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The major societies and associations often published journals, collaborated with medical schools, and sometimes maintained committees on drug adulteration to check drug samples and to publicize information. The Formulary has functioned since to provide standards for drugs omitted from the USP and to serve as a proving ground for drugs eventually transferred to the USP. But before the twentieth century there was no direct federal regulation of drugs or other consumer products.

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In , Congress forbade the importation of adulterated drugs, but the law quickly became moribund, as the drug examiners were usually untrained political spoilsmen Young , The Reconstruction years saw the formation of the U. Consisting of only a few men, the bureau did little more than request customs inspections of imported foods and to a lesser extent drugs. In , the bureau got a righteous and rambunctious chief in Harvey Washington Wiley, who campaigned for federal laws. A common pattern in the history of federal drug control has been the shocking event that unleashes new governmental powers.

In , contaminated smallpox vaccines and diphtheria antitoxins led to tetanus outbreaks and the death of several children. Vaccines, blood and blood products, extracts of living cells, and other drugs belong to a category called biological drugs. The Biologics Act of required that federal government grant premarket approval for every biological drug and for the process and facility producing such drugs.

Never before had such premarket control existed in the United States. The same premarket authority was enacted for animal biological drugs in the Virus, Serum, and Toxin Act of Miller In the most shocking incident, a worker collapses into a lard canister and is indiscriminately ground and shipped for sale.

Eventually their digestive systems showed ill effects. The law recognized the privately produced U. Pharmacopoeia and National Formulary as official standards for the strength, quality, and purity of drugs and for the tests to make such determinations. Thus, the law defined an adulterated drug as a drug that was listed in the USP but that did not meet USP specifications unless variations from the USP were clearly labeled. In addition, several states had already made reference to the USP in defining adulteration.

Thus, the federal law mandated what was already practiced widely, though not universally. A drug was considered misbranded if it contained alcohol, morphine, opium, cocaine, or any of several other potentially dangerous or addictive drugs, and if its label failed to indicate the quantity or proportion of such drugs. The law pertained only to labeling, not to advertising.

For consumers, the main result of the law was not to restrict choices but to provide more information. In addition, the scientists of the Bureau of Chemistry performed useful and important work in developing assays and tests to help identify and purify drugs and to make production uniform. Because the feds could not wield coercive premarket power, the Chemistry Bureau and industry trusted each other and cooperated to improve drug manufacturing.

Prosecutions typically resulted in confiscation and small fines. Johnson, the manufacturer, fought back, taking the case to Supreme Court. The Court agreed with Johnson, ruling that any therapeutic claim is a matter of opinion. It follows that there exists no authoritative medical opinion that coercively overrides others, and hence no charges can be brought against therapeutic claims unless the sellers actually intended fraud.

Nonetheless, the developments of this early period set a precedent for federal government activism in medicine. Meanwhile, in the regulatory functions of the Bureau of Chemistry were reorganized to become the Food, Drug, and Insecticide Administration, which in changed its name to the Food and Drug Administration. The Harrison Narcotics Act of placed a tax on the production, sale, and use of opium and required prescriptions for products exceeding the allowable limit of narcotics.

This act also mandated increased record keeping for physicians and pharmacists who dispense narcotics. Under the Harrison Act, thousands of physicians were imprisoned for prescribing narcotics. Under the new administration of Franklin D. Roosevelt, the FDA immediately began pressing for more regulatory powers, but not much happened with respect to drugs until the next shocking episode. A well-established pharmaceutical company, Massengill, released a new sulfa drug an antibacterial under the name Elixir Sulfanilamide.

The drug itself had undergone a variety of quality and safety checks, but in producing a liquid form the company failed to test the solvent. Possessing a pleasant green shade, this solvent, diethylene gycol—better known today as antifreeze—had deadly effects on the kidneys. As a result, people, mostly children, died before the product was quickly recalled.

The Elixir story is often told to lament the meagerness of federal control. The FDA could prosecute Massengill merely for misbranding: the product Elixir Sulfanilamide did not contain alcohol and therefore did not fit the definition of an elixir. Nothing could be done about the Elixir deaths, runs the usual lament, because Massengill had not made fraudulent claims for the product.

The tragedy is said to have demonstrated that unfettered markets cause reckless injury and that public safety called for additional laws. That telling of the story, however, entirely overlooks the role of tort law in providing compensation to victims and in promoting deterrence. At the time of the Elixir episode, the common law did provide remedies for harm from misbranded or adulterated drugs, and Massengill was successfully sued in tort for its gross negligence Krauss The chemist responsible for creating Elixir Sulfanilamide committed suicide.

The Constitution does not give the federal government any power to regulate drugs. The laws regulating drugs were thus written so as to apply only to drugs used or produced in more than one state. Given the broad—sometimes absurdly broad—construction the courts have given to the interstate commerce clause, in practice the law regulates every drug despite the original intent of the framers.

The Act included several provisions that would prove to be significant wedges for future power expansion. Thus, the default position was approval; the burden of proof for departure from the default position fell on the FDA, and as a result the costs of the FDA to the public were kept low. To some extent, the Act continued the information provision requirements of the Act. Other provisions did restrict choice and reduce consumer information. An obscure provision of the Food, Drug, and Cosmetic Act and of a series of subsequent FDA regulatory decisions had the effect of creating a new class of prescription-only drugs.

The original labeling laws were meant to provide more information to consumers and thus improve their ability to make good decisions. The intention of Congress in passing the act was to further the goal of creating informed consumers. Yet the FDA decided that some drugs could not be labeled safely. Traditionally the manufacturer decided whether a drug was a prescription or an over-the-counter OTC drug, and sometimes some manufacturers sold a drug by prescription only, while others sold the same drug over the counter.

Now, however, manufacturers were subject to considerable uncertainty because they had to guess whether the FDA would deem a drug prescription only or OTC. If a manufacturer thought consumers could properly use a drug, and thus labeled it and sold it OTC, the FDA might disagree, remove the product, and sue the manufacturer for misbranding. Indeed, if a patient misused the drug, even deliberately so, the manufacturer bore all resulting legal responsibility.

Divided authority began to stifle entrepreneurship. The disarray continued until , when the Congress passed the Durham-Humphrey Amendment see below. Although the FDA could not prevent a medical device from coming onto the market, as it could for drugs, it did have the authority to ask the courts to stop the production or sale of devices already entered into interstate commerce. Under this authority, the FDA removed a number of quack devices from the market Higgs c. Many important drugs could be sold only by prescription from a licensed practitioner.

Licensed doctors, therefore, became deputies and spoilsmen in the growing system of controls. Consumers had to pay for the drug and a visit to the doctor. Dependence on doctors was further institutionalized and legitimated by making it difficult for consumers to gain information, in particular by the labeling and advertising controls that prohibited information or mandated unintelligibility.

Thus, licensed doctors gained wealth and relative status by stripping others of freedom and by dumbing down consumers.


Under this amendment, manufacturers still had discretion over the classification of already approved, non-habit-forming drugs, which were to come under FDA control in The Food Additives Amendment required premarket approval of food additives. The Color Additive Amendments required premarket approval of color additives.

The so-called Delaney anticancer clause prohibits the FDA from approving any color additive that has been found to cause cancer in humans or animals regardless of the dosage levels. As a result, substances that cause cancer when rats ingest hundreds or thousands of times the typical human dose have been banned from food products. See Wildavsky on the inappropriate use of animal studies in the regulation of carcinogens. In the post—World War II era, the field of pharmacology entered a new age. People with bacterial illnesses could now be treated with a host of new antibiotics, and diabetics were likewise given the life-saving invention of insulin.

The very success of the new drugs, however, spurred new regulations. Senator Estes Kefauver, who sat on the Senate Antitrust and Monopoly Subcommittee, decided that in dealing with medications, the government must do more than control their labels, contents, and safety and their marketing and distribution processes. Each pharmaceutical company would, after three years, be required to share its new patents with competitors, while collecting an annual royalty fee of some 8 percent of the total. As with the acts of , , and , another tragedy paved the way to passage. The tragedy was so great, so sensitive, and so graphically shocking that it still evokes strong emotions and arrests intellectual discourse.

In , a West German pharmaceutical manufacturer introduced a new sedative, thalidomide , which alleviated the symptoms of morning sickness in women during the first trimester of pregnancy. Thousands of newborn babies were found to have truncated limbs that resemble flippers.

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By virtue of photojournalism, the horror and sadness were shared throughout the world. FDA officials had not even suspected that the drug caused birth defects. In , President Kennedy bestowed the Distinguished Federal Civil Service Award on the FDA physician who held up approval, Frances Kelsey, even though her withholding of approval was more a matter of bureaucratic delay than of investigation Harris The Kefauver bill was revised so that the pricing and patent-sharing provisions were deleted, and the Kefauver-Harris Amendments were soon law.

The amendments authorized the FDA to require drug companies to conduct and submit tests determining safety and efficacy. In addition, the FDA now had to preclear all human trials, drug advertising, and labeling. The FDA also increased its regulatory power over manufacturing. The Amendments significantly reduced the choices of doctors and patients, and expanded the power of the FDA, which increased its staff from one thousand members in to nearly sixty-five hundred two decades later Temin , In addition to requiring efficacy testing for new drugs, the FDA, with the help of the National Academy of Science Drug Efficacy Study Implementation , launched an investigation of the efficacy of the then-current stock of drugs.

The task of proving efficacy is much more difficult, expensive, and time-consuming than the task of proving safety. To a great extent, efficacy, which is sensitive to individual conditions and mediated by market process, had in the past always been judged jointly by doctors and consumers. Safety, naturally, always calls for strong prior assurance. In , however, the FDA began to act on the premise that it could establish authoritative knowledge of efficacy prior to experience and experimentation in actual market processes.

The time spent waiting for FDA approval and the expense and duration of the bureaucratically determined testing procedures combined to cause tremendous delays in drug development and production. Drug development declined significantly after , and the wait for new life-saving drugs increased to more than a decade by the end of the s see FDA Harm below. The role of thalidomide in the passage of the Amendments is riddled with unfortunate ironies. First, the episode aroused great public empathy for human suffering, but no thought was given to the suffering that was bound to result from the ever more confining grip on drug development, availability, and information.

Second, people cited thalidomide in claiming that drug approval delay is a blessing, but the pre FDA had proven to be sufficiently slow to avoid thalidomide harm in the United States. Third, the old law of already required premarket approval for safety. Nothing about thalidomide even superficially recommended premarket approval for efficacy.

As with drugs, the field of medical devices entered a new era after World War II. Cardiac pacemakers, renal catheters, replacement joints, and many other innovations were introduced in this period. The FDA first tried to regulate these new products by reclassifying them as drugs, but in the usual story it took a tragedy, this time over the faulty Dalkon Shield IUD, to generate new law.

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The Amendments expanded the definition of a medical device and authorized the FDA to categorize all medical devices into three classes. Class I devices—tongue depressors and gauze, for example—are subject to reporting requirements and Good Manufacturing Practices GMP regulations. Class II devices are subject to the same controls as Class I devices and the same product-specific performance standards supposedly developed by the FDA see further below.

Class III devices—artificial hearts and angioplasty catheters, for example—must pass an FDA approval process similar to that required for new drugs; that is, before marketing can begin, Class III devices have to be proven safe and effective in extensive clinical trials, and submit to and pass an FDA premarket approval process. In an excellent example of FDA thinking, new devices are automatically categorized as the most risky devices, i. See Some Remarks about Medical Devices for an absurd consequence of this procedure. The FDA, for example, did not develop any performance standards until !

Thus, Class II devices have played no role in medical device development up until recent times, and it remains to be seen whether they will become more common in the future. The reality was recognized in the SMDA, which formally made the k process into an approval process. Munsey provides a good overview of the medical device regulation.

The Infant Formula Act of was passed after thirty-one children were diagnosed with problems relating to a chloride deficiency in a particular brand of soy-based infant formula. Following an initial report on three children from a physician who suspected a problem with the soy formula, the FDA worked remarkably rapidly in consultation with pediatricians and the manufacturer to assess and identify the problem.

Within one week of the initial report, the manufacturer initiated a voluntary recall CDC The story so far shows the FDA at its best and most useful. Unfortunately, in response to this event, Congress ruled that infant formula could no longer be marketed without prior FDA approval. As a result, it has become difficult and expensive to get new infant formulas approved. In parallel with the problem of drug lag we now have a problem of infant formula lag an example of which can be found by following the link. By , the research, testing, and development of a new drug could take up to twenty years, seven of which expired in waiting for final FDA approval of the NDA.

For more recent average times, see the Drug Development and Approval Process below. Heightened awareness of patients direly waiting for pending treatment gave rise to reform. Thus, FDA regulation had especially negative consequences for people suffering from rare diseases. The Orphan Drug Act gave tax breaks, subsidies, and special exclusivity privileges to sponsors of drugs for rare diseases.

Rather than reducing the FDA barriers to producing orphan drugs, the Orphan Drug Act was meant to stimulate the development of such drugs by granting sponsors new monopoly privileges. The exclusivity granted under the act differs from a patent. A patent protects against competition from a drug with the same chemical structure. Market exclusivity as implemented by the Orphan Drug Act grants protection for seven years against competition from any drug with a similar effect. The FDA thereby bars firms from marketing drugs that treat diseases also treated and perhaps less effectively by a drug granted exclusivity.

Officials claim that this act has been a success, noting that almost a thousand drugs have been granted orphan status. The number of such drugs is misleading, however, because many would have been produced even without the act. Shortening the clinical trial period speeds critical new drugs to market, but it comes with a risk, because there is limited data to prove their safety and effectiveness. Under the fast track designation, for example, the FDA may approve a drug based on data from a single Phase 2 study. And the accelerated approval pathway allows approval based on surrogate endpoints that are reasonably likely to predict patient outcomes.

Surrogate endpoints are markers such as laboratory results or radiology images, while clinical endpoints measure the reduction in symptoms or mortality. For cancer treatments, surrogate endpoints used to approve drugs include a shrinking tumor or lower biomarker levels, instead of the clinical endpoints of longer survival or improved quality of life. Surrogate endpoints can be measured sooner, allowing patients access to new treatments much faster, but they are not always accurate indicators of how well a treatment may work, especially in a larger real world population.

Under the current regulatory structure, the FDA approves almost every new drug application it receives. In and , the FDA approved 89 percent and percent, respectively, of novel drug applications, which are defined as more innovative NDAs that involve new molecular entities.

While not unprecedented, this is a higher approval rate than the FDA generally has produced in the past; in and , for example, the FDA approved 51 percent and 71 percent of novel drug applications, respectively. Given the speed and approval rate of the FDA, there is no need to further expedite the drug approval process.

This approach would lead to additional drugs entering the market with little evidence to support their safety and effectiveness, which can harm patients. Nevertheless, many lawmakers support the 21st Century Cures Act and other similar proposals. As noted previously, the 21st Century Cures Act includes a number of troubling policies that would give FDA the authority to find a drug safe and effective on the basis of less scientifically rigorous evidence. Moreover, the legislation creates a financial incentive for hospitals to use these largely untested drugs: For each patient treated with these newly approved drugs, the hospital receives an add-on payment.

The FDA, however, already has the authority to use these data when it is most appropriate: when the drug is intended to treat a serious or life-threatening condition. It also gives industry experts an increased role in determining when it is appropriate to use these surrogate endpoints. Ultimately, however, there is no evidence that changing these standards would speed the approval of game-changing, truly innovative new products, nor is there any evidence that less rigorous review would lower drug prices.

The current expedited programs already place a premium on speed of approval. In situations where there are few existing treatments or where a new treatment can significantly improve patient outcomes, speed is a priority. But if the drugs being approved are less urgently needed or offer little to no improvement over existing treatments, the need to prioritize speed over safety diminishes.

In such cases, the benefits are much less likely to outweigh the risks to patient safety that are inherent in permitting drugs to enter the market after shortened clinical trials or based on limited data. Evidence supports this concern.

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For example, researchers have found that since , when policymakers adopted the priority review and accelerated approval programs, the number of approved prescription drugs that received black-box warnings—which is the most serious safety warning that the FDA can impose on a drug—or that were withdrawn from the market for safety-related reasons has increased 25 percent. The researchers suggest that one reason for this increase is that growing numbers of new drugs are entering the market with more limited data about their safety and efficacy.

Notably, the Government Accountability Office has already raised concerns that the FDA lacks sufficient data to thoroughly monitor the safety of new drugs after they have been approved—especially for drugs that are approved under an expedited pathway, where postapproval oversight is crucial due to the abbreviated clinical trial process.

This worry will become even more significant in the coming years, because an increasing number of drugs are being channeled into expedited programs. In , more than 60 percent of approved drugs were approved by the FDA based on reduced data and evidence requirements. The FDA now approves more than two-thirds of drugs based on data from studies lasting six months or less. Moreover, one-third of new drugs are approved on the basis of a single trial, and the median size for all such trials is just more than patients.

The FDA is also approving an increasing number of supplemental new drug applications for additional clinical uses or patient populations—including children—using surrogate endpoints and limited data. Gleevec was first approved in for the treatment of chronic myelogenous leukemia—a rare blood cancer—after only Phase 2 studies and just 2. Since its initial approval, the FDA has approved additional uses of the drug to treat several different gastrointestinal tumors, and post-marketing studies have confirmed its effectiveness.

But not all drugs that go through expedited programs are similar game-changers. Skewing the process toward greater speed is simply not necessary. And it is illogical to think that such changes will necessarily lead to future breakthroughs like Gleevec. On the contrary, Gleevec shows that the current process works to expedite innovative drugs; efforts to allow more drugs on the market with even lower evidence of safety and effectiveness will put patients at risk unnecessarily. Yet there is little indication that past policy changes to the FDA have had this effect; at the same time as the FDA has approved an increasing number of drugs through expedited pathways, drug prices have continued to rise.

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Part of the tension in this argument is that truly breakthrough products that represent significant advances or address urgent medical needs—the precise drugs that should be approved through expedited pathways based on more limited information—generally by definition have no real competition or price constraints after entering the market. Once again, Gleevec is a good example of the disconnect between expedited approvals and price.

It is true that speeding competitor drugs to market can help reduce prices in some cases. Branded competition can give payers additional leverage to negotiate sizable discounts or limit price increases by tying drug coverage to price. For example, insurers can encourage demand for a specific drug by lowering its cost-sharing in exchange for price discounts from the manufacturer.

But each situation differs based on the similarity of the competing drugs, the pricing strategies of the drug companies, and other available treatment options. A recent example is that of high-priced new cures for Hepatitis C, when Viekira Pak followed Sovaldi to market only a year later.

However, the enormous amount of media attention this received demonstrates the relative rarity of such high-profile arrangements. Notably, however, Sovaldi and its competitors received expedited approval from the FDA, which demonstrated that the agency can already act quickly to both expedite breakthroughs and help increase competition.

The FDA is not the barrier in such situations; how quickly branded competition can appear depends primarily on whether comparable drugs are already in the development pipeline. Yet, while interesting, the Sovaldi example is not representative of all drugs. Hepatitis C was an unusual situation in which an extremely high-priced breakthrough drug was followed relatively quickly by multiple competitors that had been close behind the original in the development process.

Furthermore, outrage over the high price of the original drug, Sovaldi, opened opportunities for competitors to strike exclusive deals with major payers who were growing desperate. For every example of a new drug spurring price competition, there is another of pharmaceutical companies taking advantage of shifting market dynamics in order to price their competitor drugs higher than the original drugs. Studies have found that in the absence of generic competition, increases in branded competition often only result in marginal price reductions—or as the following examples illustrate, even price increases.

For instance, although 11 major drug alternatives to treat multiple sclerosis have entered the market over the past two decades, all of them are priced in roughly the same high-cost range.