Fundamentals of Biologicals Regulation: Vaccines and Biotechnology Medicines

Fundamentals of Biologicals Regulation

Vaccines and Biotechnology Medicines

First Edition

Rebecca Sheets

Principal Consultant and Subject Matter Expert, Grimalkin Partners, Silver Spring, MD

Catholic University of America, Washington, DC, United States

Table of Contents

Cover image

Title page

Copyright

Dedication

About the Author

Preface

Acknowledgments

How to Obtain Documents From ICH and US

Section I: Regulatory Process

Introduction

Chapter 1: Introduction to the Regulatory Process for Biologicals

Abstract

1.1 Fundamentals

1.2 Some Details

1.3 Case Studies

1.4 Conclusions

Chapter 2: Discovery and Development

Abstract

2.1 Fundamentals

2.2 Some Details

2.3 Case Studies

2.4 Conclusions

Chapter 3: International Regulatory Convergence

Abstract

3.1 Fundamentals

3.2 Some Details

3.3 Case Studies

3.4 Conclusions

Chapter 4: Communications and Formal Meetings With Regulators: Focusing on the Process Before Clinical Trial Authorization (AKA PRE-IND)

Abstract

4.1 Fundamentals

4.2 Some Details

4.3 Case Studies

4.4 Summary and Conclusions

Appendix: An Example of an Assignment Testing One’s Ability to Identify Deficiencies in a Pre-IND Meeting Briefing Package and Questions and to Generate Appropriate Advice for a Fictitious Applicant

Chapter 5: Clinical Trial Authorization and Investigational New Drug Applications

Abstract

5.1 Fundamentals

5.2 Some Details

5.3 Case Studies

5.4 Conclusions

Chapter 6: Marketing Authorization

Abstract

6.1 Fundamentals

6.2 Some Details

6.3 Case studies

6.4 Conclusions

Chapter 7: Alternative Regulatory Pathways and Special Programs

Abstract

7.1 Fundamentals

7.2 Some Details

7.3 Case Studies

7.4 Conclusions

Chapter 8: Variations or Changes to an Approved Application

Abstract

8.1 Fundamentals

8.2 Some Details

8.3 Case Studies

8.4 Conclusions

Chapter 9: Audits and Regulatory Compliance Inspections

Abstract

9.1 Fundamentals

9.2 Some Details

9.3 Case Studies

9.4 Conclusions

Chapter 10: Good X Practices

Abstract

10.1 Fundamentals

10.2 Some Details

10.3 Case Studies

10.4 Conclusions

Resources

Written Assignments Exercise

Introduction to the Scenarios

Rules About Plagiarism

The Assignment and Grading

Assignment Questions and Tasks

Assignment Scenarios

Section II: Regulatory Science

Part I: Preclinical

Chapter 11: Preclinical Safety and Toxicology

Abstract

11.1 Fundamentals

11.2 Some Details

11.3 Case Studies

11.4 Conclusions

Chapter 12: Preclinical Pharmacology, Proof-of-Principle

Abstract

12.1 Fundamentals

12.2 Some Details

12.3 Case Studies

12.4 Conclusions

Chapter 13: Institutional Biosafety Committees and Regulation of Genetically Modified Organisms

Abstract

13.1 Fundamentals

13.2 Some Details

13.3 Case Studies

13.4 Conclusions

Chapter 14: Risk Assessments

Abstract

14.1 Fundamentals

14.2 Some Details

14.3 Case Studies

14.4 Conclusions

Part II: Product

Chapter 15: Product Construction, Manufacture, and Process Validation

Abstract

15.1 Fundamentals

15.2 Some Details

15.3 Case Studies

15.4 Conclusions

Chapter 16: Lot Release, Analytics, and Analytical Validation

Abstract

16.1 Fundamentals

16.2 Some Details

16.3 Case Studies

16.4 Conclusions

Part III: Clinical

Chapter 17: Regulatory Aspects of Clinical Trials

Abstract

17.1 Fundamentals

17.2 Some Details

17.3 Case Studies

17.4 Summary or Conclusions

Instructions How to Obtain Documents From ICH (Guidelines), U.S. FDA (Regulations), EMA (EudraLex), and WHO (Clinical Trial-Related Issues)

Chapter 18: Clinical Trial Ethics, Human Subjects Protections, and the Informed Consent Process

Abstract

18.1 Fundamentals

18.2 Some Details

18.3 Case Studies

18.4 Conclusions

Chapter 19: Independent Ethics Committees and Institutional Review Boards

Abstract

19.1 Fundamentals

19.2 Some Details

19.3 Case Studies

19.4 Conclusions

Section III: Product Specific

Chapter 20: Biosimilars

Abstract

20.1 Fundamentals

20.2 Some Details

20.3 Case Studies

20.4 Conclusions

Chapter 21: In Vitro Diagnostics and Biotech Medical Devices

Abstract

21.1 Fundamentals

21.2 Conclusions

Chapter 22: Regulatory Policy and Public Health Policy

Abstract

22.1 Fundamentals

22.2 Some Details

22.3 Case Studies

22.4 Conclusions

Glossary

International Biologicals Regulation: Vaccines, Biotechnology Medicines By Rebecca L. Sheets Compilation of Weblinks

Additional NRA Websites

Weblinks From Chapter 1

Weblinks From Chapter 2

Weblinks From Chapter 3

Weblinks From Chapter 4

Weblinks From Chapter 5

Weblinks From Chapter 6

Weblinks From Chapter 7

Weblinks From Chapter 8

Weblinks From Chapter 9

Weblinks From Chapter 10

Weblinks From Chapter 11

Weblinks From Chapter 12

Weblinks From Chapter 13

Weblinks From Chapter 14

Weblinks From Chapter 15

Weblinks From Chapter 16

Weblinks From Chapter 17

Weblinks From Chapter 18

Weblinks From Chapter 19

Weblinks From Chapter 20

Weblinks From Chapter 21

Weblinks From Chapter 22

Index

Copyright

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Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.

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Dedication

I dedicate this book to my husband, without whose love and support it would never have been possible. I would also like to dedicate it to our cats, Salem and Shadow, who spent hours laying by or on me while I worked on the computer. Without my students, I would not have discovered the lack of a suitable textbook, which inspired me to write one. Finally, to everyone from whom I learned all of this information, too numerous to name individually, thank you. Without your time and training or mentoring, this book would also not have been possible and I would not be able to pay-it-forward.

About the Author

Rebecca Sheets is the principal consultant for Grimalkin Partners and an adjunct professor at Catholic University of America, teaching core courses for a M.S. in biotechnology program in the Biology Department in the School of Arts and Sciences. She also serves on the board of the International Alliance for Biological Standardization and the board of Math Dojo of St. Louis.

In 2013, Rebecca Sheets retired from the U.S. Public Health Service in which she served as the Vaccine Scientific and Regulatory Specialist at the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health (NIH). In this role, she formulated regulatory strategy for the Division of AIDS on preclinical development translating research concepts into HIV vaccine candidates suitable for human clinical trials. She also served as a subject matter expert on vaccine cell substrates and vaccine preclinical safety assessments, including toxicology. Further, she simultaneously served the Vaccine Research Center at U.S. NIH in a similar capacity until 2012. She also served as a resource for other intramural and extramural NIAID divisions.

Prior to NIH, Dr. Sheets served for 9 years (1993–2002) as a scientific reviewer in the Viral Vaccines Branch of the Division of Vaccines and Related Products Applications, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, U.S. Food & Drug Administration (FDA). In 1994, to foster her commitment to public health, she became a commissioned officer in the U.S. Public Health Service (Scientist Category), in which she was promoted to the O-6 rank of Captain (CAPT) before retiring in 2013. She transferred to U.S. NIH from U.S. FDA in 2002.

Rebecca Sheets obtained her B.S. degree in biology from the California Institute of Technology; M.S. degree in Cellular, Viral, and Molecular Biology from the University of Utah School of Medicine, and Ph.D. in Pathology from the University of Southern California School of Medicine.

Both at U.S. FDA and at U.S. NIH, she strove to advance policy regarding vaccine cell substrates. She continues to influence policy in this area. Because of her virology background, a strong focus of this effort was in regard to the adventitious agent tests. From 2006 to 2014, she served as co-chair of the World Health Organization’s Study Group on Cell Substrates and as chair of the Adventitious Agents Sub-committee. This Study Group was tasked with providing technical advice to revise the WHO’s guidelines on the subject as well as a scientific principles document, which were adopted by their Expert Committee on Biological Standardization in 2010 and 2014, respectively. In 2013, she was involved in Implementation Workshops for the guidelines. Since retirement, she serves in various capacities to assist the WHO, including in regards to HIV vaccines, clinical evaluation of vaccines, human papillomavirus vaccines, and Ebola vaccines.

Further, U.S. NIH policy mandates that researchers reduce, refine, or replace animals used for product safety testing. In this spirit, CAPT (ret.) Sheets completed and published the results of regulatory science research projects with the focus of determining how to achieve this goal with animals used in adventitious agent testing. In addition, she has considered means to streamline or more rationally assure preclinical safety of vaccine candidates than the standard toxicology (drug-screening) studies currently required.

In retirement, CAPT (ret.) Sheets is at the paying-it-forward stage of her career and hopes this book and other teaching and training endeavors she has undertaken help to train and educate the next generation of regulators and biological product developers on best practices for safe and ethical development of important medicines to promote and protect the global public health. In this regard, this book would not have been possible without the myriad of scientists, clinicians, and regulators who trained and mentored her throughout her career. It is her hope that if you, the reader, find this book useful that you too, when you attain that stage of career, pay it forward to the generation that comes after you in homage to those who trained and mentored you.

About the co-author:

Ivana Knezevic, MD, PhD Scientist, Technologies, Standards and Norms Team, Group Lead, Norms and Standards for Biologicals, Department of Essential Medicines and Health Products (EMP), Health Systems and Innovation (HIS) Cluster, World Health Organization (WHO), Switzerland.

Knezevic is specialist in medical microbiology and parasitology. She received her MD from the University of Novi Sad, MSc in medicine (microbiology) and PhD in medicine (virology) from the University of Belgrade, Republic of Serbia. Ivana Knezevic has 24 years of professional experience in standardization, scientific and regulatory overview of biologicals.

Knezevic is a scientist at the WHO Biological Standardization Programme, which she joined in September 2000, and since then her activities have been devoted to the standardization and evaluation of biologicals at the global level. Since 2006, she has been leading the team for standardization of vaccines and biological therapeutics in WHO Headquarters. Main aspects of the work include development and establishment of WHO International Standards as well as the assistance to regulators, manufacturers, and other users of these standards.

In the area of biotherapeutics, she coordinated the development of WHO’s Guidelines on evaluation of Similar Biotherapeutic Products (SBPs), and organized a series of workshops to facilitate the implementation of guiding principles for evaluation of biotherapeutic products into regulatory and manufacturers' practices.

Being responsible for eight WHO Collaborating centers for standardization and evaluation of vaccines and other biologicals, Knezevic initiated numerous scientific projects of importance for global public health. In 2012, she created a network of the institutions that are playing a leading scientific and regulatory role in their countries (United Kingdom, Japan, Australia, United States, Republic of Korea, Canada, China, and Germany). In addition, continuous collaboration with National Regulatory Authorities, manufacturers, academia, and other experts in the area of biological products is one of the main aspects of her work.

Knezevic is the author of many publications that made broad audience aware of WHO initiative in the development, establishment, and implementation of standards for vaccines and biotherapeutic products. She is also contributing to the peer-review scientific journals with the international reputation.

Passionate about education, Knezevic is contributing to the development of training programs as well as materials for distance learning and teaching in class in the area of vaccinology and biologicals.

Preface

This book was written to fill a niche that was void—at the time of writing this book, there were no up-to-date books on the regulation of biologicals, particularly from the perspective of international standards. Biological medicinal products (biologicals or biologics) differ in significant and substantial ways from drugs or pharmaceutical medicinal products. While some facets of regulation of drugs are shared with biologicals, their application to biologicals is much more complex by nature of the complexities of biological products themselves. If you have ever seen the comparison of the size and complexity of a common drug, like aspirin, to that of a prototypical biological, like a monoclonal antibody, the differences are intensely and immediately apparent. So too are the significant differences in how biologicals are regulated in the United States and around the globe from how pharmaceuticals are regulated. There are commonalities, but understanding how the principles apply or do not apply is important if one is developing or regulating a biological product.

Biologicals include traditional types of products like live or inactivated vaccines or blood products purified or constituted from human plasma or whole blood. My career has been spent in the development and regulation of vaccines and many examples in this book reflect that experience. Traditional blood products will not be discussed in the book, although many of the processes are comparable to those that will be described; however, there are specific regulations for blood and traditional blood products that are outside the scope of this book. More modern biologicals are biotechnology products, which include recombinant proteins (recombinant plasma proteins, therapeutic proteins, monoclonal antibodies, subunit vaccines) and gene therapy or gene transfer vectors to be used therapeutically (gene therapy, therapeutic vaccines) or prophylactically (vaccines). The book will draw on examples for several of these classes of biotechnological products.

Regulation of biologicals entails both aspects of regulatory affairs and regulatory science. The distinction between them is that regulatory affairs entail the process of compiling necessary information and managing communications with regulators to provide them with the information needed for regulatory decision-making, while regulatory science entails implementing experiments and methods that are used to gather data and evidence for regulatory evaluation and to inform regulatory risk/benefit decision-making. The book attempts to reflect upon both aspects of regulation, with the initial part of the book focused on the process of regulatory affairs and the middle part of the book focused on the scientific principles behind the regulations.

While fairly wide-ranging, this book is not intended as a how-to guide for applicants or for regulators, but instead is intended to give a broad overview of and introduction to the regulatory processes from just when regulation enters the product development pathway (preclinical, pre-IND, or pre-CTA) through the clinical trials and product development stages (IND or CTA) and into the stage of marketing authorization (NDA, BLA, or MAA) and beyond (Phase 4 studies, changes to an approved application or variations). As stated earlier, the primary examples given to illustrate the regulatory processes will be the United States and EU regulatory systems, but regulatory processes from other countries will be included to illustrate differing approaches to solving the same regulatory problems. Attention is given to both the recommendations and guidelines issued by the World Health Organization and the International Council for Harmonisation, both of which strive to provide international regulatory convergence. Despite these efforts at international regulatory standardization, regulations and legal frameworks for regulating clinical trials and licensure (registration, approval) of biologicals differ by country. As you can tell from the parenthetical terms, which differ by regulatory region or country, I will attempt to focus on commonalities, while acknowledging differences, and in this manner, focus on the key concepts fundamentally relevant to regulation of biologicals.

The structure of the book is divided into three levels from the general to the more specific. The first 10 chapters reflect the regulatory processes themselves (regulatory affairs). The next nine chapters focus on the regulatory science that better explains the regulatory processes and why they are as they are. This section of the book truly reflects the concepts underpinning the regulations. The final three chapters cover some of the exceptions to the usual processes covered in the earlier portions of the book, including the concepts behind how biosimilars (follow-on biologics, subsequent entry biologics, similar biological medicinal products) or in vitro diagnostics are regulated, and the role of regulatory and public health policy. These latter chapters are not comprehensive, as there are many more nuances to the way such products are regulated that are beyond the scope of this book. Instead, these chapters are intended simply to highlight some of the differences between how those specific biologicals are regulated differently from others.

Each chapter¹ is divided into four sections. The first section is the basics of the topic of that chapter: the fundamentals. This level of information is suitable for classroom instruction or for the reader who simply wants to have some basic level of insight into the topic. The second section of each chapter is more detailed and gives greater insight into certain aspects of the topic, which may be beyond the fundamentals. The third section provides case studies and reflects caveats, exceptions, and anecdotes, which are more experiential and may provide the reader a more nuanced understanding. In this third section of each chapter, I often proffer opinions that are solely my own and should not be misconstrued as reflecting the policy of any government agency or international organization nor that of the University where I teach. The fourth section is a conclusion or summary.

Regulatory processes include not only complying with the regulations of a country’s National Regulatory Authority (NRA) and/or National Control Laboratory (NCL), such as the China Food & Drug Administration and National Institute for Food and Drug Control or the U.S. Food and Drug Administration (which is both NRA and NCL), but also complying with regulations pertinent to other oversight agencies. In particular, this book will reflect to some extent on agencies that may specifically regulate Genetically Modified Organisms (GMOs). Some biologicals would be considered to be a GMO, such as a gene therapy or gene transfer vector, and would be regulated in some countries by a separate regulatory authority or regulatory process in addition to the standard ones that apply to all types of biologicals. Chapter 13 covers this specific regulatory process in overview. In addition, all clinical research involving human subjects must be overseen by an Institutional Review Board or Independent (or Research) Ethics Committee. Chapters 18 and 19 cover the regulatory processes associated with clinical trial ethics and the regulatory processes of ethical oversight.

In addition, Chapter 21 covers a particular type of biotechnological product regulated differently from other biologicals because in vitro diagnostics are considered to be medical devices. This book will not cover medical device regulation in any detail, however, as there is a very good book² on that subject already available. Only the regulatory process in the United States will be briefly covered in this chapter on in vitro diagnostics, although most chapters reflect a more international perspective and cover at a minimum, processes in the United States and EU. Often, a compare/contrast approach is taken to explain these processes; but primarily, the focus is on the scientific concepts behind why products are regulated the way they are.

Chapter 1 introduces the basic regulatory process and gives insight into how these processes arose, with the history of the U.S. FDA given as an example. Chapter 2 discusses the distinctions between discovery, which is largely unregulated, and development, which is highly regulated. Chapter 3, co-authored with Ivana Knezevic, focuses on international harmonization efforts and introduces the reader to the roles of the World Health Organization and the International Council for Harmonisation to accomplish this. Chapter 4 introduces the reader to where in the development process regulations begin to need attention and how to go about getting preapplication advice from regulators. The U.S. FDA pre-IND process and formal meetings with sponsors are given as examples. Chapter 5 explains the initial application process required in order to be allowed to initiate clinical trials in various countries. These clinical trials are required in order to obtain the necessary data on safety and efficacy in humans to gain authorization to market a new biological product. This marketing authorization process is the subject of Chapter 6, which also explains the format of the ICH common technical document and its use in making the application. This chapter also introduces the ASEAN common technical document.

Chapter 7 describes alternative regulatory pathways and special programs of the U.S. FDA and the EMA. Such special programs are used in recognition that for certain products, such as those for life-threatening diseases and unmet medical needs, a different approach is necessary to speed such products to the patients needing access to them as rapidly as possible. Chapter 8 covers what needs to be done to maintain marketing authorization in the face of inevitable change and hopefully improvements over the life span of the product. Chapter 9 describes how the U.S. FDA handles assurance of compliance and inspections of manufacturing facilities, clinical trial sites and investigators, sponsors and monitors, and laboratories in which nonclinical data are obtained. Chapter 10 focuses on the Good X Practices with which these facilities, sites and investigators, sponsors and monitors, and nonclinical laboratories must comply.

Chapter 11 initiates the Regulatory Science portion of the book focusing on the nonclinical or preclinical processes necessary to obtain safety data on the research concept or product candidate to permit regulators to assess potential risks to subjects, i.e., toxicology. Chapter 12 focuses on those nonclinical or preclinical data necessary to obtain insight into the potential for benefit and potential mode-of-action and/or mechanism-of-action of the candidate product, aka pharmacology. Chapter 12 also covers animal use and care ethics and the regulatory process for governing this aspect. Between these two chapters, the reader should gain knowledge about the preclinical data needed to make risk/benefit decisions before allowing clinical trials to initiate, particularly those that will represent first-in-human studies. Chapter 13 focuses on the regulatory process needed for biotechnology products, specifically genetically modified organisms, such as Institutional Biosafety Committee review. Chapter 14 explains the concepts of risk assessment, since this is how risk/benefit decisions are made.

Chapter 15 begins explaining the science behind regulation of product aspects; i.e., Quality or Chemistry, Manufacturing, and Controls information; with a focus on the production process and process validation. Chapter 16 focuses on the analytical aspects of product testing and validation of analytical methods, including the batch and lot release process and the role of National Control Laboratories in that process.

Chapter 17 introduces the regulatory aspects of clinical trials and explains the scientific principles behind basic clinical trial design, such as trial phases, blinding or masking, randomization, controls, the role of randomized controlled trials, and so forth. This chapter also describes adverse event reporting and pharmacovigilance. Chapter 18 lays the foundation for international principles about the ethics of designing and conducting clinical trials and performing research with human subjects as participants, including the importance of the informed consent process. This chapter describes the concepts of respect for persons, beneficence, and justice and how these concepts can be applied. Chapter 19 introduces another regulatory process separate from that conducted by the NRAs and/or NCLs. That process is the review and approval by Ethics Committees or Institutional Review Boards, including their procedures, make-up, and responsibilities.

After this conclusion to the regulatory science principles, Chapter 20 begins a description of product-specific regulatory processes that differ from that described in the first 10 chapters. This chapter, co-authored with Ivana Knezevic, focuses on biosimilars that reflect for biological products the difference between how they are regulated versus generic drugs. Dr. Knezevic has been instrumental at WHO for aiding the development for international standards and norms on biosimilars. Chapter 21 focuses on In Vitro Diagnostics, which are regulated like medical devices, instead of biologicals, even though they may contain components produced by biotechnology.

Chapter 22 is not so much product-specific, but instead explains the process and necessity to develop regulatory policy and also describes public health policy. I include this topic to illustrate to students that there is a broader world of possible job opportunities than they might be aware. Policy development is a specialized endeavor for experts, which I hope they will become in their careers.

This book may be used as a textbook and in fact, the reason I wrote it was to provide a textbook for a course I teach at the Catholic University of America in the M.S. program in Biotechnology on Domestic and International Regulation of Biotechnology Products. For this purpose, the Fundamentals parts of each chapter are useful and should be sufficient. In addition, I provide some exercises or home-work assignments to practice the concepts of the book. However, this book may also be found to be useful by regulators in various countries who may wish to understand the regulatory processes in other countries a bit better; by staff in industry, including the biotech industry, who may wish to learn more about how their products are likely to be regulated and what they may face as regulatory challenges in various regulatory regions; by clinicians who want a broader picture of the regulatory processes beyond Good Clinical Practices and the functioning of IRBs; and by academic or governmental researchers, who wish to translate their basic research into products that might help the public and who are daunted and mystified by the black box of regulatory. For these individuals, this book, including the fundamentals, some details, and case studies, may serve as a reference or a primer on the world of regulation of biologicals. The book may also serve as a framework to aid in new employee training within the biotech industry, including those staff whose background has previously focused on pharmaceutical drugs rather than biologicals.

The reader will not find herein step-by-step instructions, as this is not a how-to manual, and in fact, rather than focus in great depth on any particular branch of a tree, instead this book serves to describe the forest into which the uninitiated may be venturing. Thus, the reader should not mistake this book as regulatory guidance or advice, nor anticipate that you will become an expert on the basis of reading this book. If you are developing a regulated product, the advice of a regulatory affairs expert, a regulatory scientist, a lawyer, an independent consultant, and/or a consultancy group, should be sought to aid you with the specifics of your product and its unique development aspects. Instead, this book serves as an introduction to the international regulatory arena in which biologicals are developed, giving a broad overview of the processes and insight into the scientific concepts underpinning the regulations. In addition, despite efforts to harmonize or converge regulatory practices in various countries, regulatory and legal frameworks do vary and what may be appropriate in one country or regulatory arena may not be sufficient in another. A consultant familiar with the requirements in the country in which you intend to perform clinical trials or license your product will best be able to advise you on such matters. It takes many years (the better part of a decade or more) to become an expert in the arena of regulatory affairs and/or regulatory science.

It must also be recognized that as science is ever-evolving, so too is the area of regulation of biologicals, and particularly, the newer and novel biotechnology products, sometimes referred to as advanced therapy medicinal products (ATMP). Thus, this book can only reflect a snapshot at the time of writing and focuses on the over-arching principles of regulation, which are unlikely to evolve as rapidly as any given regulatory policy or guidance document.

The perspectives presented in this book reflect my own experiences working with regulators in various countries while serving in the U.S. Public Health Service or while involved in activities conducted on the behalf of the World Health Organization as a temporary advisor or consultant. However, they may not truly reflect the situation you may experience with your own unique product. To reiterate, this book reflects solely my own experience and opinions and does not reflect any government or international agency or organization with which I have been or am affiliated.

¹ With the exception of Chapter 21.

² C.T. De Marco, Medical Device Design and Regulation, ASQ Quality Press, Milwaukee, 2011.

Acknowledgments

I would like to acknowledge my husband, Stephen Deming, without whose support I would never have been able to devote the time and energy needed to write this book. He has supported my career throughout our marriage. I would also like to acknowledge Frank Portugal, Director of the M.S. Program in Biotechnology, and Venigalla Rao, chair of the Department of Biology, for inviting me to teach at the Catholic University of America (CUA) Department of Biology, as an adjunct professor. Further, I want to recognize one of my students, Angela DeMarco, and her father, Carl T. DeMarco—author of Medical Device Design and Regulation and an adjunct professor of BioMedical Engineering at CUA. I had the idea of writing this book for some time, but they inspired me to take the plunge. In fact, I am grateful to all my students from whom I learn so much. Similarly, I am grateful to all those who have guest lectured for me over the years, enriching my courses with alternative perspectives. I also have to acknowledge the many mentors, trainers, managers, and colleagues I’ve had over the years from whom I learned almost everything that I know about biologicals regulation. Some lessons were on-the-job training, but these were supplemented by discussions and guidance from senior colleagues and managers, as well as the training opportunities made available to US FDA staff. I would be remiss not to also acknowledge colleagues in industry from whom I have learned to understand their side of the table.

Editors: I would like to acknowledge those individuals who agreed to edit chapters, including those who did not wish to be acknowledged by name—you know who you are. Thanks to Karen Goldenthal, Stuart Shapiro, Jane Halpern, and Ivana Knezevic for their edits, corrections, suggestions, and time.

Co-author: I am indebted to my co-author on certain chapters, Ivana Knezevic, who has worked on Standards and Norms on regulatory topics for biologicals at the World Health Organization for many years now. She and I have had many conversations about improvements for educating regulators for better regulatory convergence and students of other biomedical topics to inspire some to become high-quality regulators of the future or to at least appreciate the complexities and necessity of medicinal product regulation. Thank you for the many opportunities I have experienced over many years consulting for the WHO. I’m sure I have learned nearly as much about biologicals regulation from these experiences as from my own work experiences at US FDA and US NIH. I am also grateful to numerous other colleagues at WHO with whom I have interacted over the years and from whom I have learned much.

Editorial staff: I must thank the editorial staff listed at the beginning of the book who assisted me to get through the process of publishing a book. They have spent many hours walking me through the whole process and making my task more manageable. Thanks!

How to Obtain Documents From ICH and US

All ICH documents may be obtained from www.ich.org by selecting Q, S, E, or M from the upper right-hand corner. Each document is listed by title or topic area and when the drop-down carat on the right-hand side of the line is selected, you may find the PDF of the document also on the right-hand side.

All US Code of Federal Regulations citations may be obtained from here: www.gpo.gov/fdsys/. From the home page, select Code of Federal Regulations on the right-hand side of the page. (You may also find Federal Register Notices, Public Laws, and the US Code from this page.) Then select the relevant year you want to see from the drop-down menu and select go. Next, you will see a page with all CFR titles and by selecting the plus sign next to one, you get a drop-down that opens. By selecting plus signs below the original one (that is now a minus sign), you get to successively more precise citations. When you get to the citation you want to read, select XML or PDF (or more).

To find only 21 CFR citations directly, go to www.fda.gov and perform a search on the citation (e.g., 21 CFR 610). You will get a list of documents and webpages that refer to the specific citation upon which you searched. Generally, the correct item will be the first one in the list and you click on the title to get to the proper webpage.

Section I

Regulatory Process

Introduction

On the production of antidiphtheria toxin in a horse named Jim, which resulted in 13 deaths from tetanus in 1901:

This tragedy convinced Congress and the public that producing antitoxin or vaccine was not a simple matter like weighing out the dose of a drug on a scale.

Dr. Margaret Pittman in The Regulation of Biological Products, 1902-1970.

Chapter 1

Introduction to the Regulatory Process for Biologicals

Abstract

The fundamental principles behind why and how medicinal products are regulated worldwide is introduced in this chapter. How biologicals or biologics differ from chemical drugs is described. The processes whereby biologicals are regulated are illuminated by the description of relevant legislative milestones in the history of the U.S. FDA, including the Biologics Control Act, Food and Drug Act, Public Health Service Act, Human Subjects' Protection Regulations, Orphan Drug Act, Prescription Drug User Fee Act (PDUFA), FDA Modernization Act (FDAMA), FDA Amendments Act (FDAAA), Pediatric Research Equity Act (PREA), Best Pharmaceuticals for Children Act (BPCA), FDA Safety and Innovation Act (FDASIA), and FDA Reauthorization Act (FDARA). These legislative acts introduce concepts such as misbranding, adulteration, consistency of manufacture for biologicals, quality controls, and efficacy/effectiveness. The European Medicines Agency has a much shorter history, but relevant aspects are mentioned.

Keywords

Biologics; Biologicals; Biologicals regulation; U.S. FDA milestones in history; IND regulations

1.1 Fundamentals

1.1.1 Introduction to the Text

This text will focus on those biologicals and biotechnology products that are used for medicinal purposes for humans. Biologicals or biologics,¹ including those made by biotechnology, are a special category of drugs or medicines. They differ from pharmaceutical drugs derived by chemical means in that they are derived biologically by growth of micro-organisms or cells (often mammalian, including human, cells). Most biologicals are large, complex molecules (see Fig. 1.1).

Fig. 1.1 Comparison of a chemical drug to a biological (biotechnological product). This figure shows the relative size of aspirin, a chemical drug, to a monoclonal antibody, a recombinant protein consisting of four polypeptides in proper quaternary conformation. The purpose of the illustration is to clarify why biologicals are not regulated in the exact same way chemical drugs are. Regulatory processes may be the same or similar, but the scientific principles and regulatory science underpinning the regulation of biologicals differs as considerably as the size and complexity of aspirin and a monoclonal antibody, as illustrated. Taken from U.S. FDA website.

This book will discuss the following kinds of medicinal products. Traditional biologicals include serums, toxins, antitoxins, vaccines, blood,² and products derived from blood (like plasma-derived Factor VIII or Factor IX). Biotechnology medicinal products can encompass recombinant single protein products (like recombinant Factor VIII, recombinant Factor IX, recombinant interferon, or monoclonal antibodies), gene therapy vectors, cell therapies, subunit or vectored vaccines, in vitro diagnostics, and similar veterinary³ products (particularly vectored vaccines). The term advanced-therapy medicinal products (ATMP) is used in Europe to describe some of these biotech products (gene therapies, cell or tissue therapies) and U.S. FDA has taken up this term of Advanced Therapy in lieu of gene therapy recently. Recombinant therapeutic proteins may be formed by a single polypeptide molecule like recombinant insulin, or they may be like recombinant interferons or monoclonal antibodies, made of multiple polypeptides (in the case of the latter, consisting of antibody heavy and light chains). Gene therapy vectors are generally viral, but can be bacterial as well, including DNA plasmids propagated in and purified from bacteria. Various types of RNA may serve as gene therapies too. Cell therapies may be autologous or heterologous and subjected to minimal or considerable manipulation. The latter (considerable manipulation) can entail being engineered with recombinant DNA techniques ex vivo before being returned in vivo. Biotechnology vaccines may be vectored, like gene therapies, or they may be recombinant subunits that have been purified from an engineered cell line, bacteria, or yeast. In Vitro Diagnostics include medical devices like test kits, ELISAs, or tagged antibodies used to diagnose a disease or condition. Veterinary products may be any of these types of products, but are intended to address disease in animals, rather than humans (although protecting animal health often protects human health, but the purpose of the products is for use in animals directly).

Much of the text will focus on the practices and procedures of the U.S. Food and Drug Administration (U.S. FDA) and the European Medicines Agency (EMA). Some consideration will also be given to regulatory practices in developing (low and middle income, LMIC) and other developed countries, and particularly to international standards, such as those recommended by the World Health Organization (WHO) or those agreed upon by the International Council for Harmonisation. These latter two organizations will be the subject of a later Chapter 3. Some examples will come from Health Canada, the Canadian regulatory agency. An exercise in the book will reflect scenarios involving several other regulatory agencies, for which information in English is available on their respective websites. However, the focus will be on the fundamental nature and purposes of the regulatory processes and regulatory science, and in some cases, will be compared and contrasted in order to emphasize these fundamental concepts. Stress will be placed on commonalties, as underscored by general principles. So, while the U.S. FDA or EMA will be used to illustrate the concepts, it is likely that most other National Regulatory Authorities (NRAs) hold the same principles, even if they use different terms or somewhat different procedures.

Box 1.1

Critical Thinking

According to Stephen D. Brookfield [1], the basic process of critical thinking entails the following:

1. "identifying the assumptions that form [y]our thinking & determine [y]our actions,

2. checking out the degree to which these assumptions are accurate & valid,

3. looking at [y]our ideas & decisions (intellectual, organizational, & personal) from several different perspectives, and

4. on the basis of all of this, taking informed actions"

Assumptions can be of different types:

• causal, which are explanatory and predictive: if this, then that

• prescriptive: should, ought, must

• paradigmatic, which are deeply held beliefs most likely arising from culture, upbringing, mindset: things like boys don’t cry, girls can’t throw, you have to eat everything on your plate

Regulatory science involves all of these types of assumptions and critical thinking requires evaluating such assumptions. For example, root cause investigations entail causality assessments. Regulations are most often prescriptive, but they are also subject to interpretation. The Good X Practices and Quality entail thinking from paradigmatic mindsets.

Stephen D. Brookfield [1] also says that the way to think critically involves:

1. Hunting (identifying) assumptions

2. Checking (validating, invalidating) assumptions

3. Evaluating from different points of view (e.g., from a multidisciplinary team)

4. Taking informed actions (making informed decisions)

With this book, it will help to consider how to think critically by:

• Recognizing logical fallacies

• Distinguishing between bias and fact

• Distinguishing between opinion and objective evidence

• Distinguishing between judgment and valid inference

• Becoming skilled at different forms of reasoning:

• Inductive

• Deductive

• Formal

• Informal

• Analogical

Critical thinking is important to regulatory decision-making because it involves intellectual openness. It is important to let go of the mindset that answers are either right or wrong, correct or incorrect, i.e., dogmatic thinking. Regulators (or others involved in medicinal product development and marketing authorization) who are dogmatic are not intellectually open and are not fostering innovation and regulatory flexibility. Instead, the best regulators think in a relativistic or multiplistic way, i.e., answers depend on a number of factors and can change as the factors vary. So, if you hear a regulator tell you it depends, be glad, because that means they are thinking critically. This critical thinking is central to risk/benefit decision-making. (More about risk/benefit decision-making in later chapters.)

The U.S. FDA defines a drug as a substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease. Biologicals fall into this definition, although U.S. FDA uses the term biologics rather than biologicals. Most other countries term them biologicals. So, technically, biologicals are drugs in U.S. FDA parlance. EMA refers to these products as medicines, rather than as drugs. But, as highlighted earlier, biologics, biologicals, or biotechnological products are very different from chemical drugs. Biologicals are complex and generally large molecules prepared in complex biological systems (generally whole cells).

Consider comparing pharmaceutical drugs to biologicals by comparing a mechanical part being manufactured by a robotic machine to a gourmet chef preparing a meal. Chemical reactions, if you add the right chemicals at the right temperature for the right amount of time in the right proportions and order, will result in the same outcomes consistently. But, like cooking, you and your neighbor can follow the same recipe for a dish and one might come out with something delicious and the other inedible. And it will be difficult to characterize what was the exact difference between the successful dish and the inedible one, other than taste. The next time you make the same dish, you might not get the same delicious result you got the first time, because you used slightly different ingredients or sources of ingredients, temperature and time of cooking differed, or the humidity⁴ in the air was different. The production of biologicals is also susceptible to these problems of inconsistency and difficulty in characterization. This introduces the concepts of the importance of consistency of manufacturing and the importance in characterizing biological products. It also contrasts these concepts against the more readily-characterizable pharmaceutical drugs, i.e., small molecules or small molecular entities (SME).

A mantra of biologicals’ production is the process is the product; the product is the process. I like to give the example of several types of dishes made with chicken. All of them are chicken dishes, but what a difference between fried chicken, chicken adobo, and roasted chicken. They taste, smell, and feel (mouth feel) very different from each other. It is difficult to characterize the differences except to use subjective terms to describe what these senses tell the eater. So, with biologicals’ production, how you make the product, the facility⁵ in which you make it (e.g., like the difference between using an oven, a Dutch oven, and a fryer to cook your chicken), the ingredients you use, and even the order of the processes can make a big difference in the outcome. Thus, the relatively greater emphasis that has been put on the process whereby biologicals are made, in contrast to chemical drugs that can be characterized at the end to determine if the proper product was made. Quality needs to be built into biologicals—it cannot be tested in at the end. This introduces the concept of Quality by Design.

1.1.2 Regulations

Why is regulation of drugs/medicines and biologicals important? Regulations set the expected standards and norms that manufacturers must follow. In a capitalist society, companies are in the business of making money, so you may ask: shouldn’t the free market self-regulate the pharmaceutical and biologicals industries? The answer is no, because with medicines, buyer beware can have terrible, deadly consequences even on a large scale. So, standards, often minimal standards, must be met in order to assure that the marketplace does not have such deadly consequences, whenever avoidable (later, the concept of risk in balance with benefit will be discussed to explain this qualifier). Below, we will go further into the history of this recognition of the need to set standards for drugs, focusing on the history of the U.S. FDA. The EMA is a much newer organization, built on the history of regulations in the member states, so its regulations and directives were written over a much shorter span of time. Other regulatory agencies have similarly rich histories. So, it should be no surprise that regulatory agencies do not have harmonized practices, given the pathways within each country’s legislative process and history of problems with medicinal products that led to their laws and regulations and that have occurred over the decades. In fact, it is a bit amazing the extent to which regulatory convergence has been achieved, but this will be the subject for another Chapter 3.

Who sets these standards? At the level of individual countries, there are NRAs, like the U.S. FDA, and National Control Laboratories (NCLs), like the National Institute of Food and Drug Control (NIFDC) in China. Given the international nature of business today, standards are also set by international-level organizations. For large markets in developed (high income) countries, e.g., North America, Europe, and Japan, the NRAs undertook a process referred to as the International Council for Harmonisation. Even the spelling of Harmonisation was something upon which they had to harmonize in order to successfully set international standards upon which all the regions could agree. In the case of smaller markets or developing (low and middle-income, LMIC) countries, many look to the WHO to advise them, although all countries generally implement the WHO’s guidelines and recommendations.

Almost every country has an NRA that registers drugs to be marketed in their country. Some countries incorporate this function into their Ministry of Health (MOH), whereas others have a separate, specific agency, like the Pharmacy and Poisons Board of Kenya or Swissmedic in Switzerland. These specific agencies may report to the MOH or its equivalent in any given country. For example, in China, the China (or State) FDA (CFDA) is a separate agency, but reports to the MOH. The technical capacity (depth and breadth of expertise and experience of regulators) of these NRAs varies widely. The number of staff also varies widely (from thousands to about 6). The range of technical capacity includes those capable of independently evaluating data manufacturers have gathered to support marketing authorization of a new product, as well as those that primarily register drugs approved (licensed) elsewhere for import and use in their country.

In contrast, not all countries have NCLs. Sometimes, the NCL is incorporated into the NRA, like the laboratories in the Center for Biologics Evaluation and Research (CBER) at U.S. FDA or those at the Paul-Ehrlich Institut in Germany. Sometimes, the NCL is a stand-alone agency separate from the NRA like the National Institute for Biological Standards and Control in the United Kingdom (the NRA is the Medicines and Healthcare Regulatory Agency—MHRA) or the Chinese NIFDC (the NRA is the CFDA). NCLs function to independently verify laboratory controls, such as lot release tests (the subject of Chapter 16), to which the manufacturers claim their products conform. Often, NCLs establish standards or physical references (reference standards) or collaborate with other NCLs to establish international standards, for use by manufacturers and the NCLs.

NCLs may provide manufacturers with these physical references so that they may use them as reference standards in the testing of their products. For example, each year, CBER develops the reference standards needed by influenza vaccine manufacturers with U.S. licenses, in order to establish their products' potency. They also provide the seed (starting) material from which U.S. licensed influenza vaccine manufacturers can initiate their production. The WHO and CBER, upon expert advice, select the strains of influenza virus to include in the vaccines the manufacturers will make in any given year. National Institute for Biological Standards and Control (NIBSC) makes international standards (ISs), as recommended by an expert committee of the WHO, and these ISs can be purchased by manufacturers and NCLs globally.

What are the bases for setting standards? Primarily, the decision-making about standards and norms is scientific and based on evidence and data. This is a critical aspect to understand about regulatory—it consists of science-based decision-making involving balancing of risks and benefits. People perceive regulatory as merely paperwork or box-checking from a checklist. But, the reality is the best regulators are those with strong science and medical backgrounds. Regulatory decision-making requires astute judgment and critical thinking.⁶ Regulators need to be able to balance various kinds of data, sometimes contradictory, and often gaps exist in the data, but decisions have to be made nonetheless. These decisions can truly be life or death decisions. Consequently, decisions in pharmaceutical regulation are made on the basis of risk in balance to benefit (this will be covered in more detail in Chapters 5, 17, and 18).

There are other ways of determining suitability of a product for the market and acceptability of its risks. For example, when considering chemicals that might be used in the workplace or the environment in the United States: if the chemicals are determined to be carcinogens, then there is a zero-risk policy, i.e., risk-only-based decisions are made. The regulators of such chemicals are not balancing risk with benefit, because there would be no benefit to the person (e.g., worker), only to the factory or the farm, but not to the person exposed to the carcinogenic chemical. This may be contrasted with public health decision-making, which often weighs cost vs. benefit to the society at large. If the cost of adding a diagnostic test or screen for a disease far outweighs the benefit of that screen in preventing the disease from advancing before it might otherwise be detected, then it might not be recommended for implementation by public health decision-makers. This cost/benefit decision-making is different from the risk/benefit decision-making of drug and biological regulators.

Generally, medicinal regulatory decision-making involves a multidisciplinary team to review and evaluate the data. Disciplines include, but may not be limited to, various clinical specialties (such as oncology, infectious diseases, ophthalmology, pediatrics, or endocrinology), chemistry or biology (someone with product understanding or assay expertise), animal modeling, immunology, microbiology, toxicology, pharmacology, statistics, facilities design and maintenance, engineering, and others, as needed.

1.1.3 Milestones in FDA History

The FDA website provides a more comprehensive list of historical milestones at the web link below: http://www.fda.gov/AboutFDA/WhatWeDo/History/Milestones/ucm128305.htm

This web link provides a historical overview of regulation and law for food and drugs in the U.S. dating from even before the U.S. FDA was formed. Some of the more relevant historical events for biologicals are highlighted later.

In 1901, there was a diphtheria outbreak in St. Louis, Missouri. At that time, there was no diphtheria vaccine to prevent diphtheria as there is today. The way diphtheria antitoxin, the treatment of the time, was prepared was by injecting horses with the diphtheria organism (Cornyebacterium diphtheriae), permitting them to make an immune response, and then bleeding them for their sera that contained protective antibodies. Then, people with diphtheria were injected with the horse serum containing the antibodies that would treat them. In St. Louis, a horse named Jim was used for this purpose. Unfortunately, Jim became infected with tetanus (Clostridium tetani) and died. But, before he died, a lot or batch of serum was prepared from his blood and used to treat children with diphtheria. There was no specific quality testing of the serum to ensure its safety and freedom from contamination with other pathogens in order to release it for clinical use. Consequently, 13 children, who received the serum and got infected with tetanus, died. As a direct result, in 1902, the U.S. Congress passed the Biologics Control Act. So, in fact, biologicals were regulated under federal law in the United States before domestic drugs were. (There was earlier legislation for imported drugs.) This contamination event introduces the concept of "adulteration in U.S. FDA legislation. Furthermore, in this incident, serum from the last time Jim was bled, when he was infected with tetanus, were filled into bottles with the correct date and into bottles left over from and dated with a prior date, when the serum had been safe for use. This led to continued use of the contaminated serum with the wrong date. This facet introduces the concept of misbranding." Both of these concepts were addressed in the federal legislation that followed.

In 1906, the Food and Drug Act was passed by Congress. This legislation developed from public outcry over the meat-packing industry practices, as revealed in The Jungle by John Updike. Also, there was a realization that the so-called patent medicines often did not contain any active pharmaceutical ingredients (API) and could in fact, not only be ineffective, but also dangerous from the ingredients they did contain. There were several incidences of patent medicines killing people. The Food and Drug Act permitted federal agents to regulate drugs and food that were in interstate commerce, but did not cover intrastate or local drugs and food (those may have been subject to state or local laws). This aspect of interstate commerce persists in the federal regulations to this day, giving the federal government jurisdiction. Although now there is a presumption of interstate commerce, because so many components of the manufacturing are likely to be sold in interstate commerce.

In 1911, focus turned to drug labeling and the making of false therapeutic claims or false claims about the ingredients or drug identity. False claims were prohibited. This reinforces the concept of "misbranding."

In 1930, the U.S. Food and Drug Administration was officially formed, although this arose from an earlier agency formed in 1927, which arose from an even earlier federal agency.

In 1937, the Elixir of Sulfanilimide disaster occurred. This elixir contained diethylene glycol (essentially antifreeze) and killed 107 people. As a direct outcome, in 1938, Congress passed the Food, Drug, and Cosmetic Act (FD&C Act), which is still enforced today, although it has been amended in subsequent years. This act covers the safety, identity, quantity, quality, and advertising of foods, drugs, and cosmetics. This legislation introduced the concepts of safety, identity, purity, potency, and quality measures or attributes we still monitor in medicinal products today. It also introduced the regulation of what we term today as advertising and promotional labeling.

In 1944, the Public Health Service Act (PHS Act) was enacted by Congress. This act specifically covers biological products, although the FD&C Act also applies to them for certain aspects.

In 1945, U.S. FDA began to regulate the EFFECTIVENESS of penicillin and subsequently of other antibiotics. This is the introduction to the concepts of efficacy and effectiveness in addition to safety, identity, purity, quantity, and quality.

In 1948, the U.S. Congress affirmed that the federal regulations applied to products in interstate commerce.

In 1958, the concept was introduced of substances being Generally Recognized As Safe (GRAS) for oral consumption of additives that might be present in food. This web link provides more information about this designation: http://www.fda.gov/food/ingredientspackaginglabeling/gras/default.htm

There is a database of GRAS substances, which may be found here: http://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/SCOGS/default.htm

Often, when these GRAS substances are used as excipients in a drug or biological, their inclusion would not trigger additional needs for toxicology studies, as they are generally recognized as safe, even though for a different purpose and potentially a different route of administration.⁷

In 1962, the U.S. Congress granted U.S. FDA greater authority for drug safety and then, gave them the responsibility for ensuring that drugs have efficacy/are effective in the Kefauver-Harris drug amendments. Prior to this, one could market an ineffective product (or one for which no demonstration of efficacy had been made), so long as it was safe and didn't contain false claims in the labeling. But, from this point forward, not only did drugs need to be safe, but they needed to provide clinical benefit. This introduces the concept of risk/benefit decision-making.

In 1972, the responsibility for regulating biologicals shifted from the Division of Biological Standards (DBS) at U.S. NIH (National Institutes of Health) to the Bureau of Biologics (BB) at U.S. FDA. Because of this history, several laboratories in CBER remained on the U.S. NIH campus for decades; although in 2014, they were moved to the White Oak campus in Silver Spring, MD, with the rest of the U.S. FDA that has also been moved there.

In 1976, medical devices began to be regulated. Biotechnology-derived diagnostics are often considered to be a medical device, e.g., test kits for diagnosing a disease. Some of these (for blood screening) are regulated by CBER and some by the Center for Devices and Radiological Health in the U.S. FDA.

In 1981, Human Subjects' Protections Regulations arose, and these apply to clinical research being conducted with investigational as well as marketed products. It may be difficult to believe but the wide-spread application of ethics to clinical research in the United States only began to arise in the 1970s and these 1981 regulations were essentially the first of their kind in the United States. However, these concepts of protecting human subjects in medical research can trace their origins to the aftermath of the Holocaust during WWII. Nonetheless, it took about three decades before a more formalized process for considering research ethics became more widely recognized as crucial and pivotal to the conduct of clinical research in the United States. These regulations and regulatory processes will also be covered in two later chapters (Chapters 18 and 19).

In 1983, Congress passed the Orphan Drug Act in the effort to facilitate the development of products that otherwise might not be commercially viable because too few individuals need them in any given year in the United States. This Act aims to fill otherwise unmet medical needs for which product development might not be profitable enough to get companies to invest the resources needed.

In 1986, Congress enacted the Childhood Vaccine Act giving U.S. FDA greater authority for this product class of biologics.

In 1987, the Investigational New Drug (IND) regulations were revised. Much of what will be covered in the text is reflected in the IND regulations in the Code of Federal Regulations (CFR) Title 21 (the U.S. FDA regulations) Part 312. The IND regulations apply to drugs and biologicals that are being investigated to establish their safety and efficacy in order to gain marketing authorization. In order to ship these investigational drugs, which are not on the market, in interstate commerce,