Source: PhRMA’s Reporter’s Handbook. Washington, DC: Pharmaceutical Research and Manufacturers of America; 1999.

Figure 3-1 shows why this is such an expensive process. For every drug that is eventually approved by FDA, companies screen 5000 to 10,000 compounds, and the entire process consumes years of valuable patent life. According to the Pharmaceutical Research and Manufacturers of America (PhRMA), the cost of bringing one new drug to the market in the United States averages $1.2 billion.

If FDA approves the IND application, the company begins testing in people. As shown in Figure 3-1, these tests progress through three phases:

• Phase I: The investigational drug is tested in a small number (20 to 80) of healthy volunteers (people who do not have any active disease) to ensure its safety and determine appropriate doses in humans.
  
• Phase II: A slightly larger number (100 to 300) of patient volunteers (people who have the target disease) use the drug to see if it continues to prove safe and determine if it works.
  
• Phase III: If FDA allows the company to proceed into Phase III tests, the company recruits 1000 to 5000 patient volunteers to participate in a controlled clinical trial. These trials are used to test for efficacy as well as to identify adverse effects (harmful and unintended side effects) of the drug during short- and long-term use.

After Phase III trials are complete, the pharmaceutical company reviews the data. If the numbers seem to indicate safety and efficacy of the drug, the company files a New Drug Application (NDA) with FDA. The FDA can take several months or even years to review the NDA before either approving or denying the application. Even when the NDA is approved, FDA usually requires further postmarket testing, sometimes called Phase IV, to check for adverse effects that occur in very small percentages of patients taking the drug.

Despite the complexity of this process, some 20 to 50 new drugs come onto the US market each year. According to PhRMA, 3240 medicines were in development in 2011. With the new knowledge we now have about the human genome (the 46 human chromosomes), companies are increasing both the number and the types of new drugs they are researching. As this happens, scientific knowledge of pharmacogenomics and pharmacogenetics—the use and dosing of drugs with knowledge of people’s genetic makeups—will increase in frequency and importance. Currently, FDA includes pharmacogenomic information in labeling for more than 100 medications.

As a pharmacy technician, you may encounter patients who are receiving investigational new drugs. Especially in large teaching hospitals, your pharmacy may be assisting with numerous drug protocols. Special procedures and record keeping must be followed when handling these agents.

For instance, these studies are usually placebo controlled. This means that up to one-half of the patients in the study are receiving tablets or capsules that are identical in appearance but have no active drug. By using these placebos, the researchers can measure the improvements in patients’ conditions that are attributable to the new drug.

The studies are usually also double blinded, which means that neither the researchers nor the patients know who is receiving the active drug and who is getting a placebo. For this purpose, the pharmacy often prepares identical dosage forms (tablets or capsules), some with active drug and some with placebo. If these products were to get mixed up, it could ruin the study.

If your responsibilities include investigational agents, be sure that you understand the relevant policies and procedures adopted in your facility.

Therapeutic Equivalence Ratings

Once a drug product’s patents expire, any pharmaceutical manufacturer can pursue approval and marketing of a generic form of the medication through an Abbreviated New Drug Application (ANDA) process. After an ANDA is approved by FDA, the manufacturer can produce and market the generic medication.

FDA oversees the process for determining whether generic and brand medications can be substituted for one another. In other words, when a patient presents a prescription for a brand-name product in the pharmacy, the pharmacist and pharmacy technician are obligated to fill it with that product or a generic alternative that is considered to be equivalent by FDA.

Drug products classified as “therapeutically equivalent” by FDA can be substituted for one another with the full expectation that the substituted agent will have the same efficacy and safety profile as the prescribed brand-name drug product. FDA considers medications to be therapeutically equivalent if they are pharmaceutical equivalents (same ingredient, dosage form, route of administration, and strength) and meet criteria for bioequivalence (substituted product performs the same in the body as the prescribed drug).

The Orange Book is an FDA reference first published in 1980 that includes the therapeutic equivalence ratings (or “codes”) for generic and brand drugs. It is available online (www.accessdata.fda.gov/scripts/cder/ob/default.cfm) and is updated regularly.

The most commonly used equivalence code is an “AB” rating for oral medications. You may hear in the pharmacy that two drug products that are pharmaceutically equivalent (same ingredient, dose, route, and strength) are “AB rated,” to signify that they are substitutable according to FDA. Keep in mind, though, that rules for applying therapeutic equivalence ratings are set by state boards of pharmacy and differ in each state. Ask your pharmacist if you are unsure if two drug products are therapeutically equivalent and substitutable in the pharmacy.

Chapter 5 contains additional information on brands and generics in the dispensing process.

Drug Withdrawals and Recalls

Despite all the effort to make sure that drugs are safe and effective before they come onto the market, serious or fatal adverse effects sometimes occur after a medication is used widely. Even when a drug is tested in a few thousand people, rare but serious side effects may not become apparent (or even occur) until millions of people are exposed to the drug. When these situations develop, the drug product is withdrawn from the market either temporarily or permanently. While the withdrawals are often termed voluntary, the companies usually act after they and FDA officials conclude that the risk of continued use of the drug outweighs the possible benefits of keeping the agent on the market.

FDA also sometimes asks companies to recall specific batches, or lots, of their products. The reasons for recalls vary from serious situations, such as products that contain the wrong drug or too much of the correct drug, to less important situations, such as the company’s manufacturing processes have been called into question, but nothing is necessarily wrong with the drug products.

To place recalls into perspective, FDA divides them into three types, as follows:

• Class I: Continued use of the product is very likely to cause serious adverse effects or deaths in people.
  
• Class II: Use of the product could cause temporary but reversible effects or there is little chance that serious adverse effects would result from use of the product.
  
• Class III: Use of the recalled lots or product is unlikely to cause adverse effects in people.

As a pharmacy technician, you will no doubt be called on to find the affected lots of recalled drug products. These recalls are announced by the companies and publicized by FDA on its Web site at www.fda.gov/Safety/Recalls/default.htm. If an investigational drug or a radiopharmaceutical is recalled, special conditions may apply to the return, handling, or destruction of these medicines. In such cases, be sure to follow the policies and procedures of your workplace.

Dietary Supplement Health Education Act

Because consumers are bombarded by much false and misleading information about health foods, alternative medicines, and dietary supplements, pharmacists and pharmacy technicians can play an important role in helping patients sort out legitimate, useful products from those that are just quackery. The first step in providing this help is to understand the rules governing the available products and the role FDA plays in the system.

In 1994, the US Congress passed an important bill, the Dietary Supplement Health and Education Act of 1994 (DSHEA), that governs the sale and marketing of dietary supplements. Also known as alternative medicines, vitamins, minerals, herbs, medical foods, or amino acids, these products are in a gray area between regular foods and medications.

As a result of this bill, products labeled as dietary supplements may make three types of claims on their labels:

• Nutrient-content claims describe the amount of nutrients contained in the product. Examples include “High in calcium” or “Excellent source of vitamin C.”
  
• Disease claims, which must be based on established scientific evidence, describe well-established links between diet and health. Examples include prevention of certain types of birth defects by folic acid supplements and prevention of osteoporosis by calcium supplements.
  
• Nutrition support claims describe relationships between dietary intake and disease or health, such as the use of vitamin C in preventing scurvy. They may include “structure-function claims,” such as “calcium builds strong bones” or “antioxidants maintain cell integrity.”

FDA, in implementing DSHEA, required that dietary supplements carry a “Supplement Facts” panel, similar to the “Nutrition Facts” panel you see on most foods. The supplement’s panel includes the following:

• An appropriate serving size.
  
• Information on 14 nutrients, when present at significant levels, including sodium, vitamin A, vitamin C, calcium, and iron.
  
• The presence of other vitamins and minerals if they are added or are part of the product’s nutritional claims.
  
• Dietary ingredients for which no Reference Daily Intakes have been established.
  
• For proprietary blends of ingredients (for example, a mixture of herbs for the liver), the names of the ingredients and the total amount of ingredients (the specific amount of each ingredient is not required).

A key point regarding dietary supplements is that they are not reviewed and regulated by FDA in the same way as drugs. For a drug to be marketed in the United States, a sponsoring company must prove to FDA that the drug is both safe and effective. In contrast, dietary supplement companies must merely notify FDA at least 75 days before a product is to go on the market. FDA can only stop the company from marketing the product if the agency can prove that the product is not safe. Efficacy is not considered with dietary supplements. So, in terms of both FDA process and the onus of responsibility, dietary supplements are the opposite of drugs. With drugs, manufacturers must convince FDA that new medications are safe and effective before they are allowed to market products containing that agent. With dietary supplements, FDA must prove lack of safety in order to stop a manufacturer from marketing a product, and it has only 75 days to do so. In addition, manufacturing processes are not nearly as strict with dietary supplements as with drug products.

Risk Evaluation and Mitigation Strategies

For a quarter century, FDA has been looking for an effective way to communicate drug risks to patients at the dispensing point. In the 1970s, FDA began requiring patient package inserts to be dispensed with oral contraceptives and estrogen-containing drug products. These inserts were one of FDA’s first formal efforts to communicate specific drug risks to patients through added labeling.

During the 1990s, FDA began employing “restricted distribution” or “restricted access” programs to limit availability of selected drug products that were thought to be of significant risk if used inappropriately. These drug products included clozapine (Clozaril—Novartis), thalidomide (Thalomid—Celgene), isotretinoin products (Accutane—Roche, Amnesteem—Mylan, others), and dofetilide (Tikosyn—Pfizer). Drugs included in these programs had special requirements for physicians and other prescribers, patients, and pharmacies. For example, pharmacy registration and documentation of laboratory monitoring with a national registry is required to dispense clozapine to help prevent and detect life-threatening agranulocytosis (seriously low white blood cell counts) and other cardiovascular and respiratory effects.

In addition, FDA ruled in 1999 that it could require manufacturer-produced medication guides for any drug product under certain conditions in which a drug has serious risks, patient information may help prevent adverse effects, and patient adherence to directions is crucial for a drug’s safety.

The many programs and differing requirements were sometimes confusing, and it was often unclear that they had a common goal. In 2007, the Food and Drug Administration Amendments Act of 2007 granted FDA broad authority to require “Risk Evaluation and Mitigation Strategies” (REMS) for drugs for which FDA deems that use of specific strategies to increase patient awareness and education about safety and appropriate use can minimize a drug’s risk.

The advent of REMS programs brought all of the previous strategies under a larger umbrella of risk management. Required REMS components may include a medication guide, elements to ensure safe use (for example, a patient registry), a communication plan, and/or an implementation system (for example, prescriber and pharmacist training).

Medication Guides

Medication guides are the most frequently used mechanism to meet the REMS requirement. FDA can require a medication guide as part of a REMS program if one or more of the following circumstances exist:

1. Patient labeling could help prevent serious adverse effects related to the drug;
   
2. The drug poses serious risks relative to benefits, which could affect patients’ decision to use, or continue to use, the product; or
   
3. Patient adherence to directions for the drug’s use is crucial to the drug’s effectiveness and the drug is important to health.

If a medication guide is required as part of a REMS program, the guide must be dispensed to the patient or the patient’s representative upon request, or each time that a drug is dispensed in an outpatient setting and will be used without the supervision of a healthcare professional. A medication guide may also be required in other circumstances, such as after a significant change to the medication guide, or if the REMS requires medication guide review with the patient to ensure safe use.

A complete listing of drugs that require medication guides is available on FDA’s website (www.fda.gov/Drugs/DrugSafety/ucm085729.htm).

Individual REMS Requirements

Most of the drugs previously classified as restricted distribution have been transitioned to individual REMS requirements. This means that the requirement is limited to a single drug in a given category or class. Drug products with significant individual REMS requirements include the following:

• Epoetin alfa injection (Epogen—Amgen, Procrit—Janssen)
  
• Thalidomide
  
• Alosetron (Lotronex—Prometheus)

Shared Systems REMS Requirements

Some drug categories or classes have shared systems REMS. This means that all agents in the class have the same REMS requirements. Drug products with significant shared system REMS requirements include

• Isotretinoin products
  
• Extended-release and long-acting opioid products
  
• Transmucosal immediate-release fentanyl products (Actiq—Cephalon, Fentora—Cephalon, others)

It is important to follow these REMS requirements and document dispensing of these agents exactly as specified. As a pharmacy technician, you have an important role in ensuring compliance with these programs.

Centers for Medicare & Medicaid Services

The Centers for Medicare & Medicaid Services (CMS) is the agency that administers federal coverage of health care in the United States. It was known as the Health Care Financing Administration (HCFA) from its inception during the Great Society phase of the Lyndon B. Johnson Administration (1965), until it was renamed during the George W. Bush Administration in 2001.

While the Medicare and Medicaid programs are very complicated, Medicare is the program that pays for acute (hospital) care for those aged 65 years or older and for those who are disabled. Medicaid covers the indigent, meaning those without insurance or enough money to pay for care on their own.

Prescription Drug Coverage: Medicare Part D versus Medicaid

Since the 2006 implementation of a federal drug benefit, Medicare Part D has also provided prescription drug coverage for all beneficiaries. Before this legislation, Medicare paid for prescription drugs only when they were used in an acute-care institution (hospital) or in conjunction with certain medical devices such as in-dwelling catheters (tubes that go into very large veins of the body). Chapter 6 offers more background on the emergence of this benefit.

In contrast, Medicaid pays for outpatient prescription drugs and other care for indigent patients in community pharmacies, nursing homes, or hospitals. Some people qualify under both Medicare and Medicaid, and they are termed “dual eligibles.”

It’s important to note that the Medicaid program is financed jointly by the federal and state governments, with each contributing about one-half of the funds. Though Medicaid is a federal program, pharmacists’ interactions are usually with the agency within the state government that coordinates the program.

As state budgets have been squeezed more and more recently, Medicaid programs have been increasingly tightened. The effects of these economic constraints have been severe in many states. For example, Medicaid patients’ prescriptions usually must be filled off a state-approved drug list (or “formulary”), recipients may be limited to a certain number of prescriptions per month, and states have sometimes held up Medicaid payments for several months because of budgetary shortfall.

Health Care Reform

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