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`Step 3: Clinical Research | FDA
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`Step 3: Clinical Research
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`While preclinical research answers basic questions about a drug’s safety, it is not a substitute for
`studies of ways the drug will interact with the human body. “Clinical research” refers to studies,
`or trials, that are done in people. As the developers design the clinical study, they will consider
`what they want to accomplish for each of the different Clinical Research Phases and begin the
`Investigational New Drug Process (IND), a process they must go through before clinical
`research begins.
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`On this page you will find information on:
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`Designing Clinical Trials
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`Clinical Research Phase Studies
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`The Investigational New Drug Process
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`Designing Clinical Trials
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`Asking for FDA Assistance
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`FDA IND Review Team
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`Approval
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`Researchers design clinical trials to answer specific research questions related to a medical
`product. These trials follow a specific study plan, called a protocol, that is developed by the
`researcher or manufacturer. Before a clinical trial begins, researchers review prior information
`about the drug to develop research questions and objectives. Then, they decide:
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`Who qualifies to participate (selection criteria)
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`How many people will be part of the study
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`How long the study will last
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`Whether there will be a control group and other ways to limit research bias
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`How the drug will be given to patients and at what dosage
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`Clinical trials follow a typical series from early, small-scale, Phase 1 studies to late-stage, large
`scale, Phase 3 studies.
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`What assessments will be conducted, when, and what data will be collected
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`How the data will be reviewed and analyzed
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`https://www.fda.gov/patients/drug-development-process/step-3-clinical-research
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`8/23/23, 8:38 AM
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`Step 3: Clinical Research | FDA
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`Whatare the Clinical Trial Phases?
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`What Are Clinical Trial Phases?
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`Watch this video to learn about the three phasesofclinical trials.
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`Clinical Research Phase Studies
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`Phase 1
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`Study Participants: 20 to 100 healthy volunteers or people with the
`disease/condition.
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`Lengthof Study: Several months
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`Purpose: Safety and dosage
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`https://www.fda.gov/patients/drug-development-process/step-3-clinical-research
`Page2
`Exhibit2052
`Regeneron Pharmaceuticals, Inc.
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc.
`IPR2023-00884
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`2/7
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`Step 3: Clinical Research | FDA
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`During Phase1 studies, researchers test a new drug in normal volunteers
`(healthy people). In most cases, 20 to 80 healthy volunteers or people
`with the disease/condition participate in Phase 1. However,if a new drug
`is intendedfor use in cancer patients, researchers conduct Phase1 studies
`in patients with that type of cancer.
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`Phase1 studies are closely monitored and gather information about how a
`drug interacts with the humanbody. Researchers adjust dosing schemes
`based on animal data to find out how muchofa drug the bodycantolerate
`and whatits acute sideeffects are.
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`As a Phase1 trial continues, researchers answer research questions
`related to how it works in the body,the side effects associated with
`increased dosage, andearly information about how effectiveit is to
`determine how bestto administer the drug to limit risks and maximize
`possible benefits. This is important to the design of Phase 2 studies.
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`Approximately 70% of drugs moveto the next phase
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`Phase 2
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`Study Participants: Upto several hundred people with the
`disease/condition.
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`Lengthof Study: Several months to 2 years
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`Purpose: Efficacy and side effects
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`https://www.fda.gov/patients/drug-development-process/step-3-clinical-research
`Page 3
`Exhibit2052
`Regeneron Pharmaceuticals, Inc.
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc.
`IPR2023-00884
`
`

`

`8/23/23, 8:38 AM
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`Step 3: Clinical Research | FDA
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`In Phase 2 studies, researchers administer the drug to a groupof patients
`with the disease or condition for which the drug is being developed.
`Typically involving a few hundredpatients, these studies aren't large
`enough to show whetherthe drugwill be beneficial.
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`Instead, Phase 2 studies provide researchers with additional safety data.
`Researchers use these data to refine research questions, develop research
`methods, and design new Phase3 research protocols.
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`Approximately 33% of drugs moveto the next phase
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`Phase 3
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`Study Participants: 300 to 3,000 volunteers who have the disease or
`condition
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`Lengthof Study:1 to 4 years
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`Purpose: Efficacy and monitoring of adverse reactions
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`Researchers design Phase 3 studies to demonstrate whetheror not a
`product offers a treatment benefit to a specific population. Sometimes
`known aspivotal studies, these studies involve 300 to 3,000participants.
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`Phase 3 studies provide mostof the safety data. In previousstudies,it is
`possible that less commonside effects might have gone undetected.
`Because thesestudies are larger and longerin duration, the results are
`morelikely to show long-term orrareside effects
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`https://www.fda.gov/patients/drug-development-process/step-3-clinical-research
`Page4
`Exhibit2052
`Regeneron Pharmaceuticals, Inc.
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc.
`IPR2023-00884
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`4/7
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`8/23/23, 8:38 AM
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`Step 3: Clinical Research | FDA
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`Approximately 25-30% of drugs moveto the next phase
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`Phase 4
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`Study Participants:Several thousand volunteers whohave the
`disease/condition
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`Purpose:Safety and efficacy
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`Phase4 trials are carried out once the drug or device has been approved by
`FDAduring the Post-Market Safety Monitoring
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`Learn more aboutClinical(/clinical-trials-what-patients-need-know).Trials
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`
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`TheInvestigational New Drug Process
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`Drug developers, or sponsors, must submit an Investigational New Drug (IND) application to
`FDAbefore beginningclinical research.
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`In the IND application, developers mustinclude:
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`e Animal study data and toxicity (side effects that cause great harm) data
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`¢ Manufacturing information
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`¢ Clinical protocols (study plans) for studies to be conducted
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`¢ Data from any prior humanresearch
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`¢
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`Information about the investigator
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`https://www.fda.gov/patients/drug-development-process/step-3-clinical-research
`Page5
`Exhibit2052
`Regeneron Pharmaceuticals, Inc.
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc.
`IPR2023-00884
`
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`8/23/23, 8:38 AM
`Asking for FDA Assistance
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`Step 3: Clinical Research | FDA
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`Drug developers are free to ask for help from FDA at any point in the drug development process,
`including:
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`Pre-IND application, to review FDA guidance documents and get answers to questions
`that may help enhance their research
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`After Phase 2, to obtain guidance on the design of large Phase 3 studies
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`Any time during the process, to obtain an assessment of the IND application
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`
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`Even though FDA offers extensive technical assistance, drug developers are not required to take
`FDA’s suggestions. As long as clinical trials are thoughtfully designed, reflect what developers
`know about a product, safeguard participants, and otherwise meet Federal standards, FDA
`allows wide latitude in clinical trial design.
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`FDA IND Review Team
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`The review team consists of a group of specialists in different scientific fields. Each member has
`different responsibilities.
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`Project Manager: Coordinates the team’s activities throughout the review process, and
`is the primary contact for the sponsor.
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`Medical Officer: Reviews all clinical study information and data before, during, and
`after the trial is complete.
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`Statistician: Interprets clinical trial designs and data, and works closely with the
`medical officer to evaluate protocols and safety and efficacy data.
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`Pharmacologist: Reviews preclinical studies.
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`Pharmakineticist: Focuses on the drug’s absorption, distribution, metabolism, and
`excretion processes.Interprets blood-level data at different time intervals from clinical
`trials, as a way to assess drug dosages and administration schedules.
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`Chemist: Evaluates a drug’s chemical compounds. Analyzes how a drug was made and its
`stability, quality control, continuity, the presence of impurities, etc.
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`Microbiologist: Reviews the data submitted, if the product is an antimicrobial product,
`to assess response across different classes of microbes.
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`Approval
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`The FDA review team has 30 days to review the original IND submission. The process protects
`volunteers who participate in clinical trials from unreasonable and significant risk in clinical
`trials. FDA responds to IND applications in one of two ways:
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`https://www.fda.gov/patients/drug-development-process/step-3-clinical-research
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`6/7
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`Regeneron Pharmaceuticals, Inc. Exhibit 2052 Page 6
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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`8/23/23, 8:38 AM
`Approval to begin clinical trials.
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`Clinical hold to delay or stop the investigation. FDA can place a clinical hold for specific
`reasons, including:
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`Step 3: Clinical Research | FDA
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`Participants are exposed to unreasonable or significant risk.
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`Investigators are not qualified.
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`Materials for the volunteer participants are misleading.
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`The IND application does not include enough information about the trial’s risks.
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`A clinical hold is rare; instead, FDA often provides comments intended to improve the quality of
`a clinical trial. In most cases, if FDA is satisfied that the trial meets Federal standards, the
`applicant is allowed to proceed with the proposed study.
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`The developer is responsible for informing the review team about new protocols, as well as
`serious side effects seen during the trial. This information ensures that the team can monitor the
`trials carefully for signs of any problems. After the trial ends, researchers must submit study
`reports.
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`This process continues until the developer decides to end clinical trials or files a marketing
`application. Before filing a marketing application, a developer must have adequate data from
`two large, controlled clinical trials.
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`https://www.fda.gov/patients/drug-development-process/step-3-clinical-research
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`7/7
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`Regeneron Pharmaceuticals, Inc. Exhibit 2052 Page 7
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
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