The FDA's Drug Review Process: Ensuring Drugs Are Safe and Effective

The path a drug travels from a lab to your medicine cabinet is usually long, and every drug takes a unique route. Often, a drug is developed to treat a specific disease. An important use of a drug may also be discovered by accident. For example, Retrovir (zidovudine, also known as AZT) was first studied as an anticancer drug in the 1960s with disappointing results. Twenty years later, researchers discovered the drug could treat AIDS, and Food and Drug Administration approved the drug, manufactured by GlaxoSmithKline, for that purpose in 1987. Most drugs that undergo preclinical (animal) testing never even make it to human testing and review by the FDA. The drugs that do must undergo the agency's rigorous evaluation process, which scrutinizes everything about the drug--from the design of clinical trials to the severity of side effects to the conditions under which the drug is manufactured.

Investigational New Drug Application (IND)--The pharmaceutical industry sometimes seeks advice from the FDA prior to submission of an IND. Sponsors--companies, research institutions, and other organizations that take responsibility for developing a drug. They must show the FDA results of preclinical testing in laboratory animals and what they propose to do for human testing. At this stage, the FDA decides whether it is reasonably safe for the company to move forward with testing the drug in humans.

Clinical Trials--Drug studies in humans can begin only after an IND is reviewed by the FDA and a local institutional review board (IRB). The board is a panel of scientists and non-scientists in hospitals and research institutions that oversees clinical research. IRBs approve the clinical trial protocols, which describe the type of people who may

participate in the clinical trial, the schedule of tests and procedures, the medications and dosages to be studied, the length of the study, the study's objectives, and other details. IRBs make sure the study is acceptable, that participants have given consent and are fully informed of their risks, and that researchers take appropriate steps to protect patients from harm.

Phase 1 studies are usually conducted in healthy volunteers. The goal here is to determine what the drug's most frequent side effects are and, often, how the drug is metabolized and excreted. The number of subjects typically ranges from 20 to 80. Phase 2 studies begin if Phase 1 studies don't reveal unacceptable toxicity. While the emphasis in Phase 1 is on safety, the emphasis in Phase 2 is on effectiveness. This phase aims to obtain preliminary data on whether the drug works in people who have a certain disease or condition. For controlled trials, patients receiving the drug are compared with similar patients receiving a different treatment--usually an inactive substance (placebo), or a different drug. Safety continues to be evaluated, and short-term side effects are studied. Typically, the number of subjects in Phase 2 studies ranges from a few dozen to about 300. At the end of Phase 2, the FDA and sponsors try to come to an agreement on how largescale studies in Phase 3 should be done. How often the FDA meets with a sponsor varies, but this is one of two most common meeting points prior to submission of a new drug application. The other most common time is pre-NDA--right before a new drug application is submitted. Phase 3 studies begin if evidence of effectiveness is shown in Phase 2. These studies gather more information about safety and effectiveness, studying different populations and different dosages and using the drug in combination with other drugs. The number of subjects usually ranges from several hundred to about 3,000 people.

Postmarket requirement and commitment studies are required of or agreed to by a sponsor, and are conducted after the FDA has approved a product for marketing. The FDA uses postmarket requirement and commitment studies to gather additional information about a product's safety, efficacy, or optimal use.

New Drug Application (NDA)--This is the formal step a drug sponsor takes to ask that the FDA consider approving a new drug for marketing in the United States. An NDA includes all animal and human data and analyses of the data, as well as information about how the drug behaves in the body and how it is manufactured. When an NDA comes in, the FDA has 60 days to decide whether to file it so that it can be reviewed. The FDA can refuse to file an application that is incomplete. For example, some required studies may be missing. In accordance with the Prescription Drug User Fee Act (PDUFA), the FDA's Center for Drug Evaluation and Research (CDER) expects to review and act on at least 90 percent of NDAs for standard drugs no later than 10 months after the applications are received. The review goal is six months for priority drugs. (See "The Role of User Fees.")

"It's the clinical trials that take so long--usually several years," says Sandra Kweder, M.D., deputy director of the Office of New Drugs in the CDER. "The emphasis on speed for FDA mostly relates to review time and timelines of being able to meet with sponsors during a drug's development," she says.

Drug Review Steps Simplified

1. Preclinical (animal) testing. 2. An investigational new drug application (IND) outlines what the sponsor of a new drug proposes for human testing in clinical trials. 3. Phase 1 studies (typically involve 20 to 80 people). 4. Phase 2 studies (typically involve a few dozen to about 300 people). 5. Phase 3 studies (typically involve several hundred to about 3,000 people). 6. The pre-NDA period, just before a new drug application (NDA) is submitted. A common time for the FDA and drug sponsors to meet. 7. Submission of an NDA is the formal step asking the FDA to consider a drug for marketing approval. 8. After an NDA is received, the FDA has 60 days to decide whether to file it so it can be reviewed. 9. If the FDA files the NDA, an FDA review team is assigned to evaluate the sponsor's research on the drug's safety and effectiveness. 10. The FDA reviews information that goes on a drug's professional labeling (information on how to use the drug). 11. The FDA inspects the facilities where the drug will be manufactured as part of the approval process. 12. FDA reviewers will approve the application or issue a complete response letter.

Supplemental Information About the Drug Approval Process

Reviewing Applications

Though FDA reviewers are involved with a drug's development throughout the IND stage, the official review time is the length of time it takes to review a new drug application and issue an action letter, an official statement informing a drug sponsor of the agency's decision. Once a new drug application is filed, an FDA review team--medical doctors, chemists, statisticians, microbiologists, pharmacologists, and other experts--evaluates whether the studies the sponsor submitted show that the drug is safe and effective for its proposed use. No drug is absolutely safe; all drugs have side effects. "Safe" in this sense means that the benefits of the drug appear to outweigh the known risks. The review team analyzes study results and looks for possible issues with the application, such as weaknesses of the study design or analyses. Reviewers determine whether they agree with the sponsor's results and conclusions, or whether they need any additional information to make a decision. Each reviewer prepares a written evaluation containing conclusions and recommendations about the application. These evaluations are then considered by team leaders, division directors, and office directors, depending on the type of application. Reviewers receive training that fosters consistency in drug reviews, and good review practices remain a high priority for the agency. Sometimes, the FDA calls on advisory committees, who provide FDA with independent opinions and recommendations from outside experts on applications to market new drugs, and on FDA policies. Whether an advisory committee is needed depends on many things. "Some considerations would be if it's a drug that has significant questions, if it's the first in its class, or the first for a given indication," says Mark Goldberger, M.D., a former director of one of CDER's drug review offices. "Generally, FDA takes the advice of advisory committees, but not always," he says. "Their role is just that--to advise."

Accelerated Approval

Traditional approval requires that clinical benefit be shown before approval can be granted. Accelerated approval is given to some new drugs for serious and life-threatening illnesses that lack satisfactory treatments. This allows an NDA to be approved before measures of effectiveness that would usually be required for approval are available. Instead, less traditional measures called surrogate endpoints are used to evaluate effectiveness. These are laboratory findings or signs that may not be a direct measurement of how a patient feels, functions, or survives, but are considered likely to predict benefit. For example, a surrogate endpoint could be the lowering of HIV blood levels for short periods of time with anti-retroviral drugs. Gleevec (imatinib mesylate), an oral treatment for patients with a life-threatening form of cancer called chronic myeloid leukemia (CML), received accelerated approval. The drug was also approved under the FDA's orphan drug program, which gives financial incentives to sponsors for manufacturing drugs that treat rare diseases. Gleevec blocks enzymes that play a role in cancer growth. The approval was based on results of three large Phase 2 studies, which showed the drug could substantially reduce the level of cancerous cells in the bone marrow and blood. Most drugs to treat HIV have been approved under accelerated approval provisions, with the company required to continue its studies after the drug is on the market to confirm that its effects on virus levels are maintained and that it ultimately benefits the patient. Under accelerated approval rules, if studies don't confirm the initial results, the FDA can withdraw the approval. Because premarket review can't catch all potential problems with a drug, the FDA continues to track approved drugs for adverse events through a postmarketing surveillance program.

Bumps in the Road

If the FDA decides that the benefits of a drug outweigh the known risks, the drug will receive approval and can be marketed in the United States. But if there are problems with an NDA or if more information is necessary to make that determination, the FDA may issue a complete response letter. Common problems include unexpected safety issues that crop up or failure to demonstrate a drug's effectiveness. A sponsor may need to conduct additional studies-perhaps studies of more people, different types of people, or for a longer period of time.

Manufacturing issues are also among the reasons that approval may be delayed or denied. Drugs must be manufactured in accordance with standards called good manufacturing practices, and the FDA inspects manufacturing facilities before a drug can be approved. If a facility isn't ready for inspection, approval can be delayed. Any manufacturing deficiencies found need to be corrected before approval. "Sometimes a company may make a certain amount of a drug for clinical trials. Then when they go to scale up, they may lose a supplier or end up with quality control issues that result in a product of different chemistry," says Kweder. "Sponsors have to show us that the product that's going to be marketed is the same product that they tested." John Jenkins, M.D., director of CDER's Office of New Drugs, says, "It's often a combination of problems that prevent approval." Close communication with the FDA early on in a drug's development reduces the chance that an application will have to go through more than one cycle of review, he says. "But it's no guarantee." The FDA outlines the justification for its decision in a complete response letter to the drug sponsor and CDER gives the sponsor a chance to meet with agency officials to discuss the deficiencies. At that point, the sponsor can ask for a hearing, correct any deficiencies and submit new information, or withdraw the application.

The Role of User Fees

Since PDUFA was passed in 1992, more than 1,000 drugs and biologics have come to the market, including new medicines to treat cancer, AIDS, cardiovascular disease, and lifethreatening infections. PDUFA has allowed the Food and Drug Administration to bring access to new drugs as fast or faster than anywhere in the world, while maintaining the same thorough review process. Under PDUFA, drug companies agree to pay fees that boost FDA resources, and the FDA agrees to time goals for its review of new drug applications. Along with supporting increased staff, drug user fees help the FDA upgrade resources in information technology. The agency has moved toward an electronic submission and review environment, now accepting more electronic applications and archiving review documents electronically. The goals set by PDUFA apply to the review of original new human drug and biological applications, resubmissions of original applications, and supplements to approved applications. The second phase of PDUFA, known as PDUFA II, was reauthorized in 1997 and extended the user fee program through September 2002. PDUFA III, which extended to Sept. 30, 2007, was reauthorized in June 2002.

PDUFA III allowed the FDA to spend some user fees to increase surveillance of the safety of medicines during their first two years on the market, or three years for potentially dangerous medications. It is during this initial period, when new medicines enter into wide use, that the agency is best able to identify and counter adverse side effects that did not appear during the clinical trials. On September 27, 2007, President Bush signed into law the Food and Drug Administration Amendments Act of 2007 which includes the reauthorization and expansion of the Prescription Drug User Fee Act. The reauthorization of PDUFA will significantly broaden and upgrade the agency's drug safety program, and facilitate more efficient development of safe and effective new medications for the American public. In addition to setting time frames for review of applications, PDUFA sets goals to improve communication and sets goals for specific kinds of meetings between the FDA and drug sponsors. It also outlines how fast the FDA must respond to requests from sponsors. Throughout a drug's development, the FDA advises sponsors on how to study certain classes of drugs, how to submit data, what kind of data are needed, and how clinical trials should be designed.

The Quality of Clinical Data

The Food and Drug Administration relies on data that sponsors submit to decide whether a drug should be approved. To protect the rights and welfare of people in clinical trials, and to verify the quality and integrity of data submitted, the FDA's Division of Scientific Investigations (DSI) conducts inspections of clinical investigators' study sites. DSI also reviews the records of institutional review boards to be sure they are fulfilling their role in patient protection. "FDA investigators compare information that clinical investigators provided to sponsors on case report forms with information in source documents such as medical records and lab results," says Carolyn Hommel, a consumer safety officer in DSI. DSI seeks to determine such things as whether the study was conducted according to the investigational plan, whether all adverse events were recorded, and whether the subjects met the inclusion/exclusion criteria outlined in the study protocol. At the conclusion of each inspection, FDA investigators prepare a report summarizing any deficiencies. In cases where they observe numerous or serious deviations, such as falsification of data, DSI classifies the inspection as "official action indicated" and sends a warning letter or Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) to the clinical investigator, specifying the deviations that were found.

The NIDPOE begins an administrative process to determine whether the clinical investigator should remain eligible to receive investigational products and conduct clinical studies. CDER conducts about 300-400 clinical investigator inspections annually. About 3 percent are classified in this "official action indicated" category. The FDA has established an independent Drug Safety Oversight Board (DSOB) to oversee the management of drug safety issues. The Board meets monthly and has representatives from three FDA Centers and five other federal government agencies. The board's responsibilities include conducting timely and comprehensive evaluations of emerging drug safety issues, and ensuring that experts--both inside and outside of the FDA--give their perspectives to the agency. The first meeting of the DSOB was held in June 2005.

LEARNING CENTER DRUG DEVELOPMENT PROCESS: Stages of Drug Development Any drug development process must proceed through several stages in order to produce a product that is safe, efficacious, and has passed all regulatory requirements. Pacific BioLabs can assist you in this process. Our scientists can help you to determine your testing needs, and our experienced staff can perform the critical tests and studies that are necessary to win FDA approval. To get you started, below we have provided an in-depth overview of many stages in the drug development process and necessary studies. Keep in mind this is just a guide; if you have any specific questions call Pacific BioLabs at 510-964-9000 to speak to a knowledgeable resource who can help you identify what testing you may need to perform.

Detailed Stages of Drug Development

1. 2. 3. 4. 5. 6. 7. Discovery Product Characterization Formulation, Delivery, Packaging Development Pharmacokinetics And Drug Disposition Preclinical Toxicology Testing And IND Application Bioanalytical Testing Clinical Trials

Discovery Discovery often begins with target identification choosing a biochemical mechanism involved in a disease condition. Drug candidates, discovered in academic and pharmaceutical/biotech research labs, are tested for their interaction with the drug target. Up to 5,000 to 10,000 molecules for each potential drug candidate are subjected to a rigorous screening process which can include functional genomics and/or proteomics as well as other screening methods. Once scientists confirm interaction with the drug target, they typically validate that target by checking for activity versus the disease condition for which the drug is being developed. After careful review, one or more lead compounds are chosen. Product Characterization When the candidate molecule shows promise as a therapeutic, it must be characterizedthe molecules size, shape, strengths and weaknesses, preferred conditions for maintaining function, toxicity, bioactivity, and bioavailability must be determined. Early stage pharmacology studies help to characterize the underlying mechanism of action of the compound.

Formulation, Delivery, Packaging Development Drug developers must devise a formulation that ensures the proper drug delivery parameters. It is critical to begin looking ahead to clinical trials at this phase of the drug development process. Drug formulation and delivery may be refined continuously until, and even after, the drugs final approval. Scientists determine the drugs stabilityin the formulation itself, and for all the parameters involved with storage and shipment, such as heat, light, and time. The formulation must remain potent and sterile; and it must also remain safe (nontoxic). Pharmacokinetics And Drug Disposition Pharmacokinetic (PK) or ADME (Absorption/Distribution/Metabolism/Excretion) studies provide useful feedback for formulation scientists. PK studies yield parameters such as AUC (area under the curve), Cmax (maximum concentration of the drug in blood), and Tmax (time at which Cmax is reached). Later on, this data from animal PK studies is compared to data from early stage clinical trials to check the predictive power of animal models. Preclinical Toxicology Testing And IND Application Preclinical testing analyzes the bioactivity, safety, and efficacy of the formulated drug product. This testing is critical to a drugs eventual success and, as such, is scrutinized by many regulatory entities. During the preclinical stage of the development process, plans for clinical trials and an Investigative New Drug (IND) application are prepared. Studies taking place during the preclinical stage should be designed to support the clinical studies that will follow. The main stages of preclinical toxicology testing are: Acute Studies Acute tox studies look at the effects of one or more doses administered over a period of up to 24 hours. The goal is to determine toxic dose levels and observe clinical indications of toxicity. Usually, at least two mammalian species are tested. Data from acute tox studies helps determine doses for repeated dose studies in animals and Phase I studies in humans. Repeated Dose Studies Depending on the duration of the studies, repeated dose studies may be referred to as subacute, subchronic, or chronic. The specific duration should anticipate the length of the clinical trial that will be conducted on the new drug. Again, two species are typically required. Genertic Toxicity Studies These studies assess the likelihood that the drug compound is mutagenic or carcinogenic. Procedures such as the Ames test (conducted in bacteria) detect genetic changes. DNA damage is assessed in tests using mammalian cells such as the Mouse Micronucleus Test. The

Chromosomal Aberration Test and similar procedures detect damage at the chromosomal level. Reproductive Toxicity Studies Segment I reproductive tox studies look at the effects of the drug on fertility. Segment II and III studies detect effects on embryonic and post-natal development. In general, reproductive tox studies must be completed before a drug can be administered to women of child-bearing age. Carcinogenicity Studies Carcinogenicity studies are usually needed only for drugs intended for chronic or recurring conditions. They are time consuming and expensive, and must be planned for early in the preclinical testing process. Toxicokinetic Studies These are typically similar in design to PK/ADME studies except that they use much higher dose

Pre-clinical development
In drug development, pre-clinical development, also named preclinical studies and nonclinical studies, is a stage of research that begins before clinical trials (testing in humans) can begin, and during which important feasibility, iterative testing and drug safety data is collected.

The main goals of pre-clinical studies are to determine a product's ultimate safety profile. Products may include new or iterated or like-kind medical devices, drugs, gene therapy solutions, etc.

Types of preclinical research

Each class of product may undergo different types of preclinical research. For instance, drugs may undergo pharmacodynamics (what the drug does to the body) (PD), pharmacokinetics (what the body does to the drug) (PK), ADME, and toxicity testing through animal testing. This data allows researchers to allometrically estimate a safe starting dose of the drug for clinical trials in humans. Medical devices that do not have drug attached will not undergo these additional tests and may go directly to GLP testing for safety of the device and its components. Some medical devices will also undergo biocompatibility testing which helps to show whether a component of the device or all components are sustainable in a living model. Most pre-clinical studies must adhere to Good Laboratory Practices (GLP) in ICH Guidelines to be acceptable for submission to regulatory agencies such as the Food & Drug Administration in the United States. Typically, both in vitro and in vivo tests will be performed. Studies of a drug's toxicity include which organs are targeted by that drug, as well as if there are any long-term carcinogenic effects or toxic effects on mammalian reproduction.

Animal testing
The information collected from these studies is vital so that safe human testing can begin. Typically, in drug development studies animal testing involves two species. The most commonly used models are murine and canine, although primate and porcine are also used.

Choice of species
The choice of species is based on which will give the best correlation to human trials. Differences in the gut, enzyme activity, circulatory system, or other considerations make certain models more appropriate based on the dosage form, site of activity, or noxious metabolites. For example, canines may not be good models for solid oral dosage forms because the characteristic carnivore intestine is underdeveloped compared to the omnivore's, and gastric emptying rates are increased. Also, rodents can not act as models for antibiotic drugs because the resulting alteration to their intestinal flora causes significant adverse effects. Depending on a drug's functional groups, it may be metabolized in similar or different ways between species, which will affect both efficacy and toxicology. Medical device studies also use this basic premise. Most studies are performed in larger species such as dogs, pigs and sheep which allow for testing in a similar sized model as that of a human. In addition, some species are used for similarity in specific organs or

organ system physiology (swine for dermatological and coronary stent studies; goats for mammary implant studies; dogs for gastric and cancer studies; etc.).

Ethical issues
Animal testing in the research-based pharmaceutical industry has been reduced in recent years both for ethical and cost reasons. However, most research will still involve animal based testing for the need of similarity in anatomy and physiology that is required for diverse product development.

No observable effect levels

Based on pre-clinical trials, No Observable Adverse Effect Levels (NOAEL) on drugs are established, which are used to determine initial phase 1 clinical trial dosage levels on a mass API per mass patient basis. Generally a 1/100 uncertainty factor or "safety margin" is included to account for interspecies (1/10) and inter-individual (1/10) differences

. Phases of clinical research

The phases of clinical research are the steps in which scientists do experiments with a health intervention in an attempt to find enough evidence for a process which would be useful as a medical treatment. In the case of pharmaceutical study, the phases start with drug design and drug discovery, go on to animal testing, then start by testing in only a few human subjects and expand to test in many study participants if the trial seems safe and useful.

Phases
Clinical trials involving new drugs are commonly classified into four phases. Clinical trials of drugs may not fit into a single phase. For example, some may blend from phase I

to phase II or from phase II to phase III. Therefore, it may be easier to think of early phase studies and late phase studies.[1] The drug-development process will normally proceed through all four phases over many years. If the drug successfully passes through Phases I, II, and III, it will usually be approved by the national regulatory authority for use in the general population. Phase IV are 'post-approval' studies. Summary of clinical trial phases phase primary goal dose patient monitor typical number of participants notes

Nonhuman efficacy, toxicity and preclinical unrestricted pharmacokinetic information Pharmacodynamics and Pharmacokinetics very small, phase 0 particularly oral subtherapeutic bioavailability and half-life phase I Testing of drug on healthy volunteers for dose-ranging

A graduate in vitro and level in vivo researcher animal (Ph.D.) clinical 10 people researcher often skipped for phase I determines whether drug is safe to check for efficacy determines whether drug can have any efficacy; at this point, the drug is not presumed to have any therapeutic effect whatsoever determines a drug's therapeutic effect; at this point, the drug is presumed to have some effect watch drug's long term

often subtherapeutic, clinical 20-100 but with researcher ascending doses

phase II

Testing of drug on patients to assess efficacy and safety

therapeutic dose

clinical 100-300 researcher

phase III

Testing of drug on patients to assess efficacy and safety

therapeutic dose

clinical researcher and 1000-2000 personal physician personal anyone physician seeking

phase IV Postmarketing surveillance -

therapeutic dose

watching drug use in public phase V translational research no dosing none

treatment from their physician all reported use

effects research on data collected

Pre-clinical studies
Before pharmaceutical companies start clinical trials on a drug, they conduct extensive pre-clinical studies. These involve in vitro (test tube or cell culture) and in vivo (animal) experiments using wide-ranging doses of the study drug to obtain preliminary efficacy, toxicity and pharmacokinetic information. Such tests assist pharmaceutical companies to decide whether a drug candidate has scientific merit for further development as an investigational new drug.

Phase 0
Phase 0 is a recent designation for exploratory, first-in-human trials conducted in accordance with the United States Food and Drug Administration's (FDA) 2006 Guidance on Exploratory Investigational New Drug (IND) Studies.[2] Phase 0 trials are also known as human microdosing studies and are designed to speed up the development of promising drugs or imaging agents by establishing very early on whether the drug or agent behaves in human subjects as was expected from preclinical studies. Distinctive features of Phase 0 trials include the administration of single subtherapeutic doses of the study drug to a small number of subjects (10 to 15) to gather preliminary data on the agent's pharmacodynamics (what the drug does to the body) and pharmacokinetics (what the body does to the drugs).[3] A Phase 0 study gives no data on safety or efficacy, being by definition a dose too low to cause any therapeutic effect. Drug development companies carry out Phase 0 studies to rank drug candidates in order to decide which has the best pharmacokinetic parameters in humans to take forward into further development. They enable go/no-go decisions to be based on relevant human models instead of relying on sometimes inconsistent animal data.

Phase I
Phase I trials are the first stage of testing in human subjects. Normally, a small group of 20100 healthy volunteers will be recruited. This phase is designed to assess the safety (pharmacovigilance), tolerability, pharmacokinetics, and pharmacodynamics of a drug. These trials are often conducted in a clinical trial clinic, where the subject can be observed by full-time staff. These clinical trial clinics are often run by contract research organisations (CRO) who conduct these studies on behalf of pharmaceutical companies or other research investigators. The subject who receives the drug is usually observed until several half-lives of the drug have passed. Phase I trials also normally include doseranging, also called dose escalation studies, so that the best and safest dose can be found

and to discover the point at which a compound is too poisonous to administer.[4] The tested range of doses will usually be a fraction[quantify] of the dose that caused harm in animal testing. Phase I trials most often include healthy volunteers. However, there are some circumstances when real patients are used, such as patients who have terminal cancer or HIV and the treatment is likely to make healthy individuals ill. These studies are usually conducted in tightly controlled clinics called CPUs (Central Pharmacological Units), where participants receive 24-hour medical attention and oversight. In addition to the previously mentioned unhealthy individuals, patients who have typically already tried and failed to improve on the existing standard therapies"[1] may also participate in phase I trials. Volunteers are paid an inconvenience fee for their time spent in the volunteer centre. Pay depends on length of participation. There are different kinds of phase I trial: SAD Single ascending dose studies are those in which small groups of subjects are given a single dose of the drug while they are observed and tested for a period of time. Typically, a small number of participants, usually three, are entered sequentially at a particular dose.[1] If they do not exhibit any adverse side effects, and the pharmacokinetic data is roughly in line with predicted safe values, the dose is escalated, and a new group of subjects is then given a higher dose. If unacceptable toxicity is observed in any of the three participants, an additional number of participants, usually three, are treated at the same dose.[1] This is continued until pre-calculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up (at which point the drug is said to have reached the maximum tolerated dose (MTD)). If an additional unacceptable toxicity is observed, then the dose escalation is terminated and that dose, or perhaps the previous dose, is declared to be the maximally tolerated dose. This particular design assumes that the maximally tolerated dose occurs when approximately one-third of the participants experience unacceptable toxicity. Variations of this design exist, but most are similar.[1] MAD Multiple ascending dose studies are conducted to better understand the pharmacokinetics and pharmacodynamics of multiple doses of the drug. In these studies, a group of patients receives multiple low doses of the drug, while samples (of blood, and other fluids) are collected at various time points and analyzed to acquire information on how the drug is processed within the body. The dose is subsequently escalated for further groups, up to a predetermined level. Food effect A short trial designed to investigate any differences in absorption of the drug by the body, caused by eating before the drug is given. These studies are usually run as a crossover study, with volunteers being given two identical doses of the drug while fasted, and after being fed.

Phase II

Once a dose or range of doses is determined, the next goal is to evaluate whether the drug has any biological activity or effect.[1] Phase II trials are performed on larger groups (100300) and are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients. Genetic testing is common, particularly when there is evidence of variation in metabolic rate.[1] When the development process for a new drug fails, this usually occurs during Phase II trials when the drug is discovered not to work as planned, or to have toxic effects. Phase II studies are sometimes divided into Phase IIA and Phase IIB.

Phase IIA is specifically designed to assess dosing requirements (how much drug should be given). Phase IIB is specifically designed to study efficacy (how well the drug works at the prescribed dose(s)).

Some trials combine Phase I and Phase II, and test both efficacy and toxicity. Trial design Some Phase II trials are designed as case series, demonstrating a drug's safety and activity in a selected group of patients. Other Phase II trials are designed as randomized clinical trials, where some patients receive the drug/device and others receive placebo/standard treatment. Randomized Phase II trials have far fewer patients than randomized Phase III trials. Example Cancer Design In the first stage, the investigator attempts to rule out drugs which have no or little biologic activity. For example, he may specify that a drug must have some minimal level of activity, say, in 20% of participants. If the estimated activity level is less than 20%, he chooses not to consider this drug further, at least not at that maximally tolerated dose. If the estimated activity level exceeds 20%, he will add more participants to get a better estimate of the response rate. A typical study for ruling out a 20% or lower response rate enters 14 participants. If no response is observed in the first 14 participants, the drug is considered not likely to have a 20% or higher activity level. The number of additional participants added depends on the degree of precision desired, but ranges from 10 to 20. Thus, a typical cancer phase II study might include fewer than 30 people to estimate the response rate.[1] Some researchers argue that phase II studies are generally smaller than they ought to be.[1]

Phase III
This phase is designed to assess the effectiveness of the new intervention and thereby, its value in clinical practice.[1] The percentage of Phase II trials that proceed to Phase III, as of 2008, is 18%.[5] Phase III studies are randomized controlled multicenter trials on large patient groups (3003,000 or more depending upon the disease/medical condition studied) and are aimed at being the definitive assessment of how effective the drug is, in

comparison with current 'gold standard' treatment. Because of their size and comparatively long duration, Phase III trials are the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic medical conditions. Phase III trials of chronic conditions or diseases often have a short follow-up period for evaluation, relative to the period of time the intervention might be used in practice.[1] This is sometimes called the "pre-marketing phase" because it actually measures consumer response to the drug. It is common practice that certain Phase III trials will continue while the regulatory submission is pending at the appropriate regulatory agency. This allows patients to continue to receive possibly lifesaving drugs until the drug can be obtained by purchase. Other reasons for performing trials at this stage include attempts by the sponsor at "label expansion" (to show the drug works for additional types of patients/diseases beyond the original use for which the drug was approved for marketing), to obtain additional safety data, or to support marketing claims for the drug. Studies in this phase are by some companies categorized as "Phase IIIB studies."[6][7] While not required in all cases, it is typically expected that there be at least two successful Phase III trials, demonstrating a drug's safety and efficacy, in order to obtain approval from the appropriate regulatory agencies such as FDA (USA), or the EMA (European Union), Once a drug has proved satisfactory after Phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life. This collection of information makes up the "regulatory submission" that is provided for review to the appropriate regulatory authorities[8] in different countries. They will review the submission, and, it is hoped, give the sponsor approval to market the drug. Most drugs undergoing Phase III clinical trials can be marketed under FDA norms with proper recommendations and guidelines through a New Drug Application (NDA) containing all manufacturing, pre-clinical, and clinical data. In case of any adverse effects being reported anywhere, the drugs need to be recalled immediately from the market. While most pharmaceutical companies refrain from this practice, it is not abnormal to see many drugs undergoing Phase III clinical trials in the market.[9]

Phase IV
Phase IV trial is also known as Postmarketing surveillance Trial. Phase IV trials involve the safety surveillance (pharmacovigilance) and ongoing technical support of a drug after it receives permission to be sold. Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive (finding a new market for the drug) or other reasons (for example, the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials). The safety surveillance is