The Genesis of Drug Development

Everyday, health care professionals use or suggest dental care products regulated by the US Food and Drug Administration (FDA). Although the FDA regulatory environment is continually evolving, its mission has remained constant—to promote and protect the public by helping safe and effective products reach the marketplace in a timely manner through a blend of “law and science.” The agency regulatory practices vary among products depending on the laws the agency enforces and the relative risk of the product to consumers. Drugs and complex medical devices must prove safety and effectiveness before receiving FDA approval to market, whereas, lower risk products and devices such as x-ray machines and power toothbrushes must “measure up to performance standards” to receive FDA clearance. On the other hand, cosmetics and dietary supplements generally do not require approval prior to being marketed.

Dental professionals and consumers recognize the American Dental Association (ADA) Seal of Acceptance as an important symbol of dental product safety and effectiveness. To date, more than 1,300 products have received the ADA seal. However, this is a voluntary review, whereas products that fall under the jurisdiction of the FDA must comply to mandatory regulations. Products like antitartar toothpastes; fluoride gels and mouthrinses; cold sore remedies; chewing gums containing drugs; oral antiseptics; and locally delivered antimicrobials such as fibers, powders, chips, and gels may have the ADA seal but they are also regulated by the FDA because they claim “therapeutic activity.”

The FDA regulates many common dental devices such as ultrasonic scalers, hand instruments, power toothbrushes, manual toothbrushes, dental floss, implants, lasers, and x-ray systems. Medical devices are classified into Class I, II, and III, with the amount of regulatory control increasing depending on the risk. Class I devices like floss and toothbrushes are considered low risk. Ultrasonic scalers are Class II moderate risk devices. Items such as titanium endosseous implants are considered higher risk Class III devices.^1,3

The Review Process

With more than 9,000 lawyers, physicians, pharmacologists, other health care professionals, and support staff, the FDA regulates products worth about a trillion dollars a year. The FDA does not develop, manufacture, or test products, but evaluates the data submitted by the manufacturers to determine whether the product is safe and effective for its intended use (s).

Five centers within the FDA have regulatory responsibility for drugs, medical and radiological devices, foods and cosmetics, biologics, and veterinary products. Drugs fall under the jurisdiction of the Center for Drug Evaluation and Research (CDER). CDER is the largest center and is responsible for ensuring that all marketed drugs are safe and effective and for reviewing labeling and advertising. The Center for Food Safety and Applied Nutrition (CFSAN) is responsible for regulating food products, dietary supplements, and cosmetics. Products such as soaps, mouthrinses, and toothpastes, which are intended for cleansing only, are regulated as cosmetics.

Drugs are defined in the law as “articles intended for the use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man…” and “articles intended to affect the structure or any function of the body….”¹ New drugs must demonstrate they are safe and effective before marketing. Of course, no drug is 100% safe. Side effects are always a risk, however, some side effects are expected and anticipated. For example, severe nausea may be an acceptable side effect for anticancer drug therapy, but not for treatment of a simple cold sore.

Rx and OTC Drugs

Prescription (Rx) drugs are reviewed for safety and effectiveness based on the entire product, including active ingredients, inactive ingredients, and bioavailability. On the other hand, nonprescription, over-the-counter (OTC) drugs are evaluated by the agency based solely on the active ingredient and to ensure that they are properly labeled.

Currently, there are more than 100,000 OTC drugs marketed in the United States. Similar to prescription drugs, CDER regulates OTC products to ensure that their benefits outweigh their risks. Prior to the passage of laws that require proof of safety and effectiveness, OTC products were marketed without this assurance. In response, the FDA began to review OTC products and evaluate their ingredients and labeling according to standards set in the OTC Drug Review Program.

Typically, OTC drug products are approved on the basis of a drug monograph review. The FDA has established standards in the form of a drug monograph or recipe, which documents acceptable ingredients, doses, allowed combinations, and labeling information. The Federal Register contains the final monograph (FM), which is the agency’s final position on all OTC ingredients in a specific drug category. New products meeting the standards of an approved monograph may be marketed in the United States without going through the premarket approval New Drug Application (NDA) review process, while those that do not, must undergo FDA review.

Rx to OTC switch refers to the marketing of a product that was once available by Rx only. Most medications used in the United States are nonprescription products, which enable the consumer to self-treat a variety of common conditions. In order to facilitate consumers’ desire to participate in their own health care and because of rising prescription drug costs, the FDA allows certain prescription drugs to be switched to OTC if they meet specific requirements of safety and effectiveness. Generally, the OTC version is a different concentration, therefore, an NDA is submitted to the FDA OTC Advisory Review panel for approval to switch the status of a prescription drug to nonprescription.

If products demonstrate low potential for misuse or abuse, the labeling is easily understood, and consumers are able to self-treat the condition, they may be approved for OTC switch. Commonly, the switch is approved for a drug with a lower dosage and shorter treatment duration.

Generic Drugs

The FDA defines FDA-approved generic drugs as “bioequivalent and therapeutically equivalent to their brand name counterparts.” Generic drugs are chemically identical to the original drug, but are typically sold at substantially lower prices. The FDA developed guidelines and specifications for a generic product’s bioequivalency and stability, which sponsors must follow. Bioequivalence is determined by measuring the amount of active ingredient that reaches the bloodstream and comparing it to the brand name drug. These absorption rates are compared to ensure that the generic product reaches the same blood level of active ingredient in the same amount of time. To gain approval to market a generic version of the original drug, the sponsor submits an Abbreviated NDA (ANDA). The term “abbreviated” generally implies that new preclinical and clinical data are not required with the application because the safety and effectiveness were established when the original drug was approved.

Cosmetic Products

Cosmetic products are applied to the human body for cleansing or beautifying without altering the body’s structure or function. The Center for Food Safety and Applied Nutrition (CFSAN) regulates cosmetic products. Cosmetics are not reviewed or approved by the FDA prior to being sold, but may be regulated once they reach the marketplace. Some products perceived by the consumer to be strictly cosmetic might also be classified as a drug, therefore, they may make both claims. For example, toothpaste without fluoride is considered cosmetic, whereas fluoridated toothpaste is regulated as a drug because fluoride is a caries preventative, thus it has a therapeutic effect. If therapeutic claims are made, CDER regulates the product.

Supplements

A dietary supplement is defined by law as a product taken by mouth that contains ingredients intended to supplement the diet such as vitamins, minerals, herbs, or other botanicals. Dietary supplements fall under a different set of regulations than those covering traditional foods and drugs. The manufacturer of a dietary supplement submits proof of safety, then the agency (CFSAN) has 30 days to decide if the product is indeed safe. The FDA is responsible for taking action if a product proves unsafe after being marketed. The Federal Trade Commission is responsible for regulating truth in advertising.

Presently, the manufacturing practices of dietary supplements do not undergo FDA review, however, in response to numerous health concerns regarding herbal products, the FDA is reviewing regulatory practices related to dietary supplements and is actively seeking their modification.

Clinical Testing

Drug testing starts in the laboratory and in animals where researchers analyze the physical and chemical properties of a drug and evaluate its pharmacological and toxic effects. In order for clinical testing to begin in humans with an unapproved product, an Investigational New Drug (IND) application is filed with the FDA. The IND application is a request to the FDA for approval to proceed with human testing and authorization for interstate shipping. The application contains information that describes preliminary animal and lab testing that demonstrates the drug is reasonably safe to study in humans. The FDA reviews the application to ensure that the study will likely provide meaningful information and that patient volunteers will not be placed at unreasonable risk.

Well designed, randomized, controlled clinical trials are responsible for getting effective new drugs to the consumer as they progress to human testing. Typically, the FDA first becomes involved when a sponsor seeks to test a new product in humans. To conduct clinical research, the Code of Federal Regulations stipulate guidelines for good research and the protection of human subjects.² A sponsor’s failure to comply with these regulations can result in the rejection of data after years of effort and millions of dollars invested.

Not all diseases can be replicated in animals or in vitro, therefore, testing may start in individuals with the disease rather than in a healthy population. Phase I of clinical development usually begins in a small number of healthy male volunteers. If no major problems occur that can be attributed to the drug, the process of determining effectiveness in populations with the condition begins in Phase II and III. The main goals of Phase II are to evaluate the drug for safety and effectiveness and collect dose-related information. Phase III studies are usually conducted in randomized clinical trials to collect further safety and effectiveness data where the drug is generally compared to a placebo or drug alternative. Generally, clinical trials continue until there is enough evidence to support the NDA. Presently, the NDA review and approval process takes approximately 18-22 months.

Post Market Surveillance

Because of the possibility of unknown side effects, postmarket surveillance continues for the life of a drug. As a condition of FDA approval, the sponsor must report adverse reactions and may be required to complete further clinical studies to evaluate drug performance. Once approved, the sponsor may choose to further investigate the drug to receive approval to market the product for other uses or in various formulations.

MedWatch is the FDA’s safety information system, which has mandatory adverse event reporting requirements for manufacturers, but is voluntary for health professionals and consumers. Manufacturers are required to indicate possible known or predictable side effects in the product labeling. However, unknown consequences are often difficult to predict before a product goes on the market because certain side effects may only be identified when the product is exposed to a very large population under varying conditions. If problems occur, general complaints or concerns about drugs, devices, foods, and dietary supplements may be reported by contacting the MedWatch hotline at (800) FDA-1088. The MedWatch program provides a mechanism to report suspected problems directly to the FDA while maintaining confidentiality. In addition to providing a mechanism to submit concerns, the MedWatch system issues notification on recent product recalls, safety warnings, and general information about products regulated by the FDA.

If the FDA determines a product in the marketplace is unsafe and presents significant public health risk, action is taken. The most serious action is to remove a product from the market. A I recall is issued if a product has potential to cause serious adverse health consequences or death, like certain weight loss medications. A II recall is issued if a product has potential to cause temporary, but reversible adverse health consequences. A III recall is issued when a product is not likely to cause adverse health consequences. Possible actions that the agency may take for II or III recalls include requiring a label change in response to new information or issuing a warning or safety alert to the consumer.

The decision to develop a product or move from one phase of research to another is based on scientific merit, questions asked, research outcomes, economics, and timing. For example, the developer of Arestin™ (OraPharma Inc, Warminster,Pa) disclosed that the time from the initiation of Phase III clinical trials to FDA approval, took approximately 2 years, which does not take into account the time that went into preclinical and Phase I/II development. Presently, the FDA estimates that it takes approximately 8 years to take a new molecular entity through laboratory and animal testing and all phases of clinical research before it can be approved for the general public.

Even though sponsors are reluctant to disclose the economics of product development and much research and development information are considered proprietary, the FDA estimates the process of bringing a new “molecular entity” to market costs well over $800 million (in the year 2000), although this figure is disputed by some as inflated.³ On the other hand, generic drugs and products developed with an existing monograph, are usually much less expensive to develop. For example, new products developed with a variation of the existing molecular entity, Chlorhexidine, included Peridex in 1986, followed by Perioguard in 1994, and the Periochip in 1998. Doxycycline was used to develop Atridox in 1998 and Periostat in 2001.

In addition, to sponsor costs of preclinical and clinical research Congress passed the Prescription Drug User Fee Act (PDUFA) that requires industry applicants needing review of clinical data to pay the FDA a user fee of approximately $533,400 per review. The Act expires every 5 years at which time Congress and the FDA must renegotiate the stipulations. The FDA’s goal is to reduce review time for standard applications (drugs that are similar to drugs already marketed) to 12 months and priority applications (drugs that represent a significant advance over existing drugs, especially in the area of AIDS and cancer) to 6 months. ⁷

The feasibility of getting a new drug to market decreases as the research process moves forward. According to personal communication with Kenneth Kaitin, PhD, associate director, Tufts University Center for the Study of Drug Development, “Of every 100 drugs which enter clinical studies, an average of 30% are rejected during phase I, a further 37% rejected in phase II, 6% rejected in phase III, and 7% rejected in regulatory review. In total, only 20% of the drugs which reach the stage of being tested on humans are eventually approved for marketing.”

Trends in product success, effectiveness, cost, and time are documented as research builds (Table 1). With more subjects exposed to the drug under varying conditions, many reasons for halting or altering the progress of research become apparent. It is the responsibility of the FDA, in concert with the sponsor, to make decisions regarding the progress of product development.

Even though drug development is a costly and arduous process, the public benefits in terms of improved health care and quality of life. In 2002, there were 78 new drugs approved for market; including 17 new molecular entities, eight new “orphan” drugs used for rare disorders affecting populations of 200,000 or fewer, 13 Rx to OTC switches, and 152 new or expanded uses for already approved drugs.⁴ Without sponsors willing to undertake the process of new product development and the regulatory oversight of the FDA, health care professionals would not have the vast number of safe and effective products that benefit many Americans.

Research is an evolutionary process where studies evolve and one discovery leads to another. Dental professionals should be knowledgeable about the strict FDA regulatory process that products must undergo in order to be sold in the United States and to apply this knowledge to evidence-based decision making when recommending treatments and products to patients.

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