DRUG APPROVAL PROCESS

The process of discovering, developing, testing, and approving new drugs is one of the most exciting areas of scientific research today. Bringing a drug to market is typically a lengthy process involving many steps.

Step 1: Find the needle in the haystack
    Discovering a compound with therapeutic action is like finding a needle in a haystack. Thousands of chemical compounds must be created and tested to find the one that has a desired action without many side effects. The result of this costly, time-consuming search is uncertain it may turn out to be a blockbuster drug like Tylenol� or it may be a drug that has unanticipated intolerable side effects and doesn�t make it to market.

Step 2: Test and study, study and test
    Once the compound is found, the ongoing development lasts several more years. During this time, toxicologists investigate the chemical�s potential for harm. Pharmacologists determine how the drug works and confirm how the drug affects the body by testing it on animals in controlled experiments in the laboratory. Chemists analyze and assess the formulations required for the new compound. All these steps are necessary for preclinical testing. At this stage, the pharmaceutical company also attempts to patent the drug.

    If the drug candidate passes preclinical testing, the company must file an Investigational New Drug (IND) application with the FDA , in fact pharmaceutical companies work very closely with the FDA throughout all stages of the drug approval process.

    The next step is to study the drug in humans during 4 phases of clinical testing:
    • Phase 1 uses healthy volunteers to understand how the drug works in humans, determine initial dosage ranges, and establish a safety profile.
      Phase 1 is the first time a drug is tested in humans. At this stage the absorption, distribution, metabolism, and excretion of the drug in the body is evaluated. The goal is to establish a safe dosage range, measure drug toxicity, and prepare the safety profile. The subjects of phase 1 studies are usually healthy volunteers who are taking no medications, have no ailments, and will not benefit from the drug under study. As a result, they function like a control and any physiologic changes to the subject would indicate an effect of the drug. Phase 1 studies comprise small groups of approximately 10 people and are short term, lasting only several days. However, multiple studies are performed over the course of 1 to 2 years and this data is assessed before research advances to the next phase - phase 2 clinical trials.
    • Phase 2 studies use actual patients to further establish safety and dosing as well as efficacy.
      Phase 2 studies focus on determining drug efficacy and safety in patients for the first time. The drug dosage range and the safety profile, established in phase 1, are used when designing phase 2 trials. Phase 2 studies verify that the drug targets the indication for which it was created. Phase 2 trials will also measure dose response information, pharmacology, and add to the short-term safety profile of the medication. The Phase 2 study period occurs over a 1- to 2-year time frame; however, the individual trials last from several days to a few weeks. The studies are usually blinded and tightly controlled and comprised of larger groups (approximately 100 subjects) than in phase 1 studies. If the data gathered from phase 2 trials still proves the drug to be reasonably safe�and this is true for only about 30% of drug candidates�then trials advance to phase 3.
    • Phase 3 studies are conducted on a larger scale with actual patients to confirm or further establish efficacy and safety, and provide the primary data for product approval.
      Phase 3 studies verify the safety and efficacy on a much larger scale - one that mimics the way the drug will be prescribed to the general population. Phase 3 trials are randomized and gather data on the effects of the drug in patients of different age ranges, gender, and ethnicity relevant to the particular disease state. For instance, estrogen replacement therapy (ERT) trials will use women exclusively and primarily in a certain age range due to the nature of the treatment.
      Phase 3 trials are pivotal for several reasons because they provide the:
      • basis for the beneficial claims used in selling
      • safety data - including adverse events and drug interactions
      • data validating long-term use - each study ranges from 2 to more than 4 years
    • Phase 4 studies are conducted after the product approval to gather more information and will be discussed in Step 4: Develop product labeling and gain approval

Step 3: Apply for FDA approval
    If the drug candidate passes clinical trials, phases 1 to 3, then the company is required to submit a New Drug Application (NDA) to the FDA. Specifically, NDAs go to the Center for Drug Evaluation and Research (CDER) at the FDA. The NDA contains extensive information about the compound as well as data compiled from the preclinical and clinical trials (phases 1 to 3). As mentioned before, the preclinical information includes how much of a drug is absorbed into the blood, how it is broken down chemically in the body, the toxicity of the breakdown products (metabolites), and how quickly the drug is eliminated from the body. The clinical data from phase 2 and 3 typically demonstrate the safety and efficacy of the drug as therapy for a specific condition. The FDA reviews the application thoroughly and looks for objective proof that the drug candidate is safe and effective.

Step 4: Develop product labeling and gain approval
    The FDA and the company developing a drug candidate work together to create the product labeling. As you know, the prescribing information (PI) (or product labeling) is a very important document because it directs how the drug may be used in clinical practice with specific information on dosing and administration, how the medication is supplied, and the clinical pharmacology. The PI also describes the physical characteristics of the medication, structural formula, contraindications, warnings, how to identify and treat drug overdose, precautions, and adverse reactions. Often, the company and the FDA negotiate what information is included in the labeling. For instance, the FDA may request that the company provide specific information about the pharmacokinetic properties of the drug in special populations, such as elderly patients or patients with renal impairment. Or, the company may request that the FDA consider including additional data to support a particular claim (eg, data from an extension of a clinical trial to show that the drug is safe during prolonged use).

    In the past, obtaining FDA approval could have been a lengthy process - sometimes taking well over a year. Now, pharmaceutical companies pay user fees to the FDA, and the approval process usually takes about 10 to 12 months. If the drug is truly innovative, and has life-saving potential, the FDA will put it on the fast track and the approval process can take as little as 6 months.

    If the FDA officials feel that a drug candidate is safe and effective, they will deem the candidate approvable. Should they have questions about the data, the FDA may require the company to test further. When a drug company receives approvable status for the drug candidate, the PI still may need to be fine-tuned according to FDA direction; however, this is still negotiable. Approvable status means that the drug is close to FDA approval pending resolution of outstanding issues. Negotiations with the FDA over the exact language used in the PI usually take 2 to 6 months.

    Once the points have been addressed and agreed to by the FDA and the company, the FDA will send the company an official letter of approval. This signals that the company is permitted to distribute the drug and begin phase 4 clinical trials.

    Phase 4 trials are initiated after the FDA approves the drug candidate. The purpose of phase 4 trials is to reinforce the claims made about the medication. All of the postmarketing data (eg, efficacy, safety, drug interactions) is compiled and submitted to the FDA to show that the medication is safe and effective on the marketplace, where the patient population is large and uncontrolled. Another focus of the phase 4 trial is to validate any new indications for the approved drug.

Step 5: Negotiate DDMAC approval of launch materials (and start selling!)
    Once the FDA approves the drug and labeling, the manufacturer may begin distributing the product and physicians may prescribe it. However, part of the FDA mission is to make sure that the marketing information provided by pharmaceutical companies is truthful, balanced, and accurately communicated. That means there is one more step before the drug can be advertised and promoted with sales aids by sales representatives. The Division of Drug Marketing, Advertising, and Communication (DDMAC), a separate division of the FDA, evaluates the promotional pieces used to market the drug and ensures that the message promoting the drug is correct and true to the approved labeling. For example, Reminyl pieces will be sure to promote treatment of symptoms and not the cure of the disease.

    Officials from DDMAC may approve the materials as they stand, or they may request changes. DDMAC review typically takes 4 to 8 weeks. Then, marketing, regulatory, medical affairs, and advertising work together to implement the changes and produce ads for publication in journals and pieces for the representatives to use when detailing physicians.

    In some cases, the marketing team for a product may decide to allow sales representatives to detail physicians before promotional materials are ready. In that case, representatives may only provide the prescribing information (PI) to physicians. This is known as a PI launch. Typically, a PI launch is followed soon by a full product launch, in which the product is supported by selling materials, such as journal ads, brochures, and visual aids.

    As you have seen, the process of developing a new drug is costly and lengthy. That�s why there is such excitement when a new drug is launched. By the time the drug is ready for promotion by experienced representatives, it has gone through rigorous testing and a stringent approval process. Anything that survives that process is worth celebrating!
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