014

Defense Date 02/26/2014

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag biomarkers,folate receptor,hFR,OAI-PMH Harvest

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Tokes, Zoltan A. (committee chair), Danenberg, Peter (committee member), Laird, Peter W. (committee member)

Creator Email AIBraham112@yahoo.com,brahama@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c3-406178

Unique identifier UC11295193

Identifier etd-BrahamAlex-2460.pdf (filename),usctheses-c3-406178 (legacy record id)

Legacy Identifier etd-BrahamAlex-2460.pdf

Dmrecord 406178

Document Type Thesis

Format application/pdf (imt)

Rights Braham, Alexander

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

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Repository Name University of Southern California Digital Library

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