In a condition as emotionally laden as herpes, there are bound to be promises of effective treatment-even cure that do not deliver. There have been many articles in scientific journals and the lay press claiming discovery of substances effective against herpes. In most cases, proper testing has shown such treatments to be ineffective. Longtime herpes sufferers learn to discount reports of bogus treatments. Persons who suffer this disease—and those who treat them—must learn about proper drug testing in order to judge more accurately what is valid medical breakthrough and what is medical “hype.” The first part of this chapter will be devoted to a discussion of drug development, with emphasis on the Food and Drug Administration (FDA) approval process. Later I will discuss some drugs that have been used for herpes treatment without being proved effective.
Drug Development: An Overview
The development of a new drug product is a long, complex process that can begin in many places: a drug manufacturing laboratory, a chemical company, research at the Institutes of Health (NIH). If all goes well, the public eventually benefits from a drug developed over a period of years and tested on both animal and human subjects under carefully controlled circumstances. The FDA is responsible for approving the marketing of all new drugs that are sold in the United States and for monitoring their use after approval. Many Americans, particularly herpes sufferers, are rightly concerned about how long it takes a new drug to be tested and perfected prior to marketing.
Remember, however, drugs have been marketed that have been very dangerous to humans, causing serious side effects that included horrible birth defects and death. Before 1962, there was no requirement that drug developers notify the FDA when human subjects were being used to test drugs! The 1962 Kefauver-Harris Amendments to the Federal Food, Drug, and Cosmetic Act greatly strengthened the government’s authority over clinical (human) testing of new drugs. With this new regulatory authority, the FDA has taken steps to: (1) provide added safeguards for those on whom drugs are tested; (2) improve reports by drug investigators; and (3) establish investigative procedures to supply substantial scientific evidence that a drug is safe and effective.
A Word About Research Design and Valid Testing
A clinical test known as a double-blind, placebo-controlled trial is the most valid research design with which to test a new drug. If you were performing such a study, you would choose test subjects with the same disease. All would receive the same care, the same tests, and the same follow-up throughout the trial with one critical difference. One of your patient groups would receive the test drug, while the other would receive the placebo, which, you will remember, is an inert look-alike substance. Because the study is double blind, neither the test subjects nor researchers know who is getting the drug and who is getting the placebo.
Exactly what does the double-blind component effect? The patient may expect to improve or remain the same, depending on which compound-drug or inert-he receives. His expectations may in fact influence his physiological state. It is the same with the researcher, who may be very excited about a drug’s potential value. The researcher may convey unconsciously to the patient whether the latter is expected to get better or not.
There have been many studies that have not used a placebo control. We know from many tests that herpes is particularly prone to the placebo effect. To restate the principle, you can administer a sugar pill and, if the administrator is sincere about the pill’s effect, patients will have a less severe illness. People actually will the placebo to work. This is a strong phenomenon, especially with people who are desperate to rid themselves of a certain ailment.
In a well-designed study, if the test drug out-performs the placebo and if many other criteria are met, that drug is considered to be of potential value. But unless a drug is tested against a placebo in a double-blind study, there is no way of knowing whether an unknown variable may have caused the results. Any drug or compound may produce the placebo effect: many drugs may heal some of the patients some of the time. It is only in the placebo-controlled study that we learn if patients improve because of the placebo effect or because of real antiviral effects of the test drug. Such studies also make analysis of side effects more valid.
Other factors also contribute to valid test results. More than just a handful of persons should be used. The test should be repeated, with comparable results each time (replicated). Patients should be classified into different groups. For example, patients with initial herpes lesions will react differently than patients with recurrent lesions. Males may react differently than females. The drug may have a different effect on genital herpes than it will on labial herpes. All such differentials must be taken into account during design of the study or statistical analysis of results.
Learn how to evaluate research. Such skill will help you pick your way through the myriad false leads—and perhaps the few genuine ones—faster than you otherwise would.
The Long, Rigorous Road to FDA Approval
The first step in development of a new drug is research into the chemistry or anatomy of a disease. Conversely, basic researchers might discover a chemical’s possible drug effects. Recently most drugs have been developed in the laboratories of pharmaceutical companies.
The chemical in question is then subjected to screening tests and to testing in animals. Initial animal studies are performed to see if the chemical has any desired drug effects. If so, additional testing determines what effects might occur, what dosage levels are toxic, what the safe dosage range might be for humans, and whether there is a reason for testing the chemical in humans.
The FDA requires that sufficient animal studies be performed to show it is reasonably safe to begin human testing of the drug, but does not monitor the animal tests. Additional animal tests are required as human tests progress.
FDA-Monitored Stages. If initial animal results indicate that the drug may have therapeutic value and be safe for humans, the FDA becomes a very powerful monitor of further evaluation.
The Investigational New Drug. In this step toward drug approval the sponsor submits to the FDA a form known as a “Notice of Claimed Investigational Exemption for a New Drug,” and thereafter the drug is called an Investigational New Drug (IND). On this form, the sponsor must tell the FDA the complete composition of the drug, its source, and how it is made. In addition, the sponsor must submit the results of all animal studies in an attempt to show that the drug may be therapeutic for humans and pose no unreasonable risk.
The IND form also contains a detailed outline, called a protocol, describing the plan for testing in humans. The sponsor must wait 30 days after submitting the IND form to give the FDA time to review the materials and make sure patients are not being subjected to unwarranted risks. At the end of that period the sponsor may then begin the proposed clinical testing unless the FDA asks for a delay because of a potential safety problem involving use of the drug.
Phases of Development. Human testing is divided into the following three phases.
Phase I. The first phase of human testing is directed at determining the safe dosage range for a drug, how it is absorbed into the body, and its toxicity. Some evidence of the drug’s potential effectiveness must also be determined. These tests usually involve 20 to 80 patients. Much of this testing is done in normal, healthy volunteers. However, if a drug is intended for a certain disease the testing is more appropriately conducted in selected patients with that disease.
The main things investigators are looking for during Phase 1 studies are how the chemical acts in the body and if further testing should be done. Once Phase 1 studies are successfully concluded, Phase II studies can start.
Phase II. The second phase of human testing is performed on closely monitored patients to learn more about the drug’s safety and effectiveness. The number of patients depends on the nature of the drug, but seldom is more than 200.
The majority of Phase II testing is directed at treatment or prevention of a specific disease. Additional animal testing is usually undertaken to gain safety information.
If the Phase II tests show the drug may be useful in treating a disease and the long~term animal testing indicates no unwarranted harm, then the sponsor proceeds to Phase III.
Phase III. This is by far the most extensive testing. Phase III studies are intended to ascertain with precision the drug’s safety, effectiveness and most desirable dosage for treating a specific disease or symptom in a large number of patients. Additional testing to define more specifically any drug-related adverse effects is also done in Phase III testing.
As with earlier human studies, these tests are carefully controlled. The investigator must have a basis for determining that the drug-not other variables or chances-is causing the desired effect.
In Phase III, the drug is used as the way it would be when marketed. Once Phase III is completed and the sponsor believes the drug is safe and effective under specific conditions, the sponsor applies to the FDA for marketing approval. This application is called a New Drug Application (NDA).
Patient Consent and Drug Testing. The FDA does m believe that any person should be required to participate in study involving investigational drugs, or duped into taking drug he or she does not need. The law requires that physician, before using investigational drugs on human: must obtain the person’s consent. That consent must I: informed—that is, the patient must know what the risks an The only exception is when informed consent is not feasible as in the case of a small child, or a patient whose mental faculties have been affected by his disease.
The New Drug Application. By the time an NDA i submitted, a drug usually has been studied in hundreds < thousands of patients. An NDA contains everything th sponsor knows about the drug. Data usually runs into th thousands of pages.
The NDA is reviewed by the agency within the FDA’ Bureau of Drugs that is responsible for evaluating that dry category. There are six review divisions: cardio-renal, neuropharmocological, metabolism-endocrine, ant-infective, oncological and radiopharmaceutical, and surgical-dental. Each division is composed of physicians, chemists and other professionals experienced in evaluating new drugs
The FDA also makes extensive use of advisory committees, composed of experts from outside the agency, t» aid in drug evaluations. The NDA is also reviewed by a team of scientists which ascertains whether the drug is safe an: effective; what its labeling should be; and whether the drug sponsor can manufacture it properly and consistently, batch after batch.
The NDA includes the drug’s chemical structure, drug samples, the proposed drug labeling, all animal and human studies, and a scientific rationale for the drug’s intended purpose.
The FDA reviews the entire NDA to determine whether the benefits of the drug, when used properly, outweigh the risks. This is the crucial determination in evaluating a new drug.
If a drug is indicated for a cancer patient, for example, a relatively high degree of risk and adverse reactions may be tolerated if there is a reasonable likelihood some benefit may ensue, because the alternative—not to use the drug—might be death. However, if a drug is to be used as a minor tranquilizer, then a much lesser degree of risk would be acceptable, because the situation is not critical, and there may be alternative drugs available.
The benefit-risk judgment that goes into approval of a new drug is one of the hardest anyone can make. It involves not only medical but also societal considerations. How much risk is the public willing to take to obtain the benefits of a new drug, when no drug is completely free from risks?
One of the final steps in the approval of an NDA is the review of the package insert or labeling. This is a detailed explanation for physicians and other practitioners of what the drug is, how it works, for what it has been proven useful, adverse reactions, means of administration, dosages, and other pertinent information. The package insert that must accompany the drug whenever it is shipped in interstate commerce serves as the basis for all the manufacturer’s claims for the drug. The company may not make any claim that is not in the approved labeling. A summary of man: package inserts appears in the Physicians’ Desk Reference, a widely distributed book to which physicians often turn for information about prescription drugs.
Once an NDA is approved, the company is required to keep records relating to production methods for the drug an: its safety and effectiveness. Any information indicating that the drug may pose an unexpected hazard must be reported by the FDA.
A manufacturer must report to the FDA every three months during the first year of approval , every six months in the second year, and once a year after that. Immediate reports are required in case of drug mix-ups or contamination, or when unusual or especially severe adverse reactions are discovered.
At the time of an NDA approval, or any time afterward , the FDA can ask the manufacturer to perform post-marketing studies to better define the incidence of a serious adverse reaction.
These studies can also be requested by the FDA to determine the safety and effectiveness of the drug in patient populations not adequately studied , such as children. Should a new use for a drug be discovered, recommended, or evolve into medical practice after the drug has been marketed, the FDA can request studies to determine the drug’s effectiveness for this new case.
“Me-Too” Drugs. If a drug has been previously marketed by one company, another company’s version of the same drug is called a “me-too” drug. In some cases, it is necessary for a company that wants to market a “me too” drug to go through the same type of extensive testing required for the original drug. The FDA therefore has established procedures to permit “me-too” manufacturers to submit shorter applications , and to permit published studies to be submitted as evidence of a drug’s safety and effectiveness.
In the same context, it should be noted that the FDA does not issue patents for drugs. Patents are issued by the U.S. Patent ffice and are in effect for 17 years. If a firm develops a new drug, it can get a patent for it and take legal actions against any company that tries to market an identical drug during the 17-year period. Once the original patent expirees, any other company can market a “me-too” version of the drug under its generic name or under a new trade name if the drug meets all requirements of the law.
Changes in the NDA. Whenever a company wants to change any part of the procedure for making a drug, it must seek FDA approval. This is because what appears to be minor change in the manufacturing process may affect the final product. This type of approval, which is sought frequently, is called a Supplemental New Drug Application.
The FDA must also approve any change in labeling. Very often after a drug has been in use for some time, new information develops about it. Perhaps there are new purposes for which it can be prescribed, or new warning that need to be included.
FDA Functions Following Approval. The FDA role 2 a drug monitor does not end with new drug approval. The agency continues to protect the consumer in several ways.
Withdrawing Approval. If any approved drug is found to produce an unexpected side effect or to be less safe or effective than had been anticipated, the FDA can seek 1 withdraw approval. The FDA gives the firm an opportunity to present its views. In some cases, this may involve hearing. In landmark rulings in five “drug effectiveness” case the U.S. Supreme Court on June 18, 1973 supported the FDA’s authority to make the final judgment as to whether drug is safe and effective, and to deny a hearing to company that cannot show that significant facts are at issue.
Labeling for Patients. In 1970 the FDA took a major step to provide information about prescription drugs direct] to patients. The agency decided that manufacturers of or. contraceptives—“T he Pi1l”—must include in all package received by patients a statement summarizing the potential risks of the drug. Physicians were provided with brochure listing the benefits and risks of the drug in greater detail.
The reason for this decision was that the FDA believe women should be able to participate in the decision c whether to take “The Pill” as a birth control measure. Drugs used for contraception are different from others. They are to be used by healthy women, not to treat disease, and they are nonchemical alternatives for birth control.
Subsequently, the FDA added a requirement estrogen and progestin drug products must be dispensed with information for patients, because of certain risks of drugs.
Certification. The law provides that two types of drugs, antibiotics and insulin, must not only be approved generic for marketing by the FDA but also must be certified batch- batch. The manufacturers pay for this service. The FDA, tests random samples from each batch for purity 2 potency. The manufacturer may not release the batch 111 the FDA certifies it.
Advertising. One of the most significant sources information about prescription drugs is that supplied by drug manufacturers to physicians through advertising medical journals, direct mail, or sales representatives know as “detail men.”
The law requires that information supplied physicians about prescription drugs be truthful, full informative, and fairly balanced by information about its side effects. The information may not be false or misleading any way
The FDA extensively regulates prescription drug advertising and mail promotion. Whenever material is found to be misleading, the FDA can seek to seize the drug on the grounds that the product is “misbranded.” In virtually 2 cases, however, the FDA seeks alternatives that have proven more effective. For example, the FDA must require the drug company to place remedial ads in the journals in which the misleading ad appeared or send remedial letters physicians.
To help improve medical communications, the FD publishes a Drug Bulletin for all physicians, dentist: pharmacists, and other health professionals, informing the: of significant new developments.
What Consumers Can Expect. Consumer exposure to drug products of unproven safety and effectiveness i minimal in the U.S. This does not mean patients are never exposed to unnecessary hazards from prescription drugs. All medicines have the potential to harm as well as benefit, and despite all precautions, prescription medicines are misused or misunderstood at times.