Regulatory Approval and Compliances for Biotechnology ProductsNorman W. Baylor, PhDPresident & CEO, Biologics Consulting Group, Inc., Alexandria, Virginia

Chapter 25

Biotechnology Entrepreneurship. http://dx.doi.org/10.1016/B978-0-12-404730-3.00025-7Copyright © 2014 Elsevier Inc. All rights reserved.

National regulatory authorities (NRAs) regulate pharma-ceutical products to enable patient access to high-quality, safe, and effective products, and restrict access to those prod-ucts that are unsafe or have limited clinical use. When appro-priately implemented, regulation ensures a public health benefit and the safety of patients, healthcare workers, and the broader community. Before new technologies can be used, they must be assessed and approved by authorized regulatory agencies. Detailed safety review during research and devel-opment stages, regulatory approval, and legal registration are necessary stages of product development. These regulatory processes ensure that products are safe and effective.

Biomedical products must be reviewed and approved or licensed by the NRA of the country in which they will be marketed and distributed. These authorities evaluate whether a product is safe for widespread use and whether manufacturers can consistently produce high-quality prod-ucts. Among the issues regulatory authorities consider are:

l Whether the design for clinical testing is safe enough to warrant human participation.

l Whether there is sufficient data to ascertain risks and ben-efits.

l Whether the benefits from any given product outweigh the risks that may be associated with its use.

l Whether data collected in one country can be applied to the use of a product in another country.

After a product is approved, licensed, and marketed, it must be monitored throughout its lifecycle to ensure that its benefit continues to match expectations of safety and effectiveness. National and regional regulatory authorities—including the U.S. Food and Drug Administration (FDA), Health Canada, the European Medicines Agency (EMA), as well as other national regulatory authorities throughout the world over-see and manage the regulatory review and approval process. The approval process for biomedical products is similar in

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most countries; however, there are some aspects that dif-fer based on specific laws and regulations in each coun-try. In all countries, information submitted to regulatory authorities regarding the quality, safety, and efficacy of drugs is similar; however, the review process for clinical trials and marketing authorization applications may differ. The primary focus of this chapter will cover the U.S. FDA approval process. For specific information about the regula-tory approval route in other countries it is best to seek guid-ance from the specific national regulatory authority (NRA) in those countries or from external experts familiar with those processes.

Regulatory reviews of products designed for use in the developing world present unique challenges. To reflect local priorities and health conditions, a regulatory review ideally is managed by the government or regional author-ity of the people for which the product has been designed. Challenges arise when regulatory authorities in developing countries do not have the skills and/or resources to manage the review. As additional products are developed for low-income countries, the strain on the resources of develop-ing country NRAs may become even greater. The FDA and other regulatory authorities may provide assistance to these NRAs in an attempt to ultimately support product access to those who need them most. Some mechanisms, such as the EMA’s Article 58 and the World Health Organization Prequalification Program, help assure safety and efficacy of products designed exclusively for the developing world [1].

Regulatory procedures impact all stages of biomedical product development. Therefore, it is critical that developers of biomedical products (drugs, biologics, devices, in vitro diagnostics, or some combination) possess the knowledge and awareness of the regulatory challenges and opportuni-ties to expedite the development of safe and effective prod-ucts in a cost-effective manner. The pathway from discovery to marketing of a new biomedical product can be long,

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complex, and costly. A clear understanding of the FDA reg-ulatory process, regulations, and policies is essential when developing an effective product lifecycle management strat-egy, seeking product approval, and assuring that products are marketed in compliance with federal requirements. In order to minimize the risks and costs involved in the bio-medical product development process, it is imperative that clear planning is done during the early stages of product development, with regular assessment of chemistry, manu-facturing, and control (CMC), and nonclinical and clinical data as it is generated. The aim of this chapter is to provide an overview of the FDA regulatory product approval pro-cess and discuss considerations for successfully developing a regulatory strategy that leads to product marketing autho-rization from national regulatory authorities.

HISTORY OF THE FDA

The FDA is responsible for ensuring the safety of an array of consumer products. The FDA is part of the executive branch of the U.S. federal government located in the Department of Health and Human Services. The U.S. Department of Agriculture Bureau of Chemistry was the predecessor of the FDA. Prior to 1902 the manufacture of vaccines, anti-toxins, and other biologicals was unregulated by the federal government. In response to the tragic deaths of 14 children due to contaminated diphtheria antitoxin, Congress enacted the Biologics Control Act of 1902 which gave the federal government the authority to grant premarket approval for every biological drug and for the process and facility pro-ducing such drugs [2]. This legislation contained the initial concepts for the regulation of biologics. In 1906 Congress passed the Federal Food and Drugs Act, to address increas-ing consumer concern about the safety of foods and drugs in the United States. The FDA was one of the first agen-cies established by the U.S. government dedicated to con-sumer protections [3]. In 1927 the regulatory functions of the Bureau of Chemistry were reorganized to become the Food, Drug, and Insecticide Administration, which in 1930 changed its name to the Food and Drug Administration. In 1938 the FDA was overhauled with the passage of the Pure Food, Drug, and Cosmetics Act.

The oversight of medical devices was the responsibility of the U.S. Post Office Department and the Federal Trade Commission to a limited extent prior to 1938 and came under the authority of the FDA after 1938. Although premarket approval did not apply to devices, the Pure Food, Drug, and Cosmetics Act equated them to drugs for regulatory purposes [4]. With the proliferation of medical technology, and an increasing rise in the development of various types of medi-cal devices, Congress considered passing laws for the regu-lation for devices which would be comparable to the 1962 Drug Amendments Act. This legislation failed and the Sec-retary of the Department of Health, Education, and Welfare commissioned the Study Group on Medical Devices which

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SECTION | VII Biotechnology Product Development

ecommended in 1970 that medical devices be classified ccording to their comparative risk and regulated accord-ngly. In the early 1970s, a government report documented housands of injuries resulting from medical devices [5]. oon after, the Dalkon Shield intrauterine device was with-rawn from the market after more than 200 second trimester eptic abortions and 11 maternal deaths occurred. In response o these adverse events Congress enacted the 1976 Medical evice Amendments to enhance the FDA’s ability to estab-

ish the safety and effectiveness of medical devices.Additional refinements to the function, organization,

nd authority of the FDA continue as new public health hreats and issues emerge. There are several different epartments within the FDA that handle issues such as rug development, food safety, cosmetics, blood products, edical devices, vaccines, veterinary medicine, and radi-

tion-emitting products. Under current law, every medical roduct is classifiable as a drug, device, biologic, or combi-ation product. The classification of the product determines he particular review and approval processes the FDA may se in accessing the safety and efficacy of the product for uman use. In addition to evaluating new products before hey are released onto the market to determine their safety nd effectiveness, the FDA also periodically inspects exist-ng products and the facilities in which they are manufac-ured, and evaluates labeling, advertising, and other claims ade about the products for which it regulates.

The U.S. FDA’s organization includes, among other nits, the Office of the Commissioner and four directorates Medical Products and Tobacco, Foods, Global Regulatory perations, and Policy) overseeing the core functions of

he agency (Figure 25.1). The Office of Medical Products nd Tobacco provides high-level coordination and leader-hip across the Center for Drug Evaluation and Research CDER), the Center for Biologics Evaluation and Research CBER), the Center for Devices and Radiological Health CDRH), and the Center for Tobacco Products (CTP).

The agency responsible for the regulation of biological roducts previously resided under the National Institutes of ealth. This authority was transferred to the FDA in 1972. urrently, both CBER and CDER are responsible for regu-

ating therapeutic biological products, including premarket eview and oversight.

CBER regulates biological products for human use nder applicable federal laws, including the Public Health ervice Act (PHS Act) and the Federal Food, Drug, and osmetic Act (FD&C Act). (See Table 25.1.)

Products regulated in CBER include blood and blood prod-cts, vaccines, allergenics, cell and tissue-based products, gene herapy products, and therapeutic proteins derived from plants, nimals, humans, or microorganisms. New biologics are equired to go through a premarket approval process similar o that for drugs. However, the Public Health Service Act pro-ides that marketing approval for a biologic shall be obtained hrough the submission and approval of a Biologics License

343Chapter | 25 Regulatory Approval and Compliances for Biotechnology Products

Office of the Commissioner:Commissioner

Office of Medical Products andTobacco:

Deputy Commissioner for MedicalProducts and Tobacco

Center for DrugEvaluation and

Research

Center for TobaccoProducts

Center for BiologicsEvaluation and

Research

Center for Devicesand Radiological

Health

FIGURE 25.1 The organization chart of the U.S. FDA.

Application (BLA). CBER also regulates medical devices related to licensed blood and cellular products under the FD&C Act’s Medical Device Amendments of 1976 [6]. Moreover, the medical devices regulated by CBER are intimately associated with the blood collection and processing procedures as well as the cellular therapies regulated by CBER.

CDER regulates over-the-counter and prescription drugs, including biological therapeutics and generic drugs. CDER has different requirements for the three main types of drug products: new drugs, generic drugs, and over-the-counter drugs. The FD&C Act requires a sponsor to submit a new drug application (NDA) for the FDA’s evaluation to mar-ket a drug. The biological therapeutics regulated by CDER require the submission of a BLA and include monoclonal

TABLE 25.1 Acts and Regulations Pertinent to the Development and Licensure of Biomedical Products

Congressional ActsPublic Health Service Act (42 USC 262-63) Section 351Food, Drug & Cosmetic Act (21 USC 301-392)Food and Drug Administration Modernization Act, 1997Food and Drug Administration Amendments Act, 2007Title 21 Code of Federal Regulations (CFR)Subchapter A—General21 CFR 58 Good Laboratory Practices21 CFR 56 Institutional Review Boards21 CFR 50 Protection of Human SubjectsSubchapter C: Drugs: General21 CFR 20121 CFR 210-211 Good Manufacturing PracticesSubchapter D: Drugs for Human Use21 CFR 314.126 Adequate and well-controlled trials21 CFR 312 Investigational New Drug ApplicationSubchapter F: Biologics21 CFR 600-680 Biological Product StandardsSubchapter Devices21 CFR 807

antibodies for in vivo use designed as targeted therapies in cancer and other diseases; proteins intended for therapeutic use, including cytokines (interferons) and enzymes (e.g., thrombolytics); immunomodulators (nonvaccine and nonal-lergenic products) intended to treat disease by inhibiting or modifying a preexisting immune response; and growth fac-tors intended to mobilize, stimulate, decrease, or otherwise alter the production of hematopoietic cells in vivo.

CDRH regulates all medical devices under the FD&C Act, inclusive of radiation-related devices, that are not assigned categorically or specifically to CBER. The FDA has divided devices into three classes to identify the level of regulatory control applicable to them. The highest category is Class III and includes those devices for which premarket approval is required to determine the safety and effective-ness of the device. There are two primary pathways by which the FDA permits medical devices to be marketed: premarket clearance by means of a 510(k) notification, or premarket authorization by means of a premarket application (PMA) or product development protocol (PDP). In vitro diagnostic products are medical devices as defined in section 210(h) of the Federal Food, Drug, and Cosmetic Act, and may also be biological products subject to Section 351 of the Public Health Service Act. Like other medical devices, IVDs are subject to premarket and postmarket controls. IVDs are also subject to the Clinical Laboratory Improvement Amend-ments (CLIA ‘88) of 1988.

Product types continue to merge as a result of techno-logical advances and blur the historical lines of separation between the FDA’s medical product centers, i.e., CBER, CDER, and CDRH. Combination products are therapeutic and diagnostic products that combine drugs, devices, and/or biological products. A combination product is classified, assigned to a specific center within the FDA, and may be regulated as a drug, device, or biologic depending upon its primary mode of action as determined by the FDA. Because combination products involve components that would

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normally be regulated under different types of regulatory authorities, and frequently by different FDA centers, they raise challenging regulatory, policy, and review management challenges. Differences in regulatory pathways for each com-ponent can impact the regulatory processes for all aspects of product development and management, including preclinical testing, clinical investigation, marketing applications, manu-facturing and quality control, adverse event reporting, pro-motion and advertising, and postapproval modifications.

REGULATIONS RELATED TO BIOMEDICAL PRODUCT DEVELOPMENT

A single set of basic regulatory approval criteria apply to biomedical products regardless of the technology used to produce them. The current legal authority for the regulation of biologics derives primarily from Section 351 of the PHS Act and from certain sections of the U.S. Food, Drug, and Cosmetic Act [7,8]. The statutes of the PHS Act are imple-mented through regulations codified in Title 21 of the Code of Federal Regulations, parts 600 through 680 which contains regulations specifically applicable to biologics. The PHS Act requires individuals or companies who manufacture biolog-ics for introduction into interstate commerce to hold a license for these products. FDA issues these licenses. In addition, because biologics meet the legal definition of a drug under the FD&C Act, manufacturers must comply with the drug Current Good Manufacturing Practices (CGMPs) regulations (parts 210 and 211). Regulations applicable to biomedical products are summarized in Table 25.1. These regulations include the minimum requirements for the manufacturing of biologics, drug, devices, and combinations thereof, as well as the requirements for performing clinical trials.

The FDA periodically publishes various guidelines and guidance documents to assist developers of new biomedical products in regard to the manufacture and clinical evalua-tion of these products. In addition, international guidelines developed and published by the International Conference on Harmonization (ICH) have been adopted by the FDA. Guidance documents do not have the force of law, but are intended to provide useful and timely recommendations and represent the agencies’ current thinking on particular topics. These documents are particularly useful in rapidly progressing areas of science and for specifying a degree of detail beyond what is included in the regulations.

To understand how the FDA regulates biomedical products, it is important to understand some of the more per-tinent operational definitions contained in the statutes and regulations. Section 351 of the PHS Act defines a biologi-cal product as any virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product applicable to the prevention, treatment, or cure of diseases or conditions of human beings [9]. Biological products, in contrast to chemically synthesized

SECTION | VII Biotechnology Product Development

small molecules, which can be thoroughly characterized, are generally derived from living material, are complex in struc-ture, and usually cannot be fully characterized.

Safety is defined as the relative freedom from harmful effects to individuals affected directly or indirectly by a product when prudently administered, taking into consider-ation the character of the product in relation to the condition of the recipient at the time. Thus, the property of safety is relative and cannot be ensured in an absolute sense.

Purity is defined as the relative freedom from extrane-ous matter regardless of whether it is harmful to the recipi-ent or deleterious to the product. Usually, the concepts of purity and safety coincide; purity most often relates to free-dom from such materials as pyrogens, adventitious agents, and chemicals used in the manufacture of the product.

Potency is defined as the specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result. Potency, as thus defined, is equivalent to the concept that the product must be able to perform as claimed, and, if possible, this must correspond with some measurable effect in the recipient or correlate with some quantitative laboratory finding.

Standards mean specifications and procedures applica-ble to an establishment or to the manufacture or the release of products that are designed to ensure the continued safety, purity, and potency of biological products. The word stan-dard is also used with a secondary meaning, usually in the sense of a reference preparation, such as a bacterial or viral antigen that can be used in evaluating potency or, in some cases, safety and purity.

The regulations regarding biological products, in addi-tion, define effectiveness as the reasonable expectation that, in a significant proportion of the target population, phar-macologic or other effects of the biological product, when administered under adequate directions for use and warn-ings against unsafe use, will serve a clinically significant function in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans.

Current good manufacturing practices define a quality system that manufacturers use as they build quality into their products. The regulations outline the minimum manufactur-ing, quality control, and quality assurance requirements for the preparation of a drug or biological product for commer-cial distribution. For example, approved products developed and produced according to CGMPs are safe, properly identi-fied, of the correct strength, pure, and of high quality.

CURRENT REGULATORY PATHWAYS

The regulatory pathways for evaluation and approval of bio-medical products are outlined in Table 25.2.

The regulatory requirements for biomedical prod-ucts cover both the premarketing phase, consisting of the

Chapter | 25 Regulatory Approval and Compliances for Biot

investigational and licensing phases, and the postmarketing phase. These requirements can be found in the Investiga-tional New Drug (IND) or the Investigational Device Exemp-tion (IDE) regulations [10]. The first step, prior to evaluating a new product in human clinical trials, is the preclinical phase. The FDA requires that certain animal tests be con-ducted before humans are exposed to a new molecular entity. The objectives of early in vivo testing are to demonstrate the safety of the proposed product. For example, tests should prove that the compound is not toxic at the doses that would most likely be effective in humans. The results of these tests are used to support the IND application that is filed with the FDA. Sponsors are encouraged to request a pre-IND (or pre-IDE) meeting with the FDA to discuss preclinical studies, clinical study design, and data requirements that may need to be agreed upon prior to the initiation of human clinical studies.

TABLE 25.2 Current US FDA Regulatory Pathways

Biologic productsIND—Investigational new drug applicationBLA—Biologics license applicationDrugsIND—Investigational new drug applicationNDA—New drug applicationMedical devices510(k)IDE—Investigational device exemptionPMA—Premarket application21 CFR 81221 CFR 814

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TRANSLATIONAL DEVELOPMENT

The industry’s goals are to develop a commercially viable product and make a meaningful contribution to available therapeutic options while satisfying a myriad of regulatory requirements. The introduction of new biomedical products typically involves a long and expensive process that may begin with a relatively simple initial discovery but includes an extended period of development, which addresses for-mulation and manufacturing, preclinical evaluation, safety, efficacy, and commercial potential. Table 25.3 includes a list of the phases in product development from discovery through postlicensure.

TABLE 25.3 Product Development Phases

Discovery/basic research—(pre-IND)Process and analytical development (pre- and post-IND)Process—Development and optimizationManufacturing consistencyAssays—Development and specificationsIdentity, purity, potencyStability indicatingDru g substance (bulk substance) and drug product characterizationProduct development phasesPreclinical animal studies (pre-IND)Proof-of-conceptToxicologySafety pharmacologyIND submissionClinical trialsPhase 0, 1, 2, and 3Product approval/licensurePostmarket studies (phase 4)

Regulatory Affairs ImpactKey Early Development Milestones

Lead ID Proof-of-concept IND

• Line development• CMO selection• Method development

• Gap analysis• Development plan

• Pre-IND support• Pre-clinical plan• Clinical synopsis• CRO selection

• Pre-IND Follow-up• Protocol Preparation• CMO/CRO Mgmt• Quality Systems Implementation• Method Qualification

Pre-IND meeting with FDA

BasicResearch Development Preclinical

FIGURE 25.2 Impact of the regulatory process on key early development milestones.

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In order to understand the timeframe required for a prod-uct to become commercially available, one must understand how the product development stages are intertwined with the stages of the regulatory process.

Translational development involves the process of tran-sitioning from the basic research and discovery phase to a regulated product development phase beginning with the preclinical stage (Figure 25.2).

The research and discovery phase may be empirical and based on trial and error and occurs in an unregulated environment; whereas, the impact of regulatory affairs on clinical development is significant and expands the IND phases through licensure and beyond. Although there is no FDA regulatory oversight in the basic research and dis-covery phase as described at the beginning of this chapter, each of the product development stages beginning with the preclinical stage is impacted by the regulatory process. (Figure 25.3).

Failure to understand and appreciate the regulatory impact for future product development can result in signifi-cant delays when attempting to transition a product from the research lab to the clinic. A discovery process that is focused on the development of a drug for one purpose may lead to its use in another, unanticipated, disease indication. Once a potential candidate drug is identified, it must be evaluated in the structured highly regulated environment as previously described.

Once product development enters the regulated envi-ronment there are challenges that must be overcome. Preclinical studies must be done under good laboratory practices (GLP); chemistry, manufacturing, and control procedures must be done under current good manufac-turing practices (cGMP); and clinical studies must be done under good clinical practices (GCP). It is highly

SECTION | VII Biotechnology Product Development

recommended that a gap analysis of all development areas be done as part of a product development plan (PDP). Comprehensive product development planning should be based on a clear understanding of the FDA regulations and expectations. This includes effective communication with the FDA to assure concurrence with the develop-ment plan. The execution of the PDP should be overseen by a project management expert. Product development requires a team effort and success is highly dependent on support from upper management and availability of appropriate resources. Product development regulatory goals should include:

l Developing a reproducible process that can yield a consis-tent product and that can be manufactured under cGMPs.

l Developing analytical procedures that can reliably mea-sure product parameters that are stability indicating, and can demonstrate product comparability following changes to manufacturing, facilities, or equipment.

l Develop animal models that can demonstrate proof-of-concept and safety.

l Demonstrate safety and efficacy in clinical trials.

Once appropriate preclinical studies are completed, the FDA requires that sponsors of regulated products first obtain preliminary permission for conducting clinical tri-als in humans. The clinical development of a new drug in the United States usually begins with a sponsor approach-ing the FDA for permission to conduct a clinical study with an investigational product through submission of an IND application form. Clinical trials in support of a PMA may be conducted only after the FDA has issued an IDE. In the application, the sponsor (1) describes the composi-tion, source, and method of manufacture of the product and the methods used in testing its safety, purity, and potency;

Clinical Development FDA Filing,Approval &Launch

Preclinical

1st-in-human P1 P2 BLA/NDA

Phase 1 Phase 2 Phase 3

• IND preparation• Clinical site selection

• Ongoing submission• IND support• Clinical trial support

Initial IND submission

End of Phase 2 meeting

MarketApplicationsubmission

Safety update

Pre-BLA or -NDA meeting

Regulatory Affairs ImpactKey Clinical Development Milestones

FIGURE 25.3 Impact of the regulatory process on key clinical development milestones.

Chapter | 25 Regulatory Approval and Compliances for Biote

(2) provides a summary of all laboratory and preclinical animal testing; and (3) provides a description of the pro-posed clinical study and the names and qualifications of each clinical investigator. The FDA has a maximum of 30 days to review the original IND application and determine whether study participants will be exposed to any unaccept-able risks. As part of the IND process, each clinical inves-tigator files information describing his or her qualifications for performing clinical trials, details of the proposed study, and assurance that a number of conditions specified by the regulations will be met. A signed informed consent must be obtained from each study participant [11]. Approval for the study must be obtained in advance from a local insti-tutional review board. Once the FDA is satisfied with the documentation, the Phase 1 clinical trial can begin. If the documentation is inadequate, the FDA can place the IND on clinical hold [11].

HUMAN CLINICAL TESTING PHASES

Only licensed or approved biomedical products may be shipped from one state to another; however, during the pre-marketing phase, interstate shipment of products for inves-tigational use is allowed under the law and regulations [11]. There are generally three separate phases (Phase 1, 2, and 3) in the clinical evaluation of experimental biomedical prod-ucts at the premarketing stage.

These phases may overlap, and the clinical testing may be highly iterative because multiple Phase 1 or 2 trials may be performed as new data are obtained. The respec-tive responsibilities of the regulatory authority, i.e., the FDA and the sponsor are also outlined in Figure 25.4. One should note that the FDA is not responsible for completing

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the appropriate studies in support of the safety and efficacy of the product. This is the sole responsibility of the sponsor.

In a Phase 1 trial, generally, 20 to 100 volunteers are enrolled, which is primarily focused on an assessment of the safety of the product. During this stage, low doses of the prod-uct are administered to healthy volunteers who are closely supervised. During the Phase 2 trials, the drug is adminis-tered to 100 to 300 volunteers with the intent to determine the drug’s effective dose, the method of delivery, and the dosing interval, as well as to reconfirm product safety.

Pre-IND meetings with the FDA are particularly impor-tant for new sponsors and for products that incorporate novel features. Other meetings with the FDA are also encouraged at critical points throughout the IND review, including “end-of-Phase 2” meetings. The purpose of an end-of-Phase 2 meeting is to assess the adequacy of the Phase 2 safety and effectiveness data that support advancement to Phase 3, to evaluate the Phase 3 plan and draft protocols, and to identify any additional information necessary to support a marketing application for the uses under investigation. The end-of-Phase 2 meeting is generally held before major com-mitments of effort and resources to specific Phase 3 studies are made.

A Phase 3 trial may involve anywhere from 1000 or more volunteers across multiple study sites and is considered the pivotal efficacy trial. These studies are used to demonstrate further safety and effectiveness and to determine the best dosage. As far as efficacy evaluation, efficacy is demon-strated ideally in randomized, double-blind, well-controlled trials. The endpoints will be product specific. Additional controlled safety studies are often requested when the num-bers of subjects included in the efficacy studies are deemed insufficient to provide adequate safety data. The studies

Product Development Phases

CMC developmentAnimal pharm/tox.Protocol development

Pre-IND Meeting

30-Day Safety Review

Review amendments, annual reports, safety reports

6–10 Month Review

Review Phase 4 study reports

End of Phase 2 Meeting

Pre-BLA Meeting

Initial safety studies

Dose escalation and initial efficacy

Pivotal efficacy studies

Post marketingcommitments

SPONSOR:

FDA:

Preclinical Phase 1 Phase 2 Phase 3 Phase 4

IND BLA

FIGURE 25.4 Product development phases.

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need to be designed in such a way that statistical methods may be applied to their evaluation. Safety studies may be unblinded if the number of injections, route of administra-tion, or schedule differs between groups, in particular when infants and young children are involved. Phase 3 trials are the final step before seeking FDA approval.

BIOLOGICS LICENSE APPLICATION (BLA)

Biological products require FDA approval through a biolog-ics license application (BLA) as opposed to new molecular entities, which are approved through a new drug applica-tion (NDA) or new devices which are approved through the 510(k) procedures or premarket applications (PMA). Types of products requiring a BLA include vaccines, blood and blood byproducts, some types of monoclonal antibod-ies, and tissue and cellular products. Once all three phases of the clinical trials are complete, the sponsoring com-pany analyzes all of the data. If the findings demonstrate that the investigational product is both safe and effective for its intended use, the company may file a BLA with the FDA requesting approval to market and distribute the prod-uct commercially. FDA experts review all the information included in the BLA to determine if the data demonstrates that the product is safe and effective enough to be approved. Following rigorous review, the FDA can either (1) approve the BLA, (2) send the company a “complete response ” let-ter requesting more information or studies before approval can be granted, or (3) deny approval.

The review of a BLA usually includes an evaluation by an advisory committee which is an independent, external panel of FDA-appointed experts who consider data pre-sented by company representatives and FDA reviewers. The advisory committee then votes on whether the data support the safety and effectiveness of the product in order for the FDA to consider approval of the BLA, and under what con-ditions. The FDA is not required to follow the recommenda-tions of the advisory committees, but often does.

Prior to the submission of a BLA, a pre-BLA meeting with the agency is strongly encouraged to discuss the spon-sor’s product developmental plan. The FDA has determined that delays associated with the initial review of a BLA may be reduced by exchanges of information about a proposed marketing application [12]. The primary purpose of a pre-BLA meeting is to discuss any major unresolved issues, to identify those studies that the sponsor is relying on as adequate and well-controlled to establish the product’s effectiveness, to identify the status of ongoing studies, to acquaint FDA reviewers with the general information to be submitted in the BLA (including technical information), to review methods used in the statistical analysis of the data, and to discuss the best approach for the presentation and formatting of data in the application.

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The BLA should contain details of the manufacturing facility and equipment as well as data derived from nonclin-ical laboratory and clinical studies that demonstrate that the manufactured product meets prescribed requirements for safety, purity, and potency. Information should be submit-ted in the BLA that confirms that there is compliance with standards addressing requirements for:

l Organization and personnel. l Buildings and facilities. l Equipment. l Control of components, containers, and closures. l Production and process controls. l Packaging and labeling controls. l Holding and distribution. l Laboratory controls. l Records to be maintained.

Furthermore, a full description of manufacturing methods; data establishing stability of the product through the dating period; sample(s) representative of the product for intro-duction or delivery for introduction into interstate com-merce; summaries of test results performed on the lot(s) represented by the submitted sample(s); specimens of the labels, enclosures, and containers; and the address of each location involved in the manufacture of the biological product should be included in the BLA. The manufactur-ing facility must also be inspection-ready at the time the BLA is submitted. If the information provided meets FDA requirements, the application is approved and a license is issued allowing the firm to market the product. Issuance of a biologics license is the final determination that the prod-uct, the manufacturing process, and facilities meet appli-cable requirements to ensure the continued safety, purity, and potency of the product.

Regulatory oversight continues after licensure. Phase 4 studies are required to assess the safety of the product in larger populations. Additionally, any changes to the manu-facturing process or change in therapeutic indications must be reported to the FDA for approval in the form of a BLA supplement.

SUMMARY

Development of biomedical products is an expensive and lengthy process that requires significant advanced planning. Regulatory procedures impact all stages of the biomedi-cal product development process. In order to successfully develop a marketable product it is critical that developers are not only aware of, but have an understanding of regulatory obligations and opportunities. Moreover, clear regulatory planning during the early stages of product development is essential to develop a focused regulatory strategy that can be presented to the regulatory authorities.

Chapter | 25 Regulatory Approval and Compliances for Biotechn

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[2] Kondratas RA. Death Helped Write the Biologics Law. FDA Con-sumer 1982;16:23–5.

[3] Regulatory Information. “Other Laws Affecting FDA.” Legislation. http://www.fda.gov/regulatoryinformation/legislation/default.htm. March 2013. Retrieved.

[4] FDA website: http://www.fda.gov/aboutFDA/whatwedo/history/ origin/ucm055137.htm. Retrieved March 2013a.

[5] Maisel WH. Medical Device Regulation: An Introduction for the Practicing Physician. Annals of Internal Medicine 2004;140:296–302.

[6] FDA website: http://www.fda.gov/biologicsbloodvaccines/developmentapprovalprocess/510kprocess/default.htm. Retrieved February 2013b.

[7 [8

[9

[10

[11

[12

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] Federal Food, Drug and Cosmetic Act. 21 United States Code, Sec 321.] Public Health Service Act. (1944). Chap. 373, Title III, Sec.351, 58:

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] Code of Federal Regulations. (2012b). Title 21, Part 312 and Part 800, 2012b. Definitions. Washington, D.C. Office of the Federal Reg-ister, National Archives and Records Administration.

] Code of Federal Regulations. (2013c). Title 21, Part 312. Definitions. Washington, D.C. Office of the Federal Register, National Archives and Records Administration.

] U.S. Food and Drug Administration. “FINDINGS: Issues and Com-munication: Independent Evaluation of FDA’s First Cycle Review Performance—Final Report. http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm127153.htm. April 2013. Retrieved.