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Development & Approval of Drugs For Use in the U.S.

An Introduction to the Development and Approval of Drugs

American consumers benefit from having access to the safest and most advanced pharmaceutical system in the world.

The main consumer watchdog in this system is the U.S. Food and Drug Administration's Center for Drug Evaluation and Research (CDER). The center's best-known job is to evaluate new drugs before they can be sold. The center's evaluation not only prevents quackery, but also provides doctors and patients the information they need to use medicines wisely. CDER ensures that drugs, both brand-name and generic, work correctly and that their health benefits outweigh their known risks.

Drug companies seeking to sell a drug in the United States must first test it. The company then sends CDER the evidence from these tests to prove the drug is safe and effective for its intended use. A team of CDER physicians, statisticians, chemists, pharmacologists, and other scientists reviews the company's data and proposed labeling. If this independent and unbiased review establishes that a drug's health benefits outweigh its known risks, the drug is approved for sale. The center doesn't actually test drugs itself, although it does conduct limited research in the areas of drug quality, safety, and effectiveness standards.

Before a drug can be tested in people, the drug company or sponsor performs laboratory and animal tests to discover how the drug works and whether it's likely to be safe and work well in humans. Next, a series of tests in people is begun to determine whether the drug is safe when used to treat a disease and whether it provides a real health benefit.

How Drugs Are Developed and Approved?

The Center for Drug Evaluation and Research's (CDER) job is to ensure that drugs are safe and effective. CDER does not test drugs, although the Center's Office of Testing and Research does conduct limited research in the areas of drug quality, safety, and effectiveness.

CDER is the largest of FDA's five centers. It has responsibility for both prescription and over-the-counter drugs. The other four FDA centers have responsibility for medical and radiological devices, food, and cosmetics, biologics, and veterinary drugs.

It is the responsibility of the company seeking to market a drug to test it and submit evidence that it is safe and effective. A team of CDER physicians, statisticians, chemists, pharmacologists, and other scientists reviews the sponsor's new drug application (NDA) containing the data and proposed labeling.

The section below entitled From Fish to Pharmacies: The Story of a Drug's Development, illustrates how a drug sponsor can work with FDA's regulations and guidance information to bring a new drug to market.

From Fish to Pharmacies: The Story of a Drug's Development

Osteoporosis, a crippling disease marked by a wasting away of bone mass, affects as many as 2 million Americans, 80 percent of them women, at an expense of $13.8 billion a year, according to the National Osteoporosis Foundation. The disease may be responsible for 5 million fractures of the hip, wrist and spine in people over 50, the foundation says, and may cause 50,000 deaths. Given the pervasiveness of osteoporosis and its cost to society, experts say it is crucial to have therapy alternatives if, for example, a patient can't tolerate estrogen, the first-line treatment.

Enter the salmon, which, like humans, produces a hormone called calcitonin that helps regulate calcium and decreases bone loss. For osteoporosis patients, taking salmon calcitonin, which is 30 times more potent than that secreted by the human thyroid gland, inhibits the activity of specialized bone cells called osteoclasts that absorb bone tissue. This enables bone to retain more bone mass.

Though the calcitonin in drugs is based chemically on salmon calcitonin, it is now made synthetically in the lab in a form that copies the molecular structure of the fish gland extract.Synthetic calcitonin offers a simpler, more economical way to create large quantities of the product.

FDA approved the first drug based on salmon calcitonin in an injectable. Since then, two more drugs, one injectable and one administered through a nasal spray were approved. An oral version of salmon calcitonin is in clinical trials now. Salmon calcitonin is approved only for postmenopausal women who cannot tolerate estrogen, or for whom estrogen is not an option.

How did the developers of injectable salmon calcitonin journey "from fish to pharmacies?"

After obtaining promising data from laboratory studies, the salmon calcitonin drug developers took the next step and submitted an Investigational New Drug (IND) application to CDER.  

Once the IND application is in effect, the drug sponsor of salmon calcitonin could begin their clinical trials. After a sponsor submits an IND application, it must wait 30 days before starting a clinical trial to allow FDA time to review the prospective study. If FDA finds a problem, it can order a "clinical hold" to delay an investigation, or interrupt a clinical trial if problems occur during the study.

Clinical trials are experiments that use human subjects to see whether a drug is effective, and what side effects it may cause. 

New drugs, like other new products, are frequently under patent protection during development. The patent protects the salmon calcitonin sponsor's investment in the drug's development by giving them the sole right to sell the drug while the patent is in effect.   When the patents or other periods of exclusivity on brand-name drugs expire, manufacturers can apply to the FDA to sell generic versions.

Drug sponsors from small businesses can take advantage of special offices and programs designed to help meet their unique needs.

What is an Investigational New Drug?

Current Federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines. Because a sponsor will probably want to ship the investigational drug to clinical investigators in many states, it must seek an exemption from that legal requirement. The IND is the means through which the sponsor technically obtains this exemption from the FDA.

During a new drug's early preclinical development, the sponsor's primary goal is to determine if the product is reasonably safe for initial use in humans, and if the compound exhibits pharmacological activity that justifies commercial development. When a product is identified as a viable candidate for further development, the sponsor then focuses on collecting the data and information necessary to establish that the product will not expose humans to unreasonable risks when used in limited, early-stage clinical studies.

FDA's role in the development of a new drug begins when the drug's sponsor (usually the manufacturer or potential marketer) having screened the new molecule for pharmacological activity and acute toxicity potential in animals, wants to test its diagnostic or therapeutic potential in humans. At that point, the molecule changes in legal status under the Federal Food, Drug, and Cosmetic Act and becomes a new drug subject to specific requirements of the drug regulatory system.

There are three IND types:

  • An Investigator IND is submitted by a physician who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. A physician might submit a research IND to propose studying an unapproved drug, or an approved product for a new indication or in a new patient population.
  • Emergency Use IND allows the FDA to authorize use of an experimental drug in an emergency situation that does not allow time for submission of an IND in accordance with 21CFR , Sec. 312.23 or Sec. 312.34. It is also used for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist.
  • Treatment IND is submitted for experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.

There are two IND categories:

  • Commercial
  • Research (non-commercial)

The IND application must contain information in three broad areas:

  • Animal Pharmacology and Toxicology Studies - Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans. Also included are any previous experience with the drug in humans (often foreign use).
  • Manufacturing Information - Information pertaining to the composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product. This information is assessed to ensure that the company can adequately produce and supply consistent batches of the drug.
  • Clinical Protocols and Investigator Information - Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose subjects to unnecessary risks. Also, information on the qualifications of clinical investigators--professionals (generally physicians) who oversee the administration of the experimental compound--to assess whether they are qualified to fulfill their clinical trial duties. Finally, commitments to obtain informed consent from the research subjects, to obtain review of the study by an institutional review board (IRB), and to adhere to the investigational new drug regulations.

Once the IND is submitted, the sponsor must wait 30 calendar days before initiating any clinical trials. During this time, FDA has an opportunity to review the IND for safety to assure that research subjects will not be subjected to unreasonable risk.

What is the Process for Regular New Drugs?

For decades, the regulation and control of new drugs in the United States has been based on the New Drug Application (NDA). Since 1938, every new drug has been the subject of an approved NDA before U.S. commercialization. The NDA application is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U.S. The data gathered during the animal studies and human clinical trials of an Investigational New Drug (IND) become part of the NDA.

The goals of the NDA are to provide enough information to permit FDA reviewer to reach the following key decisions:

  • Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug outweigh the risks.
  • Whether the drug's proposed labeling (package insert) is appropriate, and what it should contain.
  • Whether the methods used in manufacturing the drug and the controls used to maintain the drug's quality are adequate to preserve the drug's identity, strength, quality, and purity.

The documentation required in an NDA is supposed to tell the drug's whole story, including what happened during the clinical tests, what the ingredients of the drug are, the results of the animal studies, how the drug behaves in the body, and how it is manufactured, processed and packaged.

How Generic Medications Are Approved

An Abbreviated New Drug Application (ANDA) contains data which when submitted to FDA's Center for Drug Evaluation and Research, Office of Generic Drugs, provides for the review and ultimate approval of a generic drug product. Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, low cost alternative to the American public.

A generic drug product is one that is comparable to an innovator drug product in dosage form, strength, route of administration, quality, performance characteristics and intended use.All approved products, both innovator and generic, are listed in FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book).

Generic drug applications are termed "abbreviated" because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness.Instead, generic applicants must scientifically demonstrate that their product is bioequivalent (i.e., performs in the same manner as the innovator drug).One way scientists demonstrate bioequivalence is to measure the time it takes the generic drug to reach the bloodstream in 24 to 36 healthy, volunteers.This gives them the rate of absorption, or bioavailability, of the generic drug, which they can then compare to that of the innovator drug.The generic version must deliver the same amount of active ingredients into a patient's bloodstream in the same amount of time as the innovator drug.

Using bioequivalence as the basis for approving generic copies of drug products was established by the "Drug Price Competition and Patent Term Restoration Act of 1984," also known as the Waxman-Hatch Act. This Act expedites the availability of less costly generic drugs by permitting FDA to approve applications to market generic versions of brand-name drugs without conducting costly and duplicative clinical trials.At the same time, the brand-name companies can apply for up to five additional years longer patent protection for the new medicines they developed to make up for time lost while their products were going through FDA's approval process. Brand-name drugs are subject to the same bioequivalence tests as generics upon reformulation.For more information on generic drug bioequivalency requirements, please see the chapter entitled "FDA Ensures Equivalence of Generic Drugs" in "From Test Tube to Patient: Improving Health Through Human Drugs."

The Office of Generic Drugs home page provides additional information to generic drug developers, focusing on how CDER determines the safety and bioequivalence of generic drug products prior to approval for marketing. Generic drug application reviewers focus on bioequivalence data, chemistry and microbiology data, requests for plant inspection, and drug labeling information.

What About Over-the-Counter (OTC) Drugs?

Over-the-counter drugs play an increasingly vital role in America's health care system.Today, six out of every ten medications bought by consumers are OTC drugs. OTC drugs are defined as drugs that are safe and effective for use by the general public without seeking treatment by a health professional. FDA's review of OTC drugs is primarily handled by CDER's Division of Over-the-Counter Drug Products.The Nonprescription Drug Advisory Committee meets regularly to assist the Agency in evaluating issues surrounding these products.This committee has played a major role in the growth of prescription to OTC switches in recent years.

Because there are over 300,000 marketed OTC drug products, FDA reviews the active ingredients and the labeling of over 80 therapeutic classes of drugs, for example analgesics or antacids, instead of individual drug products. For each category, an OTC drug monograph is developed and published in the Federal Register. OTC drug monographs are a kind of "recipe book" covering acceptable ingredients, doses, formulations, and labeling. Many of these monographs are found in section 300 of the Code of Federal Regulations. Once a final monograph is implemented, companies can make and market an OTC product without the need for FDA pre-approval. New prescription drugs, on the other hand, require pre-approval before they can go on the market. These monographs define the safety, effectiveness, and labeling of all marketing OTC active ingredients.New products that conform to a final monograph may be marketed without further FDA review.Those that do not conform must be reviewed by the New Drug Application process. A drug company may also petition to change a final monograph to include additional ingredients or to modify labeling.

SOURCE:

The U.S. Food and Drug Administration



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