Abstract
This article walks readers through the drug development process, which is separated into five main stages: drug discovery & development, preclinical research, clinical research, FDA review, and FDA post-market monitoring. In each stage, a lot of research and evaluations must be conducted, and lots of experiment details must be documented to ensure each drug's safety and effectiveness. Then, the article mentioned one common way for chemists to predict the efficacy of the new drug, Rule of 5. Next, the report mentioned one common confusion people have when taking medication: the difference between brand-name and over-the-counter drugs. The main difference lies in the circumstances of the drug, whether it is during the period of patency or not. By reading this article, readers can have a clearer picture of the lengthy drug development process and appreciate the work of drug manufacturers.
Introduction
As Nobel 1908 Prize winner German scientist Paul Ehrlich noted, "drug is a substance that will not work unless it is bound." A drug is efficacious only as it is bound to and modulates the action of its target and creates the binary complex between the drug and macromolecule. Target affinity and selectivity are the most important factors to consider when designing a new drug. Moreover, scientists are always seeking new drugs to overcome diseases that are currently untreatable. This research report will introduce the readers to the drug development process and some standard rules for drug design. Finally, the report will end with some knowledge about the difference between brand-name and over-the-counter drugs.
The Process of Drug Development
The process of drug development is both time and money-consuming. Typically, a drug takes up to 15 years to get approved in the US. And about 1 billion dollars are invested in the process of drug development. The process is not long for no reason. Before receiving FDA marketing approval, the newly developed drug has to go through the preclinical stage, an investigational new drug (IND) application, and complete clinical testing. Before being approved, new drug applications (NDAs) or biologics license applications (BLAs) are typically thoroughly scrutinized. Upon approval, drug performance is then again submitted to regulatory agencies for post-marketing research. This long procedure aims to provide patients with safer, more effective treatments as soon as possible following a careful medical review. There are five essential steps of the FDA drug development process. In the following report,
we will discuss each step.
a. Discovery and Development
Nowadays, drug discovery and development steps include screening hits and optimizing hits to reduce possible side effects of drugs. In other words, increasing affinity and selectivity. Efficacy, potency, metabolic stability, and oral bioavailability are also improved in these steps of the process.
Target Discovery
During target discovery, in vitro research is performed to identify a target that plays a significant role in a specific disease. A target is usually a molecule integral to gene regulation, intracellular signaling, or a protein. Afterward, scientists and researchers record the target's therapeutic characteristics. Researchers need to ensure that the molecule is efficacious, safe, usable, and capable of meeting clinical and commercial requirements.
Target Validation
After selecting a potential target, researchers must demonstrate that it is validated and its activity can be regulated. Some tests are done to test the initial hypothesis, antibody interactions. Also, scientists can modulate the drug's affinity to the target by changing the molecular structure. Conducting careful and precise target validation experiments is essential for the success of drug development.
Lead Compound Identification
Lead compound identification identifies or creates a compound that can interact with the previously selected target. Possible sources of lead compounds and novel drugs includenatural products such as plants, animals, and microorganisms. Researchers can conduct screening experiments to identify possible naturally-occurring compounds that can be altered and turned into drugs. Alternatively, synthetic compounds, which can be found in chemical libraries, are able to be designed that will both target the predicted target while not interfering with other cellular processes. In addition to testing the drug's mechanism of action, initial safety tests are conducted in cell culture. The dug's pharmacokinetics (PK) and pharmacodynamics (PD) are also tested. PK and PD refer to how the drug is metabolized and how it affects various bodily functions, respectively. During lead compound identification, various processes are conducted.
i. Hit Discover Process
Compound screening assays are developed after target validation.
ii. Assay Development and Screening
Assay development is a critical component of the drug discovery workflow. Assays are testing systems used to assess the effects of a new drug candidate at the cellular, molecular, and biochemical levels.
iii. High Throughput Screening
High Throughput Screening (HTS) utilizes robotics, data processing/control software, liquid handling devices, and sensitive detectors to quickly perform millions of pharmacological, chemical, and genetic tests, saving scientists labor hours. HTS looks for active compounds, genes, or antibodies interacting with human molecules.
iv. Hit to Lead
Small molecule hits from an HTS are evaluated and optimized in a limited way into lead compounds in the Hit to Lead (H2L) process. These compounds are then subjected to the lead optimization process.
Lead Optimization
In the lead optimization process, the identified lead compounds discovered in the H2L process are being optimized for efficacy and safety. The drug is synthesized and modified to improve potency and prevent off-target binding, reducing side effects. Lead optimization conducts experimental testing using animal efficacy models and ADMET tools, designing the drug candidate. Additionally, the optimal dosage and introduction route (oral, injection) is tested on two- and three-dimensional cell culture platforms.
When one lead compound for a drug candidate is discovered, the drug discovery process narrows, and the rest of the process begins.
b. Preclinical Research
The preclinical phase of drug development begins with research to determine the efficacy, safety, toxicity, and pharmacokinetics PK of the drug. These trials are conducted by scientists in vitro and in vivo.
Absorption, Distribution, Disposition, Metabolism, & Excretion
A pharmacokinetic (PK) process called Absorption, Distribution, Disposition, Metabolism, and Excretion (ADME) measures how the new drug impacts the body. Each effect in ADME is described mathematically.
In Vivo, In Vitro, And Ex Vivo Assays
In vivo refers to research done in an entire living organism. Preclinical research examples of in vivo are drug testing using mice, rat, and dog models. In vitro is research performed in a laboratory. Ex vivo uses animal tissues or cells that are taken from dead animals. Finding effective cancer treatments, measuring tissue attributes (physical, thermal, electrical, and visual), and creating accurate models for new surgical techniques are examples of ex vivo research experiments. A cell is always the starting point for tiny explant cultures in an ex vivo test, which offers a dynamic, regulated, and sterile environment.
In Silico Assays
Test systems or biological investigations carried out digitally or through computer simulation known as "in silico assays." With the continued advancements in computational power, behavioral understanding of molecular dynamics, and cell biology, these are anticipated to grow in popularity.
Drug Delivery
There are many drug delivery methods, which include oral, topical, membrane, intravenous, and inhalation. Drug delivery systems must be carefully studied because physiological barriers in human bodies may prevent drugs from reaching the right target area or releasing at the right time.
i. Oral
Medication administration via the oral route is dependable, economical, and patient-friendly. Although oral drug delivery may not be able to monitor precise amounts to the desired area, it is perfect for nutritional regimens and preventive immunizations. Patients must be aware throughout the administration to avoid delayed effect, stomach enzyme breakdown, inconsistent absorption, or patients with gastrointestinal difficulties or distress.
ii. Topical
Topical drugs are ointments, creams, lotions, etc., which deliver a drug by absorption into the body. It is common for patients with skin or muscular conditions.
iii. Membrane
This kind of drug delivery through the membrane includes intramuscular (IM), intraperitoneal (IP), or subcutaneous (SC). It is frequently applied to patients who are unconscious and avoids epithelial barriers that are challenging for medications to pass through.
iv. Intravenous
Intravenous injection is one of the fastest drug delivery absorption methods. IV injection ensures that entire doses of drugs enter the bloodstream, and it is more effective than drug delivery through membranes.
v. Inhalation
The medicine is quickly absorbed into the mucosal lungs, nasal passages, throat, or mouth through inhalation drug delivery. Small mucosal surface areas make it difficult to give the recommended dosage, and patient discomfort is another issue with inhalation delivery. Drugs are delivered by pulmonary inhalation using tiny drug powders or macromolecular drug solutions. Because lung fluids resemble blood, they can quickly and easily take in tiny particles and convey them to the bloodstream.
Investigational New Drug (IND) Application
Before the clinical trials, manufacturers must submit an IND application to the FDA with documents including animal study data and toxicity, manufacturing information, clinical protocols for the proposed human trials, data from any prior human research, and information about the principal investigator.
FDA will conduct a thorough review of the IND. After thirty days, the drug development company may get approval to continue the clinical trial, a temporary hold, or a stop of the new drug investigation.
c. Clinical Development
Clinical drug development includes clinical trials and volunteer studies to optimize the drug for human use.
Dose Escalation, Single Ascending & Multiple Dose Studies
The most effective patient dosage is determined via clinical trials considering dose escalation, single ascending, and multiple-dose investigations.
Phase I – Healthy Volunteer Study
The most effective patient dosage is determined via clinical trials considering dose escalation, single ascending, and multiple-dose investigations.
Phase II Patients Study
Phase II evaluates the safety and effectiveness of the therapy in an additional 100–500 patients, some of whom may also receive a standard medication or a placebo. While adverse events and dangers are being documented, schedules are made to analyze the ideal dosage, frequency of intake, and its effect on the condition.
Phase III Patients Study
Phase III involves 1,000–5,000 patients, allowing for the creation of medicine labels and usage guidelines. In preparation for large-scale production after drug approval, phase III studies need significant coordination, organization, Independent Ethics Committee (IEC) or Institutional Review Board (IRB) cooperation, and regulation.
During clinical trials, patient information is carefully protected. Also, Good Clinical Practices (GCP), the Health Insurance Portability and Accountability Act (HIPAA), and adverse event reporting to IEC/IRB regulate and ensures their safety.
d. FDA Review
A New Drug Application (NDA) is submitted to the FDA for assessment and potential approval following the completion of clinical trials. The goal of this document is to show that the drug is suitable for marketing and that clinical trials have established its safety and efficacy. Much information is needed, such as details on all phases and research, clinical findings, safety precautions, and possible drug interactions. FDA conducts a holistic review after the new drug has been developed for its maximum efficacy and safety. FDA either approves or does not approve the new drug submitted by the pharmaceutical company. Depending on its applications and patient needs, the regulatory approval process for new drugs may be a standard, fast track, breakthrough, accelerated approval, or priority review. The approval period may be up to a year if a standard or priority review is necessary. Accelerated, fast-track or breakthrough approvals could happen sooner. If a drug is approved at this stage, the labeling process—involves creating the prescribing information.
e. FDA Post-Market Safety Monitoring
The FDA mandates that pharmaceutical companies use the FDA Adverse Event Reporting System (FAERS) database to track the safety of their drugs once they have been manufactured and approved. FAERS supports FDA's post-marketing safety surveillance program implementation. The amount of post-approval monitoring that pharmaceutical companies must carry out while their drug is on the market is something that the majority of the public needs to be made aware of. Manufacturers, medical experts, and patients can report issues with licensed medications using this service.
Rules for drug design
Additionally, one common rule people follow when designing drugs is the "Rule-of-Five,"
initially formulated by chemist Lipinski. The original rules are:
No more than 5 hydrogen bond donors.
No more than 10 hydrogen bond acceptors
A molecular mass of less than 500 daltons
A calculated octanol-water partition coefficient (Clog P) that does not exceed 5
It has been proven that many effective drugs in the market comply with the Rule of 5.
Usually, drugs following Ro5 have better absorption and permeation. Furthermore, the Rule of 5 is an easy way for chemists to predict the effectiveness of the new drug's
pharmacokinetics.
The Difference between brand name drug and over-the-counter drug
After a drug is finally approved to be sold in the market, the company that develops the drug would apply for patency in order to prevent other companies from selling drugs that have the same chemical structure. The patent may take up to 20 years, and the company will sell the drug under a brand name, hoping to profit from their product. Once the period of patency is over, other companies are allowed to produce a similar drug with an identical chemical structure. Therefore, the drug becomes a generic drug. So the main difference is the circumstances of producing the drug. Brand-name drug can only be sold under one brand and one name, while a generic drug can be sold under different names with the same active ingredients.
Usually, a generic drug is much cheaper than a brand-name drug. Some may pose concerns regarding its effectiveness. However, a lower price will not affect its quality. The price difference is because the cost of production for generic drugs does not include the cost of development and marketing, which needs a great amount of funding.
This is why the law allows the brand name company to recover its investment before
allowing generic drug producers to manufacture and sell the same drug. In some ways, generic drugs are permitted to reduce costs and make drugs more affordable to a broader range of people.
Conclusion
The drug development process is challenging and needs much effort. Therefore, it is
important that the public recognize the hard work everyone in the industry has done. A new drug cannot be given to the people who need it without the help of every department involved. The author believes that in the future, there is no doubt that innovation in this industry will continue to happen and save millions of lives.
Citation:
(Cover Image Source: PharmaNewsIntelligence)
Benet, L. Z., Hosey, C. M., Ursu, O., & Oprea, T. I. (2016). BDDCS, the rule of 5 and
Drugability. Advanced Drug Delivery Reviews, 101, 89–98.
https://doi.org/10.1016/j.addr.2016.05.007
Wikimedia Foundation. (2023, March 5). Lipinski's rule of five. Wikipedia. Retrieved
April 2, 2023, from https://en.wikipedia.org/wiki/Lipinski%27s_rule_of_five
Mitchell, C. H. (2023, March 2). The Drug Discovery Process. rodent research
models. Retrieved April 2, 2023, from
https://www.taconic.com/taconic-insights/quality/drug-development-process.html
Seladi-Schulman, J. (2019, August 19). In vivo vs. in vitro: Definition, examples, and
more. Healthline. Retrieved April 2, 2023, from
https://www.healthline.com/health/in-vivo-vs-in-vitro#real-life-examples
Difference between brand name and Generic Drugs. Difference Between Brand Name
and Generic Drugs: Rose Urgent Care and Family Practice: Urgent Care. (n.d.).
Retrieved April 2, 2023, from
https://www.rosemedicalgroups.org/blog/difference-between-brand-name-and-generic
-drugs
Vipin Agarwal, P. D. (2023, February 7). Phases of drug development process, Drug
Discovery Process. NorthEast BioLab. Retrieved April 2, 2023, from
https://www.nebiolab.com/drug-discovery-and-development-process/
Comments