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Navigating the Paradigm Shift in Biomedical Research and Development:Orphan Drug Regulation and Prod 작성일 2016.06.08

Navigating the Paradigm Shift in Biomedical Research and Development:
Orphan Drug Regulation and Product Development Strategy

전문가
Eunjoo Pacifici
GPKOL 위원
상임 컨설턴트
학력사항
  • 1992 University of Southern California 독성학, 박사
  • 1988 University of Southern California 약학(Pharm D.)
  • 1984 Univerisyt of California Los Angeles 생화학, 학사
경력사항
  • 2012-현재 International Center for Regulatory Science, Assistant Professor of Clinical Pharmacy,Associate Director
  • 2015-현재 SC-CTSI Regulatory Knowledge and Support, Director
  • 2012-2013 SC CTSI Preclinical Translation & Regulatory Support, Member
  • 2003-2012 University of Southern California, Adjunct Professor
  • 1992-2000 Amgen Inc., Associate Director, International Product Development, Asia Pacific - Latin America
  • 1990-1991 Hospital of Good Samaritan, Clinical Pharmacist
  • 1988-1992 University of Southern California, Research Assistant
세부 전문분야 및 컨설팅 내용
  • 임상실험, 임상개발 치료, 제품개발(특히 아시아 태평양 및 남미 지역), 규제과학
이미지1

Figure 1. Number of Orphan Drug Designation Requests by the U.S. FDA (Karst 2016)
(reproduced with permission from the author)

Ⅰ. Introduction

Korean biopharmaceutical industry is poised to undergo a transformation from an industry focused on generics and, more recently, on biosimilars, toone that develops and commercializes novel and innovative products(Pacifici, 2015). At the same time, the traditional multinational biopharmaceutical industry is also undergoing its own paradigm shift to meet the needs of a changing research, development, and commercialization landscape(Au, 2014). The new model favors drug development approach that is smaller, faster, and more predictable, based on the scientific understanding of mechanisms of diseases. This may be a great opportunity for Korea to leap frog the traditional industry paradigm and explore new frontiers in science, technology, and healthcare. This new model also favors development of orphan drugs to treat rare diseases, an approach that merits consideration by the Korean industry.

Ⅱ. Orphan Drugs for Rare Diseases

As the biopharmaceutical industry faces challenges of expiring patents, late phase clinical trial failures, and an outdated business model, there is a growing interest in developing therapeutics for rare and neglected diseases. Even large pharmaceutical companies have become attuned to this change and have entered the rare disease space, which they have traditionally avoided— choosing instead to focus on developing potential blockbuster products for large disease populations. The annual number of orphan drug designation requests received by the United States Food and Drug Administration (FDA) reflects this shift. As can be seen in Figure 1, the number of requests increased almost five folds from just 88 designation requests in 2000 to 467 in 2014 and 472 in 2015 (Karst 2016).

Following the initial passage of the Orphan Drug Act in 1983 in the United States, there was an immediate increase in the number of requests for designation, which then stayed relatively flat for almost two decades, fluctuating between 80 and 100. However, since 2001, the number of requests has been rising almost every year, with 2015 reaching an all-time high. It is also worth noting that there was a clear surge in 2003, which coincides with the year that the human genome was sequenced(NIH 2015). As most rare diseases have a single associated genetic defect, completion of the human genome sequencing project clearly represents a disruptive technology that has spurred innovation in this field.

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Figure 2. Number of Orphan Drug Designation by the U.S. FDA (Karst, 2016)
(reproduced with permission from the author)

Not all but most orphan drug designation requests are granted by the FDA (Figure 2). The list of criteria for orphan drug designation, provided by the FDA (FDA 2015), includes description of the rare disease with the documentation to support that it affects fewer than 200,000 people in the United States and the scientific rationale that provides support for studying the drug in the proposed rare disease population. Although human data from clinical trials would be most informative for this purpose, the pharmaceutical company can apply for orphan designation without any human data. In this case, the company would need to provide convincing preclinical data demonstrating that the proposed orphan drug has efficacy in an animal model that is appropriate for the rare human disease.
It is important to note that for the orphan drug designation considerations, it is the efficacy data that provide the critical scientific component. Data from animal toxicology studies are not considered to be relevant(FDA 2015).
This move toward development of drugs for orphan indications should be of particular interest to the Korean companies. As a latecomer to the innovative drug development space, Korean biopharmaceutical industry can bypass the drug development paradigm of a bygone era and avoid emulating big pharma’s outdated model of chasing blockbuster products that target large disease populations but are associated with high failure rates or that of “me-too” or “me-better” products that may not demonstrate the comparative effectiveness outcome measures necessary for reimbursement. Instead, it can pursue breakthrough drug candidates that target small disease populations with well characterized genetic characteristics and validated biomarkers. Orphan drug development in rare diseases fits this model. Korea’s activity in the orphan drug development arena, however, has not been notable. Recent developments such as the creation of Korean Rare Disease Knowledge Base (KRDK) is encouraging and, hopefully, will lead to greater interest and investment in this field by private and public entities. Large multinational biopharmaceutical companies now see orphan drug development as an attractive path but, historically, this was an area that was embraced by small biotechs and start-ups. In fact, many were founded on the orphan disease business model focusing on genetic anomalies associated with rare and hard to treat conditions. For companies with limited resources, the financial benefits of pursuing an orphan drug strategy including clinical research cost reimbursements, user fee waivers, and longer market exclusivity can be key to their viability. Furthermore, it provided a safe harbor for these small companies, away from the big pharma’s competitive reach.
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Figure 3. Clinical Trial Success Rates (Hay, et al. 2014)

The large companies were not interested in the small orphan drugs. They were busy searching for the next blockbuster product — ¬another Zantac® or Prozac® —to replace there venue loss resulting from patent expirations. However, this high-risk, high-reward approach became unstainable in the face of low productivity and high failures. At the same time, increased patient engagement, greater understanding of genetic basis of diseases, and introduction of new regulatory incentives have altogether created a favorable condition for developing drugs for rare diseases. Although orphan drugs may target small disease populations, they provide companies with opportunities to develop innovative products in new therapeutic areas that have enormous unmet medical needs.
This new and growing interest has fueled increasing number of orphan drug approvals. Of the 45 new drugs approved by the U.S. FDA in 2015, 21 (47%) were orphan-designated for rare diseases and helped to make 2015 a great year for the industry (Mullard 2016). Moreover, there is growing evidence that early phase clinical trial success rates are much higher for orphan indications. This is welcome news for an industry fatigued by costly failures of its most promising pipeline candidates. Analysis by Hay et al. showed that phase 1 and 2 success rates for orphan indications were 86.8% and 70.0%, respectively, whereas those for all indications were 64.5% and 32.4%, respectively (Hay, et al. 2014). The more than two-fold difference in the phase 2 success rates is especially impressive and perhaps indicative of a more solid scientific basis behind the orphan programs (Figure 3).

Ⅱ.Ⅰ History of Orphan Drug Legislation

Efforts to advance orphan drug development began in the United States in the 1970s, initiated by patients and physicians who voiced their concerns regarding the lack of access to existing and new pharmaceutical treatments for patients suffering from rare diseases (Huyard 2008)(National Organization for Rare Disorders 2016). With the introduction of laws in the United States that require new drugs to undergo costly clinical trials to demonstrate safety and efficacy, profitability became central to a company’s decision in choosing which diseases to target with its development efforts and even which products to maintain on the market. Therefore, the pharmaceutical industry became focused on addressing conditions that affected large numbers of patients (tens of millions), like hypertension, heart disease, diabetes, and Alzheimer’s disease. Rare conditions that affect small populations were neglected by the industry and potential treatments for these conditions were without sponsors to develop them. Hence, the term “orphan-drug” was conceived. The companies had little incentive to work on developing new products for these patients or even keeping existing products on the market. Patients and their families, affected by a rare disease, grew frustrated, helpless, and isolated. They realized that different rare disease groups must work together to have a louder voice and make a stronger impact. Therefore, several patient advocacy groups that represented different “rare” diseases combined to form a single powerful political coalition, which later became the National Organization for Rare Disorders (NORD). This group worked tirelessly to increase the public’s awareness, lobby the politicians, and collaborate with the policy makers. Their largest accomplishment was the passage of the Orphan Drug Act of 1983 (ODA). This U.S. law provides incentives for pharmaceutical companies to work on developing orphan products and has changed the drug development landscape.

Ⅱ.Ⅱ National and Regional Differences

Other regions and countries have followed by establishing their own orphan drug policies and laws (Table 1). Of these, Japan and EU have adopted orphan drug mechanisms that are closest to those of U.S. in that they have legal frameworks in place, provide market exclusivity, include financial incentives, and incorporate regulatory assistance. Others including Australia, Canada, South Korea, and Taiwan only have some of the elements that are in common with the U.S. For example, South Korea does not provide financial incentives or regulatory assistance and Australia does not provide market exclusivity specific for orphan drugs. There are still many countries around the world, including China and India, without any established legal frameworks or incentives. Even among those that do have orphan programs, there is no harmonization in terms of the definition of rare diseases, period of market exclusivity, or financial or regulatory considerations(Gammie, Lu and Babar 2015).For example, U.S. provides 7 years of market exclusivity while EU, Japan, and Taiwan provides 10 years (Song, et al. 2012)(Gammie, Lu and Babar 2015). South Korea provides 6 years of market exclusivity while Canada and Australia provide none. Although Australia provides 5 years of exclusivity as noted in some literature, this is a general exclusivity for all new chemical entities and not specific to just orphan drugs. The lack of a harmonized regulatory framework makes it difficult for a company to formulate a worldwide regulatory strategy in this increasingly global enterprise.

European Union (EU) provides a centralized framework for definition and regulatory incentives but a decentralized scheme for financial incentives such as tax credits and research grants. In addition, the EU definition specifies not only the number patients (fewer than 5 in 10,000), but also the nature of the condition in that it needs to be life-threatening or chronically debilitating. The orphan drug designation application is evaluated by the European Medicines Agency (EMA)’s Committee for Orphan Medicinal Products (COMP) and the European Commission (EC) may grant the orphan status following the committee issues a positive opinion. There are centralized financial incentives through the EMA in the form of fee reductions for regulatory inspection, market authorization application, and scientific advice. There may also be other financial incentives that are available through EC grants for orphan drug development. Member states may have their own grants and tax incentives. Orphan designated drugs are required to be evaluated centrally through the EMA’s Committee for Medicinal Products for Human Use (CHMP) and are not eligible for mutual recognition, decentralized, or national route (European Medicines Agency 2016).

Japan amended its Pharmaceutical Affairs Law in 1993 to incorporate a robust orphan drug framework that includes market exclusivity, tax incentives, priority review and fast track approval, lower fees, 50% reimbursement of clinical and non-clinical development expenses, and a longer re-examination period.

Table 1. Comparison of orphan drug regulatory frameworks (Gammie, Lu and Babar 2015) (Song, et al. 2012) (Franco 2013)

Country/Region

Orphan Drug
Legislation

Definition

Market
Exclusivity
(years)

Financial
Incentives

Regulatory
Incentives

Australia

Yes

< 2000 per year

No special
consideration

Yes

Yes

Canada

No

 

 

Yes

Yes

China

No

 

 

No

Yes

European Union

Yes

< 5 in 10,000

10

Yes

Yes

India

No

 

 

No

No

Israel

No

 

 

No

Yes

Japan

Yes

< 50,000

10

Yes

Yes

South Korea

Yes

< 20,000

6

No

No

Taiwan

Yes

< 1 in 10,000

10

Yes

Yes

United States

Yes

< 200,000

7

Yes

Yes

Ⅱ.Ⅲ The U.S. Orphan Product Development Program

Of all the regions and countries around the world, the U.S. provides the most comprehensive and attractive program. It is the first country to establish a national legislation (ODA) and has continued to strengthen its commitment with further legislative and regulatory actions. In fact, the annual number of orphan designations in the U.S. far surpasses that of EU and Japan(Premier Research 2015). The ODA defines rare disease as a condition that affects fewer than 200,000 people and orphan drug as a drug or biological for the prevention, diagnosis, or treatment of a rare disease in the U.S. or one that will not be profitable within 7 years following FDA approval. The U.S. FDA has a dedicated office, The Office of Orphan Products Development (OOPD) with a mandate to help advance the development of promising products including drugs, biologics, devices, and medical foods that may help patients with rare diseases. The ODA has proven to be very effective. For the decade prior to 1983, the FDA approved only about one orphan drug per year. In contrast, since the passage of ODA in 1983, there have been about 2100 orphan designations of drugs and biologics leading to over 350 approvals or about ten approvals per year. In addition to drugs and biologics, the OOPD also oversees Humanitarian Use Device (HUD) designation program to encourage the development of medical devices for use in a disease or condition affecting less than 4000 individuals in U.S. per year. Once designated as HUD, the device may be eligible for approval via a Humanitarian Device Exemption (HDE) pathway. To date, over 130 HUD designations were granted and over 50 HDEs were approved.

The ODA encourages companies to consider orphan drug strategy early in the development process by providing development and regulatory assistance, access to the clinical research grant program, a 50% tax credit for the cost of clinical research, and waiver of FDA user fees. The user fee for a New Drug Application (NDA) or a Biologics License Application (BLA) is $2.3 million dollars in 2016, which represents a significant savings especially for a small company. With an annual budget of $14 million dollars, the OOPD’s clinical research grant program has funded over 508 grants totaling approximately$261 million dollars. This investment has led to the approval of over 44 products and numerous publications. But for many large pharmaceutical companies, the seven-year market exclusivity that accompanies an orphan drug designation may be the most valuable incentive, in this era when drug development takes many years and erodes a molecule’s effective patent period.

In addition to all the financial and exclusivity benefits granted by ODA, most orphan drugs can take advantage of other regulatory benefits afforded by the FDA including Fast-Track designation, Accelerated Approval, Priority Review designation, and Breakthrough Therapy designation(U.S. Food and Drug Administration, Guidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics 2014, U.S. Food and Drug Administration, Rare Diseases: Common Issues in Drug Development Guidance for Industry 2015). In fact, a close examination of orphan drug approvals since ODA was enacted reveals that FDA has used all of its regulatory tools to be reasonable and flexible in its review of orphan drug applications. According to a comprehensive analysis by Sasinowski, et al., most of the orphan drug approvals were based on “one adequate and well-controlled” clinical trial to demonstrate substantial evidence of effectiveness instead of the conventional standard of “two adequate and well-controlled” trials(Sasinowski, Quantum of Effectiveness Evidence in FDA's Approval of Orphan Drugs 2012)(Sasinowski, Panico and Valentine 2015). Furthermore, many of the orphan drugs were approved based on surrogate endpoints or intermediate endpoints instead of clinical endpoints. Taken together, the regulatory and administrative flexibility allows an orphan drug to reach the market more quickly and based on a much smaller and shorter development program.

Ⅱ.Ⅳ A Detailed Look at the FDA’s Expedited Programs

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An orphan drug candidate in U.S. can potentially qualify for one or more of the four regulatory programs to expedite its development and review. They are fast track designation, accelerated approval pathway, priority review designation, and breakthrough therapy designation(U.S. Food and Drug Administration, Guidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics 2014).
These programs are designed to shepherd promising therapeutics that target serious and unmet medical needs to the market as quickly as possible. Many rare diseases fall under the “serious” and “unmet” classification. The FDA defines “serious” as “…a disease or condition associated with morbidity that has substantial impact on day-to-day functioning” and that “…if left untreated, will progress from a less serious condition to a more serious one”. The qualification of an unmet need can be complicated in that it includes cases where there is no existing treatment and where there is inadequate treatment.

A “Fast Track” designation allows the company to interact closely with FDA to expedite product development, including review of study design, safety concerns, and biomarkers. It also allows the FDA to consider reviewing portions of a marketing application earlier through a rolling-review process.

An “Accelerated Approval” may be granted for a drug that treats a serious condition and provides meaningful advantage over existing therapies. The key stipulation in this program is that the drug can be approved much earlier based on its effect on surrogate endpoint that may be predictive of clinical benefit or a clinical endpoint that can be measured earlier than irreversible morbidity or mortality or other clinical benefit. The accelerated approval, however, must be followed by post-marketing confirmatory trials to demonstrate the drug’s effect on clinical endpoint, by improving how a patient feels, functions, or survives. If the confirmatory trial fails to demonstrate clinical benefit or if the company fails to conduct the studies, the FDA may withdraw the approval of a drug or indication. For example, the FDA recently withdrew NDA for EMD Serono’s fertility drug Luveris® for failing to conduct the post-marketing confirmatory trial, and in 2011, the agency withdrew breast cancer indication for Avastin® because the post-marketing trial failed to show clinical benefit (Food and Drug Administration 2016)(Food and Drug Administration 2011). A surrogate endpoint can be a biomarker, such as a laboratory test measurement, radiographic image, or other measures that is likely to predict the targeted clinical benefit. There are some therapeutic areas that are more favorable for biomarker application. For example, suppression of HIV viral load in plasma and blood T-cell counts are considered to be predictive of longer term clinical benefit and evidence of tumor shrinkage is considered to be predictive of improvement in overall survival. In fact, of the 73 new molecular entities that received accelerated approvals between 1992 and 2004, 29 were for HIV and 26 were for cancer. For many other therapeutic areas, including rare diseases, development of biomarkers is an area of tremendous unmet need. In fact, for orphan drug development, biomarkers could potentially be qualified as primary endpoints for standard approvals in cases where clinical endpoints are not attainable due to the rarity of the condition. Successful biomarker development requires an in-depth understanding of the pathophysiology of a disease process and the ability to target key interventional points that may impact the clinical outcome.

A “Priority Review” designation provides a shorter review time of 6 months compared with a standard review time of 10 months. For a drug to qualify for this program, it must target to treat a serious condition and demonstrate the potential to provide a significant improvement in safety or effectiveness.

For a product to be eligible for the “Breakthrough” designation, it must demonstrate some preliminary clinical evidence that the drug or biologic may be effective. The designation provides increased communication with FDA during drug development and review to ensure that the program receives the agency’s attention and guidance. Obtaining clinical efficacy in early development may be quite challenging and points to the need for thoughtful study design. Not surprisingly, therefore, most requests for Breakthrough designation are denied and the most common reason (72%) for denial is due to the reliability of clinical evidence (Food and Drug Administration 2015). Since the designation is initially based on preliminary evidence, the designation may be rescinded if the product no longer meets the Breakthrough criteria. As of September 30, 2015, there were 282 requests, 88 granted, 144 denied, and 4 rescinded (Raggio 2015). For those products that are granted Breakthrough designation, the impact is significant. First of all, more than one-third are anti-cancer drugs. It is striking that most were approved based on early phase data. Of the 12 that were approved between January 1, 2013 to December 31, 2015, 6 were approved based on phase 2 data and 2 were approved based on phase 1 data (Shea, et al. 2016). Biomarkers provided a clear advantage in receiving Breakthrough designation in that 65% of requests with prognostic biomarkers received designation compared to 29% of requests without (Food and Drug Administration 2015). This again points to the value of effective biomarkers and the need for further development in this area.

Ⅱ.Ⅴ Patient Advocacy and Orphan Drug Development

Following the successful passage of ODA in 1983, National Organization for Rare Disorders (NORD)continued its mission to identify, treat, and cure rare disorders. This was accomplished by increasing awareness, enabling basic and translational research, influencing regulatory policy, and providing support for patients and their families. The organization has grown over the years to include more than 230 different patient groups that worked together to pass a new law, “The Rare Diseases Act”, which created the Office of Rare Diseases Research (now the Genetic and Rare Disease Information Center) at the National Institutes of Health. This law also established the NIH Rare Diseases Clinical Research Network, which provides support for clinical studies and facilitates collaboration, study enrollment and data sharing. Most recently, NORD led the efforts to include key orphan drug provisions into the latest reauthorization of the User Fee Act in 2012, the “FDA Safety and Innovation Act” (FDASIA) to provide further clarity and direction for companies working in the orphan disease arena.
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Specifically, FDA was to explore complex issues in developing drugs and biologics for rare diseases and to encourage and accelerate the development of new therapies for pediatric rare diseases. Since then, The FDA has issued final regulations to provide clarification and enable the implementation of the ODA(U.S. Food and Drug Administration, Federal Register 2013). This final rule clarified the concept of “orphan subset” of a “non-rare” disease or condition to mean that such subset should be identified based on scientific or medical parameters. For example, the orphan drug would be inappropriate for use in the “non-rare” population due to its toxicity profile, mechanism of action, or previous clinical experience. The FDA also clarified that multiple orphan-drug exclusive approvals would be permitted for multiple subsets of the same underlying orphan disease or condition. For example, same drug could be approved with orphan designation for difference subsets of T-cell non-Hodgkin’s lymphomas, such as anaplastic large cell lymphoma or angioimmunoblastic T-cell lymphoma. This would incentivize one or more companies to continue to develop multiple subsets of the same underlying condition even after a product is on the market. Therefore, a company may request orphan-drug designation of a previously unapproved drug, or of a new use for an already marketed drug.
NORD has continued to work with the FDA to provide further clarifications for the companies working on rare diseases. For example, the draft guidance “Rare Disease: Common Issues in Drug Development” emphasizes the scientific approaches to guide drug development including the importance of understanding the natural history of a disease and its pathophysiology, of elucidating a drug candidate’s proposed mechanism of action, appropriateness of the proposed nonclinical studies, and relevance of selected endpoints and outcome assessments.

Patient involvement remains critical in stimulating orphan drug development. By combining their efforts, disease organizations have become very powerful and effective in bringing about legislative actions that have transformed drug development landscape. Having achieved great success in the legislative and regulatory realm, a number of patient advocacy organizations have gone further to be more directly involved in the scientific process of drug development. These organizations are often referred to as “Disease Foundations” and there are now quite a few of them that are very active. In addition, through formation of patient advocacy groups and disease foundations that have become partners with other key stakeholders in the process. They work closely with companies and in some cases, as with certain disease foundations like the CHDI Foundation (for Huntington’s Disease), Michael J. Fox Foundation for Parkinson’s Research, and the Cystic Fibrosis Foundation, are driving the process as full-fledged drug discovery and development operations. Many are working to de-risk drug development programs and making them more attractive to potential big pharma partners as evidenced by recent high-profile partnerships and licensing deals. (CHDI Foundation 2013)(The Cystic Fibrosis Foundatioin 2016)(Video: Pfizer and The Michael J. Fox Foundation — Partners in Advancing Research 2015)

Ⅲ. Orphan Drug Strategy in the Post-Genomic Era

There are approximately 7000 rare diseases just in the U.S., collectively representing 30 million patients in need of safe and effective treatments. With only 4% of the rare diseases having approved treatments, many patients still lack treatment options. With over 80% of rare diseases having genetic basis.the current “post-genomic” era is ripe for unraveling mechanisms of diseases in ways that are unprecedented. Contrary to common diseases, like obesity or hypertension, that may have complex genetic and environmental interplay, most rare diseases have a single genetic defect. They can, hence, be viewed as simpler models of more complex diseases and could facilitate the understanding of normal biology as well as more complex pathophysiology.

Korea may be ideally positioned to pursue orphan drug development. Known worldwide as early adopters of technology, the country has already embraced digital health, which by all accounts is far more advanced than in U.S. Korea could take digital health a step further by establishing a national gene registry that contains de-identified health and genetic information, creating a database that can be available to researchers for probing potential therapeutic targets. These registries can then be used to gather rare disease natural history data, gain insights into disease progressions, and identify points of therapeutic interventions.
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Figure 4. Precision medicine (NIH National Cancer Institute)

President Obama’s announcement of Precision Medicine Initiative in January 2015 has launched actions across different governmental agencies. The National Institutes of Health (NIH) is spearheading the effort by building a large scale national patient database of more than one million through the Precision Medicine Initiative (PMI) Cohort Program (Figure 4) (NIH National Cancer Institute 2016). The Korean National Cancer Center has also announced that it will cooperate with the U.S. NIH in the PMI Cohort project (Tomale 2015). The “big data” here is limited to cancer patients but the concept could be expanded to be more comprehensive. Such an initiative would require coordination across national policy, sharing of databases, and appointment of orphan disease experts in the public agencies.

Pursuing orphan drug development in this post-genomic era provides an advantage to innovators who are new to this field in that they can work nimbly in this environment without the burden of an existing institutional infrastructure. We will continue to see consolidation of the industry and collaboration across academia, government, and industry. And we should expect to see more partnering across the industry in the pre-competitive space along with the entry of new players. These activities are fundamentally changing the way new drug research and development is conducted in that greater emphasis will be placed in biology driven, patient centered activities that will aim to track disease, behavior, treatment, response, and safety. Korean companies can take advantage of this changing landscape and find ways to be leaders in this new space. As the big pharmaceutical companies strive to reinvent and revitalize their existing research and development structures, Korea can move swiftly and nimbly to embrace the new model.
Korea is at the forefront of technology and maybe poised to embrace digital monitoring and biometric sensor technology to understand patient experience and identify therapeutic needs that are important to the patients. Securing patients as partners and allowing them to contribute health and medical data to be mined may benefit all stakeholders. In the U.S., The Office of the National Coordinator for Health Information Technology was established to foster health information sharing and interoperability. It would be interesting to see how and if such measures will be able to accelerate therapeutic development. In addition to enabling access to genetic and health information, enabling biomarker development is critical to precision medicine for the reason that an effective biomarker is crucial in identifying the “right drug for the right patient at the right dose” (Whitehouse.gov 2015).

Ⅳ. Big Pharma and Orphan Drugs

Over the past two decades, drug development landscape has dramatically changed. Lipitor® could be taken as an example. It is a small molecule used to treat a broad population targeting a well-established molecular target, 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase. The development of the molecule followed a classic example of testing of analogs that originated from a natural products (Tobert 2003). The relationship between elevated serum cholesterol and cardiovascular disease was based on more than 100 years of medical and scientific observations. Once the causality was established, diagnosis criteria were very simple — a blood test carried out in the doctor’s office. Anyone with increased blood cholesterol became a candidate to receive a statin prescription. How Pfizer was able to command the market with its version of a statin drug when there were many other statins already available is a marketing marvel that has been extensively studied and points to the marketing genius of Pfizer. It is interesting to note that it took over a decade to show long term safety and efficacy of statins and the impact of lowering cholesterol on the mortality.

Cholesterol synthesis pathways were elucidated in the 1950s and 60s and the first statin was developed in the 1970s. This example highlights the long timeline from identification of a molecular target to the development of therapeutics for the target. When the first statins appeared on the market in the 1980s, the uptake was slow. Doctors, patients, and payers were not convinced that high cholesterol was directly linked to heart disease, morbidity, and mortality. It took another decade for the idea to take hold, which was perfect timing for Lipitor’s entry into the market with data pointing to its increased potency, post-marketing study demonstrating the benefits of a lower LDL cholesterol, aggressive marketing, and strategic pricing. Within just a few years, Lipitor became the market leader in the cardiovascular therapeutic area where a great number of patients were prescribed statins to decrease and maintain their serum cholesterol levels within normal range. Recently, however, it became evident that not everyone with elevated cholesterol should be treated with statins — pointing away from the traditional “one-size fits all” approach taken by blockbuster products(Culver, et al. 2011).
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Figure 5. Comparison of traditional vs. orphan

The days of chasing blockbuster drugs like Lipitor that target a broad patient population and rely heavily on the marketing prowess of a large salesforce may be over. This may be due to decreasing productivity, increasing failure rates, saturation in certain areas (for example, HMG-CoA Reductase Inhibitor space), higher regulatory requirements, and challenging reimbursement hurdles. Pharma’s low productivity, high costs, and increasing failures have been extensively analyzed and published(Paul, et al. 2010).
During the same period, the industry has become aware of the benefits of pursuing orphan development strategy in the form of shorter clinical development timeline, more flexible regulatory requirements as well as higher probability of approval (Premier Research 2015).
As it becomes clear that traditional drug candidates are failing at an even higher rate than previously thought, with only one in ten indications achieving FDA approval, orphan indications may be more attractive for companies looking to increase productivity of their research and development efforts (Figure 5).

Ⅴ. Conclusions

This is a critical period overall for the biopharmaceutical industry but, in particular, for the Korean companies that are eyeing the global biopharmaceutical market. As the biopharmaceutical industry transitions from a blockbuster or “me-too” centered business models to one that develops innovative products to treat serious unmet needs, there may be unique opportunities for Korea. Efforts under way to make clinical trial data transparent and accessible (Eichler, et al. 2012) would allow companies to learn from previous attempts and formulate study designs that are innovative and better informed. The current move toward open science provides precompetitive space where companies can work together to better understand disease mechanisms or to develop useful biomarkers. Advances in mobile health and digital health may provide ways to improve clinical trial design and implementation as well as help to mitigate safety risks in the post-market setting.
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Figure 6. Contributing factors for successful orphan drug development

As FDA and EMA continue move toward incorporating patient reported outcomes and view patients as partners in drug development, Korea may look to organize and support patient groups associated with various diseases as well as to integrate other activities to enable success in this exciting a promising therapeutic space (Figure 6). Understanding the mechanism of an orphan disease that has a specific genetic basis can provide researchers with an insight into the biology and the mechanisms of other related diseases and help bring forth a learning research system. For example, unraveling the pathophysiology associated with Huntington’s disease may open the door to understanding other neurodegenerative diseases and expand the therapeutic opportunities.

Ⅵ. Bibliography

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