Compliance Quality Assurance

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Compliance with the regulations, and the assurance that a company is in compliance, underlies all the regulatory aspects that have been discussed thus far in this chapter. The FDA requires that any drug or biologic product, whether at the investigational stage or being marketed, is manufactured, studied, and marketed in accordance with its regulations, and the FDA has substantial power to enforce their compliance to the regulations. Even the most innovative product for a highly unmet medical need cannot be expected to reach the market, or stay on the market, if there are serious compliance issues surrounding it.

Thus, a critical function of a regulatory affairs organization in any pharmaceutical or biotechnology company is quality assurance. It is the responsibility of quality assurance to both monitor a sponsor's adherence to the compliance requirements and to help the organization establish systems and processes that build compliance into the development (research), manufacture, and marketing of a drug or biologic product.

Compliance is generally divided into the six categories listed in Fig. 7.31. Like all FDA regulations, there is a great deal of interpretation of the regulations addressing these areas of compliance. FDA issues guidance documents to further explain to the regulated industry their views on compliance. Additionally, the FDA makes selected documents on their compliance findings of pharmaceutical and biotechnology companies available to the public. These documents are used by the industry as a judge of what is, and is not, acceptable to the FDA.

The compliance regulations apply to both a sponsor company and any service provider (e.g., contract research organization or contract manufacturer) that a sponsor company contracts with to conduct their work. The sponsor is ultimately responsible for ensuring that any service provider that they hire conducts their services consistent with the compliance regulations.

Good laboratory practices (GLPs) regulate the conduct of nonclinical laboratory studies that support or are intended to support NDAs or BLAs. The GLP regulations cover all aspects of a nonclinical trial that involves the use of animals and the laboratory practices associated to support animal studies. Good manufacturing practices (GMPs) regulate the manufacture, control, accountability, and documentation of drug or biologic substances and products manufactured for r Good Laboratory Practices (GLP)

r Good Manufacturing Practices (GMP)

r Good Clinical Practices (GCP)

r Electronic Records (Part 11)

r Prescription drug advertising and promotion r FDA enforcement activities

Fig. 7.31. Compliance human use. These regulations ensure that products introduced into humans are of acceptable quality and that a product is appropriately labeled. The regulations also require adequate controls for the release and security of the products before they are allowed to go into the general marketplace. Good clinical practices (GCPs) address the conduct of clinical trials and the rights and safety of human subjects. These regulations cover the conduct of the sponsoring company, the clinical investigators, and the institutional review boards responsible for review and approval of the conduct of a protocol. The GCPs cover not only the technical aspects of a clinical trial but also the ethical considerations and informed consent process involved in inviting someone to participate in a clinical trial.

Certain electronic records and electronic signatures used to create and maintain records in support of GLPs, GMPs, and GCPs are subjected to regulation. The regulations that cover electronic records are in Part 11 of the Code of Federal Regulations and are commonly known simply as "Part 11" regulations. The intent of the Part 11 regulations is to ensure that electronic records of documents required under the other regulations are authentic and have the same basis of integrity as paper documents with handwritten signatures.

Lastly, the FDA regulates the advertising and promotion of marketed pharmaceuticals and monitors the industry to ensure they do not inappropriately promote products or indications that are not yet approved. FDA regulates all promotional aspects, from the direct-to-consumer ads seen on TV to what research publications are actively shared with prescribers.

The power of the FDA in the area of compliance is extensive. They have the right to inspect a sponsor company, a nonclini-cal or clinical investigative site, and a manufacturing site with or without notice. In the worst of offenses, they can bar a clinical investigator from conducting any future clinical trials, close down an institutional review board, seize manufactured product from being marketed, and deny or withdraw drug approvals. Therefore, the compliance regulations are to be taken seriously, as negative consequences can be significant.

Good laboratory practices are a set of regulations designed to establish standards for the conduct and reporting of non-clinical laboratory studies and to ensure the quality and integrity of nonclinical safety data submitted to the regulatory authorities (Fig. 7.32). It is not required that every nonclinical study (e.g., experimental pharmacology study) be conducted to the GLP standard. However, for studies that are considered pivotal to determining the safety of a drug in animals (e.g., carcinogenicity study), it is required that the study be conducted in compliance with the GLP regulations.

The GLP regulations have major categories, each of which describes the requirements that a sponsor must meet in that area. The first of these is the personnel who work in the laboratory facility and their responsibilities. Each study is to have a study director who is a scientist with the appropriate education, training, and experience. This person has overall responsibility for the technical conduct of the study, as well as for the interpretation, analysis, documentation, and reporting of results. Additionally, a quality assurance (QA) unit is required. It is the responsibility of the people in this unit to monitor each study to ensure that the facilities, equipment, personnel, methods, practices, records, and controls are in compliance. The QA unit must be independent of the personnel engaged in the conduct of the study, to ensure there is no conflict of interest in their reporting.

The regulations describe the required physical facilities needed to conduct a GLP trial. The regulations stipulate that appropriate animal care facilities, as well as laboratory space, be available to conduct the study. Equipment that is used in the collection or assessment of data collected in the study must be appropriately maintained and calibrated to ensure the equipment is generating accurate data. The laboratory must have standard operating procedures (SOPs) written, and in effect, that set forth the procedures to be done in order to ensure the quality and integrity of the collected data. In addition, it is necessary to document that laboratory personnel have been trained on these SOPs.

It is a tenet in regulatory compliance that "if it's not documented, it didn't happen." An inspector from the FDA can only inspect the documentation that supports the conduct of a study, as they are not present to observe the study as it is being conducted. Regardless of whether or not a procedure was done, if a procedure has not been documented, it is presumed that the procedure was not completed. Therefore, the documentation that allows an inspector to see that all regulations are being followed is absolutely critical.

The consequences of a pivotal nonclinical safety trial not being conducted in compliance with GLPs are substantial. In the worst cases, the FDA may disqualify a study if it was not conducted according to the compliance standards. In the case of a 2-year carcinogenicity study, a disqualification would be a serious blow to the ongoing development of a drug product, the timing of its submission for approval, and the loss of patent life.

The regulations for good manufacturing practices are intended to ensure that minimum manufacturing standards are r Intended to establish standards for conduct and reporting of nonclinical laboratory studies and to assure quality and integrity of safety data submitted to FDA

r Required for selected, but not all laboratory studies r GLP elements: c Personnel, including Study Director and QA unit o Facilities for animal care, test article control, specimen control c Equipment maintenance and calibration c Appropriate Standard Operating Procedures (SOPs) for all aspects of nonclinical study conduct o Documentation of study conduct r Study results can be disqualified if study not in compliance.

Fig. 7.32. Good Laboratory Practices (GLP)

established and adhered to, such that only quality products are produced and/or sold in the United States (Fig. 7.33). These regulations apply to all drug and biologic products intended for human consumption, without exception. The location of the manufacturing plant can be anywhere in the world. As long as the plant is producing product that will be sold in the United States, it is subjected to these regulations and to inspection by the FDA. These regulations apply to both the manufacture of the drug or biologic substance and the drug or biologic product.

The regulations set forth the minimum methods, facilities, and controls to be used for the manufacture, processing, packing, or holding of a drug product, to ensure that the drug has the identity and strength as labeled and meets the required quality and purity characteristics. The GMP regulations establish the minimum standards for the personnel manufacturing the product, along with the facilities and the equipment used to make the product. The regulations in these respects are extensive. Examples of some of the items described in these sections of the regulations include the protective gear worn by personnel during the manufacturing process, the air-handling systems in the manufacturing plant, and the cleaning of equipment that comes into contact with the drug product.

It is required that all components of the drug product, the containers into which it is packaged, and the labels used to identify the product are controlled at all times to avoid any contamination or use of the wrong component. Multiple layers of control are necessary during the actual manufacture of a product and once a finished product has been produced.

Once a product comes off the manufacturing line, it is the responsibility of a quality control unit to conduct the testing to determine that the finished product has the appropriate identity, strength, quality, and purity to meet predetermined specifications. A product is placed in quarantine until all the testing has been completed and the product is determined to pass all specifications. Once it has been determined that the product meets specifications, it is formally "released," which allows it to enter commercial distribution. If a product is produced that does not meet specifications, it must be quarantined indefinitely and an investigation conducted to determine the cause of the manufacturing failure.

r Intended to ensure that minimum manufacturing standards are adhered to, thereby helping to ensure the quality of drug products produced and/or sold in the US

r Required for all drug products intended for human consumption r GMP elements: o Organization and personnel, building and facilities, equipment c Controls of components and drug product containers and closures, production and process controls, packaging and labeling controls o Holding and distribution, laboratory controls, records and reports, returned and salvaged product r Misbranded and/or adulterated product

Fig. 7.33. Good Manufacturing Practices (GMP)

Documentation during all steps of the manufacturing process is required and critical. Documentation must be maintained on each manufacturing lot for the length of time that the product is presumed to be in potential human use. In the event of a problem identified after it has reached the commercial marketplace, these records will be carefully reviewed to determine if an error was made, and mistakenly overlooked, during manufacturing.

Unfortunately, even with all the many layers of control, manufacturing errors do happen on occasion. Oftentimes, a problem is reported to a sponsor, an investigation is conducted, and a determination is made that an error has resulted in a misbranded or adulterated product reaching the marketplace. Depending on the nature of the misbranding or adulteration, this can result in a drug recall to the wholesale level, pharmacy level, or, in the most serious case, to the patient level. In August 2004, the biotechnology company Chiron® identified bacterial contamination in some lots of their influenza vaccine and advised the FDA and the CDC of their ongoing investigations. Subsequently, the FDA inspected the manufacturing facility in the United Kingdom and announced that none of the 48 million doses of vaccine were safe for use because of significant deficiencies in quality control. Ongoing FDA oversight will be significant to monitor that the appropriate corrective actions have been taken to ensure that Chiron's manufacturing facility can produce safe and effective vaccines.

Good clinical practice (GCP) regulations are designed to both ensure the integrity of clinical data upon which product approvals are based and protect the rights, safety, and welfare of human subjects (Fig. 7.34). The FDA has written regulations for GCPs, and the International Conference on Harmonization has also written extensive guidance on GCPs. It is required that all clinical trials being conducted under a U.S. IND are conducted to GCP standards, regardless of the country in which the trial is being conducted. This includes clinical trials being conducted on either investigational r Intended to ensure integrity of clinical data on which product approvals are based and to help protect rights, safety, and welfare of human subjects r Both FDA regulations and ICH guidelines govern conduct of trials involving human subjects r Required for all clinical trials r GCP elements:

o Institutional Review Board review and approval c Informed consent o Qualified investigators o Adequate sponsor oversight o Scientifically sound clinical protocols o Documentation of study conduct r Study results can be disqualified; investigators can be debarred

Fig. 7.34. Good Clinical Practices (GCP)

or marketed products. There are no exceptions to this requirement.

A major component of GCPs includes the protection of the human volunteers who elect to participate in a clinical trial. The primary body responsible for protecting people who may potentially participate in the trial is the institutional review board (IRB). It is the responsibility of the IRB to evaluate the clinical protocol, available safety and efficacy on the finished product, and the informed consent. The purpose of this review is to ensure that the protocol is scientifically worthy of exposing volunteers to the products and procedures outlined, that the product is reasonably safe as used in accordance with the protocol, and that the patient is adequately informed of the risks they are assuming by participating. Most institutions (e.g., hospitals, academic centers) have an institutional review board that is responsible for the review of all clinical trials conducted in that institution. There are also commercial IRBs, who for a fee will conduct all the necessary work and assume all the responsibilities of IRB oversight. Commercial IRB s are typically used by clinical investigative sites that are not part of an institution. Regardless of the affiliation of the IRB, all are required to follow the appropriate GCP regulations and are subjected to FDA inspection.

The GCPs also require that clinical investigators are qualified by training and experience to do the work required of them in the conduct of a clinical protocol. The clinical investigator is responsible for seeing that the study is conducted according to the protocol, that the rights, safety, and welfare of the individual volunteer are maintained, and that the inves-tigational drug product is controlled. The principal clinical investigator must sign a FDA Form 1572, in which they commit to conduct the trial according the applicable regulations and in which they assume responsibility for the conduct of subinvestigators and staff during the study.

The regulations further outline a host of responsibilities of the sponsor in the conduct of the trial. This starts first with the requirement to write scientifically sound clinical protocols. It would not be ethical to expose volunteers to the potential risks of the drug and procedures required in a clinical protocol if the protocol wasn't appropriately designed to allow valid scientific conclusions to be made. The regulations require that the sponsor monitors each clinical investigator and clinical site to ensure that the conduct of the protocol and the informed consent process is proceeding as planned and that the data being collected are accurate and have integrity. The sponsors are also responsible for keeping all investigators informed of any new pertinent safety data that might become available during the conduct of the trial.

As with all other compliance regulations, it is necessary that the IRB, the clinical investigator and staff, and the sponsor have adequate written documentation of all the procedures followed during the study so they can withstand FDA inspection. There are potential consequences for IRBs, clinical investigators, and sponsors if GCPs are not followed. The operations of an IRB can be closed down, a clinical investigator may no longer be able to conduct clinical trials, and/or the study results can be disqualified from use by a sponsor in support of a new drug approval.

Perhaps the most currently controversial set of compliance regulations is those regulating electronic records (commonly referred to as Part 11; Fig. 7.35). These regulations were written to ensure that electronic records and electronic signatures have the authenticity, integrity, and confidentiality of their equivalent paper records. The FDA wrote them in response to the reality that many records are kept electronically and those records need to be subjected to control so they cannot be altered, either intentionally or unintentionally. The scope of the regulations is limited to those records required under other regulations (e.g., GLP, GMP, and GCP records). They became controversial when their interpretation by both sponsors and FDA inspectors made them overly burdensome. The FDA is currently evaluating the regulations, with the intent of achieving the goal of integrity of electronic records without the unintended consequences wrought by the early interpretations.

The Part 11 regulations require that selected computer systems be validated. This validation procedure requires an analysis of risk and that an installation qualification and operation qualification be completed and documented. This validation is intended to demonstrate that a particular computerized system, be it hardware and/or software, functions in the way it is designed, preserves data integrity, and provides an audit trial of any changes to an electronic record. There must also be security, both physical and password protection, on systems to ensure that no unauthorized individual can make a change, either intentional or unintentional, to an electronic record.

For business purposes, a sponsor may want to have the capability to have electronic signatures of required documents. The regulations are written to ensure that an electronic signature is considered the legally binding equivalent of traditional handwritten signatures, which requires a sophisticated level of security on that electronic signature. And as true with all other compliance regulations, extensive documentation is required on not only the configuration of computerized systems but also risk analyses, validation, and security of these systems.

The regulation of prescription drug advertising and promotion by FDA is intended to achieve two main purposes: (1).

r Intended to ensure authenticity, integrity and confidentiality of electronic records r Applies to records in electronic form that are used to fulfill FDA regulated records requirements r Part 11 elements: c Validation of computerized systems c Security of electronic records, including audit trails o Electronic signatures o Computer systems documentation

Fig. 7.35. Electronic Records (Part 11)

ensure that the pharmaceutical industry does not promote unapproved drugs or unapproved indications of marketed products, and (2). ensure that prescribers and consumers are not misled through advertising that is false and misleading or lacks "fair balance" (Fig. 7.36). Every promotional advertisement or piece shown or given to prescribers (e.g., drug brochures or calendars) is submitted by the sponsor to the FDA for review. The FDA also has the authority to regulate all direct-to-consumer advertising for prescription drugs, including both written ads and those used in the broadcast media. Unlike other compliance regulations that are written to inform a sponsor on what they should do to be in compliance, many of the regulations for drug advertising are written to tell a sponsor what they can't do. It is not the intent of the FDA to stifle promotional creativity, which would result if they only dictated all the features of a drug advertisement.

Advertisements cannot be false or misleading with respect to side effects, contraindications, or effectiveness, nor can advertisements fail to present a fair balance between information relating to side effects and contraindications, and information relating to effectiveness. The regulations require a brief summary of the side effects and contraindications of the drug product to accompany each advertisement. For these reasons, drug ads in the written media are accompanied by a brief summary of the side effects and contraindications from the package insert, and direct-to-consumer ads have statements concerning the side effects and contraindications included in the voice-over of the advertisement. Under very limited circumstances, sponsors are allowed to advertise that a new product is coming to the market in the near future. For example, separate "coming soon" advertisements can state the name of the product or the disease to be treated, but no linkage of the two concepts can be made, and the two advertisements can never be used together.

The FDA recognizes that full exchange of scientific data on drug products and discussions of those data fulfill an important educational need. Educational activities that are deemed by the FDA to be independent from influence by the pharmaceutical company and nonpromotional in nature have not been treated as advertising or labeling and have not been subjected to the agency's regulatory scrutiny.

r Intended to ensure that unapproved products are not promoted r Intended to ensure a product is not misbranded through advertising that has false and misleading statements, and lacks fair balance r Applies to all written and broadcast ads to both prescribers and consumers r Applies to verbal exchanges between prescribers and pharmaceutical sales representatives r Does not apply to non-promotional and independent scientific and educational exchanges

Fig. 7.36. Prescription Drug Advertising & Promotion r Types of GMP inspections: ^ Pre-approval inspection ^ Post-approval inspection

^ Surveillance good manufacturing practice inspection r GCP and GLP Inspections: o Inspection of clinical sites ^ Inspection of animal testing facilities r The inspection process: c May or may not be announced o Site receives "Notice of Inspection" c Inspector's observations -Form FDA 483 o Establishment Inspection Report (EIR)

Fig. 7.37. FDA Inspections -1

In order to enforce the above-described FDA regulations on compliance, the agency is authorized to conduct inspections at any time to ensure that a sponsor, manufacturer, animal laboratory, or clinical investigator is following the regulations (Fig. 7.37). As FDA is responsible for ensuring that drugs and drug products are not adulterated or misbranded and are manufactured, packaged, tested, and distributed in accordance with good manufacturing practices, they conduct periodic inspections of facilities engaged in these activities. There are three types of GMP inspections: preapproval, postapproval, and surveillance good manufacturing practice inspections. A preapproval inspection is conducted when the NDA, BLA, or ANDA is under review at the agency. The purpose of the inspection is to confirm that the application accurately reflects the chemistry, manufacturing and control activities in the facility and that there are no significant GMP issues that need to be resolved prior to product commercialization. If there are significant issues, approval of the application will be delayed until corrective action is taken. After the drug product is approved, FDA will reinspect the facility to evaluate validation and testing data associated with manufacturing multiple large-scale commercial lots. They will also confirm that any changes to the process or test methods have been appropriately documented and, if required, submitted to FDA. Both of the above inspections are usually product specific. During a surveillance GMP inspection, a FDA inspector looks at the overall manufacturing facility, personnel, and operating systems and does not focus on one product. These inspections can be biannual or inspections "for cause." If the FDA receives product complaints such as product tampering or faulty packaging, the agency can send a team to do a "for cause" inspection to investigate the potential causes for the manufacturing problem.

The NDA/BLA preapproval process also includes clinical site inspections. Typically, several sites from the key pivotal trials are inspected to determine if the investigational product was appropriately dispensed, patients gave informed consent, study records were maintained appropriately, and there was appropriate clinical investigator oversight during the patient r FDA inspection classification system: ^ No action indicated - NAI o Voluntary action indicated - VAI o Official action indicated - OAI

r Debarment list r Disqualified/restricted/assurances list for clinical investigators

Fig. 7.38. FDA Inspections -2

visits and evaluation of test results. The intent of the clinical site inspection is to ensure the studies were conducted in accordance with good clinical practices and that there were no fraudulent data reported. Case report forms can be checked against actual patient records to assess fraud. The FDA will also conduct an inspection of selected animal testing site(s) to ensure animal handling and testing was done in accordance with good laboratory practices.

Inspectors from the FDA can notify the company or site of their upcoming inspection or they can arrive unannounced. When an inspector(s) arrives, they provide the company or site with a "Notice of Inspection," which contains the purpose of the inspection. At the conclusion of the inspection, which can last a few hours to several weeks, specific and significant inspection observations are identified on Form FDA 483, with the most significant observations listed first. The inspectors will meet with key company individuals or the clinical investigator to review the results of the inspection, including the Form FDA 483 observations, prior to their final departure. The company or site is obligated to respond to the observations in Form FDA 483. An establishment inspection report (EIR) is issued, which provides a detailed summary of the overall inspection. Both the Form FDA 483 and the EIR are available to the general public, although certain proprietary information is redacted.

Once the EIR has been prepared, the inspection is given one of three classifications: no action indicated (NOI), voluntary action indicated (VAI), or official action indicated (OAI) (Fig. 7.38). A classification of NOI indicates there are no FDA findings that are objectionable and that there are no obligations by the company or site to institute any changes. The classification of VAI is assigned if inspection findings are not serious in nature, and particularly if the company or site has already voluntarily made corrections at the time of completion of the EIR. A company or investigator receives an OAI classification when the inspection findings are substantive enough to warrant regulatory or administrative action. Some types of regulatory actions include civil penalties, injunctions, product seizures, voluntary recall, or a warning letter.

Individuals who have committed criminal acts associated with the activities of drug development can be debarred. Types of debarment acts include falsifying data, lying to inspectors, enrolling nonexistent patients, and reporting false test results for manufacturing lots. All of these activities serve to seriously undermine the safety of the general public. Debarred individuals are forbidden from working for companies involved in drug development. The names of debarred individuals are public information. It is important that pharmaceutical companies be very familiar with this list so that they do not hire anyone debarred in any capacity in the company or as a consultant or investigator for the company. At the time of submission of the NDA/BLA/ANDA, the sponsor must certify that no debarred individuals have worked on the product's development, either within the company or as a consultant or investigator. If the company has used a debarred person, it can be fined up to $1 million and the debarred individual up to $250,000.

Clinical investigators who repeatedly or deliberately fail to comply with good clinical practices or submit false information during the conduct of clinical trials, if not debarred, may be disqualified from participating in future studies. Investigators who are "totally restricted" are not allowed to receive investigational drug, and investigators who are "restricted" can participate in the conduct of studies in accordance with the defined restrictions.

FDA has several formal enforcement avenues to deal with companies and individuals who are not complying with the appropriate regulations and statutes (Fig. 7.39). Warning letters, sent from the FDA to a sponsor or individual, outline compliance violations that need to be corrected immediately. For example, warning letters are typically issued when a company fails to adequately correct numerous manufacturing issues or is consistently using advertising and promotional materials that are misleading or lack fair balance, or when a clinical investigator is consistently not providing adequate oversight to patients in a clinical trial. If the infractions are related to good manufacturing practices, the FDA can use recalls and field corrections to remove potentially unsafe products from the market. A sponsor can initiate a voluntary recall of product, or the FDA can order a recall. The extent of a recall is determined by the potential seriousness of the health issue. Product may be recalled from the wholesaler and/or pharmacy and in the most extreme cases from the patient. Recall information is made public weekly in the FDA

r Warning letters: o Letter to correct violations promptly or enforcement action could be taken r Recalls and field corrections: o Action taken by firm to remove product from field or conduct a field correction r Injunction:

c Civil action to stop production or distribution of violative product r Seizures:

o FDA initiates seizure based on violation of the law. U.S. Marshal takes possession of goods. r Consent Decree r Product/license suspension or revocation Fig. 7.39. FDA Enforcement Activities

Enforcement Report. For products that pose a serious risk, a public warning will be issued via various media avenues such as radio and television news broadcasts, as was done in the case of Tylenol® tampering several years ago.

If the FDA cannot convince a company to voluntarily cooperate, they can petition a federal court for an injunction to legally mandate that a company cease making and distributing a product or products. An example of such a situation is products containing ephedra. After determining that the ingredient provided only short-term weight-loss benefits with potentially serious risks of heart ailments and stroke, FDA ordered ephedra manufacturers to cease distribution and have all products containing ephedra removed from the market permanently. Those companies that did not voluntarily comply were subjected to seizures and injunctions. By filing a formal complaint with a U.S. District Court, the FDA can also initiate enforcement activities in the form of a seizure of product. If granted by the court, a federal marshal can physically seize the product until the issue is resolved. In general, companies voluntarily comply with FDA directives, and seizures are not required.

A consent decree is yet another option the FDA has to enforce compliance. A consent decree is an agreement between the FDA and the sponsor submitted in writing to a court. Once approved by a judge, it becomes legally binding. Consent decrees usually occur when companies continually fail to correct deficiencies or meet correction deadlines despite multiple warning letters and FDA inspections. To date, it has been primarily used in cases of egregious manufacturing noncompliance. A consent decree is very serious. It binds the sponsor to precise ways of doing their work, with appropriate external and FDA oversight. It can take years of intense corrective work, independent outside audits, and FDA interactions to have the decree lifted.

Lastly, the FDA has the authority to suspend or revoke any product approval. The primary reason for a product suspension or revocation would be a serious safety issue with a product that a sponsor refused to voluntarily withdraw from the market.

The responsibilities of the FDA and sponsors are enormous. They both have a profound potential to impact the nation's public health, and they do so in a competitive marketplace, where public companies are held accountable to provide their shareholders with a reasonable return on their investment. Not only is the public health at issue but also the financial health of companies. Over the years, these tensions have given rise to controversies in regulatory affairs that are not easily resolvable (Fig. 7.40).

r Balancing Priorities:

o Speed of new product approvals versus sufficient safety assessment o Innovative pharmaceutical companies, versus generic companies, versus payers (health care)

One of the long-standing controversies is the balance between the speed with which a new product becomes available to patients who desperately need access to new therapies and the sponsor and FDA fully understanding its safety profile. The faster a drug is developed and approved, the less likely the safety profile is fully known. This puts the FDA in the position of judging whether it is better to approve a drug quickly or to wait until additional safety studies have been performed. This is also a dilemma for a sponsor. Whereas the sponsor would like to begin selling a product as soon as possible, they do not want to prematurely sell a product that may unpredictably cause harm.

Another long-standing controversy is that of balancing the interests of innovative pharmaceutical companies, generic companies, and the payors of health care. Innovative companies would like to have their investment in research and development be protected as long as possible, through patent protection and market exclusivity. Generic companies want to be able to compete with brand products as soon as possible. And the payors of health care, the largest being the federal government, would like the prices of pharmaceuticals to be as low as possible. The balance of these forces has led to intricate laws, which through FDA regulations try to effectively balance these two interests. As pressures continue to mount on the cost of health care, this issue will surely continue to be read-dressed. The FDA is also making contributions to streamline the development of new products through reevaluation of the regulatory requirements. If the agency can lessen the regulatory burden on companies while not compromising on demands to demonstrate safety and efficacy, this should reduce the investment needed by sponsors to bring new therapies to the market.

The above examples are just a couple of many classic controversies that continue to shape the thinking and performance of both the FDA and sponsor companies. These interests are served through the enactment of laws, which lead to regulations, which lead to the discipline of regulatory affairs.

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