CASE STUDY Drug Approval—Bringing a New Drug to the Market Sept 2015

known as SGLT2 inhibitors. The A SMALL PHARMACEUTICAL COMPANY REVIEWS SGLT2 inhibitors treat diabetes by inhibiting the sodium glucose THE PATH LEADING TO FDA APPROVAL TO MARKET A co-transporter 2 (SGLT2) in NEW DRUG IN THE UNITED STATES the kidneys. This decreases the reabsorption of urinary glucose and This fictionalized case study is part of an educational series increases excretion of the urinary published by the Center for Drug Evaluation and Research, glucose. Professional Affairs and Stakeholders Engagement, U.S. Food and Drug Administration. The drug aims to prevent the Questions to consider as you read Green replied, “Yes, in 2012, 29.1 intestinalLowagliflozin, absorption however, of glucoseis different. this fictional case study: million Americans, or 9.3 percent in addition to blocking glucose of the population, had diabetes. Out reabsorption in the kidneys. Green 1. What are the objectives of the of those, 90–95 percent are type 2 drug development and approval diabetic patients1 and the numbers treatment for patients with type process? have been growing.”2 2envisioned diabetes unable lowagliflozin to adequately as a 2. What are the major activities control the disease with diet and Five years ago, Abby Green, soon exercise. that occur during the drug after receiving her M.D. and development and approval Ph.D. degrees, started a small “But aren’t there already a lot of process from nonclinical testing pharmaceutical company called to market approval? diabetes drugs on the market?” Soto Green Pharmaceuticals. asked. 3. What are the major elements and steps required to conduct a “I was able to get funding from Green answered, “Yes, there are at clinical trial? multiple investors to start this least 10 classes of drugs that work company because of my interest in to treat type 2 diabetes, but they all Preparing to Meet a Big researching a disease that impacts have limitations. (Appendix A) Some Need at a Small Company so many people,” Green remarked. work better in some people, and some of the drugs have side effects 9.3 percent. Dr. Abby Green circled Her company had developed a that some patients cannot tolerate. the number and snapped the cap drug aimed at type 2 diabetes: back in place on the dry erase novel mechanism of action, may marker. similarly to a class of drugs haveI think much that tolowagliflozin, offer patients. with The its lowagliflozin. The drug works drug is ready to be tested in healthy Green and her new operations 1Centers for Disease Control and Prevention volunteers, and I am excited to see manager, Jon Soto, looked at the (CDC) 2014 National Diabetes Statistics if it lowers blood glucose in people Report Infographic. Diabetes in the United with type 2 diabetes.” whiteboard. “That’s almost 10 States: a Snapshot. percent!” he exclaimed. 2CDC. Long-term Trends in Diabetes.

1 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued

The company was almost done of the drugs do not work or they with the basic laboratory work the lab and later in lab animals,” are too dangerous. The drugs that Green“Potential said. drugs She explained are first tested that most in make it through the initial stages necessary animal studies to initiate drugs undergoing animal testing then undergo the FDA’s evaluation Phaseon lowagliflozin, 1 studies in including patients. the Green never make it to human testing and and her colleagues now faced the review by the FDA. She drew a large everything about the drug—from task of beginning the clinical trials funnel on the board. Pointing at the theprocess, design which of clinical scrutinizes trials to the needed to obtain approval from the wide end of the funnel she said, “At severity of side effects to how the U.S. Food and Drug Administration the mouth of the funnel, there are drug is manufactured. Even fewer (FDA) to market the drug in the tens of thousands of potential drugs United States. being developed in laboratories. (drugsExhibit have 1 and the Appendix safety and B efficacy) “Can you give me a big picture profile needed for approval.” overview of the drug development the funnel, the number decreases Green said that, given Green and approval process?” Soto asked. asAs thethe developersdrugs begin discover flowing somethrough Pharmaceuticals’ inexperience

“Sure, I will start at the very beginning with how the Federal Exhibit 1. Drug Development Funnel Food, Drug, and Cosmetic Act websitedefines a and drug.” angled Green her said. tablet She towardslocated the him: definition on the FDA’s

The term “drug” means (A) articles recognized in the official United States Pharmacopoeia, official Potential New Drugs: Homoeopathic Pharmacopoeia Tens of Thousands of the United States, or official National Formulary, or any Drug Discovery 3–6 years supplement to any of them; and (B) articles intended for use in the diagnosis, cure, mitigation, Nonclinical Studies* treatment, or prevention of disease

in man or other animals; and (C) M Clinical Trials 6–7 years articles (other than food) intended As drugs travel through the funnel, their number to affect the structure or any decreases as studies FDA Review 6–12 months function of the body of man or other indicate problems with safety and/or effectiveness animals; and (D) articles intended for use as a component of any article specified in clause (A), (B), or (C).3

3Section 201 (g)(1) of the Federal Food, Drug, *Nonclinical*At times, Nonclinical Studies Studies may overlap may overlap with to ClinicalClinical T rialsTrials and Cosmetic Act; 21 U.S.C. 321. http://www.fda.gov/downloads/AboutFDA/Transparency/Basics/UCM247465.pdf

2 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued interacting with the FDA, she was the time and money needed to bring “That’s us!” Green and Soto agreed. it to market.” Roberts asked if the company navigate the drug approval company was done with animal Roberts walked to the whiteboard process.going to find a consultant to help the testing and could now focus on near the head of the table. She clinical trials. announced, “The drug development Following a Logical Path process is lengthy and detailed, with Clear Milestones “That is a good question, and but it is a logical path with clear the answer is yes and no,” Green milestones.” She chose a marker Green hired Dr. Sheryl Roberts, a replied. physician and regulatory affairs where does this logical path go?” she “We know we will eventually need turnedand drew and a asked.long, horizontal line. “So guiding smaller pharmaceutical additional nonclinical studies to companiesconsultant whothrough specialized the drug in support the safety of the clinical Safety and Efficacy development and approval process. trials as the trials become larger Green asked Soto to join her in the and of longer duration. Also, there “The path leads to FDA approval initial meeting with Roberts, “You are some safety endpoints that we for marketing the drug or biologic have a lot of experience developing in the United States. And it is and managing processes. I’d like to in nonclinical studies, such as the designed to demonstrate the safety can only characterize sufficiently get your perspective as we make risk of cancer and teratogenicity and of the drug or biologic sense of what we need to do to meet from the drug. We need to match for the proposed indication,” she FDA requirements.” nonclinical studies for dose, announced.efficacy Soto scooted his chair schedule, and duration. Adequate closer to the whiteboard and added nonclinical studies will assist in Nonclinical Testing: Initial Drug identifying parameters for clinical the end of the line on the board. Development Steps safety monitoring and guide patient Robertsthe words nodded “safety and and continued, efficacy” at eligibility, as well as assist in “Before your company can test On the day of the meeting, the three managing risk. But we do not need a new compound in humans, it claimed the small company’s one that information yet to support our must show FDA the results of the conference room. Green reported early clinical trials.” nonclinical tests in laboratory that they were concluding the initial animals and tell FDA what you nonclinical studies and were ready “Then let’s move on and talk propose to do during testing on to begin testing the drug in humans. about the requirements for a New (Appendix C1) Molecular Entity, known as an NME, milestone: the Investigational New since your drug is an NME,” Roberts Drughumans. (IND) This Submission.” brings us to ( Exhibityour first 2) “That’s good to hear,” Roberts noted. replied. “It sounds as if you have Soto leaned over and added “IND made good progress and met the “What’s an NME—in layman’s submission” to the path on the objectives of the initial nonclinical terms?” Soto asked. Roberts shared whiteboard. is reasonably safe for initial use in active ingredient that has never Green asked, “What do we do if we humanstesting: To and find if the out compound if the compound shows beforethe FDA’s been definition marketed of inan the NME: United An have questions before we submit pharmacological activity and effect States in any form. the IND? Can we talk to FDA at that early stage?” on a disease marker that justifies 3 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued

Exhibit 2. Milestone 1

Conduct basic research, discovery, Safety and nonclinical and ecacy activities Milestone 1: IND submission

Roberts answered, “Yes, sometimes will answer our questions in writing Act, and it becomes a new drug companies seek advice from the at this stage.” (Appendix C2) FDA before they submit an IND. If requirements. Current Federal we have questions regarding the Milestone 1: Submitting an lawsubject requires to specific that a regulatory drug be the IND, we may request a meeting with IND Application subject of an approved marketing the appropriate division within application before it is transported “As you know, once your compound or distributed across state lines. which, in the case of a drug to treat completes the initial nonclinical Because the sponsor, meaning your the Office of New Drugs (OND), diabetes, would be the Division testing phase, the next step is to company, will probably want to ship of Metabolism and Endocrinology test it in humans,” Roberts said. the investigational drug to clinical Products. Although there are “At that point, the compound’s investigators in multiple states, instances when a pre-IND meeting legal status changes under the it must seek an exemption from would be necessary, many divisions Federal Food, Drug, and Cosmetic that legal requirement. Companies

IND Content and Submission Resources

The FDA’s IND web page outlines the need for this application, the kind of information to include, and the Federal regulations that apply.

http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/ investigationalnewdrugindapplication/default.htm

Resources include: ✓ ✓An Investigator’s Checklist for IND Application Submission http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ ApprovalApplications/InvestigationalNewDrugINDApplication/UCM368873.pdf ✓ ✓A Guidance for Industry, titled “Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products.” This Guidance lists and explains the IND sections required by the regulations. (Appendix C3)

4 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued get this exemption by submitting Absorption, distribution, 3. Clinical Protocols and an Investigational New Drug metabolism, and excretion Investigator Information. application to FDA,” she reported. (ADME) The FDA will review your Short-term general toxicity proposed study to ensure it What Does the IND Include? studies in two animal does not expose the subjects species to unnecessary risks. FDA “So what do we have to include in will review the full protocol the IND submission, and how do we An in vitro gene toxicology for your Phase 1 trial and assessment detailed information about the There is an FDA Guidance that “Iorganize will be it?”mentioning Green asked. some FDA recommends the nonclinical investigators who will run the Guidance documents as we talk, safety studies that would qualifications of the clinical but don’t worry about writing them support human clinical trials, their duties. trial to ensure they can fulfill all down. I have a reference list I and the FDA can always answer 4. Informed Consent. Sponsors will give to you at the end of our often submit informed consent meeting,” Roberts said. (Appendix C1) documents, and FDA will (Appendix C) more specific questions. review them if submitted. 2. Chemistry, Manufacturing, and Controls Information Roberts explained that, in general, comment on adverse events in (CMC). The relevant regulation4 the IND application must provide humansFor lowagliflozin, yet. However, we cannot if you and Guidance documents outline information about four broad topics adverse the amount of CMC information (Appendix C3): event in the nonclinical studies, required at all phases of drug aobserved statement a significant in the informed development. (Appendix 1. Animal Studies (also called consent should report the event, C4) For Phase 1, you need to nonclinical data). These as it could be an important describe the drug substance safety signal. to support the safety of initial or active ingredient, the initial testingstudies inprovide humans. the The first amount data Where Do We Send the IND? and type of nonclinical data and the composition. You will alsostructural need tocharacterization, describe how it is required at this stage depend on “You will submit the IND application the proposed development plan. manufactured, the results of tests to show that it is stable, to the appropriate review division 5 and comparative impurity the IND should include: within the Center for Drug For lowagliflozin, at a minimum, in the Office of New Drugs (OND)6 Proof-of-concept batches and clinical batches. The Evaluation and Research (CDER) in pharmacology studies FDAprofiles reviews for the this toxicology manufacturing FDA. CDER regulates prescription Safety pharmacology information to ensure that drugs and over-the-counter drugs,” studies, including an you can produce adequate, Roberts remarked as she shared a assessment of the effects on consistent batches of the drug. the central nervous system, FDA. (Appendix D) copy of an organizational chart from cardiovascular effects, 421 CFR Part 312.23(a)(7)(i). liver, renal, and respiratory 5 6Center for Drug Evaluation and Research. effects Office of New Drugs.

5 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued

“Remember, you submit the IND review board (IRB) also reviews Roberts noted that the IRB reviews before your company tests a drug in the proposed studies and informed the proposed study and approves consent,” Roberts answered. “IRBs the following: are panels of scientists and non- Thehumans,” Role Roberts of the Institutionalemphasized. scientists that oversee clinical Clinical trial protocols Review Board research. IRBs make sure the study describing the type of people is well designed, participants who may participate in the trial “Does anyone else review the IND?” are fully informed of the risks, Schedule of tests and Green asked. participants have given informed procedures consent, and researchers take Medications and dosages to be “Yes, in addition to the FDA appropriate steps to protect people studied reviewing the IND, the institutional from harm.”

Exhibit 3. The basic elements of an Informed Consent Form

State that the study involves research, explain the purposes of the research, and report how long the person is 1 expected to participate.

2 Describe the study procedures and identify any experimental procedures.

3 Describe any foreseeable risks or discomforts to the subject.

4 Describe any benefits to the subject, or to other people, that may reasonably be expected from the research.

5 Identify other appropriate studies or courses of treatment, if any, that might benefit the subject.

Describe how much, if at all, records identifying the subject will be kept confidential. Explain that the FDA may 6 inspect the study records. Explain, for any research posing more than a small risk, if the subject will be compensated or receive medical 7 treatment for any injuries arising from the study. If yes, describe the available compensation, treatment, and where the subjects can get more information. Provide contact information for a person who can answer questions about the research and the rights of the 8 subjects. Also identify the contact person for any research-related injuries.

State that participation is voluntary. If subjects choose not to participate—or want to stop participating—they will 9 not be penalized or lose benefits that belong to them.

The required elements of the informed consent are found in the regulation at 21 CFR Part 50.25: http://www.accessdata.fda.gov/scripts/cdrh/ cfdocs/cfcfr/CFRSearch.cfm?fr=50.25 6 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued

Length or duration of the study FDA also has a Guidance covering 3. Partial clinical hold. The Study objectives and other informed consent for IRBs, clinical proposed trial may proceed only details investigators, and study sponsors. with restrictions that FDA will (Appendix C5) describe in their letter to the sponsor. Informed Consent The 30-Day Waiting Period If FDA places your IND on a clinical “You mentioned informed consent. hold, we will work with FDA to I’m familiar with the concept, “Once we submit the IND, when can but can you outline the basic we start our Phase 1 trial?” Green prepare and submit a response requirements?” Soto asked. asked. toresolve the critical the deficiencies. issues that We led wouldto the clinical hold. You may need to “I’m glad you asked,” Roberts Roberts answered, “After the IND submit additional nonclinical data, answered. “It is important to is received by FDA, you must wait explain existing data, or modify understand that informed consent is 30 calendar days before initiating the protocol to ensure patient an ongoing and interactive process. any clinical trials. During that time, safety. The FDA then has 30 days It is not a one-time event where FDA reviews the IND to ensure that from receipt of the information to a person reads and signs a form. you will not expose your research review the new data and decide The purpose of informed consent subjects to unreasonable risks. is to give potential research study adequately addressed. When FDA subjects the information they need By the 30-day date, one of the considerswhether the the deficiencies initial trial safehave to been to make an educated decision to join following will occur: proceed and communicates that a study or continue participating.” decision to you, you have reached (Exhibit 3) 1. Safe to proceed. FDA another milestone: You may initiate in writing that their proposed the Phase 1 trial.” (Exhibit 4) Roberts explained that the initialsometimes trial maynotifies start. sponsors The FDA’s study sponsor needs to letter, however, may contain provide a statement written in Milestone 2: Initiate the comments and suggestions understandable language—not Phase 1 Trial for the trial and your overall legalese. The sponsor must allow the development program. The potential subjects the opportunity “While we are conducting our Phase sponsor can assume that it is to ask questions and time to think 1 trial, I imagine there are some safe to proceed if they do not about participating in the study. The reporting obligations to the FDA. receive one of the clinical hold study sponsor must also continue to Can you tell us about them?” Green letters. provide information to the subjects, asked. as needed, during the study. She 2. Clinical hold. The proposed noted that FDA’s informed consent trial is not safe to proceed. If this “Yes, as you are conducting the requirements are found in the FDA’s happens, after a call between initial trial under the IND, there are regulation on the Protection of the sponsor and FDA, the FDA’s Human Subjects.7 letter will explicitly state why the reporting requirements in the it’s not safe to proceed and what letterspecific you obligations. will receive FDA at thewill end detail These regulations apply to clinical you need to do to reverse the of the 30-day IND review period,” investigations regulated by FDA. The clinical hold. Roberts replied.

7The Protection of Human Subjects is found in the regulation at 21 CFR Part 50. 7 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued

Exhibit 4. Milestone 2

Conduct Phase 1 and Phase 2 trials

Conduct basic research, discovery, Safety and nonclinical and efficacy activities Milestone 1: Milestone 2: IND Begin submission Phase 1 trial

Phase 1 Reports studies were permitted to begin),” Roberts continued, “This meeting she noted. precedes the big End-of-Phase 2 Roberts described the IND safety meeting, but it is no less important. reporting8 obligations: Green responded, “Those Usually the EOP2A meeting occurs requirements seem reasonable. after the completion of Phase 1 Report any suspected fatal The FDA wants to know about any or life-threatening adverse concerning safety signals and also response trials in patients, but reactions to the FDA no later wants general annual updates about beforetrials and beginning the first Phase set of 2Bexposure- (i.e., than 7 calendar days after your the status of the application.” patient dose-ranging trial) and initial receipt of the information. Phase 3 Phase 2 Protocols and Reports Report other serious or An EOP2A clinical meeting efficacy-safety would occur trials. after the completion of clinical trials unexpected suspected adverse that provide data on the relationship significant issues: (1) serious, you will submit a study report “After you finish your Phase 1 trials, of dosing and response for the other clinical, animal, or in vitro particular intended use, including reactions, (2) findings from trial,” Roberts noted. “Assuming nonclinicalsummarizing studies the results and the of Phasethe trials on the impact of dose ranging human risk, and (3) a clinically 1 trials are completed with no on safety, biomarkers, and proof of importantstudies that increase suggest in significant the rate concerning safety issues observed, of a serious suspected adverse you will submit your Phase 2 the optimal dose and save money, reaction. Report to FDA and protocol, or protocols, to the FDA’s concept. This helps sponsors to find all investigators no later than Review Division. The Division may late-stage clinical trials.” 15 calendar days after you or may not have comments about while maximizing the success rate in determine you need to report the protocols. Once the Phase 2 the information. Preparing for a Major trials begin, the general reporting Milestone Meeting: requirements are similar to what “In addition, you will submit annual we discussed for the Phase 1 trials. End-of-Phase 2 progress reports within 60 days of However, before we proceed, I the anniversary of the date your IND “Let’s assume our Phase 1 and Phase would like to mention one very good went into effect (the date clinical 2 trials run smoothly. Once Phase 2 opportunity to obtain input from ends, how soon can we move on to the FDA for your drug development the important Phase 3 trials?” Green 8The IND Safety Reporting regulation is program: the End-of-Phase 2A asked. found at 21 CFR Part 312.32. (EOP2A) meeting.” 8 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued

Roberts responded, “This is a major Examine sampling plans for earlier, to the meeting, you will point in the development program. population pharmacokinetics submit a meeting package that Up to this time, you hopefully will and exposure/response includes your plan for Phase 3. If have shown that your drug has determination. you do not submit this package, biological activity, have begun FDA may cancel the meeting. This endpoint—the main package will include the Phase 3 documented some preliminary outcomeDiscuss the used primary to evaluate efficacy the protocols, summaries of the Phase to establish a safety profile, and effectiveness of treatment in the 1 and 2 investigations, and plans 3 is vitally important because it is clinical trial. for pediatric studies,” Roberts theefficacy. Phase Proper 3 trial planning or trials thatof Phase will answered. be used to support your eventual Examine key aspects of trial drug approval application. The FDA design for the Phase 3 program. Special Protocol Assessments understands the importance of Review the adequacy of the this step in the drug development safety data that will be collected “One more thing, once a drug process. And the FDA strongly in Phase 3. company and the FDA agree to encourages companies to request Discuss whether the Phase 3 an End-of-Phase 2 (EOP2) meeting population will adequately drug, it is considered a binding before the start of the Phase 3 represent the population who agreement.”a specific Phase 3 protocol for a program.” Roberts said. will use the drug, e.g., securing racial and/or gender diversity “Can you explain how this She described what the company and addressing pediatric needs. works? I thought the point of the and FDA would do during the EOP2 EOP2 meeting was to reach an Review development activities meeting: agreement,” Green asked. to ensure they satisfy relevant regulatory requirements. Examine whether the “That is a great point,” Roberts pharmacology and toxicology Determine whether the CMC said. “You are referring to a special information supports Phase 3 protocol assessment, also known program) is supportive of Phase studies, as discussed in FDA’s as an SPA. For diabetes drugs, 3profile studies. (i.e., nonclinical published guidelines. (Appendix existing Guidance documents and C4) Examine the clinical the Package Inserts of recently pharmacology and clinical approved products already “And, within 60 days of the EOP2 data that support Phase 3 dose meeting, we are required to submit selection. trials that form the basis for the pediatric study plan,” Roberts approval,characterize so anthe SPA types is usuallyof clinical not Examine the dosing and remarked. (Appendix C6) necessary. SPAs are also submitted administration strategy. for review of carcinogenicity Clinical Pharmacology data “It sounds like we will discuss just protocols. There is an FDA Guidance will guide administration about everything about the Phase document with more information concurrent with other 3 trial. How do we prepare for this medications, administration meeting?” Green asked. out more about these agreements.” conditions (fasted/fed), and (aboutAppendix the SPAs C7) if you want to find

necessary. with FDA, about a month prior, or dosing in specific populations if “To maximize your interaction

9 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued

Green rose, “I suggest we all take a information needed to label the break before we continue.” drug for the physicians who will (Appendix C9) prescribe it. In addition, because independent evidence of efficacy. Milestone 3: Conducting the your drug is intended for the Roberts reviewed why FDA prefers Pivotal Phase 3 Trials long-term treatment of a non-life- at least two adequate and well- threatening condition, you will also controlled trials: “Are you ready to talk about Phase want to consider the International 3, our next milestone?” Roberts Conference on Harmonisation (ICH) Protects against the possibility asked as she returned to the guidelines for assessing its clinical that an occurrence in a single conference room. safety.” (Appendix C8) study will lead to an erroneous conclusion that a treatment is Soto said, “Let me update our path. The Role of the Pivotal Trial: effective. It may be my process-engineering Phase 3 Reduces the false positive rate. Ensures the consistency of display the steps and activities. “Phase 3 is often a pivotal trial, a I’llmind, update but Iit find as we it helpful go and totransfer term you’ll hear often in the drug the information to a permanent development and approval process. clinical trial findings, providing document later.” (Exhibit 5) Pivotal trials are the clinical trials largersome confidence population. when that serve as the basis of FDA generalizing the results to a “See? That’s why I asked you to join “Would the FDA ever consider the meeting,” Green replied. approving a drug based on a Sheapproval,” went on Roberts to explain emphasized. that the “Only 9 percent of the drugs make Federal Food, Drug, and Cosmetic (Appendix C9) it to Phase 3,” Roberts continued as Act guides the FDA’s review of new single efficacy trial?” Green asked. they settled around the conference drug applications. This law requires “Only in certain instances, such as table. “You will then use the Phase “adequate and well-controlled for a drug intended to treat a rare 3 trials to gather more information investigations” to determine the disease,” Roberts replied. “This would typically not be the case for information is vital for evaluating FDA Guidance on this topic suggests drugs intended for the treatment of about efficacy and safety. This thatefficacy drug of manufacturers a drug. She noted submit that atthe type 2 diabetes, and most Phase 3 of the drug and providing the least two controlled trials providing programs for drugs that treat type the overall benefit-risk relationship

Exhibit 5. Milestone 3

Conduct Phase 1 Conduct and Phase 2 trials Phase 3 trials

Conduct basic research, discovery, Safety and nonclinical and ecacy activities Milestone 1: Milestone 2: Milestone 3: IND Begin Begin submission Phase 1 trial Phase 3 trials

10 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued

2 diabetes have multiple trials. You several secondary endpoints, that might cause a member to be such as changes in fasting plasma glucose, that support the indication.” will be hidden. The purpose of duringwill discuss your theEOP2 specific meeting number with thebiased committee in favor isof to a specificprovide outcome an FDA,”of trials she required said. for lowagliflozin Safety Issues Related to independent assessment of the Diabetes Drugs causes of any cardiovascular events How Will it Help Patients? A during the trials.” Meaningful Primary Efficacy “I also want to alert you to a special Endpoint requirement. The development Phase 3 Reporting

“I mentioned the importance of safety concerns, which led FDA in “What kinds of reports should we 2008of diabetes to require drugs additional raises specific data plan to submit to FDA during Phase our earlier discussion of the EOP2 from sponsors. Because diabetes 3?” Green asked. meeting.the primary To obtainefficacy marketing endpoint in is associated with increased cardiovascular risk, sponsors must “During Phase 3, while you are endpoint in the Phase 3 trials should demonstrate that their drugs do not conducting the trials, you will measureapproval, something the primary that efficacy matters to result in an unacceptable increase continue to submit safety reports a patient,” Roberts stated. in cardiovascular risk,” Roberts and annual reports. Remember, reported. Phase 3 can last several years. With “In essence, the primary endpoint some exceptions, the next face- of a clinical trial is the endpoint “How do we demonstrate it?” Green to-face interaction you will have asked. with the FDA will be the pre-NDA and for which the trial is powered. meeting,” Roberts said. Itfor is which the outcome subjects used are torandomized evaluate “The FDA outlined the requirements the effectiveness of treatments in a in a Guidance document. (Appendix Milestone 4: Submission of clinical trial. Secondary endpoints C10) One of the major points in the New Drug Application are endpoints that can be used to the Guidance is that sponsors explore other important aspects should establish an independent “We have reached another of an intervention for which the cardiovascular endpoints milestone: the submission of the trial may not be powered nor committee. This committee will New Drug Application, or NDA,” prospectively adjudicate, in a Roberts announced. (Exhibit 6) blinded fashion, cardiovascular Sherandomized.” noted, “The established primary events during all Phase 2 and Phase “Once your Phase 3 trials are done, 3 trials,” Roberts replied. you should have all the data, from mellitus is the change from baseline your animal studies to the pivotal inefficacy hemoglobin endpoint A1c for (HbA1c). type 2 diabetes HbA1c trials, you need for your NDA. is a lab test that reports the average said waving his hand, “What does The NDA is the major submission level of blood sugar (glucose) prospectively“Layman’s clarification, adjudicate please,”in a blinded Soto you will use to request marketing over the previous 3 months. The fashion mean?” approval.” test shows how well patients are controlling their diabetes and, more Roberts answered, “The phrase “There are three approval pathways recently, is also used to diagnose means the committee members will for a new drug. (Appendix E) We type 2 diabetes. A protocol for a type review any cardiovascular events will focus on the standard NDA 2 diabetes drug will also include that arise, while any information

11 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued

Exhibit 6. Milestone 4

Conduct Phase 1 Conduct and Phase 2 trials Phase 3 trials

Conduct basic research, discovery, Safety and nonclinical and ecacy activities Milestone 1: Milestone 2: Milestone 3: Milestone 4: IND Begin Begin NDA submission submission Phase 1 trial Phase 3 trials

Discuss the content, structure, charge user fees for certain drugs a generic drug, and you are relying and format of the application, and biological product applications. onpathway your own because investigations lowagliflozin to is not including the presentation of (Table 1) These user fees support complete your application,” Roberts the integrated analyses of safety timely reviews for drugs, and we said. will talk about the timelines when Determine whether the type we discuss the FDA’s review of your and efficacy. The Pre-NDA Meeting and amount of CMC information application. There are exceptions to be included in the NDA will to the user fee requirement, such “The FDA encourages you to request as drugs for designated orphan what is called a pre-NDA meeting. thorough understanding of the diseases. And there is an FDA The FDA has found that meeting productbe sufficient and manufacturingto demonstrate a Guidance that discusses the user fee before you submit the NDA helps process. waivers, reductions, and refunds for resolve problems early, reducing drugs and biological products,” she delays associated with the FDA’s noted. (Appendix C11) NDA User Fees initial review of your application.” “One of the situations in which Roberts continued, “Many FDA will grant a fee waiver is when Roberts described the objectives of researchers and young companies the applicant is a small business the pre-NDA meeting: are surprised to hear that they may need to pay a user fee with the NDA. Uncover any major unresolved application for review. I believe we The Prescription Drug User Fee Act submitting its first human drug problems. of 1992 (PDUFA) Determine the adequacy of would fit into this situation, and the sponsor’s dossier for the authorizes FDA to submission of an NDA. Table 1. PDUFA Categories and Costs Review the status of ongoing Associated with the NDA Application studies to assess pediatric safety and effectiveness. Fee Category for Applications Fee Rates for Fiscal Year 2015 Acquaint FDA reviewers with Requiring clinical data $2,335,200 the general and technical information that will be Not requiring clinical data $1,167,600 submitted in the marketing Supplements requiring clinical data $1,167,600 application. 12 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued this would be a huge advantage for documents.9 These resources Seriousness of the disease your small, but growing, company,” outline the NDA content, format, and Roberts said. Duration of the treatment process. And there are links to the Expected benefit of the drug NDA Content and Format relevantclassification, laws, plusregulations, the NDA policies, review Seriousness of known or and procedures,” Roberts replied. potential adverse events Roberts continued, “Let’s discuss Status of the drug, e.g., is it a “But don’t get overwhelmed looking your NDA preparation. I think it New Molecular Entity? is helpful to think of the NDA as a at all of the information,” she cautioned. “We will have several story. And this story will tell FDA Roberts described the potential meetings focused just on your NDA reviewers what happened during elements of a REMS: a Medication preparation when we reach that the clinical tests, the ingredients of Guide or Patient Package Insert, step.” the drug, the results of the animal a communication plan, elements studies, how the drug behaves to assure safe use or ETASU (e.g., in the body, and how the drug is “It’s a lot to think about,” Green manufactured, processed, and agreed. “Let me propose a break before we continue.” packaged.” ofhealth dispensing care provider to certain certification, health care settings,pharmacy restriction certification, of dispensing restrictions She advised them to provide FDA Assessing the Need for a Risk only to patients with documentation reviewers with enough information Evaluation and Mitigation of a safe-use condition, such to answer some key questions: Strategy as laboratory test results), an implementation system, and a Is the drug safe and effective for After returning to the conference timetable for submission of REMS its proposed use? room, Roberts scanned her notes. assessments. Looking up, she remarked, “Before outweigh the risks? Do the benefits of the drug we will need to discuss whether information for the three SGLT2 Is the drug’s proposed labeling therewe submit may bethe a NDA need for for lowagliflozin, a REMS, drugs“Is there already a way on to the find market?” REMS Green (the Prescribing Information) or a risk evaluation and mitigation inquired. appropriate and complete? strategy. For most approved drugs, Are the methods used to the product labeling and routine “Yes, you can review a list of manufacture the drug—and reporting requirements are enough approved REMS on the FDA’s the process controls used to to mitigate risks and preserve website to see if this class of drugs maintain the drug’s quality— requires REMS.10 From what I recall, adequate to preserve the drug’s more serious risks.” none of the SGLT2 Inhibitors have identity, strength, quality, and benefits. However, some drugs pose a REMS at this time, but there are purity? REMS in place for other type 2 considers when determining the diabetes therapies,” Roberts replied. “Are there resources we can use to needShe identified for a REMS: the factors FDA develop our NDA?” asked Green. “When do we determine if we need a REMS?” Green asked. “Yes, the FDA has multiple resources use the drug Size of the population likely to for drug development information, 10The list of currently approved individual including more than 20 Guidance 9FDA drug development information. REMS.

13 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued

“At the time of the NDA application, (‘the Program’) were changed. The “Let me use a regulatory term of art: we can propose a REMS. changes were intended to improve A lot!” Roberts said with a grin. Alternatively, FDA may inform you of the need for a REMS during the FDA 60-Day Notification decreasethe efficiency the number and effectiveness of review the REMS before the end of the cyclesof the firstneeded cycle to review obtain process,approval “Once you submit the NDA, the FDA review cycle.process. FDA We will will tell finalize us the (without changing the standards for has 60 days to tell us if the Agency required elements, but it will be our approval), and ensure patients have considers our application complete. responsibility to submit the REMS in timely access to safe, effective, and Or, using FDA language, ‘FDA has the form of a detailed plan,” Roberts high-quality drugs.” answered. “And, if we submit a application.’ Just a quick reminder, REMS proposal, it must include 60 days to determine if they file the a timetable for submitting our timelines for NME NDAs and submission date. An application is assessments.” OriginalShe summarized BLAs reviewed the two under review the completethe filing dateif the is initial not the submission same as the Program: contains all of the information FDA “We are now ready to talk about an needs to perform a full review and important phase: FDA’s review of Standard Review: This review make a decision on the proposed your NDA,” Roberts announced. lasts for 12 months total. It labeling, it contains all of the required elements, it is legible, FDA Review Process date, which is 60 days after you and it is easy for FDA reviewers to submitends 10 the months application. after the filing navigate the contents,” Roberts said. Standard Review and Priority Priority Review: This review She told them that a complete Review lasts for 8 months total. A Priority Review is one of several application includes: Roberts continued, “When you available expedited programs. Proposed indications submit your NDA, either a Standard The FDA grants a Priority Review or a Priority Review Review if you demonstrate that Data required to assess the timeline will be applied to your a drug (or biologic) has the application. You may discuss the drug, including any required review timeline designation options improvement in the safety or long-termsafety and safetyefficacy data of the and the with FDA at the pre-NDA meeting, effectivenesspotential to provide of the treatment, a significant pediatric plan information but FDA’s review division makes the diagnosis, or prevention of needed to evaluate and approve formal decision when you submit a serious or life-threatening the manufacturing facilities the NDA. In 2012, when Congress condition. and proposed manufacturing renewed the Prescription Drug User Fee Act (i.e., PDUFA V), the The total time for a non-Program review timelines for NME NDAs application review is 10 months and “If thespecifications application is not complete, and original Biologics License 6 months respectively. FDA halts its review and takes Applications BLAs submitted under the Program for Enhanced Review “What does FDA do during the need to address the issues and Transparency and Communication review period?” Soto asked. resubmita ‘refuse to the file’ entire action. application,” You then she

emphasized. 14 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued

FDA Efficiency Requirements

Congress has renewed and modified the Prescription Drug User Fee Act (PDUFA) multiple times. The last renewal, PDUFA V, was passed in 2012. This version added enhanced transparency and communication between FDA and drug sponsors during the review cycle. The law also modified the review timelines for the applications of original biologics and New Molecular Entities. This enhanced review program is referred to as the “Program.”

A major objective of the Program is to improve the efficiency and effectiveness of the “first cycle” review process—the first time a company submits the NDA/BLA to FDA for review. The Program extends the PDUFA clock by 2 months. Before the Program, the goal date—the latest date FDA could take an action—was 10 months after FDA receipt of a standard review application. This change added more time at the end of the review cycle to address serious issues that commonly arise, such as issues noted during an inspection or feedback from an Advisory Committee. This opportunity to resolve serious issues during the first cycle review potentially reduces the number of drugs that have to go through a “second cycle” review.

Under the Program, FDA begins the review immediately after the submission. But the PDUFA clock starts on the filing date, which is 60 days after the date the application is submitted.

“And we want to avoid that,” Green “If you believe FDA needs the data FDA Negotiation of the Drug agreed. for the review, you can submit it. Label/Package Insert However, FDA will decide whether FDA Information Requests or not they will review the data “Another activity that occurs during the current review cycle and during the FDA’s review is the “By the way, once you submit your if reviewed, there is a possibility review and approval of the drug’s application, don’t be surprised if you that FDA will call this submission label. I think the drug label is a receive information requests from a ‘Major Amendment’ to the misunderstood document,” Roberts FDA. They may ask you to provide application and extend the review said. “What people typically call more data, conduct alternative timeline,” Roberts responded. the label is actually the Package analyses, or clarify information. Insert, or PI. The Package Insert Generally, FDA expects a timely She continued, “During the review is intended for the doctors who response. And it’s in your best of Program applications, FDA will prescribe the drug. Your NDA interest to facilitate the FDA’s will tell us through a mid-cycle will include a proposed Package review,” Roberts instructed. communication about any important Insert. This document includes issues that have arisen. your proposed indications for the drug, dosing information, warnings we didn’t submit with the original and precautions, results of the application,“What if we realizebut we therethink areFDA data needs has any major concerns, and it is an clinical trials, chemistry, and clinical This is a great way to find out if FDA the data for its review?” Green opportunity for you to respond to pharmacology information, to name wondered. potential issues.” a few of the sections.”

15 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued

FDA Product Quality Review and Inspections of Manufacturing, Testing, and Packaging Sites

Form 356h of the NDA requires a complete list of all manufacturing, testing, and packaging facilities used for the commercial product (drug substance and drug product). This list includes contract facilities, contact information for each facility, and a statement that each facility is ready for the Current Good Manufacturing Practice (cGMP) inspection at the time of the NDA submission. FDA inspectors determine the cGMP compliance status of each facility based on inspection of the facility, sample analyses, and compliance history. In addition to determining the cGMP compliance status of all of the facilities, FDA will review the Product Quality, or Chemistry, Manufacturing, and Controls (CMC), information in the NDA. This review determines whether or not the information is sufficient to demonstrate the sponsor’s thorough understanding of the product and manufacturing process and to assure a consistent, high-quality production of the commercial product during its lifecycle. FDA will evaluate the analytical data to bridge the commercial product to the investigational product that had been used in clinical and nonclinical studies. FDA will also review the stability data to establish an expiration dating period and instructions for storage of the product. Links to relevant FDA information about Product Quality, cGMP, and CMC are in Appendix C3.

She explained that the company FDA Inspections of Clinical decides which clinical sites to would negotiate the label with the Sites inspect. It is also possible that FDA will inspect your company or any the review cycle. “The FDA reviews “While FDA is reviewing your NDA, companies you contracted to help FDA, typically in the final half of the proposed PI, makes edits, and be prepared for the FDA to conduct with the clinical trials. Because of returns the PI to the company. inspections. When you submit your the planning involved, especially The process may go back and application, Federal law allows if there are international sites, the forth several times before you and inspections do not begin until a FDA concur on the contents of the the accuracy of your clinical study few months after the application is records.FDA access Every to your year, sites FDA to inspects confirm received,” Roberts reported. approved version of the PI with about 700 clinical sites to support PI. The FDA will send the final, the approval letter. The duration of the approval of drugs, biologics, and “Can you tell us a little more the labeling negotiations depends devices,” Roberts announced. about what to expect during these upon the nature and volume of edits inspections?” Soto asked. required,” she reported. Roberts “How do we know if we will get paused and typed on her tablet for inspected?” Soto asked. Roberts explained that most a moment. “Here’s an example of a inspections last about 5 days. Package Insert11 for another SGLT2 During that time, the inspector drug,” she said as she passed the drug, you should expect inspections. will interview research staff, look tablet to Green and Soto. They“Because are conductedlowagliflozin by isa largea new at study records, examine patient charts, and ensure the clinical study 11An example of a Package Insert. the U.S. and overseas, and FDA was performed properly. At the end office of inspectors throughout

16 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued of the inspection, the FDA inspector post-approval activities, such which may take a long time. But as a REMS or a postmarketing and concerns with the research staff FDAfiled convenesthe application Advisory for review,Committees requirement. Once you receive will discuss any significant findings to seek input on a broad range of this letter, you may market your FDA form. topics. The Committees provide and document them on an official FDA with independent opinions approval letters at Drugs@FDA. drug. You can find examples of and recommendations from outside Complete response (CR) letter experts on drug applications. (letter is not public). The “The inspection findings are Compliance and the Division’s Based on the information they other possibility is to receive a provided to the FDA’s Office of review team. When all of the receive from FDA and the sponsor, complete response letter. This inspections are complete, the the Committee may recommend letter means that the FDA has approval or non-approval of a not approved the drug during summary report and makes a drug. Because there have been a that review cycle. The letter Office of Compliance finalizes a recommendation regarding the number of other SGLT2 inhibitors details the reasons why FDA reliability of the data to the review approved, it is unlikely that an did not approve the application Advisory Committee meeting and what the company needs Drugs. Ideally, FDA considers the would be needed. However, if any to do to resolve the issues division in the Office of New information found at the clinical issues arose with our drug, such that prevented approval. The sites reliable for approval of the as an unexpected safety signal that drug. If it is not deemed reliable, the an Advisory Committee meeting todeficiencies a request couldfor an rangeadditional from an confounds the risk-benefit balance, review division to decide how, or if, might be possible. It is important clinicaleasy-to-fix trial. manufacturing When you submit issue Office of Compliance works with the the data should be used,” Roberts to understand that, although the data to address the issues, the said. Advisory Committees provide application must be resubmitted recommendations to FDA, FDA and the submission initiates a FDA and the Potential Role of new review cycle.12 an Advisory Committee makes the final decisions.” FDA Review Results “So even if you fail to get approval about the inspections and looked “Let’s look ahead to the end of opportunity to take corrective up.Green She finished asked, “We writing have her seen notes the FDA’s review and the all-important actionthe first and time, try youagain,” have Soto an observed. FDA convene Advisory Committee decision,” Roberts suggested. meetings for many drugs. How “As long as you still have funding,” does the FDA decide which drugs She described the two types of Green said. are taken to these meetings? How letters the company could expect to will we know if our drug will be receive from FDA: “That’s true,” Roberts replied. “It presented before a committee?” becomes a business decision for the Approval letter. The best- company and its investors.” Roberts answered, “Well, we case scenario is to receive an won’t know the FDA’s preliminary approval letter. This letter 12The complete response letter regulation 21 thinking on the need for an advisory CFR Part 314.110. committee meeting until FDA has and details about any required includes the final Package Insert

17 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued

Expedited Review Programs as soon as it is apparent that the about their intention to apply for one of these programs, you should “I have heard that the drug know that you have to offer strong development process can be designationbenefits justify determination.” the risks,” Roberts evidence to show you meet these sped up sometimes. With our explained. “FDA makes the final initial promising results, is there Two Criteria: Unmet Medical about the requirements in the FDA’s any way that could be done with Need and a Serious Condition Guidancecriteria. You document. can find (outAppendix more C12)

“While all four options are different, All of my clients ask about “FDAlowagliflozin?” has four programs Green asked. intended the common link is an effort to the expedited programs, so I to expedite the review of new drugs address an unmet medical need prepared this summary table. This to address unmet medical needs in the treatment of a serious information is from FDA’s Guidance for serious or life-threatening condition.” Roberts advised. “While on Expedited Programs,” Roberts conditions. These programs exist to the FDA encourages companies to said as she pulled a document from get therapies for serious conditions communicate early in the process a folder. (Table 2) approved and available to patients

Table 2: Summary Descriptions of Expedited Programs

Expedited Summary Descriptions of Drugs Eligible for Expedited Review Programs ✓ ✓A drug intended to treat a serious condition, and clinical or nonclinical data demonstrate it has 1. Fast Track the potential to address an unmet medical need Designation ✓ ✓A qualified infectious disease product ✓ 2. Breakthrough ✓A drug intended to treat a serious condition, and preliminary clinical evidence shows the drug Therapy may demonstrate substantial improvement on a clinically significant endpoint over available Designation therapies ✓ ✓A drug that treats a serious condition and generally provides a meaningful advantage over available therapies 3. Accelerated The drug demonstrates an effect on: Approval ¡¡ A surrogate endpoint that is reasonably likely to predict a clinical benefit, or Pathway ¡¡ A clinical endpoint that can be measured before irreversible morbidity or mortality (IMM), or ¡¡ The drug is reasonably likely to predict an effect on IMM or on an intermediate clinical endpoint ✓ ✓An application (original or efficacy supplement) for a drug that treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness 4. Priority Review ✓ Any supplement that proposes a labeling change related to pediatric studies Designation ✓ ✓ ✓An application for a drug that has been designated as a qualified infectious disease product ✓ ✓Any application or supplement for a drug submitted with a priority review voucher

18 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued

Recap: Meetings and Type C meetings are any Green said, “It sounds like we will meeting other than a Type A or gather valuable information in those Communications with FDA Type B meeting between FDA meetings.” and a sponsor regarding the As Green examined the summary development and review of a table she asked, “Before we Summary of Meetings product. The FDA will schedule continue, can we review the various a Type C meeting to occur meetings and other opportunities to Both women looked over as they within 75 days of receipt of a get feedback and advice from FDA?” noticed Soto drawing a large box company’s written request for on the whiteboard. “What are you the meeting. Roberts answered, “That’s a good creating?” Green asked. idea. There is an entire Guidance “These meetings offer a lot of document devoted to meetings. “I want to make a reference table possibilities for interaction,” said (Appendix C2) But, in general, of these meeting opportunities,” he Green. “But we are a small company. there are three types of meetings answered. How can we obtain FDA preliminary a company can request, depending thoughts while our application is on the urgency of the issue and the “Great idea,” Roberts agreed, “Let’s under review? impact on the development of the recap and document it all in one place.” Roberts replied, “That’s a good Type A, Type B, or Type C.” drug. The meetings are classified as question and one many companies Soto drew the table, as Roberts face. Let me tell you about an Roberts described the three major and Green called out the necessary interesting meeting opportunity.” types of FDA meetings: information. (Table 3)

Type A meetings are held The Late-Cycle Meeting Post-Approval Activities, to help restart a stalled Postmarketing development program. For “Companies may now meet with FDA in what is called a late-cycle Requirements, and example, you can use a Type A Postmarketing meeting to discuss and resolve meeting near the end of FDA’s responses to a clinical hold. review cycle. This meeting is Commitments The FDA will schedule a Type required for all drug applications After Soto rejoined them at the A meeting to occur within 30 covered by the 2012 renewal of conference table, Roberts said, days of receipt of a company’s the Prescription Drug User Fee Act written request for the meeting. Program,” Roberts reported. “In addition, a mid-cycle meeting is also the company will continue to Type B meetings are the required. The meetings give your “After lowagliflozin13 getsThere approved, is a milestone advice meetings, company the chance to discuss the including EOP2 and pre-NDA status of your application with the file13Safety safety reporting reports. requirements for meetings. These are not urgent, sponsors and investigators on human drug so they feature a different in your application, the possible and biological products that are being review team, any major deficiencies investigated under an investigational new timeline. The FDA will schedule need for a REMS, FDA’s information drug application (IND) can be found in the a Type B meeting to occur needs, any major issues related regulations and at within 60 days of receipt of a to the proposed labeling, and the http://www.fda.gov/downloads/drugs/ company’s written request for status of any inspections.” guidancecomplianceregulatoryinformation/ the meeting. guidances/ucm227351.pdf 19 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued

Table 3: FDA and Sponsor Meeting Opportunities Meetings When Held End-of-Phase 2A Meeting After the completion of clinical trials that provide data on the relationship of dosing and (EOP2A) response for the intended use End-of-Phase 2 Meeting (EOP2) After Phases 1 and 2 are complete, but before the start of Phase 3 trials Pre-NDA Meeting After Phase 3, but before submission of the NDA Mid-Cycle Meeting By month 5 for PDUFA Program and standard reviews, by month 3 for priority reviews Late-Cycle Meeting Generally no later than 3 months prior to the review’s goal date for a standard review Type A Meetings A company may request this meeting to help restart a stalled development program Type B Meetings The milestone advice meetings, including EOP2 and Pre-NDA Type C Meetings Any other type of meeting held between a company and FDA

continuing obligation to report any “Before we wrap up, I wanted to smile, “It’s time to start the path new safety information that arises let you know that FDA created an towards approval. Let’s open our after the FDA approves a drug for infographic14 that displays many of calendars and choose a day to meet marketing. Postmarket studies or the steps and activities we discussed about your IND preparation.” clinical trials may be required to today. I’ll send you the link; you may assess a known serious risk, signals Disclaimer: The information in of a serious risk; or the potential for meeting notes,” Roberts said. this case study is accurate as an unexpected serious risk related find it helpful when you review your of September 2015. Processes to the use of the drug; detect new She stood, selected a marker, and occasionally change. Contact FDA uses for the product; and determine with any specific questions. the effectiveness of the labeled during their meeting. (Exhibit 7) indications under conditions of finishedTurning, theshe path announced they had with created a This case study was prepared by widespread use. But we will cross Francis Kalush, Ph.D.; Naomi Lowy, that bridge when we get there!” 14FDA Drug Approval Process Infographic. M.D.; and John Whyte, M.D.

Exhibit 7. Milestone 5

Conduct Phase 1 Conduct and Phase 2 trials Phase 3 trials Post-Approval

Conduct basic research, discovery, Safety and nonclinical and efficacy activities Milestone 1: Milestone 2: Milestone 3: Milestone 4: Milestone 5: IND Begin Begin NDA submission Approval submission Phase 1 trial Phase 3 trials

20 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued

Appendix A: AVAILABLE THERAPIES FOR TYPE 2 DIABETES

1 Sulfonylurea: Glimepiride, Glyburide, Glipizide, Chlorpropamide

2 Biguanide: Metformin

3 Meglitinide: Repaglinide, Nateglinide

4 Thiazolidinedione: Pioglitazone, Rosiglitazone

5 DPP-4 Inhibitor: Sitagliptin, Saxagliptin, Linagliptin, Alogliptin

6 Alpha-Glucosidase Inhibitor: Acarbose, Miglitol

7 Synthetic Amylin: Pramlintide

8 Insulin: NPH, Detemir, Glargine, Pre-mixed, Regular, Lispro, Aspart, Glulisine, Afrezza

9 Bile Acid Sequestrant: Colesevelam

10 GLP-1 Receptor Agonist: Exenatide, Exenatide LAR, Liraglutide, Albiglutide, Dulaglutide

11 SGLT2 Inhibitor: Canagliflozin, Dapagliflozin, Empagliflozin

12 Bromocriptine

21 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued

Appendix b: Number of Novel New Drugs Approved and Applications Filed 10 Calendar Year Progression

50 Approved Applications Filed 50 Novel New Drugs Approved

40 40

30 30

20 20

Applications Filed 10 10

0 0 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Calendar Year

Source:Notes: The 2014 2014 Novel filed New numbers Drugs includeSummary those filed in CY 2014 plus those currently pending filing (i.e., within their 60-day filing period) in CY http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugInnovation/UCM430299.pdf2014; Receipts that received a “Refuse to File” (RTF) or “Withdrawn before Filing” (WF) identifier are excluded.

Appendix C: REFERENCE LIST OF FDA GUIDANCE DOCUMENTS MENTIONED IN CASE STUDY

1. Nonclinical Safety Studies 2. Meetings with FDA Guidance on Nonclinical Safety Studies for the Guidance for Industry: Formal Meetings Between Conduct of Human Clinical Trials and Marketing the FDA and Sponsors or Applicants http://www.fda.gov/downloads/Drugs/Guidance ComplianceRegulatoryInformation/Guidances/ Authorization for Pharmaceuticals M3(R2) UCM153222.pdf http://www.ich.org/fileadmin/Public_Web_Site/ICH_ 3. IND Applications AlsoProducts/Guidelines/Multidisciplinary/M3_R2/Step4/ see: M3_R2__Guideline.pdf Guidance for Industry: Content and Format of http://www.fda.gov/downloads/drugs/guidance Investigational New Drug Applications (INDs) complianceregulatoryinformation/guidances/ for Phase 1 Studies of Drugs, Including Well- ucm292340.pdf2 Products Characterized, Therapeutic, Biotechnology-derived 22 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued

http://www.fda.gov/downloads/drugs/guidance 7. Special Protocol Assessments complianceregulatoryinformation/guidances/ Guidance for Industry: Special Protocol ucm071597.pdf Assessment Guidance for Industry: INDs for Phase 2 and Phase http://www.fda.gov/downloads/Drugs/Guidances/ 3 Studies: Chemistry, Manufacturing, and Controls ucm080571.pdf Information 8. Assessing the Clinical Safety of Drugs for Long- http://www.fda.gov/downloads/Drugs/Guidance ComplianceRegulatoryInformation/Guidances/ Term Treatment UCM070567.pdf ICH E1—The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for 4. Quality-Related Guidance Documents Long-Term Treatment of Non-Life-Threatening A sortable list of the International Conference on Conditions E1 Harmonisation—Quality Guidance Documents http://www.fda.gov/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/ucm065005.htm pdfhttp://www.ich.org/fileadmin/Public_Web_Site/ICH_ A sortable table of Pharmaceutical Quality/CMC Products/Guidelines/Efficacy/E1/Step4/E1_Guideline. 9. Clinical Trials and Effectiveness Guidances Guidance for Industry: Providing Clinical Evidence http://www.fda.gov/Drugs/GuidanceCompliance of Effectiveness for Human Drug and Biological RegulatoryInformation/Guidances/ucm064979.htm Products A sortable listing of Pharmaceutical Quality/ http://www.fda.gov/downloads/Drugs/.../Guidances/ Manufacturing Standards (cGMP) Guidances ucm078749.pdf http://www.fda.gov/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/ucm064971.htm 10. Cardiovascular Endpoints Committees A sortable listing of Pharmaceutical Quality/ Guidance for Industry: Diabetes Mellitus— Microbiology Guidances Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes http://www.fda.gov/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/ucm064983.htm http://www.fda.gov/downloads/drugs/guidance complianceregulatoryinformation/guidances/ Drug Applications and Current Good ucm071627.pdf Manufacturing Practice (cGMP) Regulations 11. NDA Fees and Fee Waivers http://www.fda.gov/Drugs/DevelopmentApproval Process/Manufacturing/ucm090016.htm Guidance for Industry: User Fee Waivers, Reductions, and Refunds for Drug and Biological 5. Informed Consent Products (DRAFT FDA document) Informed Consent http://www.fda.gov/downloads/Drugs/Guidance Information Sheet: Guidance for IRBs, Clinical ComplianceRegulatoryInformation/Guidances/ Investigators, and Sponsors UCM079298.pdf http://www.fda.gov/RegulatoryInformation/ 12. Expedited Programs Guidances/ucm404975.htm Guidance for Industry: Expedited Programs for 6. How to Comply with the Pediatric Research Serious Conditions—Drugs and Biologics Equity Act http://www.fda.gov/downloads/Drugs/Guidance http://www.fda.gov/downloads/Drugs/Development ComplianceRegulatoryInformation/Guidances/ ApprovalProcess/DevelopmentResources/UCM077855. UCM358301.pdf Pdf 23 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued

Appendix D: CDER’S OFFICE OF NEW DRUGS ORGANIZATIONAL CHART

OFFICE OF NEW DRUGS

OfficeOffice of ofthe the Director—Im Director— - Immediatemediate Office Office

Office of Hematology Office of Office of Office of Office of Office of and Oncology Antimicrobial Products Drug Evaluation I Drug Evaluation II Drug Evaluation III Drug Evaluation IV Products

Division of Division of Anesthesia, Division of Division of Anti- Division of Pediatric Division of Oncology Cardiovascular and Analgesia, and Dermatology and Infective Products and Maternal Health Products (DOPI) Renal Products Addiction Products Dental Products

Division of Metabo- Division of Division of Antiviral Division of Neurology Division of Medical Division of Oncology lism and Endcrinology Gastroenterlogy and Products Products Imaging Products Products (DOP2) Products Inborn Errors Products

Division of Transplant Division of Pulmonary, Division of Bone, Division of Division of Psychiatry Division of Hematology and Ophthalmology Allergy, and Reproductive, and Nonprescription Drug Products Products Products Rheumatology Products Urologic Products Products

Note: Drug Shortages Program now relocated under the Office of the Division of Center Director Hematology Oncology Toxicology

Therapeutic Biologics Guidance OND Learning and Rare Disease Study Endpoints and Biosimilars Team and Policy Team Career Deelopment Program Team Immediate Office

Pharmacology/ Program Management Regulatory Safety Policy and Labeling Toxicology Staff and Analysis Staff Affairs Staff Research Team Development Team

24 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued

Appendix E: APPROVAL PATHWAYS FOR NEW DRUG APPLICATIONS

505(b)(1) 505(b)(2) 505(j) Standard New Drug Rapid New Drug Application Approval Abbreviated New Drug Application Approval Pathway Application (ANDA) (for generics) Pathway An application containing full reports of An application containing information An application containing full investigations of safety and effectiveness. But that shows the proposed product—a reports of investigations of safety some of the information required for approval generic form of an existing drug— is as and effectiveness conducted by is obtained from studies conducted by other equally safe and effective as the existing the applicant. entities for drugs already approved by the FDA. drug. Federal Food, Drug, and Cosmetic Act Sec. 505 (21 U.S.C. 355)

Glossary

Adverse event: An unintended, harmful medical effect sources—human, animal, or microorganism—and in a human subject, including any abnormal sign (for may be produced by biotechnology methods and other example, an abnormal physical exam or laboratory cutting-edge technologies. Gene-based and cellular biologics, for example, often are at the forefront of the subject participates in the research, but it may or biomedical research, and they may be used to treat mayfinding), not besymptom, caused byor thedisease. research The effecttreatment. occurs while a variety of medical conditions for which no other treatments are available. Approval letter: a New Drug Application (NDA) sponsor that allows the Biologics License Application (BLA): The Biologics commercial marketing An official of the communication product. from FDA to License Application (BLA) is a request for permission to introduce, or deliver for introduction, a biologic Biological products: Biological products include a product into interstate commerce (21 CFR 601.2). The wide range of products such as vaccines, blood and BLA is regulated under 21 CFR Part 600–680. blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. Clinical investigators: Professionals, generally Biologics can be composed of sugars, proteins, or physicians, who oversee the administration of an nucleic acids or complex combinations of these experimental compound during clinical trials or substances, or may be living entities such as cells and studies. tissues. Biologics are isolated from a variety of natural

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Complete response letter: designated to review and monitor biomedical research from FDA to the sponsor of a New Drug Application to involving human subjects. The purpose of the IRB inform the sponsor that theAn review official period communication for a drug review is to assure, both in advance and by periodic is complete, but the application is not yet ready for review, that appropriate steps are taken to protect the rights and welfare of human subjects. Under FDA and, when possible, will outline recommended actions regulations, an IRB has the authority to approve, theapproval. applicant The may letter take will to describe gain approval. specific deficiencies

Controlled trials or studies: Investigations that requireIn vitro: modificationsLatin term meaning of, or disapprove “in glass.” An research. in vitro test compare a test article—a drug, for example—with a is one that is done in glass or plastic vessels in the treatment that has known effects. The control group laboratory. In vitro is the opposite of in vivo. may receive no treatment, active treatment, placebo, or dose comparison concurrent control. In vivo: Latin term meaning “in a living organism.” For example, an experiment that is done in vivo is done in NOTE: For further information on “adequate and well- the body of a living organism. In vivo is the opposite of controlled study” see regulation 21 CFR Part 314.126. in vitro. Effectiveness: The desired measure of a drug’s Label: found inside the drug product’s packaging. The FDA- by substantial evidence from adequate and well- approved The label official includes description indication(s) of a drug (what product the drugoften influence on a disease or condition as demonstrated controlled investigations. is used for); who should take it; adverse events (side The capacity of a drug or treatment to effects); instructions for uses in pregnancy, children, and other populations; and safety information for the aEfficacy: disease at the dose tested and against the illness (and patient. produce beneficial effects on the course or duration of patient population) for which it is designed. Life-threatening: Any adverse drug event that places Guidance: Documents that represent the FDA’s current the patient or subject, in the view of the investigator, thinking on a particular subject. They are not binding at immediate risk of death from a reaction as it occurs on FDA or users except as stated. (i.e., it does not include a reaction that, had it occurred in a more severe form, might have caused death). Indication or indications: A particular aspect of a disease/medical condition for which the drug is safe New Drug Application (NDA): A formal request to and effective. FDA for a license to market a new drug in the United States. When the sponsor of a new drug believes that Informed consent: A process that provides research enough evidence on the drug’s safety and effectiveness subjects with explanations to help them make educated has been obtained to meet FDA’s requirements for decisions about starting or continuing participation marketing approval, the sponsor submits an NDA to in a research study or trial. Informed consent is an ongoing, interactive process. It does not waive the technical viewpoints for review, including chemistry, subject’s legal rights, and it does not release the pharmacology,FDA. The application medical, must biopharmaceutics, contain data from and specific investigator or sponsor from liability for negligence. statistics. If the NDA is approved, the product may be marketed in the United States. For internal tracking Institutional Review Board (IRB): A group of medical, purposes, all NDAs are assigned an NDA number. scientific, and non-scientific members formally 26 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued

New safety information: Facts and data about a Post-approval studies and trials, investigations that serious risk or unexpected serious risk associated occur after drug approval: Studies that occur after FDA with use of a drug since the drug was approved, since approves a drug to determine additional information a risk evaluation and mitigation strategy (REMS) was required, or since the REMS was last assessed. and optimal use. These studies may be required or requestedabout the drug’s by FDA risks, in conjunction benefits, manufacturing, with the marketing Nonclinical: A stage of research that evaluates a drug’s approval. toxic and pharmacologic effects through in vitro tests and in vivo laboratory animal testing. Prescription drug: Drug products that require a Phase 1: The initial introduction of an investigational new drug into humans. Phase 1 studies are typically doctor’sProtocol authorizationor protocols: Ato written purchase. description of what closely monitored and may be conducted in patients researchers plan to do during a clinical study. or normal volunteer subjects. Phase 1 studies are designed to determine the metabolism and Risk: The probability of harm or discomfort for pharmacologic actions of the drug in humans, the subjects in a clinical trial. side effects associated with increasing doses, and, if Safety: Risks that are acceptable in relation to the possible, to gain early evidence of effectiveness.

Phase 2: Clinical studies conducted to evaluate the from harm. Safety may be assessed by laboratory observed benefit for the indication. Relative freedom effectiveness of the drug for a particular indication or testing of biological samples, special tests and indications in patients with the disease or condition procedures, psychiatric evaluation, and/or physical under study. They are also used to determine the examination of the research subjects. common short-term side effects and risks associated Sponsor: Sponsors may include physicians, with the drug. foundations, medical institutions, voluntary groups, Phase 2A: Clinical studies that occur after the and pharmaceutical companies, as well as Federal agencies such as the National Institutes of Health, FDA, exposure-response studies in patients. They are the Department of Defense, and the Department of conductedcompletion before of Phase the 1 Phase studies 2B and (i.e., the patient first set dose- of Veterans Affairs that conduct and oversee research. Type 2 diabetes: Type 2 diabetes mellitus is studies. ranging trial) and Phase 3 clinical efficacy-safety Phase 3: These studies are expanded controlled combination of resistance to insulin action, inadequate characterized by hyperglycemia and results from the trials. They are performed after preliminary evidence insulin secretion, and excessive or inappropriate suggesting effectiveness of the drug has been glucagon secretion. obtained. Phase 3 studies are intended to demonstrate effectiveness and safety in a clinically and statistically meaningful way to confirm the drug’s efficacy and basisevaluate for the overallphysician benefit/risk labeling. relationship of the drug. The Phase 3 findings also provide an adequate

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Student Activities

Learning Objectives for the Case Study Engaging Students: During the session, use the discussion questions below to review and 1. State the objectives of the drug development and approval process. Immersing Students: Choose an application emphasize the major points of the case study. 2. Identify the major activities that occur during exercise for your class. There are several the drug development and approval process shorter activity options and one longer option from nonclinical tests through approval from listed below. the U.S. Food and Drug Administration (FDA). 3. Describe the major elements and steps to Review the following materials conduct a clinical trial. before the session: 1. Mandatory Reading New Molecular Entity (NME) diabetes drug. a. Drug Approval Case Study 4. Apply the drug approval process to a fictional Topics: Regulatory pathways, drug approval process, 2. Optional Viewing and Reading drug development, protection of human subjects a. FDA Video—JumpStarting Drug Review Assumptions http://www.fda.gov/drugs/resourcesforyou/ consumers/ucm397921.htm Target audience consists of medical, pharmacy, b. The FDA’s Drug Review Process: Ensuring and nursing students who have no experience Drugs Are Safe and Effective with drug development and approval processes. http://www.fda.gov/drugs/resourcesforyou/ Students are expected to work on the case consumers/ucm143534.htm before, during, and after class. c. FDA Drug Approval Process Infographic Users of the case study are instructors who http://www.fda.gov/downloads/Drugs/ may have some knowledge of the FDA and its ResourcesForYou/Consumers/UCM284393.pdf website. Instructors have 1–2 class sessions to cover the QUESTIONS FOR CLASS DISCUSSION materials involved in the case study. 1. What are the milestones in the drug Suggested Instructional Approach development and approval process? 2. Why is informed consent required for people Preparing Students: Ask students to read the case study before class. Recommend that they participating in clinical studies? scan or review the other suggested materials 3. What is the role of an IRB? listed below. 4. What types of nonclinical and clinical tests are completed before submission of a New Drug Application? 28 DRUG APPROVAL—BRINGING A NEW DRUG TO THE MARKET continued

5. How are adverse events reported to FDA? 3. True or false? A drug intended for type 2 diabetes will likely be eligible for the FDA’s expedited review. FDA during the drug development and approval 6. process?What are some of the benefits of meeting with 4. True or false? All drugs for type 2 diabetes need a REMS. 7. What are the two available FDA review timelines for new drugs and biologics, and what 5. True or false? The advisory committee provides is the difference between them? recommendations to FDA, and FDA makes the 8. List the four expedited drug development and review programs. What do they share in 6. finalTrue decision.or false? Secondary clinical trial endpoints common? are the endpoints for which subjects are 9. What is the role of an Advisory Committee in the drug approval process? Shorterrandomized Activity and Options for which (For the small trial groups is powered. or solo work) 10. Apply the drug development and approval processes to a diabetes drug: 1. STEM Presentation You have been asked to develop a short addressed when developing a diabetes presentation about the drug development a. drug?What specific health risk needs to be and approval process for high school students How are sponsors supposed to mitigate this attending a STEM (science, technology, risk? engineering, and mathematics) conference. You will have 15 minutes to explain the process.

diabetes drug must demonstrate at the end Create a topic outline for the presentation. b. ofWhat Phase is the 3 trials? primary efficacy endpoint a 2. Next Steps for Dr. Green Why was this endpoint chosen? with Dr. Roberts. Dr. Green returns to her office after the meeting drug to be granted an expedited review by List at least four tasks she adds to her to-do c. FDA?Why is it unlikely for this fictional diabetes list based on her meeting with Dr. Roberts. APPLICATION: STUDENT ACTIVITIES Explain your choices. 3. Patient Counseling Pre-Activity: Check Your Understanding (Answers are located after the activities) A patient—who has struggled to manage his type 2 diabetes—shows you an article about a 1. True or false? The main objective of the drug promising new drug for type 2 diabetes. He asks approval process is to demonstrate the safety of you why the drug is not available yet. You have a drug. 10 minutes to answer him. 2. True or false? The majority of new drugs being What do you tell him? List at least three developed will not be approved by FDA for main points you want to convey. marketing in the United States.

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Longer Activity: Mock Company 3. True or false? A drug intended for type 2 diabetes will likely be eligible for the FDA’s Ask students to form small groups. expedited review. Each group will represent a company and False: FDA’s expedited review programs are complete these tasks: intended for drugs that address unmet medical needs for serious or life-threatening conditions. 1. Choose the company’s new drug: These programs exist to get therapies for Drug A: a new drug for asthma serious conditions approved and available management OR to patients as soon as it is apparent that the Drug B: a new drug for melanoma treatment must offer strong evidence to show the new drugbenefits meets justify these the criteria. risks. The Because drug developerthere are 2. Suggest the best FDA review option for multiple drugs available for the treatment of your drug to your investors and justify this option. a case for an expedited review. 3. Explain how your company will determine type 2 diabetes, it would be difficult to establish 4. True or false? All drugs for type 2 diabetes need that the drug is reasonably safe and a REMS. effective. False: None of the SGLT2 inhibitors have a 4. List your company’s reporting and meeting REMS at this time, but there are REMS in place obligations to FDA during the different for other type 2 diabetes therapies. phases of drug development. 5. True or false? The advisory committee provides 5. Identify three types of information your recommendations to FDA, and FDA makes the company must include in your proposed Package Insert. True: final decision. 6. Share at least two lessons learned during drug approval. this exercise. FDA always make the final decision on 6. True or false? Secondary clinical trial endpoints Post-Activity: Check Your Understanding are the endpoints for which subjects are

1. True or false? The main objective of the drug False: The primary endpoint of a clinical approval process is to demonstrate the safety of randomized and for which the trial is powered. trial is the endpoint for which subjects are a drug. False: The objective of the drug approval It is the outcome to evaluate the effectiveness process is to demonstrate both the safety and ofrandomized treatments and in afor clinical which trial. the trialSecondary is powered. endpoints are endpoints that can be used to explore other important aspects of an 2. efficacyTrue or false?of the The drug. majority of new drugs being intervention for which the trial may not be developed will not be approved by FDA for marketing in the United States. True: Most potential new drugs fail to powered nor randomized.

point in the drug development process: nonclinicaldemonstrate studies, safety clinicaland/or studies,efficacy orat someFDA review. 30