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The FDA is responsible for regulating the communications between the pharmaceutical, biotechnology, and medical device companies and the prescribing physicians, other providers, institutions, and patients who use their products. First and foremost, FDA fulfills this mission through approving the language in the package inserts of all drug and biological products, and regulating the educational and advertising materials for drug products. FDA communicates directly to the public through press releases and postings on its web site. These communications are usually directed at informing the public of the approval of a new product that serves an unmet medical need, or of a significant safety issue with a product on the market.

FDA also provides the executive and congressional branches of government with information about drugs on the market and in research, the processes and procedures about research, industry regulation, and communications to the public and health care community. The FDA works cooperatively with other federal agencies, (e.g., Office of the Surgeon General, Centers for Disease Control and Prevention, and the National Institutes of Health) to communicate directly with the nation's public on issues of public health that are aligned with drugs and biologics. For food safety issues, the FDA

would be collaborating with the Agriculture Department and the Environmental Protection Agency for toxins introduced into foods.

On a limited basis, the FDA engages in scientific study with the goal of advancing the regulatory process. For example, they may study the limits of changes in drug formulations that have a real impact on the quality of a drug product. By knowing these limits, they have the data to define what changes a drug manufacturer may make in the manufacturing process of a drug product with, and without, prior agency approval.

The FDA resides in the executive branch of the federal government and is composed of certain offices, centers, and divisions as shown in Fig. 7.2. The FDA commissioner is selected by the president and is confirmed by the U.S. Senate. Thus, the agency's policies and initiatives, and even the occasional product approval or marketing withdrawal, are politically influenced. There are more than 9,000 people who work in the FDA organization, with oversight for items accounting for 25% of consumer spending. While the entire structure of FDA is quite complex, the following discussion highlights the primary organizational units that routinely interact with the pharmaceutical and biotechnology industries.

The Center for Drug Evaluation and Research (CDER) is responsible for the evaluation of all drugs under investigation; the evaluation and approval of new drugs; and the continual safety surveillance of drugs already on the market. The Center for Biologicals Evaluation and Research (CBER) has the same responsibilities for biological products. These two centers are being combined to gain efficiency and consistency in the review and approval of products, whether they are drugs or biologics, except for blood products and vaccines remaining within CBER.

Within CDER, there are several offices that have primary responsibility for the regulation of the industry. The Office of New Drugs is divided into smaller units, aligned into five offices covering 14 therapeutic areas (e.g., anti-infective and gastrointestinal), which have responsibility for investigational drugs and the evaluation and approval of new drugs.

r Office of the Commissioner r Center for Drug Evaluation and Research (CDER): o Offices of New Drugs (5 Offices) o Office of Generic Drugs (OGD) o Office of Drug Safety (ODS) o Office of Biostatistics o Office of Pharmaceutical Sciences (Chemistry, Pharmacology, etc) o Division of Drug Marketing, Advertisement and Communications (DDMAC)

C Division of Scientific Investigation (DSI) r Center for Biologics Evaluation and Research (CBER) r Center for Devices and Radiological Health (CDRH) Office of Regulatory Affairs (ORA)

Fig. 7.2. FDA Organization

Additional offices participate in the review and approval of new drugs. The Office of Biostatistics, the Office of Clinical Pharmacology and Biopharmaceutics, and the Office of New Drug Chemistry work with the five therapeutically aligned review offices providing expertise in their respective disciplines to evaluate drugs during both investigational and approval stages. There are separate offices for review and approval of generic drugs and for pediatric drug development.

Separate from the Office of New Drugs, the Division of Drug Marketing, Advertising and Communications (DDMAC) regulates the advertising and educational programs used by the pharmaceutical industry to promote their products to both prescribers and consumers of approved drugs, devices, and biologics. The Office of Drug Safety is responsible for adverse-event monitoring and safety assessment for marketed products and related interactions with the industry. Their review can lead to a product withdrawal after approval if new serious safety concerns arise during the general use of a product by the medical community.

The Division of Scientific Investigations has the responsibility for the inspection of clinical study sites, where trials on investigational drugs have been conducted. FDA inspectors from this division work with the Office of New Drugs to routinely inspect clinical study sites involved with pivotal trials for drugs being evaluated for approval. The Center for Devices and Radiological Health is responsible for the review and approval of medical devices (e.g., from surgical catheters to prosthetic hips). The center is also responsible for the regulation of radiation-emitting products (e.g., x-ray equipment). Finally, the Office of Regulatory Affairs (ORA) is the network of field FDA offices located across the country. The ORA has a wide range of responsibilities, including the inspection of pharmaceutical and biotechnology manufacturing facilities to the seizure of contaminated food.

The regulatory authority of the FDA has been shaped by many different laws since its origin 100 years ago. Figure 7.3 highlights those laws that are most significant in the establishment of the FDA's regulatory authority and have an important impact on the way FDA conducts its business today. Often, a health crisis in the United States creates a public outcry for legislation to change the regulatory authority of the FDA, to

Federal Food and Drugs Act -1906 r Federal Food, Drug and Cosmetic Act -1938 ^ Public Health Service Act -1944 r Kefauver-Harris Drug Amendments -1962 r Orphan Drug Act -1983

r Drug Price Competition & Patent Term Restoration Act -1984

Prescription Drug User Fee Act -1992, 1997, 2002 r Food and Drug Administration Modernization Act -1997 ^ Pediatric Research Equity Act -2003

Fig. 7.3. Laws for FDA Regulation of Pharmaceutical & Biotechnology Industry either protect the health of the public or make drugs more readily available.

The Federal Food and Drugs Act of 1906 for the first time added regulatory functions to the agency. Prior to this act, states exercised the principal control over foods and drugs. The Federal Food, Drug and Cosmetic Act of 1938 was a milestone in that it was the first law requiring that new drugs had to be shown to be safe before they could be marketed. This act remains one of the cornerstone pieces of legislation that the FDA still operates under today. The Public Health Service Act of 1944 established the regulatory authority of the FDA over biological products. The Kefauver-Harris Drug Amendments of 1962, named after the legislators who sponsored the legislation, required for the first time that drug manufacturers prove the effectiveness of their products in order for FDA to grant a drug product approval.

The Orphan Drug Act enables the FDA to promote research and marketing of drugs needed for treating rare diseases, defined as those having a prevalence of less than 200,000 in the U.S. population. This act provides financial incentives to the pharmaceutical and biotechnology industries to develop and commercialize drug and biologics products for patients whose diseases are not prevalent enough to be otherwise commercially attractive to the industry. The Drug Price Competition and Patent Term Restoration Act is oftentimes referred to as Waxman-Hatch legislation, named after the legislators who sponsored the legislation. This legislation expedites the commercial availability of generic products by permitting FDA to approve generic products without requiring repeat testing to demonstrate that the generic product is safe and effective.

The Prescription Drug User Fee Act of 1992 (PDUFA) requires pharmaceutical and biotechnology companies to pay fees for the FDA to review applications for new drugs and biologics and changes to approved drugs and biologics. The act also requires that FDA use these fees to pay for more reviewers to speed the review process. This act provides targeted periods of time for FDA to review an application and more accountability to meet these review deadlines. Today, the fee for a new drug or biologic product to be reviewed is more than $500,000, and typically the fee is raised each year. Another important provision of PUDFA in accelerating product approvals codifies some of the communications that occur between FDA and sponsors during the development of a drug to facilitate more rapid and efficient drug development and approval; for example, interim NDA deficiency letters from FDA during a review; a meeting upon the company request usually at key milestones such as end of phase 2, which will clarify development issues before the NDA either is filed or acted upon by FDA. This legislation has been so successful that both the government and the pharmaceutical industry have consistently supported its renewal.

The Food and Drug Administration Modernization Act of 1997 mandated the most sweeping reform of the FDA since the Food, Drug and Cosmetic Act of 1938. It provides many changes in the way FDA conducts its regulatory functions. Some highlights of those changes include the modernization of the regulation of biologics and streamlining the approval process for manufacturing changes of drug and biologics products. It also allows for drugs and biologics that can potentially treat serious and life-threatening diseases to be under a "fast-track" review process at the FDA. The Pediatric Research Equity Act of 2003 amended the 1938 Food, Drug and Cosmetic Act to authorize the FDA to require certain research on drugs used in pediatric patients be conducted by the pharmaceutical industry. Until this law, the pharmaceutical industry could elect whether or not it wanted to conduct trials with its products in pediatric populations. A benefit to the company for conducting pediatric product studies to their development plan and product labeling was extended patent exclusivity.

For legislative and therefore regulatory purposes, there are definitions of drugs, drug products, and biologics that form the basis of regulations (Fig. 7.4). These legislative definitions serve to clarify the authority of the FDA and what they are responsible for regulating.

The definition of a drug most commonly referred to is that of a substance "intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease." This definition, along with the other definitions of a drug in Figure 7.4, serves to differentiate a drug substance from a drug product. The same drug substance can be found in many drug products (e.g., oral and parenteral drug products containing the same drug substance).

Biologic products are a subset of drug products and are distinguished by the biological manufacturing process. Drugs are sometimes differentiated by referring to them as "small molecules," and biologics are referred to as "large molecules".

The regulatory authority of the FDA starts with acts of Congress that grant them that authority and provide, at a r Drug:

o Recognized by official pharmacopoeia or formulary o Intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease o Substance other than food, intended to affect the structure or any function of the body c A substance used as a component of a medicine but not a device or a component, part or accessory of a device r Drug Product:

c Finished dosage form that contains the drug substance r Biologic Product: O Any virus, serum, toxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product applicable in prevention, treatment, or cure of disease or injuries. They are a subset of "drug products", distinguished by the biological manufacturing process.

Fig. 7.4. FDA Definitions of Drugs & Biologics high level, direction in how the agency is to exercise its authority. As mentioned in Fig. 7.5 two acts of Congress, the Federal Food, Drug and Cosmetic Act and the Public Health Service Act, are fundamental to the establishment of the FDA and its authority over drugs and biologics. Drug products are regulated and approved under the Federal Food Drug and Cosmetic Act, and biologic products are regulated and licensed under the Public Health Service Act. Over the years, several changes have occurred so that today, there are fewer regulatory differences between drugs and biologics.

Once an act is passed, it is the responsibility of the FDA to write regulations consistent with the legislative intent of the act, in order to enforce the statutes passed by Congress (Fig. 7.5). These regulations are legally binding, and it is necessary for the pharmaceutical and biotechnology industries to comply with these regulations or risk running afoul of the FDA from a compliance perspective. An example of a set of regulations is those requiring an Investigational New Drug Application to be submitted to the FDA before an investigational product can be administered to humans. These regulations describe at a high level the content needed in this application.

As a next step, the FDA writes guidance documents that serve to further explain how the industry can specifically do its work in order to be compliant with the regulations. These guidance documents are not legally binding, and the industry can elect to not comply with them, as long as they have good reason not to do so. The intent of the guidance documents is to provide the industry with as much of the FDA's thinking on a given topic as needed so the industry has an increased opportunity to satisfy the FDA's requirements the first time, rather than to guess what data the FDA will require. An example of a guidance document is one that describes in detail the necessary chemistry, manufacturing and controls data needed at the time of submission of an Investigational New Drug Application.

Any interested party or individual has an opportunity to participate in the writing of regulations by the FDA. FDA drafts regulations and has them published in the Federal Register, an official document of the federal government that is publicly r Congress enacts Acts o Federal Food, Drug and Cosmetic Act o Public Health Service Act r FDA interprets Acts c Regulations (legally binding) o Guidances(not legally binding) r Industry/individual participation in rule making o Regulations proposed in Federal Register c Submission of petitions r Code of Federal Regulations

Fig. 7.5. Congressional Acts - Regulations & Guidances available. At the time of publication, the FDA states that it will accept comments on the proposed regulations until a certain deadline. Anyone can respond, and the pharmaceutical and biotechnology industries typically do make comments. It is their opportunity to tell the FDA if their proposed regulations are going to have any unintended consequences on the industry and to seek clarifications to be written into the regulations. After this comment period, the FDA publishes final regulations in the Code of Federal Regulations, taking into account the comments received.

Any interested party or individual doesn't have to wait for FDA to publish regulations to make comments on how the agency does its work. At any time, they can submit a Citizen's Petition and ask that the FDA stop or start a particular practice. The pharmaceutical industry often uses this mechanism when they believe the FDA has overstepped its bounds or misinterpreted the law.

As for all federal government agencies, the regulations of the FDA reside in the Code of Federal Regulations (CFRs). The CFRs are divided into parts, and there are several parts that pertain to the pharmaceutical industry. The government makes the CFRs available in both bound paper volumes and online. A link to the parts of the CRFs that apply to the pharmaceutical and biotechnology industries is found on the FDA web site:

The FDA has a variety of tools with which it can communicate to the industries it regulates and to consumers. As mentioned in Fig. 7.6 one of the primary mechanisms by which the industry is informed of FDA's thinking is in the publication of guidance documents. These guidance documents are typically issued first in draft form and are open to public comment. Although guidance documents are not legally binding, they provide an excellent road map into the particulars of what FDA is most likely going to require of a sponsor. Guidances range from the acceptability of data from clinical studies conducted in foreign countries, to r Guidance documents:

c Generated by CDER and CBER c Span scientific issues to administrative procedures o Guidelines, Point to consider r Advisory committee meetings:

c Public meetings sponsored by Divisions within CDER and CBER

* Drug approval packages:

f FDA reviewer comments on data to support drug/biologic product approvals

* Warning letters:

c. Illustrate what is not acceptable

* Podium policy:

c FDA speeches to outline very latest thinking r

c Information for both regulated industries and

Fig. 7.6. FDA Communication Tools reporting of adverse drug events, to the process to be followed when requesting a formal meeting with the FDA. In many therapeutic areas, there are guidance documents for specific diseases and pharmacologic drug categories to guide sponsors in the clinical evaluations of their investiga-tional products. More than 100 guidances, clinical guidelines, and points to consider have been promulgated by the FDA from 1977 to 2001 and are available from the FDA in pamphlets or online.

The FDA uses advisory committee meetings to provide a public forum for scientific and regulatory issues to be discussed. Advisory committees are composed of scientific experts from outside the FDA and are usually composed of academic and practicing physicians (majority of members), nurses and clinical pharmacists, and other technical experts such as statisticians, toxicologists, or epidemiologists. The core characteristics of members and the committees are recognized technical competence (primary criterion), personal integrity, commitment to public interest, objectivity, independence, and no conflict of interest. They meet on a periodic basis to discuss either a drug or biologic that is under review at the FDA (NDAs, ANDAs, prescription to nonprescription switch) or to discuss a scientific/regulatory issue that spans across a number of products. The advisory committee often will vote on whether or not a new product under review should be approved. This vote is advisory only and nonbind-ing on the FDA. These meetings are usually open to the public, and there is an opportunity for the public to comment on the issue being debated.

The FDA makes available, either on paper and/or at their web site, the comments of FDA reviewers on drugs and bio-logics that have been approved. These drug approval packages provide the basis of the judgment of the FDA scientific review team that a new drug or biologic has been found to be safe and effective. These drug approval packages help the industry to understand what development programs have been successful with other drugs or biologics that are similar to ones they are developing.

The compliance arm of FDA issues warning letters to the industry. These letters will be discussed further in the compliance section of this chapter and are recognized as important tools to communicate to the regulated industries on what they should not do. The industry reads and follows these warning letters to avoid their own compliance issues with the agency.

The FDA is also very visible at professional meetings, and the regulators speak frequently and formally from the podium on topics of recent interest: podium policy. Their presentations are oftentimes opportunities to understand how the FDA interprets certain processes, regulations, or guidances, and can provide opportunities to hear what the FDA is contemplating in upcoming requirements or regulatory controversies. Whereas podium policy is very informative, it is not legally binding.

Lastly, the agency maintains an excellent web site at This web site is very informative for both the r Health and Human Services: O Food and Drug Administration (FDA) c National Institutes of Health (NIH) o Agency for Health Care Research and Quality (AHRQ) c Centers for Disease Control and Prevention (CDC) c Office of the Inspector General (OIG) o Centers for Medicare and Medicaid Services (CMS) r Other regulatory agencies: o Consumer Products Safety Commission (CPSC) c Federal Trade Commission (FTC)

Fig. 7.7. Roles of Select Government Agencies regulated industries and consumers and is a very convenient tool for the regulatory affairs professional to keep abreast of the latest at the FDA.

Administratively, the FDA resides in the Department of Health and Human Services (HHS) within the executive branch of the federal government. In addition to the FDA, there are a number of other agencies in HHS that may interact with the pharmaceutical and biotechnology industries (Fig. 7.7). The National Institutes of Health (NIH) is the steward of medical and behavioral research for the nation. Its mission is "science in pursuit of fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to extend healthy life and reduce the burdens of illness and disability." The NIH works with both the FDA and industry to conduct basic and advanced research to determine underlying mechanisms of action of drugs and to advance the development of new clinical indications. The NIH can contact companies with research proposals, companies can contact NIH, or the FDA can request research to be undertaken. An example of NIH research is the study of important pediatric indications for approved products with no patent protection, when the sponsor does not want to develop a pediatric indication.

The Agency for Health Care Research and Quality's (AHRQ) mission is "to support research designed to improve the quality, safety, efficiency, and effectiveness of health care for all Americans." The research sponsored, conducted, and disseminated by the agency provides information that helps people make better decisions about health care. The AHRQ sponsored an assessment of the safety and efficacy of ephedra and ephedrine for weight loss and athletic performance enhancement. A systematic comprehensive literature review with meta-analysis was undertaken, as well as a review of FDA's extensive safety database. Conclusions were presented that led to further investigations and the eventual withdrawal from the market of products containing these ingredients.

The Centers for Disease Control and Prevention's (CDC) mission is "to promote health and quality of life by preventing and controlling disease, injury, and disability." CDC seeks to accomplish its mission by working with partners throughout the nation and world to monitor health, detect and investigate health problems, conduct research to enhance prevention, develop and advocate sound public health policies, implement prevention strategies, promote healthy behaviors, foster safe and healthful environments, and provide leadership and training. One very important task the CDC undertakes every year is identification of the likely leading strains of influenza so that vaccine manufacturers can produce a vaccine and have it available prior to the start of the flu season. In the case of a vaccine shortage, CDC attempts to coordinate with the manufacturers and distributors so that individuals at greatest risk are identified and receive the vaccine.

The mission of the Office of Inspector General (OIG) is "to protect the integrity of Department of Health and Human Services (HHS) programs, as well as the health and welfare of beneficiaries of those programs." The duties of the OIG are carried out through a nationwide network of audits, investigations, inspections, and other mission-related functions performed by OIG components for all agencies within HHS and also for government funded programs, such as the Veterans Administration's or Medicare's drug purchasing and related marketing practices. These investigations and inspections have uncovered pricing fraud, kickbacks and fraud with human growth hormones, drug diversion and substitution, and lack of protection of patient privacy during the conduct of certain clinical studies. Many of these cases resulted in very large financial settlements. Marketing practices for appropriateness of educational programming between the industry and health providers has become part of the purview of OIG because of its influence on product decisions. OIG has issued operating guidelines for the industry, which carry legal consequences if they are not followed.

The Centers for Medicare & Medicaid Services (CMS) "administers the Medicare program, and works in partnership with the States to administer Medicaid, the State Children's Health Insurance Program (SCHIP), and health insurance portability standards." Obtaining Medicare reimbursement, if possible, is an important hurdle after drug or biologic approval. Companies can meet with CMS prior to the design of the phase 3 trials to obtain early feedback on a design that would maximize the opportunity for reimbursement. In general, the study or studies must demonstrate that the product is safe and effective, and there is an improvement in net health outcomes, such as improvements in function, quality of life, morbidity or mortality. The product must be generalizable to the Medicare population and at least as good as if not better than similar products already covered under Medicare. Therefore, in the drug development plans for a product, in addition to proving safety and efficacy for regulatory approval, pharmacoeconomic and quality of life studies have become core studies in the plan for later marketing success.

Other important regulatory agencies in the health arena that are not directly under the HHS umbrella include the Consumer Product Safety Commission (CPSC) and the Federal Trade Commission (FTC). The CPSC is "charged with protecting the public from unreasonable risks of serious injury or death from consumer products under the agencies jurisdiction."

Regulations applying to child-resistant packaging are governed by the CPSC. The Federal Trade Commission (FTC) "enforces consumer protection laws that prevent fraud, deception and unfair business practices." They are responsible for truth-in-advertising for over-the-counter drugs and monitoring health benefit claims for foods and dietary supplements. The FTC is also responsible for reviewing proposed company mergers to assure there is no possibility of unfair business practices or anticompetitive activities that could harm the consumer. As part of the merger process, the product portfolio of marketed products and products in the development pipeline are examined by the FTC to determine if there could be a monopoly in a therapeutic or pharmacologic category of products. After evaluating the potential acquisition of Immunex by Amgen, Immunex was required to divest Leukine® (sargramostim), which was purchased by Berlex®, prior to FTC approval. Amgen already had two related hematopoietic stimulating products, Neupogen® (filgrastim) and Neulasta® (pegfilgrastim).

Global harmonization of regulatory requirements was recognized as an urgent need in the 1980s, as the costs of drug development continued to escalate and the public began to demand that innovative products become approved and available in their country as soon as possible (Fig. 7.8). It was also at this time that the globalization of the pharmaceutical industry became more oriented to getting new drug products approved in as many countries around the world in as short a period of time as possible. The top 10 companies for product sales worldwide in 2004 were Pfizer, GlaxoSmithKline (British), Merck, Johnson & Johnson, Sanofi-Aventis (French), AstraZeneca (British/Swedish), Novartis (Swiss), Bristol-Myers-Squibb, Wyeth, and Eli Lilly.

As a result, parties from the regulatory authorities and the regulated industry around the world mounted an effort that came to be known as the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, or simply shortened to the International Conference on Harmonization, or ICH.

r International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) initiated in 1990 r "brings together the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of product registration" r "The purpose is to make recommendations on ways to achieve greater harmonization in the interpretation and application of technical guidelines and requirements for product registration in order to reduce or obviate the need to duplicate the testing carried out during the research and development of new medicines."

Fig. 7.8. Global Regulatory Harmonization

A process began to harmonize the data and process requirements for the successful development and approval of new drugs and biologics, such that a study conducted to meet the requirements of one country could be assured of also meeting the requirements of another country. This offered the opportunity to reduce the overall costs of drug development, as it became possible to reduce the amount of testing required.

The International Conference on Harmonization was officially initiated in 1990. The primary participants came from countries that represent the largest pharmaceutical and biotechnology markets in the world: Europe, Japan, and the United States. Organizations and smaller countries were invited as observers to the process. The parties involved in the ICH process have addressed such widely diverse topics as the testing of the stability of a drug product, the appropriate length of animal toxicology studies, and uniform definitions and requirements for reporting of serious adverse events that occur in clinical trials. Additionally, the parties addressed the format of documentation that can be submitted to regulatory authorities. Before the ICH process began, a pharmaceutical company had to conduct stability testing of drug products at slightly different temperatures and humidities, conduct toxicology studies for different lengths of time in different animal species, or conduct duplicate clinical studies in different countries due to concerns about ethnic differences. This duplicate testing was all to satisfy different requirements by different regulatory authorities. Although a large number of topics have already been addressed by ICH, the organization continues to address new topics and to reassess topics already addressed, all based on scientific evidence.

The regulatory authorities involved in the ICH process include the FDA and its counterparts in Europe (EMEA) and Japan (MHLW) (Fig. 7.9). The official observers of ICH include the World Health Organization, the European Free Trade Area (represented by Switzerland), and Canada. The major pharmaceutical trade organizations in the United States, Europe, and Japan coordinate the representation from the pharmaceutical and biotechnology industries, with the representatives being recognized experts in their areas in the industry. This ICH process has resulted in a greater appreciation and understanding of the challenges from both the perspective of r Regulatory Authorities: c US - Food and Drug Administration (FDA) e Europe - European Medicines Agency (EMEA) o Japan - Ministry of Health, Labor and Welfare (MHLW) k Industry representatives: ° US - Pharmaceutical Research and Manufacturers of America (PhRMA)

o Europe - European Federation of Pharmaceutical Industries and Associations (EFPIA) o Japan - Japan Pharmaceutical Manufacturers Association (JPMA]

Fig. 7.9. ICH Parties r Expert Working Groups from the ICH parties developed guidelines addressing technical requirements for: r Quality c Safety c Efficacy

P Common Technical Document r Medical Dictionary for Regulatory Activities (MedDRA) r FDA, EMEA, MHLW responsible for implementation of guidelines in their countries

Fig. 7.10. ICH Regulatory Harmonization Process the regulators and the regulated industries. It has also resulted in greater informal collaboration among the regulators on product-specific issues.

Representatives from the regulatory authorities and the regulated industry have been formed into Expert Working Groups to address the technical requirements for the quality (manufacturing, product testing, and product formulation), safety, and efficacy of drug and biologic products (Fig. 7.10). Their work is based on available scientific and regulatory data that support appropriate guidelines for the development of drug and biologic products. For example, the Expert Working Group assigned to work on the acceptability of clinical trials in ethnically different populations evaluated available data on pharmacokinetic and pharmacodynamic differences, if any, of drugs in different populations to determine if ethnic differences were clinically significant.

In addition to addressing technical and scientific requirements, groups also addressed two administrative areas: the "Common Technical Document" (CTD) and a medical dictionary (medDRA), especially for adverse events, that could be used to report data to regulatory authorities. Once the technical requirements have been established and agreed upon by all the parties in the harmonization process, the FDA and its counterpart agencies in Europe and Japan are responsible for formally implementing the ICH guidelines in their countries. In the United States, the ICH guidelines are published as guidance documents, as referenced in Fig 7.10.

Topics for the ICH process were well developed in advance of the Expert Working Groups actually starting their work (Fig. 7.11). The technical requirements for developing and registering new drug products were grouped into three primary categories. The first of these categories, quality, is directed toward the development, manufacturing, and control of the actual drug product. Technical requirements in this area address such issues as stability testing, analytical validation, impurity profiles in both drug substances and drug products, quality of biotechnology products, and specifications for drug substances and drug products.

The safety category is directed toward preclinical testing, including both in vitro and in vivo animal testing of new drugs. Technical requirements addressed in this area include toxicity testing, carcinogenicity testing, reproductive toxicology, and r Technical requirements for developing and registering new drug products containing new drug substances as they relate to:

p Quality - those relating to chemical and pharmaceutical

Quality Assurance p Safety - those relating to in vitro and in vivo pre-clinical studies p Efficacy - those relating to clinical studies in human subjects r Common Technical Document (CTD) - organization of the common elements of a registration submission r Medical Dictionary for Regulatory Activities (MedDRA): o international medical terminology for electronic transmission of adverse event reporting, both in the pre-and post-marketing areas, as well as the coding of clinical trial data r

Fig. 7.11. ICH Topics toxicokinetics. The efficacy category is focused on the appropriate development of drugs during the clinical testing phase. Technical requirements in this category include the collection and reporting of clinical safety data, dose-response studies, ethnic considerations in conducting foreign trials, and studies in special populations such as geriatrics and pediatrics.

The ICH process has addressed one of the most frustrating registration issues for the pharmaceutical industry. Prior to ICH, each country had its own set of requirements for the formating and organization of documents to be submitted for review of a submission package by the regulatory authorities. Thus, sponsors found themselves reformating and reorganizing essentially the same data just to fit the requirements of different countries. With the development of the common technical document (CTD), pharmaceutical companies can now prepare one fundamental set of documents with one set of requirements for formating and organization. This set of documents can be submitted to all the regulatory authorities without making changes for each country. The CTD will be further discussed later in the chapter.

A Medical Dictionary for Regulatory Authorities (MedDRA) was also developed through the ICH process. This provides a single dictionary that is required for use for all adverse event reporting. Prior to the development of this international dictionary, pharmaceutical companies were coding the same adverse events to different medical terms, based on the medical dictionary required in each country. This created repeat, and often confusing work, for companies, and if anything, it served to obfuscate the interpretation of clinical safety data.

The ICH process has clearly advanced regulatory science around the world and has brought efficiencies to the development of drugs and the registration and reporting process. The ICH organization maintains an excellent and informative web site:

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