health care Applications
Biotechnology tools and techniques open new research avenues for discovering how healthy bodies work and what goes wrong when problems arise. Knowing the molecular basis of health and disease leads to improved methods for diagnosing, treating and preventing illness. In human health care, biotechnology products include quicker and more accurate diagnostic tests, therapies with fewer side effects and new and safer vaccines.
Diagnostics
We can now detect many diseases and medical conditions more quickly and with greater accuracy because of new, biotechnology- based diagnostic tools. A familiar example is the new generation of home pregnancy tests that provide more accurate results much earlier than previous tests. Tests for strep throat and many other infectious diseases provide results in minutes, enabling treatment to begin immediately, in contrast to the two- or three day delay of previous tests.
A familiar example of biotechnology’s benefits is the new generation of home pregnancy tests that provide more accurate results much earlier than previous tests. Biotechnology also has created a wave of new genetic tests. Today there are more than 1,200 such tests in clinical use, according to genetests.org, a site sponsored by the
Biotechnology has lowered the cost of diagnostics in many cases. A blood test developed through biotechnology measures low-density lipoprotein (“bad” cholesterol) in one test, without fasting. Biotech-based tests to diagnose certain cancers, such as prostate and ovarian cancer, by taking a blood sample, eliminate the need for invasive and costly surgery.
In addition to diagnostics that are cheaper, more accurate and quicker than previous tests, biotechnology is allowing physicians to diagnose diseases earlier, which greatly improves prognosis. Proteomics researchers are taking this progress a step further by identifying molecular markers for incipient disease before visible cell changes or symptoms appear.
The wealth of genomics information now available will greatly assist doctors in early diagnosis of diseases such as type I diabetes, cystic fibrosis, early-onset Alzheimer’s disease and Parkinson’s disease—ailments that previously were detectable only after clinical symptoms appeared. Genetic tests will also identify patients with predisposition to diseases such as various cancers, osteoporosis, emphysema, type 2 diabetes and asthma, giving patients an opportunity to prevent the disease by avoiding triggers such as poor diet, smoking and other environmental factors.
Some biotechnology tests even act as barriers to disease—these are the tests used to screen donated blood for the pathogens that cause AIDS, hepatitis and other infections.
Biotech-based tests also are improving the way health care is provided. Many diagnostic tests are portable, so physicians conduct the tests, interpret results and decide on treatment at the point of care. In addition, because many of these tests give results in the form of color changes (similar to a home pregnancy test), results can be interpreted without technically trained personnel, expensive lab equipment or costly facilities, expanding access to poorer communities and developing countries.
Therapeutics
Biotechnology will make possible improved versions of today’s therapeutic regimes as well as tomorrow’s innovative treatments. Biotech therapeutics approved by the U.S. Food and Drug Administration (FDA) are used to treat many diseases and conditions, including leukemia and other cancers, anemia, cystic fibrosis, growth deficiency, rheumatoid arthritis, hemophilia, hepatitis, genital warts and transplant rejection. Some biotech companies are using emerging biological knowledge, the skills of rational drug design, and high-throughput screening of chemical libraries to find and develop small molecule therapies, which are often formulated as pills. Others focus on biological therapies, such as proteins, genes, cells and tissues—all of which are made in living systems. These therapies are what people often first think of when they hear the term biotechnology.
The therapies discussed below all make use of biological substances and processes designed by nature. Some use the human body’s own tools for fighting disease. Others are natural products of plants and animals. The large-scale manufacturing processes
for producing therapeutic biological substances also rely on nature’s molecular production mechanisms.
33
Using Natural Products as Therapeutics
Many living organisms produce compounds that have therapeutic value for us. For example, many antibiotics are produced by naturally occurring microbes, and a number of medicines on the market, such as digitalis, are made by plants. Plant cell culture, recombinant DNA technology and cellular cloning now provide us with new ways to tap into natural diversity.
As a result, scientists are investigating many plants and animals as sources of new medicines. Ticks and bat saliva could provide anticoagulants, and poison-arrow frogs might be a source of new painkillers. A fungus produces a novel antioxidant enzyme that is particularly efficient at “mopping up” free radicals known to encourage tumor growth. Byetta™ (exenatide) was chemically copied from the venom of the gila monster and approved in early 2005 for the treatment of diabetes. PRIALT (ziconotide), a recently approved drug for pain relief, is a synthetic version of the toxin from a South Pacific marine snail. The ocean presents a particularly rich habitat for potential new medicines. Marine biotechnologists have discovered organisms containing compounds that could heal wounds, destroy tumors, prevent inflammation, relieve pain and kill microorganisms. Shells from marine crustaceans, such as shrimp and crabs, are made of chitin, a carbohydrate that is proving to be an effective drug-delivery vehicle. Marine biotechnologists have discovered organisms containing compounds that could heal wounds, destroy tumors, prevent inflammation, relieve pain and kill microorganisms.
RECOMBINANT PROTEIN Therapeutics
Some diseases are caused when defective genes don’t produce the proteins (or enough of the proteins) the body requires. Today we are using recombinant DNA and cell culture to produce these proteins. Replacement protein therapies include:
●● factor VIII—a blood-clotting protein missing in some hemophiliacs. Marketed by several companies under various brand names.
●● insulin—a hormone that regulates blood glucose levels. Diabetes results when the body can no longer make insulin (or can no longer respond to it). Marketed by several companies under various brand names.
●● human growth hormone—a hormone essential to achieving normal height. Children with growth disorders may be prescribed a recombinant version of this protein. Marketed by several companies under various brand names.
●● betaglucocerebrosidase—a protein whose absence results in Gaucher’s disease, a rare genetic disorder. Marketed as Cerezymeｮ.
Other protein therapies do not treat a protein deficiency per se. Instead, they introduce or boost levels of a protein in order to fight a symptom or disease process. For example, anemia patients may be treated with recombinant erythropoietin (Epogenｮ and Procritｮ), which stimulates the formation of red blood cells. Heart attack and some stroke patients are often given a bolus of recombinant tissue plasminogen activator to break up blood
clots. Protein drugs can be life-savers for acute conditions, but they are also used to treat chronic diseases, such as rheumatoid arthritis, Crohn’s disease and multiple sclerosis.
MONOCLONAL ANTIBODIES
Because monoclonal antibodies (MAbs) offer highly specific darts to throw at disease targets, they are attractive as therapies, especially for cancer. The first anticancer MAb, Rituxan™ (rituximab), was approved in 1997 for the treatment of non-Hodgkin’s
lymphoma. Since then, many other MAb-based therapies have followed, including:
●● Avastinｮ (bevacizumab), which binds to vascular endothelial growth factor (VEGF) and prevents its interaction with the VEGF receptor, which helps stimulate blood vessel formation, including the blood vessels in tumors. Avastin has been approved for the treatment of metastatic colorectal cancer, non-small cell lung cancer and metastatic breast cancer.
●● Bexxarｮ (tositumomab), a conjugate of a monoclonal antibody against CD20 and the radioactive isotope iodine I-131. It has been approved to treat non-Hodgkin’s lymphoma.
●● Campathｮ (alemtuzumab), which binds to CD52, a molecule found on white blood cells, and treats B-cell chronic lymphocytic leukemia.
●● Erbituxｮ (cetuximab), which blocks epidermal growth factor receptor (EGFR), has been approved to treat colorectal cancer and squamous cell head and neck cancer.
●●Herceptinｮ (trastuzumab), which binds to the HER2 receptor to treat breast cancer.
●●Mylotarg™ (gemtuzumab ozogamicin), which uses a monoclonal antibody to deliver a chemotherapy agent to treat some leukemia patients.
●● Zevalinｮ (ibritumomab tiuexetan), which, like Bexxar, is a conjugate of a monoclonal antibody and a radioactive isotope. It is approved for non-Hodgkin’s lymphoma.
34
Monoclonal antibodies are also used to treat immune-related disorders, infectious diseases and other conditions that are best treated by blocking a molecule or process.
Using Genes to Treat Diseases
Gene therapy presents an opportunity to use DNA, or related molecules such as RNA, to treat diseases. For example, rather than giving daily injections of a missing protein, physicians could supply the patient’s body with an accurate “instruction manual”—a nondefective gene—correcting the genetic defect so the body itself makes the proteins. Other genetic diseases could be treated by using small pieces of RNA to block mutated genes. Only certain genetic diseases are amenable to correction via replacement gene therapy. These are diseases caused by the lack of a protein, such as hemophilia and severe combined immunodeficiency disease (SCID), commonly known as the “bubble boy
disease.” Some children with SCID are being treated with gene therapy and enjoying relatively normal lives, although the therapy has also been linked to developing leukemia. Hereditary disorders that can be traced to the production of a defective protein, such as
Huntington’s disease, may be best treated with RNA that interferes with protein production.
Medical researchers also have discovered that gene therapy can treat diseases other than hereditary genetic disorders. They have used briefly introduced genes, or transient gene therapy, as therapeutics for a variety of cancers, autoimmune disease, chronic
heart failure, disorders of the nervous system and AIDS.
In late 2003,
Cell Transplants
Approximately 18 people die each day waiting for organs to become available for transplantation in the
A patient receiving cells from a donor must take powerful drugs every day to prevent the immune system from attacking the transplanted cells. These drugs have many side effects, prompting researchers to seek new ways to keep the immune system at bay.
One method being tested is cell encapsulation, which allows cells to secrete hormones or provide a specific metabolic function without being recognized by the immune system. As such, they can be implanted without rejection. Other researchers are genetically
engineering cells to express a naturally occurring protein that selectively disables immune system cells that bind to it. Other conditions that could potentially be treated with cell
transplants are cirrhosis, epilepsy and Parkinson’s disease.
Xenotransplantation
Organ transplantation provides an especially effective treatment for severe, life-threatening diseases of the heart, kidney and other organs. However, the need greatly exceeds the availability of donor organs. According to the United Network of Organ Sharing (UNOS), in the United States almost 100,000 people were on organ waiting lists as of April 2008.
Organs and cells from other species—pigs and other animals— may be promising sources of donor organs and therapeutic cells. This concept is called xenotransplantation. Organs and cells from other species—pigs and other animals—may be promising sources of donor organs and therapeutic cells. This concept is called xenotransplantation. The most significant obstacle to xenotransplantation is the immune system’s self-protective response. When nonhuman tissue is introduced into the body, the body cuts off blood flow to the donated organ. The most promising method for overcoming this rejection may be various types of genetic modification. One approach deletes the pig gene for the enzyme that is the main cause of rejection; another adds human genetic material to disguise the pig cells as human cells.
The potential spread of infectious disease from other species to humans through xenotransplantation is also a major obstacle to this technology.
Using Biopol ymers as Medical Devices
Nature has also provided us with biological molecules that can serve as useful medical devices or provide novel methods of drug delivery. Because they are more compatible with our tissues and our bodies absorb them when their job is done, they are superior
to most human-made medical devices or delivery mechanisms. For example, hyaluronate, a carbohydrate produced by a number of organisms, is an elastic, water-soluble biomolecule that is being used to prevent postsurgical scarring in cataract surgery; alleviate pain and improve joint mobility in patients with osteoarthritis; and inhibit adherence of platelets and cells to medical devices, such as stents and catheters. A gel made of a polymer found in the matrix connecting our cells promotes healing in burn victims. Gauze-like mats made of long threads of fibrinogen, the protein that triggers blood clotting, can be used to stop bleeding in emergency situations. Adhesive proteins from living organisms are replacing sutures and staples for closing wounds. They set quickly, produce strong bonds, and are absorbed.
Personalized Medicine
In the future, our individual genetic information will be used to prevent disease, choose medicines and make other critical decisions about health. This is personalized medicine, and it could revolutionize health care, making it safer, more costeffective and, most importantly, more clinically effective.
Pharmacogenomics, which refers to the use of information about the genome to develop drugs, is also used to describe the study of the ways genomic variations affect drug responses. The variations affecting treatment response may involve a single gene (and the protein it encodes) or multiple genes/ proteins. For example, some painkillers work only when body proteins convert them from an inactive form to an active one. How well these proteins do their jobs varies considerably between people. As another example, tiny genetic differences can change how statin drugs work to lower blood cholesterol levels.
Biotechnology researchers are interested in the use of gene-based tests to match patients with optimal drugs and drug dosages. This concept of personalized medicine—also called targeted therapy—is beginning to have a powerful impact on research and treatment, especially in cancer. This concept of personalized medicine—also called targeted therapy—is beginning to have a powerful impact on research and treatment, especially in cancer.
Cancer
The biotech breast cancer drug Herceptinｮ (trastuzumab) is an example of a pharmacogenomic drug. Initially approved in 1998, Herceptin targets and blocks the HER2 protein receptor, which is overexpressed in some aggressive cases of breast cancer. A test can identify which patients are overexpressing the receptor and can benefit from the drug. New tests have been launched recently that identify patients likely to respond to Iressaｮ (gefitinib), Tarcevaｮ (erlotinib), Gleevecｮ (imatinib) and Campath (alemtuzumab), and patients developing resistance to Gleevec. Tests are available to choose the correct dosage of a powerful chemotherapy drug for pediatric leukemia; the tests have saved lives by preventing overdose fatalities. One of the most exciting new tests is Genomic Health’s Oncotype DX™, which examines expression of 21 genes to quantify risk of breast cancer recurrence and predict the likelihood that chemotherapy will benefit the patient. Impressed with the product’s results in recent studies, the National Institutes of Health (NIH) in May 2006 launched a large new study called TAILORx (Trial Assigning Individualized Options for Treatment [Rx]) that will utilize Oncotype DX™ to predict recurrence and assign treatment to more than 10,000 women at over 1,000 sites in the United States and Canada.
Many more pharmacogenomic cancer products—both medicines and tests—are in development. In fact, oncology may be entering an era when cancer treatment will be determined as much or more by genetic signature than by location in the body.
The idea is simple, but the project is monumental, given the variety of genetic tools cancer cells use to grow, spread and resist treatment. The NIH in December 2005 announced it was taking on this challenge through The Cancer Genome Atlas. The project aims to map all gene variations linked to some 250 forms of cancer, not only the variations that help cause cancer, but also those that spur growth, metastasis and therapeutic resistance.
Other Applications
In December 2004, the FDA approved Roche and Affymetrix’s AmpliChipｮ CYP450 Genotyping Test, a blood test that allows physicians to consider unique genetic information from patients in selecting medications and doses of medications for a wide variety of common conditions such as cardiac disease, psychiatric disease and cancer.
The test analyzes one of the genes from the family of cytochrome P450 genes, which are active in the liver to break down certain drugs and other compounds. Variations in this gene can cause a patient to metabolize certain drugs more quickly or more slowly than average, or, in some cases, not at all. The specific enzyme analyzed by this test, called cytochrome P4502D6, plays an important role in the body’s ability to metabolize some commonly prescribed drugs, including antidepressants, antipsychotics, beta-blockers and
some chemotherapy drugs.
AmpliChip was the first DNA microarray test to be cleared by the FDA. A microarray is similar to a computer microchip, but instead of tiny circuits, the chip contains tiny pieces of DNA, called probes.
Race- and Gender-Based Medicine
In 2005, the FDA for the first time approved a drug for use in a specific race: BiDilｮ (isosorbide and hydralazine), a life-saving drug for heart failure in black patients. In the 1990s, the drug had failed to beat placebo in a broad population but showed promise
in black patients. Further testing confirmed those results. Although BiDil thus far is the only drug to win a race-specific approval, it’s far from unique in its varied effects across populations. Many drugs, including common blood-pressure medicines and
antidepressants, exhibit significant racially correlated safety and efficacy differences.
For example, in a large study of one of the most common blood pressure medications, Cozaarｮ (losartan), researchers found a reduced effect in black patients—a fact that has been added to the prescribing information for the drug. Interferon, likewise, appears
to be less effective in blacks with hepatitis than in non-Hispanic white patients (19 percent vs. 52 percent response rate), according to a study in the New England Journal of Medicine.
Another study found Japanese cancer patients are three times more likely to respond to Iressa, apparently because of a mutation in a gene for the drug’s target, epidermal growth factor receptor.
Genetic variations—mutations that affect drug receptors, pathways and metabolizing enzymes—are thought to underlie most of the racial, ethnic and geographic differences in drug response, making the field ripe for biotech-style personalized medicine.
NitroMed, for example, is collecting genetic material with the hope of developing a test to identify all patients—irrespective of race—likely to respond to BiDil. Some companies are exploring the concept of gender-based medicine to take into account the differences in male and female response to medicine. Some companies are exploring the concept of gender-based medicine to take into account the differences in male and female response to medicine. Aspirin, for example, prevents heart attacks in men but not in women. At least one biotech company is developing a lung cancer drug that shows greater promise in women.
Regenerative Medicine
Biotechnology is showing us new ways to use the human body’s natural capacity to repair and maintain itself. The body’s toolbox for self-repair and maintenance includes many different proteins and various populations of stem cells that have the capacity to cure
diseases, repair injuries and reverse age-related wear and tear.
Tissue Engineering
Tissue engineering combines advances in cell biology and materials science, allowing us to create semi-synthetic tissues and organs in the lab. These tissues consist of biocompatible scaffolding material, which eventually degrades and is absorbed, plus living cells grown using cell-culture techniques. Ultimately the goal is to create whole organs consisting of different tissue types to replace diseased or injured organs.
The most basic forms of tissue engineering use natural biological materials, such as collagen, for scaffolding. For example, two layer skin is made by infiltrating a collagen gel with connective tissue cells, then creating the outer skin with a layer of tougher protective cells. In other methods, rigid scaffolding, made of a synthetic polymer, is shaped and then placed in the body where new tissue is needed. Other synthetic polymers, made from natural compounds, create flexible scaffolding more appropriate for soft-tissue structures, like blood vessels and bladders. When the scaffolding is placed in the body, adjacent cells invade it. At other times, the biodegradable implant is seeded with cells grown in the laboratory prior to implantation. Simple tissues, such as skin and cartilage, were the first to be engineered successfully.
Recently, however, physicians have achieved remarkable results with a biohybrid kidney (renalassist device, or RAD) that maintains patients with acute renal failure until the injured kidney repairs itself. In a clinical trial of the RAD in patients with acute kidney injury, patients receiving the RAD were 50 percent less likely to die. The hybrid kidney is made of hollow tubes seeded with kidney stem cells that proliferate until they line the tube’s inner wall. These cells develop into the type of kidney cell that releases hormones and is involved with filtration and transportation.
The human body produces an array of small proteins known as growth factors that promote cell growth, stimulate cell division and, in some cases, guide cell differentiation. These natural regenerative proteins can be used to help wounds heal, regenerate injured tissue and advance the development of tissue engineering described in earlier sections. As proteins, they are prime candidates for large-scale recombinant production in transgenic organisms, which would enable their use as therapeutic agents.
37
Some of the most common growth factors are:
●● epidermal growth factor, which stimulates skin cell division and could be used to encourage wound healing;
●● erythropoietin, which stimulates the formation of red blood cells and was one of the first biotechnology products;
●● fibroblast growth factor, which stimulates cell growth and has been effective in healing burns, ulcers and bone, and in growing new blood vessels in patients with blocked coronary arteries;
●● transforming growth factor-beta, which helps fetal cells differentiate into different tissue types and triggers the formation of new tissue in adults; and
●● nerve growth factors, which encourage nerve cells to grow, repair damage; they could be used in patients with head and spinal cord injuries or degenerative diseases such as Alzheimer’s disease.
Vaccines
Vaccines help the body recognize and fight infectious diseases. Conventional vaccines use weakened or killed forms of a virus or bacteria to stimulate the immune system to create the antibodies that will provide resistance to the disease. Usually only one or a few proteins on the surface of the bacteria or virus, called antigens, trigger the production of antibodies. Biotechnology is helping us improve existing vaccines and create new vaccines against infectious agents, such as the viruses that cause cervical cancer and genital herpes.
Biotechnology Vaccine Production
Most of the new vaccines consist only of the antigen, not the actual microbe. The vaccine is made by inserting the gene that produces the antigen into a manufacturing cell, such as yeast. During the manufacturing process, which is similar to brewing beer, each yeast cell makes a perfect copy of itself and the antigen gene. The antigen is later purified from the yeast cell culture. By isolating antigens and producing them in the laboratory, it is possible to make vaccines that cannot transmit the virus or bacterium itself. This method can also increase the amount of vaccine that can be manufactured because each manufacturing cell can produce many antigens for purification.
Using these techniques of biotechnology, scientists have developed antigen-only vaccines against life-threatening diseases such as hepatitis B and meningitis. Researchers have discovered that injecting small pieces of DNA from microbes is sufficient for triggering antibody production. Such DNA vaccines could provide immunization against microbes for which we currently have no vaccines.
Biotechnology is also broadening the vaccine concept beyond protection against infectious organisms. Various researchers are developing vaccines against diseases such as diabetes, chronic inflammatory disease, Alzheimer’s disease, cancer and autoimmune disorders.
Vaccine Delivery Systems
Most vaccines require special handling—many require refrigeration during shipping and storage—syringes and skilled professionals to administer them. Some researchers are working to create new vaccine delivery technologies that simplify distribution and use. Technologies under study include oral vaccines, vaccines administered via patch, and even edible vaccines manufactured by plants and animals.
Academic researchers have obtained positive results using human volunteers who consumed hepatitis vaccines in bananas, and E. coli and cholera vaccines in potatoes. In addition, because these vaccines are genetically incorporated into food plants and
need no refrigeration, sterilization equipment or needles, they may prove particularly useful in developing countries. Researchers are also developing skin patch vaccines for tetanus, anthrax, influenza and E. coli.
Plant-Made Pharmaceuticals
Advances in biotechnology have made it possible to genetically enhance plants to produce therapeutic proteins essential for the production of a wide range of protein pharmaceuticals—such as monoclonal antibodies, enzymes and blood proteins.
Plant-made pharmaceutical production is regulated under stringent rules of the
Therapeutic proteins produced by transgenic plants to date include antibodies, antigens, growth factors, hormones, enzymes, blood proteins and collagen. These proteins have been grown in field trials in a wide variety of plants, including alfalfa, corn, duckweed, potatoes, rice, safflower, soybeans and tobacco. Field trials with protein-producing plants are providing the essential building blocks for innovative treatments for diseases such as cancer, HIV, heart disease, diabetes, Alzheimer’s disease, kidney disease, Crohn’s disease, cystic fibrosis, multiple sclerosis, spinal cord injuries, hepatitis C, chronic obstructive pulmonary disease, obesity and arthritis. In addition, scientists have made excellent progress in using plants as vaccine-manufacturing and -delivery systems. They have used tobacco, potatoes, tomatoes and bananas to produce experimental vaccines against infectious diseases, including cholera, a number of microbes that cause food poisoning and diarrhea (e.g., E. coli and the
Economic and access benefits
Since most proteins cannot be chemically synthesized, there are very few options for protein production for pharmaceutical purposes: mammalian and microbial cell cultures and plants. More than $500 million and five years are required to build a facility for mammalian cell cultures. Because protein-producing plants require relatively little capital investment, and the costs of production and maintenance are minimal, they may provide the only economically viable option for independent production of therapeutic proteins in underdeveloped countries.
Therapeutic Development Overview
In the
Biologics & Drugs Many biotech therapies 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 (FDC) Act. Approval of a new drug application (NDA) is required before such a drug can be marketed. (Note: A few biologics, notably insulin and growth hormone, are regulated under the FDC 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, postmarketing 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.
39
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 for efficacy evidence in support of 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.
Clinical Trials
A drug that passes animal safety studies may move into human testing following the submission of an investigational new drug (
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, 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 health care 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 health care 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 health care professionals conducting a trial.
●● Institutional review boards—local oversight groups at hospitals, universities and other health care facilities who 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 2 diabetes) or it may be narrower (for example, insulin-dependent Type 2
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 pvalue. 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 only a one 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 five 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 (PDUFA), the FDA has a goal of acting on 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(s), 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. Because clinical trials are not large enough to detect rare side effects, new drugs must be monitored once they enter the market. Drug makers are required by law to report adverse events to the FDA, and patients and physicians may also report problems to the agency through its MedWatch Web site (www.fda.gov/medwatch/).
To cast a wider net and pick up adverse events physicians and patients may not even realize are related to a drug, the Food & Drug Administration Amendments Act of 2007 (FDAAA) mandates a private-public partnership to conduct active postmarket surveillance through the analysis of large patient databases (such as those maintained by major insurers and the Centers for Medicare and Medical Services).
Additionally, for some new drugs, the FDA and a company may create a Risk Evaluation and Mitigation Strategy (REMS) to ensure the drug’s benefits outweigh the risks. A Phase IV clinical trial may be designed to refine knowledge about the drug. Initial drug approvals usually cover only a single indication, often a narrow one. Although drugs may be prescribed off-label for other indications, companies often conduct additional Phase II and III trials to confirm the drug works in those indications. If successful, they submit the new data to the FDA for approval through a supplemental NDA or BLA. If approved, a new indication is added to the product label, allowing the company to market the drug for that indication.
No comments:
Post a Comment