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In the United States, the Food & Drug Administration regulates the development, manufacturing and marketing of most biotechnology therapeutics used in healthcare.
BIOLOGICS & DRUGS
Many biotech products are biologics, meaning they are derived from living sources such as cells. Biologics are complex mixtures whose active ingredients-usually proteins-are hundreds of times larger than the compounds found in most pills. These products usually must be injected or infused directly into the bloodstream to be effective.
Biologics include blood and blood-derived products and vaccines, as well as biotechnology-based recombinant proteins and monoclonal antibodies. Most biologics are regulated by the FDA under the Public Health Service Act and require approval of a biologic license application (BLA) prior to marketing.
Through the late-1990s, biotechnology was closely associated with recombinant and antibody-based biologics, but increasingly biotech companies are using genetic and other biological discoveries to develop so-called small-molecule drugs. These are the chemically simple compounds that are so familiar on pharmacy shelves. They are often formulated as pills (although small-molecule products may also be injected or infused) and most are easily duplicated by generic manufacturers through well-understood chemical processes.
The FDA regulates small-molecule drugs under the Food, Drug and Cosmetic (FD&C) Act. Approval of a new drug application (NDA) is required before they can be marketed. (Note: A few biologics, notably insulin and growth hormone, are regulated under the FD&C Act as well.)
Although drugs and biologics are subject to different laws and regulations, drugs and most therapeutic biologics both fall under the purview of the FDA's Center for Drug Evaluation and Research (CDER, usually pronounced "cedar"). Vaccines, blood products, and cell and gene therapies are regulated by the FDA's Center for Biologics Evaluation and Research (CBER, usually pronounced "seeber").
PRODUCT DEVELOPMENT
It typically takes 10 to 15 years and an average of more than $800 million (including the cost of failures) to develop a new therapy. The process is rigorous and conducted in multiple stages, beginning with lab and animal testing, followed by clinical trials in humans, regulatory review and, if a product is approved, post-marketing studies and surveillance.
ANIMAL TESTING
Once a potential drug has been identified, animal testing is usually the first step, typically in two or more species, since drug effects vary across species. Many of these studies are ADME (absorption, distribution, metabolism and excretion) and toxicity studies. They document absorption of the drug, how the body breaks it down chemically, the toxicity and activity of the breakdown products (called metabolites), and the speed at which the drug and its metabolites are cleared from the body.
Scientists also use animal models of particular diseases to test for efficacy signals that can guide further refinement of a drug or clinical testing. Although animal efficacy results are important to drug development, they may be used to support FDA approval for human use only for biodefense products. Biodefense products can be tested for safety in humans, but not for efficacy, because it would be unethical to expose volunteers to chemical warfare agents, anthrax and the like in order to test whether a medicine or vaccine works.
Scientists hope someday to supplement or replace some animal testing with advanced technologies such as computer models of human biological pathways. But some animal testing is likely to remain necessary for maximizing safety before products are tested in humans. BIO members abide by BIO's Ethical Principles for the Care and Use of Animals in Biotechnology Research (see BIO Statement of Ethical Principles).
CLINICAL TRIALS
A drug that passes animal safety studies may move into human testing following the submission of an investigational new drug (IND) application to the FDA. Most studies, or trials, of new products may begin 30 days after the agency receives the IND.
Almost every new drug goes through multiple clinical trials, beginning with early studies (Phase I) in small groups of patients to test safety. Larger mid-stage trials (Phase II) examine safety and obtain preliminary efficacy data. The final stage of pre-market testing (Phase III) seeks to gather convincing efficacy data in the specific patient population the drug's developer hopes to treat.
The design, or protocol, of clinical trials varies tremendously, depending on the nature of the product, the patient population, and efficacy of existing treatments. Some drugs, for very rare and devastating diseases, have been approved after studies in only a handful of patients; others, often products for milder conditions and/or for which therapies are already available, must be tested in thousands of patients to win approval.
In many trials (especially those for diseases lacking effective existing treatment), one group of patients (or arm of the study) receives the drug being tested, while another group (the control group) receives a placebo that looks just like the drug and is administered the same way. Patients are randomized-that is, randomly assigned-to one or the other arm.
A trial in which the healthcare provider knows whether the patient is receiving the placebo or active drug, but the patient does not, is a single-blind trial. One in which neither the patient nor the healthcare provider knows whether the drug or placebo is being administered is called double-blind. Especially for trials measuring efficacy, double-blinded, randomized trials are considered the gold standard.
Other key terms for clinical trials:
Investigators-the doctors or other healthcare professionals conducting a trial. Institutional review boards-local oversight groups at hospitals, universities and other healthcare facilities that ensure trials are conducted ethically and as safely as possible. Endpoints-a clinical trial's outcome measures (such as tumor shrinkage, viral clearance, or survival). Indication-the specific condition a drug aims to treat; an indication may be broad (for example, Type II diabetes) or it may be narrow (for example, insulin-dependent Type II diabetes).
Clinical trials must be sufficiently powered-that is, must enroll enough patients with appropriately selected endpoints-to deliver meaningful conclusions.
Once data from a well-designed trial are recorded and analyzed, researchers convey how confident they are that their conclusions are meaningful through a statistic called the p-value. This is a calculated measure of the likelihood that a trial's conclusion resulted from chance. For example a p-value of 0.01 means there is a 1 percent likelihood the outcome resulted from chance. For a clinical trial to be counted as a success, it must typically meet its endpoints with a p-value of 0.05 or less-meaning there is no more than a 5 percent probability the outcome resulted from chance.
PHASE I
Usually, the first study a drug or biologic enters is a Phase I trial enrolling a small number (fewer than 100) of healthy volunteers to test safety and obtain data on dosing, metabolism and excretion. Some Phase I trials are conducted in patients with a condition the drug might someday treat. Interesting signs of efficacy may be noted at this stage, but have little or no statistical weight.
A new type of early human testing, called Phase 0, or microdosing, is popular with some who hope to lower preclinical development time and cost. Conducted under an exploratory investigational new drug application, these tests may involve fewer than 10 patients who receive less than 1 percent of a standard drug dose. Using cutting edge technologies such as accelerated mass spectrometry, Phase 0 studies seek to characterize drug metabolism and toxicity.
PHASE II
In Phase II, testing expands to include (usually) 100 to 300 participants who have a disease or condition the product may treat. Additional safety data are gathered, along with evidence of efficacy. Researchers may conduct Phase II trials of a drug in several related conditions-for example, testing a cancer drug in a variety of cancers-in order to define the best patient population(s) for Phase III trials.
PHASE III
Phase III brings one or more even larger trials (often about 1,000 to 5,000 patients) in the specific patient population for which the drug developer hopes to win FDA approval. Phase III trials test efficacy and monitor for side effects, and multiple Phase III trials in one or more indications may be conducted for a single product.
APPROVAL PROCESS
If a therapy succeeds in clinical trials, the next step is applying for approval with the FDA by filing either a new drug application (NDA) or biologics license application (BLA). These applications can run hundreds of thousands of pages and include details on the product's structure, manufacturing, lab testing and clinical trials.
As part of the Prescription Drug User Fee Act, the FDA has a goal of acting on a priority review products (those addressing unmet medical needs) by six months after the application receipt. For a standard review product, the agency's goal is a 10-month
review. The term PDUFA date is the date by which the FDA must act to meet this goal for a particular product.
In weighing an NDA or BLA, particularly for a novel product, the FDA may seek the guidance of one of its independent advisory committees. Each committee has 10-15 members and includes experts and representatives of the public. The committees host public meetings, often attracting media coverage, at which the pros and cons of the products in question are presented and debated, culminating with a recommendation either for or against approval.
Advisory committee recommendations are non-binding, however. The final regulatory decision rests with the agency.
POST-APPROVAL
Every approved drug comes with an official product label, in a standardized format, whose contents are developed by the FDA and the company marketing the drug. The label contents include the approved indication, as well as a description of the drug, its side effects, dosage, clinical trial summaries and other information useful to physicians. Although doctors may prescribe a therapy "off-label" for indications not expressly approved by the FDA, manufacturers are prohibited from marketing off-label indications, and insurance does not always cover such uses.
The story does not end with approval and labeling. Companies often conduct additional Phase II and III trials in other indications and may apply for approval through a supplemental NDA or BLA. If approved, the new indication is added to the product label.
Companies also conduct Phase IV trials to refine knowledge about the drug. In addition, drug makers are required by law to report adverse events to the FDA, and they are subject to ongoing manufacturing and marketing rules.
Biotech Drug Development Process
Source:
Ernst & Young
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