FDA Product Regulations Part 1 of 7

[00:00] Welcome to FDA Product Regulation. My name is Dr. Chris Geneskis. I am the director of the Office of Regulatory Operations and associate director for review management at the Center for Biologic Evaluation and Research in the US Food and Drug Administration. This module

[00:20] of the course is called FDA Product Regulation, and along with my fellow presenters, we'll be talking a little bit about how FDA regulates products in clinical investigations. For the regulation of drugs and biological products, a little bit about FDA, its mission, and its organization. FDA is you well-known.

[00:40] that was a sister agency to the National Institutes of Health under the Health and Human Services, and it has several missions. We are responsible for protecting the public health by ensuring the safety and efficacy and security of all the products that we regulate, such as human and veterinary drugs, biological products, medical devices, and so on. We regulate the manifestation.

[01:00] We manufacture marketing and distribution of tobacco products to protect the public health and to reduce tobacco use by minors. We advance the public health by helping to speed innovations and make medicines more effective, safe, and affordable, and by helping the people get accurate science-based information they need to use these medical products and foods to maintain and improve their health. And finally, FDA plays a very significant role in the world.

[01:20] nation's counterterrorism capability. We fulfill this responsibility by ensuring the security of food supply, by fostering development of medical products to respond to deliberately deliberate and naturally occurring or emerging public health threats. This has recently been tested over the last several years by the emergence of COVID and

[01:40] more recently, monkeypox under the declared public health emergencies. FDA has had an all-hands-on-deck approach to move these developmental therapeutics, vaccines, testing kits, and other modalities forward to both diagnose and treat the public in response to the COVID and monkeypox pandemic. FDA is organized.

[02:00] And as you can see here, it's composed of multiple centers that focus on specific products like drugs, biologics, veterinary medicine, and so on, and other organizational proponents. FDA is approximately at 18,000 full-time equivalents of staff with additional contractors. Most have scientific disciplines, including medical disciplines.

[02:20] and other disciplines as well, we all contribute towards fulfilling our mission and the regulatory approach. We organize in such a way that we can share resources as needed to adjust a variety of review and regulatory policy questions and so on. So the Medical Product Centers shown here are the centers for biologic evaluation and research, divided by health, and health.

[02:40] and radiologic health, drug evaluation and research, and oncology center of excellence. And as the names imply, they typically will regulate the products as their centers are named. So typically, biologics, devices, and radiologic health, drugs, and so on, and then oncology products, the oncology center of excellence works with both with all three of the centers in

[03:00] love to regulate various types of oncology products as well in a sharing fashion. The other major centers are listed here, Food Safety and Applied Nutrition, Tobacco Products, Veterinary Medicine, Center for Toxicological Research, and the Office of Regulatory Affairs. The Office of Regulatory Affairs does most of the inspectional type of issues for all of the products.

[03:20] products that the FDA regulates. These also, these organizations and centers will actually also interact with us in certain types of regulation as well. For example, we may get involved with the Center for Food Safety as it related to a transgenic prop used to produce the biologic for the Center for Veterinary Medicine for an animal that's used to produce a transgenic biologic.

[03:40] biologic as well. So we will also interact with various issues as appropriate. So a little bit about the regulatory history and framework of how we regulate all of the medical product. So unfortunately, tragedies have led to legislative and regulatory actions, often by garnering overwhelming public support. And these are

[04:00] Some notable examples in the history here is originally 13 children died from tetanus in 1901 because they were given contaminated horse serum containing diptheria antitoxin. Diptheria antitoxin were basically antibodies, if you will, actually used and manufactured in a horse and because it was contaminated and resulted in a horse.

[04:20] resulted in the death of many children. It led to the passage of what's known as the Biologic Control Act of 1902. This is actually probably the oldest public health law of its kind in the world. The BCA Act was passed to ensure the purity and safety of serums, vaccines, and similar products used to treat diseases and various types of humans.

[04:40] There was an overwhelming outcry in leading up to the 1906 passage of the Food and Drug Act that there were multiple cures and claims for worthless and dangerous medicines. So Congress passed the Food Joint Cosmetic Act of 1906, which only prohibited interstate commerce and misbranded and multirate foods.

[05:00] strengths, and drugs. It had nothing to do with assuring the safety or efficacy of any of these products. In 1938, or just before 1936, I should say, there were 100 individuals who died due to ethylene, glycol, contamination in the elixir of sulfonamide. And that led to the federal food drug and cosmetic drug in 1938.

[05:20] At this point, the law required new drugs to be shown to be safe before marketing and this started a whole new approach to drug regulation. Again, proving that safe tolerances be set for unavoidable poisonous substances. A few others, more recent approaches. In 1955, there was something known as the Cutter Incident.

[05:40] with 260 children who either contracted polio or died because the Salk vaccine was not properly inactivated by the manufacturer. And this led to the formation of the Division of Biological Standards created within NIH in 1955. And the Division of Biological Standards actually oversaw

[06:00] of biological products as such. In 1972, the regulation of biologics was transferred from NIH to the fact that the volitamide saving pills resulted in severe birth defects in thousands of babies in Western Europe in early 1962. Volitamide was kept off of the market because of the insistence of several evidence-based patients.

[06:20] FDA staff and the FDA organization that there were serious side effects as a result of non-clinical or animal studies to ensure the safety of the product. So this led to the passage of the Kefaufer-Hares Drug Amendment Act of 1962, which passed to ensure greater drug efficacy now and drug safety. So for the first time in the world, it was a very important process.

[06:40] manufacturer's record required to prove to the FDA that the products were effective before they could be marketed. And of course, we had the unfortunate cyanide poisoning with several of the Tylenol capsules in 1982, and that led to the Federal Anti-Campering Act of 1983, which resulted in a whole series of additional changes to how we package and monitor and control various types of drugs.

[07:00] of drugs on the market. So the framework in which we regulate all these products start with essentially the laws. And so the laws are, of course, as I've given you some examples of, are passed by Congress. And then we have to interpret how we're going to apply these laws. And the laws therefore then we promulgate.

[07:20] various types of regulations or rules, and those become codified into code of federal regulations. That interprets the higher level direction that is set by Congress in how we interpret these laws. FDA then develops a series of documents called guidances, which basically provide our current thinking on how one can get into the law.

[07:40] from applied with these various types of regulations or rules. There are also external standards. Standards are typically developed by what's known as consensus organizations in various areas. There are a large number of consensus organizations and a large number of standards that can facilitate development of drugs and biologics. This has become incredibly important.

[08:00] working in the past 10 to 15 years is the number of these standards have continued to increase and I found a niche in how we regulate these types of products. And then we have various types of SOPPs or standard operating procedures with how we do our internal business. They may contain certain types of policies and precedents as well to some extent or how we actually operate. Policies and precedents

[08:20] are harder to be seen visibly to the external population because all of the above are all published, the policies and precedents sometimes are included in various types of guidance and eventually they will make their way up to the guidance level. But a lot of these are evolving. We have many new and novel products in the FDA, especially biologics such as.

[08:40] cellular therapies, gene therapy, new types of vaccines, phages, FMPs, people, biotico transplantations. And so a lot of these are done, we don't have enough information, enough consistency or understanding to feel comfortable developing guidance. So a lot of these, how we address some of these things are dealt with in a policy.

[09:00] precedent area, which makes it very important if you're developing these types of products to interact with us through meetings and various other kinds of interactions so you can understand how we're going to take this and so on. Some of the notable laws and statutes up here are the Public Health Service Act, which is what's used to regulate a lot of biological products and of course, the Federal Food, Drug and Cosmetic Act.

[09:20] which is used to regulate drugs devices and hormones to both of them. So there are some other regulatory laws here that have influenced how FDA works over the years, some of which I've talked about already. I'm just going to hit a few highlights here that may help to explain certain things. The 1944, the Public Health Service Act is a covers

[09:40] broad spectrum of health concerns, part of which is how we regulate biological products and how we control communicable diseases. We actually still use the communicable disease division to provision 361 in terms of how we would regulate tissue transplantation essentially, for example tissue banks and so on. That is a different regulatory method than

[10:00] more traditional drugs or biologes. The Medical Device Amendments Act 1976 actually added devices to the overall regulation of FDA-included diagnostic products. It talks about following quality control procedures, pre-market approval for some, or of immediate performance standards for others. So up until that time, regularly, the devices were not

[10:20] not really regulated by FDA to any great extent. Again, the Orphan Drug Act, which promoted research on orphan drug products and facilitated through various types of patent issues and other issues that facilitated how one could get orphan drugs onto the market. The Drug Price Competition and Patent Term Restoration Act is the

[10:40] basically the law that allowed for generic drugs, not biologics, but drugs, and provided the whole framework for how a lot of studies would not have to be repeated on those drugs, such as for clinical studies and preclinical studies and such. I provided a more leveraged what was already done for the initial approval of these types of

[11:00] drug products. The National Childhood Vaccines Injury Act basically gave FDA the authority to recall a whole series of biologics and authorize civil penalties. But it also, in large part, facilitated the use of vaccines in that it provided compensation to people who were found to be injured by certain vaccines.

[11:20] out the necessity of going through tort procedures. And the manufacturers were not held liable for civil actions through vaccine damages with death. So that facilitated how one can take various types of vaccines and pass through the whole ability to use those in a variety of patients. In 1992, the prescription drug user feed.

[11:40] Act required biologics and drug manufacturers to pay for applications and supplements for review. This has been authorized every five years and is followed by a whole series of user fees for things like generic drugs, medical devices, by assemblies, and so on. The best pharmaceuticals for Children's Act or the BPCA Act

[12:00] did a lot to facilitate safety and efficacy of both patent and off-patent medicines for children. But more importantly, or as important I should say, it gave us biosimilars, biosimilars being additional biologics that could be improved in a somewhat similar way to generics for drugs. So biosimilars would be the equivalent.

[12:20] in the sense for generic drugs for those who are already approved. Pediatric research equity at allowed required sponsors to conduct clinical research and pediatric applications for a whole series of drugs and biological products facilitating their use in pediatric populations is appropriate. And one last thing I'll just mention is.

[12:40] The Food Drug Administration Safety Innovation Act had a lot of, authorized a lot of different things. The one thing it did in particular was in 2012, we had an outbreak of fungal meningitis that was clearly linked to contaminated compounded drugs and unfortunately, it resulted in the loss of 64 lives and caused more than 700 illnesses.

[13:00] Though Congress enacted the Drug Quality and Security Act at that point to ensure greater regulatory oversight of facilities creating compounded drugs. So like I mentioned in the beginning, way back in the early 1900s, unfortunately, there are still outbreaks or occasional tragedies that do occur that also will

[13:20] facilitate and foster the need to have various types of legislation. Most of these other legislations did not resolve backburden any, if any, resulted from any kind of tragedy or loss of life. They resulted from basically Congress and others looking at systems and seeing what's the best way to facilitate an effective drug regulation system and which is the best way to facilitate the development of these drugs.

[13:40] Many of these laws do facilitate that through a whole series of expedited reviews and accelerated approvals and so on and so forth. The regulatory law, the last one would be the Food Drug Administration Reauthorization Act for DARA, which again, reauthorizes all of these use of these initially starting with the PDUFA.

[14:00] do for user fees for drugs and biologics, and devices, generics, and biosimilants. These get reauthorized every five years. They provide additional resources, they provide performance goals, which FDA has to try to meet in order to review and regulate a whole variety of these types of medical products across. So I mentioned earlier that we had

[14:20] have the regulations which is how we interpret the laws. So the Code of Failure Regulations Title 21 contains most of the rules that are used by FDA and they are organized here as you can see. So the various sub-chapters related to medical products of drugs, biologics, medical devices.

[14:40] and real logical health issues and so on. There are also some other regulations that are covered in some of these areas which also will impact, including impact on clinical research, such as protection of human subjects, financial disclosure by clinical investigators, which is required, institutional review boards, which is required.

[15:00] every drug or biologic initial drug application when it's going to be studied in patients. Good laboratory practices, phenomenal lab studies which are used to support those initial investigations and such. And again, some of the labeling and advertising is present as well. So there are other interventions in the future.

[15:20] and they're quite extensive, as you can see in the printed form. The three major ones that will be of most use to, I think, people moving into a clinical investigation, initial studies, let's say, in humans, which would be investigation on the drug application, or the new drug application, which is when an individual, you have enough sufficient information developed in very

[15:40] clinical studies, non-clinical studies, manufacturing to actually submit what's known as an application for marketing. That would be an NDA here or a BLA if it's a by-law. And then of course for devices they have similar mechanisms for initial studies of various patients or marketing applications or also the ability to meet certain

[16:00] performance criteria in order to be marketable. These are the major CFR parts that direct what we do in the initial development, regulation, marketing, and actually some of the post-marketing as well of this product. Guidances, there are a ton of guidances which have developed over the years.

[16:20] on a variety of subjects that help to guide individuals through the initial drug application or when you want to study something with a first time man, humans, or marketing applications as opposed to approval. So again, it is our current banking on matters under our jurisdiction. It's how we are interpreting policy.

[16:40] It's how we're interpreting these regulations and rules. It provides new or different regulatory expectations that really aren't apparent in the statute or regulations. Again, we're drilling down further and giving, in some cases, examples. In some cases, they'll be in a question and answer format a variety of different ways in which one can provide input. They're usually written.

[17:00] and at FDA with input. So these are always just about always submitted or provided as draft for public comment. And so various individuals will comment on those from academics, government agencies, domestic and foreign industry, regulators, and so on and so forth. A lot of people provide their input. We look at all of those input and we figure out, you know.

[17:20] Could we have said how many clarers or something we forgot to include? Is there a different approach we should be taking? Often sometimes these can be discussed in forums and workshops. These guidances, we have to follow it as known as good guidance practices on these. They are not legally binding unlike regulations and laws.

[17:40] which are legally binding. These are our best thinking on matters, how one can apply if you will to fulfilling the various types of regulations and laws. They're not legally binding on the applicants, on the public. However, FDA employees can only depart from the guidance only with appropriate justification and supervisor.

[18:00] So in other words, even though this is our best thinking and such, it may not work in all cases because it's a new or novel kind of an approach and the particular individual's following is in the guidance and it just doesn't really fit in the situation, maybe because the clinical situation is different, the manufacturing situation is changed and so on.

[18:20] can deviate from these, but again, those are internals of the process we like to go to. Although the good guidance of the guidance does provide our current thinking and the ways in which one can comply with these various things, industry can choose any approach they want that meets those relevant statutes and regulations. And then often is the subject of the discussion with the agency.

[18:40] novel products there for where standardized approaches just don't work. We experience that a lot in CBER with the cellular and gene therapies and vaccines and other new developing products. There's a lot of interaction, a lot of discussion over time to go back and forth to figure out, okay, how can we assure certain level of safety and efficacy with these products?

[19:00] works in this particular situation. One thing I will mention is the International Council for Harmonization, or ICH. ICH has been in existence for actually greater than 30 years, and it develops various types of guidances in the areas of quality or product quality, if you will. Advocacy or clinical areas.

[19:20] and safety, safety being mostly the non-clinical types of pharmacology or safety for patients, and also multidisciplinary, so things related to electronic submissions and format and content of applications and so on. Originally it was founded and participants included, you were US, Japan, US, US, US, US,

[19:40] Canada and Switzerland were observers. Over those years, recently, its change includes many worldwide regulatory agencies and it provides guidance on harmonization that helps ensure safe, effective, and high-quality products, and especially for industries and such, they do not have the meat.

[20:00] individual requirements, the requirements are considered harmonized so that hopefully one study taking into consideration a variety of factors can work in these various regions across the globe. Development of medical products is in many ways global and so the regulation and such should be to the point that that's feasible.

[20:20] These ICH guidance are basically FDA guidance once we have adopted these. It's a whole regulatory consensus of going through, working with regulatory and industry experts. They go out for public comment just like all of our guidance is to. It helps to facilitate mutual acceptance of data so that you don't have to have different

[20:40] clinical studies and various jurisdictions. And one thing we have well over 10 years ago is the common technical document which is agreed upon format for how we look at the presentation of summaries, reports, and data as to the various worldwide regulatory authorities. There are also, for example, many may be familiar with the World Health Organization, which

[21:00] also develops a large number of guidance documents. FDA will often work closely with the World Health Organization, but although while ICH documents are considered FDA documents because we doubt those, World Health Organization documents are not. They may be appropriate for certain situations for how one can comply with the GAN.

[21:20] regulations and laws and so on, but you really need to have that discussion with the FDA prior to using those. Because they're sort of in many ways set up for a different audience and different levels of approach and considerations, if you will, for developing. So let's talk about this real quickly so you can understand.

[21:40] Again, we have drugs, biologics, and devices, and there's a little bit of an overlap, but we generally try not to do that. So we formally define a drug in our law, no regulations, excuse me, as a substance recognized by an official compendium, a formulary, a substance that's intended to diagnose, cure, or mitigate, treat, or prevent a disease.

[22:00] A substance other than the fluid intended to affect the structure or any function of the body, a substance intended to use as a component of a medicine that's not a device or a component part or accessory of a device. It's important to understand that biological products are included within this definition and are generally covered by the same laws and regulations.

[22:20] regulations, but differences exist regarding their manufacturing processes. Drugs are chemically synthesized versus biological products which are manufactured through biological processes. It is now feasible to chemically synthesize some types of biological products, but not all, although commercially

[22:40] that really doesn't happen in the world. And I should say this is a law of legal definition. This is a definition from the law, not from the regulations. Biologic is virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component, derivative, allergenic product, protein, or an alleris product.

[23:00] or a set of phenamine or derivatives of isofenamine or any other trivalent organic arsenic compound applicable with reducing treatment of cure-over disease or condition of human beings. You can see that this definition clearly reflects the heritage of bileis.

[23:20] for products of antitoxin. A lot of these derivatives here were related to treating public health and community disease as such. Medical devices can be defined as an instrument, apparatus, implement, machine, contrivance, implant, in vitro, reagent, or other similar related article, including component, part of an accessory.

[23:40] which is the substance recognized by the national formulary or US pharma papa, intended for the use and the diagnosis of disease or other condition or mature mitigation treatment or prevention of disease in man or other animals, or intended to affect the structure or function of the body of man or other animals and does not achieve it as well.

[24:00] is primarily intended purpose through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purpose. The term does not include software functions excluded pursuant to another regulation or, excuse me, people. So this course is going to be a part of the course.

[24:20] focus on drugs and biologics. There will be a few comments on devices at the end because just about everything we are seeing now would be defined as a combination product, which is a combination of a biologic in the drug or a device in a biologic or a device in a drug or a biologic in the drug. They can get very confusing. We are just going to basically

[24:40] touch a little bit on devices at the end so you can understand them and their role. The last part I would like to discuss is the product lifecycle. Here is a hypothetical, if you will, or traditional or ideal lifecycle in the development and regulation of a drug or a bile.

[25:00] Often there is typically a preclinical phase and then a clinical development phase. There is a preclinical phase in which there is discovery of a certain particular type of compound and biologic has been synthesized and developed and tested in various models and determined that they would have an effect to affect a particular type of disease.

[25:20] At some point in time, they're most likely, but not always, maybe some type of pharmacological and toxicological testing, sometimes involving animals. Often lots of laboratory work to better characterize and understand the product can be able to control its quality and purity and safety.

[25:40] to a point. So all this work happens is what we call the pre I and D phase or prior to filing an investigation on the drug application. And I and D is required and must be approved by the FDA. That's approved in quotes prior to studying this in patients. And so a lot

[26:00] of this work that you see here, including, and this will be covered in subsequent sessions, will be submitted along with information on the clinical trials and other areas and placed into investigational new drug development. We typically have a traditional investigational new drug development program.

[26:20] various phases. The first phase is really assessing the safety of the product in humans. Second phase is sort of dose finding safety as well, perhaps understanding a little bit more about the efficacy of that. And phase three would be typically looking at the safety. And again, but really the efficacy does this product. This is efficacious.

[26:40] would be the indication that this product were to be marketed, how would it be used, how would it be treated, and so on. And of course, there's manufacturing that goes on during this as well so that one can consistently make a product that's going to deliver the intended therapeutic effect. But again, this is really an ideal or traditional area with a lot of products now, depending on

[27:00] upon orphan disease, for example, where there's very limited numbers of patients. We may not have these three distinct bases and three distinct trials. There could actually in some cases be only one trial that's set up in such a way that it's an adaptive trial that depending upon the results that happen, they determine the next course of the study and so on. So sometimes

[27:20] again with very rare patients, will also compress this into one or maybe two trials to try to, again, determine appropriate safety and efficacy and what's the appropriate dose and so on. Assuming that a product is then submitted for marketing, which is when it can be commercialized, there will be a submission of a biologic flow.

[27:40] license application or new drug application or for devices of premarket application. Though both do in review, we have to assure that the manufacturing facilities are in compliance with what's in the current good manufacturing principles and so on. And if it's marketed, that can be then a post-marketing phase if you will, the post-marketing phase.

[28:00] may be making changes to the manufacturing process and maybe adding a new indication for a new patient population or a new dosage form to make it easier to administer and so on. So you think about it, this can be overall and at a high level the life cycle of a drug and biological product. Thank you.

[28:20] You