Medicines in America: land of plenty?
Jan was visiting her son in the United States when the arthritis in her neck began to bother her. A quick trip to the local pharmacy only made her pain and frustration worse. The familiar medicine that brought her relief back home in England was nowhere to be found. The reason, she learned, was that her medication contained codeine -- a product not approved for over-the-counter use in this country.
Jan's frustration is not unique. A growing number of Americans with illnesses are discovering that many medicines available in Europe and other countries can't be obtained in the United States. Others, like jan's pain reliever, are available in the United States, but only with a prescription.
According to 1989 figures, there are at least 25 such medicines currently on foreign markets, including Australia, Canada, Denmark, France, Germany, Japan, Sweden and the United Kingdom. Some may never be available here. Others are being investigated by the United States Food and Drug Administration (FDA) through a process that is consistently slower than that of comparable agencies in other western countries.
From 1977 to 1987, for example, new medicines generally became available in the United Kingdom an average of 28 months before becoming available in the U.S., according to a study done at Tufts University in Boston. The study further showed that, of the new drugs approved by the FDA between 1985 and 1986, 72 percent had been approved in foreign countries more than five years beforehand. "This difference generally is due to differences between our regulatory agencies," says Dr. Frank Dudley Hart, a rheumatologist at Westminster Hospital in London. Dr. Hart is a past advisor on the approval of arthritis drugs for England's Medicines Control Agency (MCA), the United Kingdom's version of the FDA. "But there are other factors as well, such as the amount of funds available in each country for research and development. There are also differences in medical practice and culture."
Some of these differences control not only the length of time it takes a drug to be approved, but also the types of drugs that are approved. The Tufts study showed, for example, the United States approved new types of cephalosporin antibiotics faster than other countries because those drugs are more widely used here.
The Cultural Factor
The fact that some drugs are more frequently used in one country than in others is not uncommon. The types of medicines available, how they're used, what types are developed and what types are approved for consumers, depend on a nation's medical philosophy -- how doctors view and treat disease, according to Dr. Hart.
In the U.S. and U.K., for example, doctors tend to focus on the agents that cause disease, such as bacteria and viruses. Medicines to fight these invading organisms often are more widely used in these countries. In France and Germany, on the other hand, general medical thinking focuses on the body's reaction to disease. So French and German doctors tend to prescribe more treatments that modify the body's reaction, such as tonics, vitamins and ways to stimulate the immune system.
These differences exist because medicine has evolved not only from scientific discovery, but also from early philosophical movements, influencing the way humans saw themselves in relationship to the world. The Romanticism movement, for instance, valued human feelings rather than intellectual thought. It encouraged people to view the world as an organism rather than a machine.
This movement was particularly prevalent in Germany during the 18th and 19th centuries, and its influence is apparent in the Germans' general view of the heart. In contrast to the American view of the heart as a mechanical pump, the Germans see it as a nonmechanical organ, influenced by feelings and events that affect the entire body. German doctors are noted for attributing many illnesses to "heart insufficiency," and German drug manufacturers are often leaders in the development and use of cardiovascular drugs. Although the death rate from heart problems is similar in Germany, France and England, the Germans use six times the amount of heart drugs per capita than the French or English.
Another cultural factor influencing drug development and consumption is patient response to medical treatment. "French patients," says Dr. Hart, "are less likely to question their medical treatment than English patients. They tend to accept whatever the doctor prescribes." This may be one reason France has the world's highest consumption of certain sedatives. "English patients are similar to Americans," he adds. "They tend to take an active role in their treatment." In England, the same sedatives so widely used in France have declined steadily in usage over the last decade.
The Economic Factor
Money talks. It affects drug usage and consumption in different countries. Whether patients pay for their own medicines or have the cost subsidized by the government can affect the types available and the dosages prescribed. "Generally, we pay nothing at all or only a small fee for medicines," says Jan, who benefits from Britain's National Health Service.
In the interest of saving money, any country is likely to favor drugs that are effective but less costly than their more expensive competitors. Yet, the price-control policies set up by governments can create very different prices for the same medicine in different countries. For example, the nonsteroidal anti-inflammatory drug Indocin is 10 times more expensive in the Netherlands than in Greece.
Money factors can also affect the dosages prescribed for certain medicines. Japanese physicians, for example, are known for overprescribing medicines. Many of these medicines are sold only in Japan and many have questionable effectiveness. The reason, in part, is that Japanese doctors are allowed to sell the drugs they prescribe. Drug companies sell their products to the doctors at prices far below the Japanese government's official reimbursement prices. The physicians profit by selling their patients large quantities at higher prices -- to a tune of nearly $10 billion per year in profits, according to 1989 estimates. Not only has this system created a massive economic drain, but it has also created a threat to public health because patients may be sold prescribed drugs they do not need.
FDA Delays: A Help or Hindrance?
Diverse attitudes toward treatment affect not only the types of medicines available, but what types are developed and how closely foreign products are scrutinized before reaching consumers. But is the lengthy drug approval process in the U.S. necessarily a disadvantage for Americans? Many experts believe it may be, although the FDA would argue that such a long process is needed to do the required testing that deems a drug to be safe for humans.
The drug approval process, both here and abroad, has developed in part from past errors. At the beginning of the 19th century, pharmaceutical products were traded freely between nations. England did not have any pharmaceutical regulation until after World War 1. At this time, both the United States and Germany required drug products only to be inspected and tested for safety before reaching the market.
"In 1962, the thalidomide disaster effectively tightened drug regulation and testing in England and in the U.S.," recalls Dr. Hart. After the deforming effects of this drug were discovered, the FDA was required to test drugs for effectiveness as well as for safety. The drug-testing procedures of the FDA are now the most stringent in the world.
Yet many claim the FDA is overly cautious. The Tufts University study, for example, found that although the U.S. took longer to approve a drug, its safety record did not differ significantly from countries that approved drugs faster.
"The FDA is much more protectionist," says Kenneth Kaitin, Ph.D., assistant director of the Tufts University Center for the Study of Drug Development, who conducted the research. "The general philosophy has been that they'd rather keep a drug off the market and avoid problems than take a risk by trying it."
In 1989 the U.K.'s MCA reorganized in an effort to speed up its drug approval process. The MCA no longer receives government funds, for example, but instead is funded by drug companies who pay the MCA to review their products -- whether or not the products are actually approved for marketing. Drug applications are processed in the order in which they are received, although exceptions are made for certain drugs with life-saving properties. Due to these and other changes, the MCA now processes drug applications faster than almost any other agency in the world.
"On average, the MCA requires about 115 days to approve an NCE, or new chemical entity," says a spokesperson from England's Department of Health. Before the changes were made in 1990, this process could have taken five or six years.
After approval, the drugs are monitored by their manufacturers, as well as by physicians. "The MCA uses a yellow card system," the spokesperson says. "When doctors notice a problem with the medicine, they record the problem on the yellow card and send it to the MCA." However, there are critics who argue that, under this new system, the MCA may be unduly influenced by pharmaceutical companies and, therefore, unable to adequately protect public safety.
"Overall, it's a good system," says Dr. Hart. "Sometimes medicines are pulled from the U.K. market simply because they require very careful use and may be misused by physicians. This happened in the mid-1980s with the arthritis drug Opren (benoxaprofen), which was recalled due to dangerous side effects."
"One reason the MCA is so much faster than the FDA," adds Kaitin, "is that the English have a better system for tracking a drug once it's on the market. The MCA approves a drug and lets public usage determine how effective it is in the long run. But FDA prefers not to let any questionable drugs on the market in the first place."
Opening the World Market
It's no secret that substantial resources are invested in the research and development of new medicines. Many industry leaders believe that fewer drugs will be available in the future because development and marketing, at $359 million per drug in 1990,(*) are so costly. Of the few compounds (1 of 100) that are approved for testing in humans, less than 23 percent are actually approved for use in humans. And only 30 percent of this fraction actually earn the manufacturer more money than it spent on development and marketing.
International safety and quality standards would help eliminate massive duplication of effort around the world and would make more medicines available to the public sooner. Such "harmonization" efforts are now under way.
In 1985 the European Commission (EC), the governing body of the 12 member states of the European Community, attempted to unify licensing of drugs. The Commission asked each country to automatically recognize drugs licensed in other countries. To date, this system has not worked well because each country has different standards by which it approves drugs. And, for many of the cultural and economic reasons cited earlier, the countries are not eager to accept the safety and quality standards of other nations.
Therefore, to standardize approval of new medicines in these countries, the EC is now working to develop a centralized regulatory agency that will facilitate drug approvals for all countries. Guidelines to ensure consistency in the quality of each country's drug evaluation procedures are being established. These guidelines will: 1) regulate the laboratories; 2) regulate drug studies carried out by manufacturers; 3) affect how medicines are licensed; and 4) affect pricing, labeling, distribution and manufacturing of drugs. "The MCA favors international harmonization," says the Department of Health spokesperson in England; "however, its primary concern will always be public safety."
The success or failure of these international efforts will inevitably affect the drug regulatory process in the U.S. "I think it's just a matter of time before the FDA begins to accept more drugs based on foreign studies," says Kaitin. "However, differences in medical culture and in perceptions of risk and benefit must also be dealt with."
U.S. Drugs -- On the Fast Track?
In 1991, under pressure from AIDS advocates and other interest groups, the FDA began instituting changes to speed up its drug approval process. Particularly affected were drugs to treat life-threatening or severely disabling conditions.
The accelerated process includes letting a drug on the market in a controlled fashion before its long-term value has been proven through the usual lengthy efficacy studies. This system processes drug applications faster by employing non-FDA scientists to review them. Drug manufacturers and FDA officials meet early in the drug development process to avoid problems that may delay a drug's availability to the public.
Provisions to accept drugs approved by other nations are also included in the plan. Currently, such drugs must be tested again in the U.S. The accelerated system is designed to cut the approval time by 50 percent. In addition, the President's Council on Competitiveness aims to cut development and approval times by 45 percent for therapeutic breakthrough drugs and by 5 percent for all other drugs by 1994.
In a recent follow-up study, Kaitin concluded that the FDA's initiatives have helped speed drug approvals somewhat. Recently, for example, the AIDS drug DDI (didanosine) benefited from the FDA's new initiatives and was approved in near-record time: just over six months.
"I think we'll soon see a gradual shift by the FDA," observes Kaitin. "There's a definite philosophical change occurring due to the AIDS advocates. Their message is that there are times when there is a greater risk in keeping drugs off the market than in letting them on.
"Still, making the process work for other drugs will take some time," he cautions. "The U.S. public might not be ready for some of the changes. For instance, consumers may fear that non-FDA reviewers may be too easily influenced by industry rather than by safety.
How Safe Is Safe?
The race toward faster approval of medicines is not without its own pitfalls. Patients may have access to drugs much sooner. But with quicker access come ethical and safety issues.
For example, should proof of a drug's effectiveness be left to the pharmaceutical companies? Should these companies be required to monitor their own drugs after they have been approved by the FDA, or should they be tracked by a nonbiased organization? Should patients be allowed to decide the level of risk they wish to take, if the drug has not been proven safe and effective in long-term studies?
These are only some of the issues being debated as the U.S. drug industry and the FDA work to bring more medicines to the market much sooner.
And, as the world market moves toward standards that will enable the industry to work cooperatively, efforts toward international harmonization in all facets of drug production are now under way. In Australia, for example, the Therapeutic Goods Administration is accelerating its drug approval process by agreeing to accept drug evaluation studies from other nations. The Koseisho, the drug regulatory agency of Japan, is accepting clinical data from other countries, but is also requiring testing in Japanese patients.
Because most major drug manufacturers are now international corporations, there's a strong economic incentive to streamline drug development and approval.
It Pays to Be Vocal
Jan may never be able to purchase her codeine-containing pain reliever in the U.S. without a prescription. U.S. officials may not believe that such medication is more effective than over-the-counter pain relievers with fewer side effects. But if recent trends continue, life-saving drugs may become available faster than ever before. "The current initiatives to accelerate drug approvals are due in part to public pressure from interest groups," says Kaitin. "These groups play an important role because they help determine the critical issues surrounding certain illnesses."
Only time will tell just how much such groups will influence public policy about drug availability, says Kaitin. "But it certainly pays to be vocal," he advises. "If a drug is available in another country that's not available here, let the public and your government officials know it's available and is benefiting other people. The publicity certainly couldn't hurt, and it just might push a drug approval along a little faster." (*) Editor's note: This figure was cited in Pharmaceutical Research and Development: Costs, Risks and Rewards, a report issued in May 1993 by the U.S. Congress, Office of Technology Assessment.