Contributions of Research to the Fight Against Drug Resistance
The antibiotic revolution was facilitated by the discovery of many new classes of antibiotics in the 1940s and 1950s, which both offered treatments for diseases previously not susceptible to existing drugs and gave physicians alternatives for treating diseases caused by organisms that had become resistant to formerly effective drugs. However, the pace of discovery for new antibiotic drugs has slowed over the past half-century, and relatively few new antibiotics are currently undergoing the drug approval process. One way that research can aid in the fight against drug resistance is by encouraging the development of new antibiotics, an effort that can be furthered by financial incentives and international cooperation.
THE DRUG DEVELOPMENT PROCESS
The drug development process is time consuming and expensive. This means that when a new health threat is identified, it may be years before an effective drug to treat it can be developed (and, of course, there is no guarantee that such a drug will even be found at all). It also means that pharmaceutical manufacturers tend to invest their resources in researching drugs that they believe will bring them the greatest financial returns. One result of these financial calculations is that often, more resources are devoted to developing drugs to treat chronic conditions common in developed countries than to developing drugs to treat infectious diseases more common in developing nations.
Because the time to develop new drugs is measured in years, people often speak of new drugs as being “in the pipeline,” meaning that they are at some stage in the drug development process. While different countries have different procedures governing drug development, the process required by the U.S. Food and Drug Administration (FDA) is similar to that employed in many industrialized countries. The FDA drug development process involves five stages: (1) discovery and development; (2) preclinical research; (3) clinical research; (4) FDA review; and (5) FDA postmarket safety monitoring.
The discovery and development stage involves identifying a promising compound for further development. This process can begin in many ways: for instance, a researcher may note the unanticipated effects produced by an existing drug. The drug discovery process may begin with a researcher observing that an existing treatment produces such effects and deciding to see if those effects can be harnessed for therapeutic purposes. New insights from research may allow the researcher to design a drug specifically to attack one disease or symptom, or new technologies may facilitate the development of different ways of treating a disease. Or a team of researchers may screen thousands of molecular compounds against many different diseases to identify any compounds that may yield beneficial drugs. Most compounds studied in this phase are eliminated early in the process, while those that remain are scheduled for future testing. In the development half of this stage, researchers gather information through experimentation in order to learn how the compound is processed by the body, what side effects are associated with its use, the best way to administer the drug (e.g., orally or by injection), how it compares with other drugs, and its mechanism of action (that is, how the compound achieves its pharmaceutical effect).
In the preclinical research stage, two types of research are conducted: in vitro, meaning outside a living organism (in vitro means “in glass” and refers to lab glassware such as test tubes and petri dishes), and in vivo, meaning “in living organisms” (including animals and plants). Preclinical studies are not usually large, but they are designed to provide detailed information on matters such as toxicity levels and dosing. The results of the preclinical stage are used to determine which drugs should be advanced to the next stage: clinical research.
In the clinical research stage, drugs are tested in the human body through a series of clinical trials. Because human beings are involved, this phase is highly regulated and has four phases, each of which includes trials conducted to gather specific information and answer particular questions about the compound. In Phase 1, which typically lasts several months, the drug is tested on 20 to 100 volunteers, who may be well individuals or people with the disease that the drug is intended to treat. The purpose of Phase 1 trials is to establish the safety and dosage of the drug, and about 70 percent of new drugs move through this stage successfully. In Phase 2, which typically lasts from several months to two years, the drug is tested on up to several hundred people who have the disease or condition that the drug is intended to treat. The purpose of Phase 2 testing is to determine the drug’s efficacy and side effects, and about one-third of drugs pass through this stage successfully.
Many more volunteer research subjects, typically from 300 to 3,000, are involved in Phase 3 trials. These volunteers are people who have the disease or condition that the drug is intended to treat, and the purpose of this phase is to further establish the drug’s efficacy and monitor for adverse reactions. Phase 3 typically lasts from one to four years, and 25 to 30 percent of drugs move through this phase successfully. In Phase 4, the drug is tested on several thousand people who have the disease or condition that the drug is intended to treat. The purpose of this phase is to further study the drug’s safety and efficacy. Phase 4 testing is conducted with already-approved drugs and is sometimes referred to as “postmarketing” monitoring. Only rarely is a drug removed from the marketplace in this phase.
The fourth stage in the drug approval process, FDA review, requires the drug developer to submit a New Drug Application (NDA) to the FDA. The NDA contains detailed information about the drug gathered from all studies and analyses conducted from the preclinical phase through Phase 3 of the clinical research stage. The drug developer also must include the data from studies conducted both within and outside the United States, safety updates, patient information, proposed labeling and directions for use, and information about the research process’s compliance with institutional review board procedures.
The NDA is reviewed by a team at the FDA, who must complete their task within 6 to 10 months. The review team is made of up individuals with particular specialties, each of whom reviews the section relevant to his or her technical knowledge; for instance, a medical officer will review the clinical data, while a pharmacologist will review the animal data. In addition, FDA inspectors travel to the clinical study sites and conduct an inspection intended to reveal anything suspicious about the data submitted, such as if some data were fabricated, withheld, or manipulated. When the review is complete, an “action package” is assembled containing the individual reviews, the inspection report, and other relevant information; this action package becomes the official record of the FDA review. The review team also will issue a recommendation on the drug, and a senior FDA official will make the final decision as to whether it should be approved.
If the FDA determines that a drug is safe and effective for its intended use, the drug is approved, and the organization then works with the drug developer on the labeling process, which includes developing and refining prescribing information. If the FDA determines that additional information is required before the drug can be approved, they may require the developer to conduct additional studies (a decision that that developer may appeal).
The fifth stage of the drug approval process, FDA postmarket safety monitoring, takes place after the drug has been approved for human use. This stage is necessary because although the previous stages may have involved thousands of human research subjects, this still provides an incomplete picture of the drug’s effects on people. For instance, persons approved to take part in clinical trials are often selected in ways (such as age limitations or lack of complicating conditions) that do not make them representative of the entire population of people who may take the drug. Another factor is that some drugs may be taken for many years, and complications that did not occur during the studies conducted as part of the drug approval process may show up when the drug is taken over a longer period of time.
Several mechanisms exist to facilitate reporting problems with drugs that have received FDA approval, including the Internet-based program MedWatch. MedWatch is a searchable database of clinically important safety information about medical products. It includes a portal for individuals to report problems with specific human medical products (including prescription and over-the-counter drugs, dietary supplements, and medical devices); compilations of safety alerts for human medical products; and information about drug safety labeling changes. The FDA is also developing a system of active surveillance, the Sentinel Initiative, to monitor large databases such as electronic health records systems and medical claims databases in order to identify problems with approved drugs. A drug that has been approved by the FDA may be removed from the market later if postapproval surveillance indicates that the risks of the drug outweigh its benefits. Drugs are typically removed from the market for safety reasons, such as the emergence of serious side effects, but evidence about this harm must be balanced by harms that could be caused by withdrawing the drug, particularly if it is the only drug available to treat a serious medical disease or condition. Examples of drugs removed from the market following FDA approval include rofecoxib (Vioxx), diethylstilbestrol (DES), and temafloxacin (Omniflox).
During the FDA postmarket safety monitoring phase, the FDA may continue to conduct inspections of plants (including overseas plants) where the drug is manufactured in order to determine if good manufacturing practices are being followed. If a manufacturer wants to make changes in the original NDA, such as changes to the formulation, dosage, or labeling of the drug, it must file a supplemental application with the FDA.
ANTIBIOTICS IN THE DRUG DEVELOPMENT PIPELINE
As more microorganisms become resistant to existing antibiotics, new drugs must be developed to replace drugs that have become ineffective. Because of the lengthy process required to bring a new drug to market, public health officials monitor what new antibiotics are currently in development. Many people working in medicine and public health have reported their anxiety about the low number of new antibiotics currently in the pipeline, particularly given that the process of microorganisms becoming antibiotic resistant is likely to continue.
Several reasons have been offered for the dearth of new antibiotics in the drug development pipeline. One is that it becomes more and more difficult to come up with novel and effective compounds. Another reason is that pharmaceutical companies, which seek to earn a profit on their products, see antibiotic development as less lucrative than developing other types of drugs. Antibiotics are usually taken for only a short period of time (e.g., 10 days), while drugs to treat chronic conditions such as high blood pressure or diabetes may be taken for years—proving to be far more lucrative. In addition, the greatest health threats in industrialized countries are mostly chronic conditions, and those suffering from these diseases are the customers willing and able to pay high prices for drugs, and over their entire lifetimes. Also, some diseases that have become resistant to one or more existing drugs, such as malaria, are primarily a problem in the developing world, while drug manufacturers are headquartered in countries in the industrialized world.
A survey of major international pharmaceutical companies in 2008 found that only five—AstraZeneca, GlaxoSmithKline, Merck, Novartis, and Pfizer—had active programs to discover new antibiotics. A study that included many smaller firms, also conducted in 2008, found that only 15 of the 167 antibiotics under development had a new mechanism of action, a characteristic that could make them more likely to be effective in treating diseases caused by organisms that are already resistant to one or more existing antibiotics. Most of the 15 drugs in question were in the early stages of development, meaning that it could be years before they are brought to market, if they even make it that far.
On the positive side, scientists know that there are many possible compounds that could create effective antibiotics. For instance, some estimate that less than 1 percent of the bacteria on Earth have been cultured, and many antibiotics were discovered as a by-product of culturing bacteria. This suggests that the problem of new antibiotic development will require a considerable investment of resources if it is to succeed. Some have proposed public-private partnerships to spur the development of new antibiotics, while others have suggested that further international cooperation is the key to the process.
A survey of U.S. drug manufacturers found that as of March 2015, only 36 new antibiotics intended to treat bacterial infections were currently in the clinical stage of the FDA approval process, with an additional 5 antibiotics approved between May 2014 and February 2015. The most frequently approved drug was Avycaz, approved on February 25, 2015. This is a combination of ceftazidime, a cephalosporin, plus avibactam, a novel beta-lactamase inhibitor brought to market by AstraZeneca/Actavis; it is intended to treat complicated infections of the urinary tract and abdomen and and acute kidney infections.
Four antibiotics were approved in 2014. Sivextro (tedizolid phosphate), brought to market by Cubist Pharmaceuticals (a wholly owned subsidiary of Merck), is in the oxazolidinone class and is intended to treat acute bacterial skin and skin structure infections. Dalvance (dalbavancin), brought to market by Actavis, is in the lipoglycopeptide class and is intended to treat acute bacterial skin and skin structure infections. Orbactiv (oritavancin), brought to market by The Medicines Company, is in the glycopeptide class and is intended to treat acute bacterial skin and skin structure infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Zerbaxa (ceftazidime plus tazobactam), brought to market by Cubist Pharmaceuticals, is the combination of a novel cephalosporin plus a beta-lactamase inhibitor and is intended to treat complicated urinary tract infections (UTIs), complicated intra-abdominal infections, and acute kidney infection.
Of the 36 antibiotics identified as being in the U.S. pipeline as of March 2015, 8 were in Phase 3, 20 were in Phase 2, and 8 were in Phase 1. The conditions targeted by drugs in Phase 3 (which are the closest to being approved among the drugs still in the approval process) include Clostridium difficile–associated diarrhea, bacterial pneumonia, gonorrhea, complicated UTIs, complicated intra-abdominal infections, hospital-acquired bacterial pneumonia, acute bacterial skin and skin structure infections, and prosthetic joint infections.