Friday, March 04, 2005 | 10:58 AM
About the Medicines You Are Taking
Information provided by Micromedex
New drugs: From idea to marketplace
To be sold legitimately in the United States, new drugs must pass through a rigorous system of approval specified in the Food, Drug, and Cosmetic Act and supervised by the Food and Drug Administration (FDA). Except for certain drugs subject to other regulatory provisions, no new drug for human use may be marketed in this country unless the FDA has approved a "New Drug Application" (NDA) for it.
The IdeaThe creation of a new drug usually starts with an idea. Most likely that idea results from the study of a disease or group of symptoms. Ideas can also come from observations of clinical research. This may involve many years of study, or the idea may occur from an accidental discovery in a research laboratory. Some may be coincidental discoveries, as in the case of penicillin.
Idea development takes place most often in the laboratory of a pharmaceutical company, but may also happen in laboratories at research institutions like the National Institutes of Health, at medical centers and universities, or in the laboratory of a chemical company.
Animal testing
A new drug is first tested on animals to help determine how toxic the substance may be. Most drugs interfere in some way with normal body functions. These animal studies are designed to discover the degree of that interference and the extent of the toxic effects.
After successful animal testing, perhaps over several years, the sponsors of the new drug apply to the FDA for an Investigational New Drug (IND) application. This status allows the drug to be tested in humans. As part of their request, the sponsoring manufacturer must submit the results of the animal studies, plus a detailed outline of the proposed human testing and information about the researchers that will be involved.
Human testing
Drug testing in humans usually consists of three consecutive phases.
"Informed consent" must be secured from all volunteers participating in this testing.
Phase I testing is most often done on young, healthy adults. This testing is done on a relatively small number of subjects, generally between 20 and 80. Its purpose is to learn more about the biochemistry of the drug: how it acts on the body and how the body reacts to it. The procedure differs for some drugs, however. For example, Phase I testing of cancer drugs involves actual cancer patients from the beginning of testing.
During Phase II, small controlled clinical studies are designed to test the effectiveness and relative safety of the drug. These are done on closely monitored patients who have the disease for which the drug is being tested. Their numbers seldom go beyond 100 to 200 patients. Some volunteers for Phase II testing who have severely complicated conditions may be excluded.
A "control" group of people of comparable physical and disease types is used in double-blind, controlled experiments for most drugs. These experiments are conducted by medical investigators thoroughly familiar with the disease and this type of research. In a double-blind experiment, the patient, the health professional, and other personnel do not know whether the patient is receiving the drug being tested, another active drug, or no medicine at all (a placebo or "sugar pill"). This helps eliminate bias and assures the accuracy of results. The findings of these tests are statistically analyzed to determine whether they are "significant" or due to chance alone.
Phase III consists of larger studies. This testing is performed after effectiveness of the drug has been established and is intended to gather additional evidence of effectiveness for specific uses of the drug. These studies also help discover adverse drug reactions that may occur with the drug. Phase III studies involve a few hundred to several thousand patients who have the disease the drug is intended to treat.
Patients with additional diseases or those receiving other therapy may be included in later Phase II and Phase III studies. They would be expected to be representative of certain segments of the population who would receive the drug following approval for marketing.
Final approval
When a sponsor believes the investigational studies on a drug have shown it to be safe and effective in treating specific conditions, a New Drug Application (NDA) is submitted to the FDA. This application is accompanied by all the documentation from the company's research, including complete records of all the animal and human testing. This documentation can run to many thousands of pages.
The NDA and its documentation must then be reviewed by FDA physicians, pharmacologists, chemists, statisticians, and other professionals experienced in evaluating new drugs. Proposed labeling information for the physician and pharmacist is also screened for accuracy, completeness, and conformity to FDA-approved wording.
Regulations call for the FDA to review an NDA within 180 days. This period may be extended if additional data is required and, in some cases, may take several years. When all research phases are considered, the actual time it takes from idea to marketplace may be 8 to 10 years or even longer. However, for drugs representing major therapeutic advances, FDA may "fast-track" the approval process to try to get those drugs to patients who need them as soon as possible.
After approval
After a drug is marketed, the manufacturer must inform the FDA of any unexpected side effects or toxicity that comes to its attention. Consumers and health care professionals have an important role in helping to identify any previously unreported effects. If new evidence indicates that the drug may present an "imminent hazard," the FDA can withdraw approval for marketing or add new information to the drug's labeling at any time.
Generic drugs
After a new drug is approved for marketing, a patent will generally protect the financial interests of the drug's developer for a number of years. The traditional protection period is for 17 years. In reality, however, the period is much less due to the extended period of time needed to gain approval before marketing can begin. Recognizing that a considerable part of a drug's patent life may be tied up in the approval process, in 1984 the U.S. Congress passed a law providing patent extension for drugs whose commercial sale may have been unduly delayed by the approval process.
Any manufacturer can apply for permission to produce and market a drug after the patent for the drug has expired. Following a procedure called an Abbreviated New Drug Application (ANDA), the applicant must show that its product has a comparable potency and effect to the original product.
Although the extensive clinical testing completed by the originator during the drug's development does not have to be repeated, comparative testing between the products must be done.
Drug names
Every drug must have a nonproprietary name, a name that is available for each manufacturer to use. These names are commonly called generic names.
The FDA requires the generic name of a drug product to be placed on its labeling. However, manufacturers often use brand names in promoting their products. In general, brand names are shorter and easier to use than the corresponding generic name. The manufacturer then emphasizes its brand name (which cannot be used by anyone else) in advertising and other promotions.
Often, the consumer may not realize that a brand name drug is also available under other brand names or by generic name. Ask your pharmacist if you have any questions about the names of your medicines.
Drug quality
After an NDA or an ANDA has been approved for a product, the manufacturer must then meet all requirements relating to production. These include the FDA's current Good Manufacturing Practice regulations and any applicable standards relating to strength, quality, purity, packaging, and labeling that are established by the United States Pharmacopeia (USP).
Routine product testing by the manufacturer is required by the Good Manufacturing Practice regulations of the FDA (the FDA itself does not routinely test all products, except in cases where there is a suspicion that something may be wrong). In addition to governmental requirements, drug products must meet public standards of strength, quality, and purity that are developed by USP. In order to market their products, all manufacturers in the United States must meet USP-established standards unless they specifically choose not to meet the standards for a particular product. In this case, that product's label must state that it is "not USP" and how it differs from USP standards (this occurs very rarely).
Differences in drug products
Although standards to ensure strength, quality, purity, and bioequivalence (comparable potency and effect) exist, the standards allow for variations in certain factors that may produce other differences from product to product.
These product variations may be important to some patients, since not all patients are "equivalent." For example, the size, shape, and coating may vary and, therefore, be harder or easier for some patients to swallow; an oral liquid will taste good to some patients and bad to others; one manufacturer may use lactose as an inactive ingredient in its product, while another product may contain a different inactive ingredient; one product may contain sugar or alcohol while another product does not.
In deciding to use one therapeutically equivalent product over another, consumers should keep the following in mind:
Consider convenience factors of drug products (for example, ease of taking a particular dosage form). Don't overlook the convenience of the package. The package must protect the drug in accordance with USP requirements, but packages can be quite different in their ease of carrying, storing, opening, and measuring.
If you have an allergy or any type of dietary restriction, you need to be aware of the "inactive" ingredients that may be present in different medicines. These inactive ingredients may vary from product to product.
Price is always a consideration. The price difference between products (e.g., different brands, or brands versus generics) may be a major factor in the overall price of a prescription. Talk to your pharmacist about price considerations. Some states require that the pharmacist dispense exactly what is prescribed. However, other states allow the pharmacist to dispense less expensive medicines when appropriate.
Aside from differences in the drug product, there are many other factors that may influence the effectiveness of a medicine. For example, your diet, body chemistry, medical conditions, or other drugs you are taking may affect how much of a dose of a particular medicine gets into the body.
For the majority of drugs, slight differences in the amount of drug made available to the body will not make any therapeutic difference. For other drugs, the precise amount that gets into the body is more critical. For example, some heart or epilepsy medicines may create problems for the patient if the dose delivered to the body varies for some reason.
For those drugs in the critical category, it is a good idea to stay on the specific product you started on. Changes should only be made after a consultation with the health care professional who prescribed the medicine.
If you feel that a certain batch of your medicine is more potent or does not work as well as other batches, or if you have other questions, check with your health care professional.
New drugs: From idea to marketplace
To be sold legitimately in the United States, new drugs must pass through a rigorous system of approval specified in the Food, Drug, and Cosmetic Act and supervised by the Food and Drug Administration (FDA). Except for certain drugs subject to other regulatory provisions, no new drug for human use may be marketed in this country unless the FDA has approved a "New Drug Application" (NDA) for it.
The Idea
Idea development takes place most often in the laboratory of a pharmaceutical company, but may also happen in laboratories at research institutions like the National Institutes of Health, at medical centers and universities, or in the laboratory of a chemical company.
Animal testing
A new drug is first tested on animals to help determine how toxic the substance may be. Most drugs interfere in some way with normal body functions. These animal studies are designed to discover the degree of that interference and the extent of the toxic effects.
After successful animal testing, perhaps over several years, the sponsors of the new drug apply to the FDA for an Investigational New Drug (IND) application. This status allows the drug to be tested in humans. As part of their request, the sponsoring manufacturer must submit the results of the animal studies, plus a detailed outline of the proposed human testing and information about the researchers that will be involved.
Human testing
Drug testing in humans usually consists of three consecutive phases.
"Informed consent" must be secured from all volunteers participating in this testing.
Phase I testing is most often done on young, healthy adults. This testing is done on a relatively small number of subjects, generally between 20 and 80. Its purpose is to learn more about the biochemistry of the drug: how it acts on the body and how the body reacts to it. The procedure differs for some drugs, however. For example, Phase I testing of cancer drugs involves actual cancer patients from the beginning of testing.
During Phase II, small controlled clinical studies are designed to test the effectiveness and relative safety of the drug. These are done on closely monitored patients who have the disease for which the drug is being tested. Their numbers seldom go beyond 100 to 200 patients. Some volunteers for Phase II testing who have severely complicated conditions may be excluded.
A "control" group of people of comparable physical and disease types is used in double-blind, controlled experiments for most drugs. These experiments are conducted by medical investigators thoroughly familiar with the disease and this type of research. In a double-blind experiment, the patient, the health professional, and other personnel do not know whether the patient is receiving the drug being tested, another active drug, or no medicine at all (a placebo or "sugar pill"). This helps eliminate bias and assures the accuracy of results. The findings of these tests are statistically analyzed to determine whether they are "significant" or due to chance alone.
Phase III consists of larger studies. This testing is performed after effectiveness of the drug has been established and is intended to gather additional evidence of effectiveness for specific uses of the drug. These studies also help discover adverse drug reactions that may occur with the drug. Phase III studies involve a few hundred to several thousand patients who have the disease the drug is intended to treat.
Patients with additional diseases or those receiving other therapy may be included in later Phase II and Phase III studies. They would be expected to be representative of certain segments of the population who would receive the drug following approval for marketing.
Final approval
When a sponsor believes the investigational studies on a drug have shown it to be safe and effective in treating specific conditions, a New Drug Application (NDA) is submitted to the FDA. This application is accompanied by all the documentation from the company's research, including complete records of all the animal and human testing. This documentation can run to many thousands of pages.
The NDA and its documentation must then be reviewed by FDA physicians, pharmacologists, chemists, statisticians, and other professionals experienced in evaluating new drugs. Proposed labeling information for the physician and pharmacist is also screened for accuracy, completeness, and conformity to FDA-approved wording.
Regulations call for the FDA to review an NDA within 180 days. This period may be extended if additional data is required and, in some cases, may take several years. When all research phases are considered, the actual time it takes from idea to marketplace may be 8 to 10 years or even longer. However, for drugs representing major therapeutic advances, FDA may "fast-track" the approval process to try to get those drugs to patients who need them as soon as possible.
After approval
After a drug is marketed, the manufacturer must inform the FDA of any unexpected side effects or toxicity that comes to its attention. Consumers and health care professionals have an important role in helping to identify any previously unreported effects. If new evidence indicates that the drug may present an "imminent hazard," the FDA can withdraw approval for marketing or add new information to the drug's labeling at any time.
Generic drugs
After a new drug is approved for marketing, a patent will generally protect the financial interests of the drug's developer for a number of years. The traditional protection period is for 17 years. In reality, however, the period is much less due to the extended period of time needed to gain approval before marketing can begin. Recognizing that a considerable part of a drug's patent life may be tied up in the approval process, in 1984 the U.S. Congress passed a law providing patent extension for drugs whose commercial sale may have been unduly delayed by the approval process.
Any manufacturer can apply for permission to produce and market a drug after the patent for the drug has expired. Following a procedure called an Abbreviated New Drug Application (ANDA), the applicant must show that its product has a comparable potency and effect to the original product.
Although the extensive clinical testing completed by the originator during the drug's development does not have to be repeated, comparative testing between the products must be done.
Drug names
Every drug must have a nonproprietary name, a name that is available for each manufacturer to use. These names are commonly called generic names.
The FDA requires the generic name of a drug product to be placed on its labeling. However, manufacturers often use brand names in promoting their products. In general, brand names are shorter and easier to use than the corresponding generic name. The manufacturer then emphasizes its brand name (which cannot be used by anyone else) in advertising and other promotions.
Often, the consumer may not realize that a brand name drug is also available under other brand names or by generic name. Ask your pharmacist if you have any questions about the names of your medicines.
Drug quality
After an NDA or an ANDA has been approved for a product, the manufacturer must then meet all requirements relating to production. These include the FDA's current Good Manufacturing Practice regulations and any applicable standards relating to strength, quality, purity, packaging, and labeling that are established by the United States Pharmacopeia (USP).
Routine product testing by the manufacturer is required by the Good Manufacturing Practice regulations of the FDA (the FDA itself does not routinely test all products, except in cases where there is a suspicion that something may be wrong). In addition to governmental requirements, drug products must meet public standards of strength, quality, and purity that are developed by USP. In order to market their products, all manufacturers in the United States must meet USP-established standards unless they specifically choose not to meet the standards for a particular product. In this case, that product's label must state that it is "not USP" and how it differs from USP standards (this occurs very rarely).
Differences in drug products
Although standards to ensure strength, quality, purity, and bioequivalence (comparable potency and effect) exist, the standards allow for variations in certain factors that may produce other differences from product to product.
These product variations may be important to some patients, since not all patients are "equivalent." For example, the size, shape, and coating may vary and, therefore, be harder or easier for some patients to swallow; an oral liquid will taste good to some patients and bad to others; one manufacturer may use lactose as an inactive ingredient in its product, while another product may contain a different inactive ingredient; one product may contain sugar or alcohol while another product does not.
In deciding to use one therapeutically equivalent product over another, consumers should keep the following in mind:
Consider convenience factors of drug products (for example, ease of taking a particular dosage form). Don't overlook the convenience of the package. The package must protect the drug in accordance with USP requirements, but packages can be quite different in their ease of carrying, storing, opening, and measuring.
If you have an allergy or any type of dietary restriction, you need to be aware of the "inactive" ingredients that may be present in different medicines. These inactive ingredients may vary from product to product.
Price is always a consideration. The price difference between products (e.g., different brands, or brands versus generics) may be a major factor in the overall price of a prescription. Talk to your pharmacist about price considerations. Some states require that the pharmacist dispense exactly what is prescribed. However, other states allow the pharmacist to dispense less expensive medicines when appropriate.
Aside from differences in the drug product, there are many other factors that may influence the effectiveness of a medicine. For example, your diet, body chemistry, medical conditions, or other drugs you are taking may affect how much of a dose of a particular medicine gets into the body.
For the majority of drugs, slight differences in the amount of drug made available to the body will not make any therapeutic difference. For other drugs, the precise amount that gets into the body is more critical. For example, some heart or epilepsy medicines may create problems for the patient if the dose delivered to the body varies for some reason.
For those drugs in the critical category, it is a good idea to stay on the specific product you started on. Changes should only be made after a consultation with the health care professional who prescribed the medicine.
If you feel that a certain batch of your medicine is more potent or does not work as well as other batches, or if you have other questions, check with your health care professional.
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