Registration of Innovative Medicinal Product in the US

The Food and Drug Administration is in charge of making sure: the safety, efficacy, and security of human and veterinary pharmaceuticals, biological products, and medical equipment are safe for use. To protect public health and limit tobacco use by minors, the FDA is also responsible for regulating the manufacturing, marketing, and distribution of tobacco products. FDA is responsible for advancing public health by assisting in the development of medical products that are more effective, safer, and affordable, as well as assisting the public in obtaining the accurate, science-based information they require in order to use medical products and foods to maintain and improve their health. Historically, the pharmaceutical industry has always been a reactionary one. Many tragedies had to occur for the FDA to take action, but from its early days to the present day, the FDA is renowned for continual improvement and high standards. It wasn’t known as the FDA until the 1930s, but it began as we know it today in 1906 as a reaction to a novel that shocked the nation, and in an attempt to stop the misbranding of drugs (A. Heath, 2020). Upton Sinclair’s novel ‘The Jungle’, describing filthy conditions in the Chicago meat-packing industry, caused an outrage in 1906 and stirred passage of the Pure Food and Drugs Act. The Food and Drug Administration later was established to administer the law, and a number of tougher measures were proposed in 1933. The organization within the FDA that regulates prescription and generic drugs is known as CDER. This stands for the center for drug evaluation and research. They play a huge role in ensuring the safety and efficacy of all drugs within the United States and they approve many different new drug applications each year. As recently as 2017, CDER embarked on an initiative to modernize the New Drugs Regulatory Program. The key areas of focus in this program are scientific leadership, integrated assessment, benefit-risk ratio monitoring, managing talent, operational excellence, and knowledge management. Programs such as this are testament to the continual improvement the FDA as a whole is renowned for. Within CDER is the Office of New Drugs (OND) (Office of New Drug Products, n.d). The Office of New Drug Product (ONDP) protects and advances public health through the review and regulation of pharmaceutical quality in drug substances and new drug products. They evaluate and review investigational new drug (IND) submissions, original new drug application (NDA) submissions, and active pharmaceutical ingredient (API) information supporting all new and abbreviated new drug applications in a team-based, cross-office collaborative manner (ANDAs).

If a company wants to bring a new drug to market it will take several years before this can be achieved. One of the first things that must be decided and one of the most crucial parts of the new drug application is choosing the correct regulatory pathway. When bringing a new drug to the market where its active ingredient has never been on the market, the 505 B1 regulatory pathway is the correct route to take as it will ultimately send a company down the route which requires pre-clinical and clinical trials. The next step in the process requires that an (IND) investigational new drug must be filed before the official (NDA) new drug application is applied for. This is the step where a company sends its drug to a lab for clinical trials on humans. This is a long process for any new drug being brought to market which takes years before it’s FDA approved. When a new drug is discovered, anywhere from 3 to 6 years is spent testing the drug on animals during pre-clinical trials before a decision is made to move forward with human trials (Clinical Trial Phases, n.d.). Deciding whether a drug is ready for clinical trials (the so-called move from bench to bedside) involves extensive preclinical studies that yield preliminary efficacy, toxicity, pharmacokinetics, and safety information. Wide doses of the drug are tested using in vitro (test tube or cell culture) and in vivo (animal) experiments, and it is also possible to perform in silico profiling using computer models of the drug-target interactions. All this information will be used later as part of the NDA. Clinical trials begin with a research being done with a small but controlled number of participants, and then it progresses to a large-scale research in patients as more data is acquired. These large-scale studies will frequently compare a new product against an existing treatment to evaluate how they compare. As more information becomes available, a larger number of patients will be exposed to the new product, allowing safety data to be compiled that demonstrates the product's safety in the intended patient group. Before the clinical trial program begins, information on the product's quality and non-clinical safety will have been acquired. Once clinical trials begin on humans, an even longer period of testing can be expected. On average clinical trials take around 6 to 7 years to complete. This period is broken into 3 phases. Phase 1 usually consists of 20 to 100 participants. In phase 2 the number of participants increases by 100 to 500 taking part, and finally in phase 3 is when the greatest number of participants with a figure of between 1000 to 5000 take part in the studies. The very nature of a clinical trial means that it naturally comes with a certain amount of risk for the people involved. The FDA is committed to protecting the participants of clinical trials, as well as providing reliable information to those interested in participating (Conducting Clinical Trials, n.d.). Recently, unethical behavior on the part of some researchers has shaken the public trust and prompted the federal government to establish regulations and guidelines for clinical research to protect participants from unreasonable risks. Although efforts are made to control risks to clinical trial participants, some risks may be unavoidable because of the uncertainty inherent in clinical research involving new medical products. It's important, therefore, that people make their decision to participate in a clinical trial only after they have a full understanding of the entire process and the risks that may be involved. Once phase 3 is finished and the company is satisfied with how testing went and wants to bring the drug to market, then they will proceed with the NDA to the FDA. The FDA has 60 days to review the application, after which it will decide whether it qualifies for further review or has been rejected. There are times when this process can be speeded up if the drug in question is thought to have a demonstrable positive effect on patients (‘Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review’, 2018). Speeding the availability of drugs that treat serious diseases is in everyone's interest, especially when the drugs are the first available treatment or if the drug has advantages over existing treatments. The Food and Drug Administration has developed four distinct and successful approaches to making such drugs available as rapidly as possible which are priority review, breakthrough therapy, accelerated approval, and fast track. The FDA begins its review by examining the drug's labelling to make sure that it provides medical professionals and customers with sufficient and correct information about the drug. This method also ensures that no fraudulent promises are placed on the labels of the final product. An FDA advisory board, made up physicians and other professionals, meets to discuss the NDA with FDA reviewers and the product's producer. These gatherings usually last one or two days. Following the meeting, the advisory board will make a recommendation to the FDA for approval or rejection, which will usually be decided by a vote. The FDA frequently accepts the board's recommendations, although it is not compelled to do so. Physicians, pharmacists, chemists, pharmacologists, statisticians, and even patient representatives make up this advisory board.

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As part of any NDA submission, the correct regulatory pathway is an important factor to consider as it will make it clear to a company whether pre-clinical trials are required as part of the NDA. Which regulatory approach to pursue is a critical question for each drug development effort. The amount of clinical and nonclinical investigations that must be done, as well as how the NDA will be presented to regulators, are all factors to consider early on. It also has a significant impact on a variety of other decisions, ranging from early development to approval. Of the more obvious questions that are asked early on is if the drug in question is a new chemical entity (‘What Is a New Chemical Entity (NCE)?’, n.d.). A new chemical entity (NCE) is a drug that does not contain any active moiety that has been approved by the United States Food and Drug Administration (USFDA) with any other application. The manufacturers of an innovator drug generally develop an NCE during the early development stage of the product cycle. The NCE, then, undergoes various clinical trials in order to transform into a drug product. Another question that needs to be asked is if the new drug is new or is it a novel formulation. Does it qualify as an NME? Certain drugs are classified as new molecular entities (‘NMEs’) for purposes of FDA review. Many of these products contain active moieties that FDA had not previously approved, either as a single ingredient drug or as part of a combination product. These products frequently provide important new therapies for patients. Some drugs are characterized as NMEs for administrative purposes, but nonetheless contain active moieties that are closely related to active moieties in products that FDA has previously approved. FDA’s classification of a drug as an ‘NME’ for review purposes is distinct from FDA’s determination of whether a drug product is a ‘new chemical entity’ or ‘NCE’ within the meaning of the Federal Food, Drug, and Cosmetic Act. The most popular kind of NDA submission is the 505(b)(2). Most 505(b)(2) applications consist of changes to a previously approved drug product. When a company decides to submit this application, it comes with changes to a product that has already been approved by the FDA. One of which is the route of administration. This is an important factor as questions such as the safety of the drug on the patient after it’s been administered must be taken into consideration, along with the overall effectiveness of the drug on the patient. Another time-saving decision a company can make as part of their application is to find out if there are any data from the approved product or published literature that you can use to reduce the necessity for your own research. From a research point of view, this is certainly advantageous to a company compared to when a 505 (b)(1) application is submitted where this is not possible.

If a company is making a product that is not innovative there are two options available. The first is the 505(b)(2) application. Companies need to determine early on if their drug is different from an already approved drug. Unlike the 505(b)(1) which requires a full investigation of testing as it’s a new drug, the 505(b)(2) pathway allows for a bit more flexibility to the company. The goal of this flexibility is to avoid needless testing and make it easier for follow-on products to reach the market. It remains the most popular pathway used by pharmaceutical companies today. As a second option for a company if they’re intending to make a generic drug then the regulatory pathway, they would choose would be the 505 (j) ANDA as part of their application. The 505 (j) ANDA is based on the FDA's determination that a drug that they have already approved, such as a reference listed drug (RLD), is safe and effective. An ANDA must generally include information demonstrating that the proposed generic product is safe and effective. Both of these options are popular as they make use of previous studies and by doing so save a lot of time thus getting the product to market much quicker.