DRUG DISCOVERY AND DEVELOPMENT

Pharmaceuticals have undoubtedly revolutionized the medical industry, offering a vast array of treatments and cures to patients worldwide. However, the road to drug discovery and development has been paved with challenges and milestones that have significantly influenced the pharmaceutical industry. Today, we will take a closer look at the history of drug testing and the pivotal role played by the U.S. Food and Drug Administration (FDA) in shaping the landscape of pharmaceutical regulation.

The Pure Food and Drug Act of 1906 was a landmark legislation that mandated the truthful labeling of medications, thus setting the stage for drug regulation. This law aimed to protect consumers and promote transparency in the pharmaceutical industry. However, despite these regulations, a tragic incident occurred in 1937 when a company marketed a medication containing diethylene glycol, a toxic substance commonly used in antifreeze and other industrial products, as a treatment for infections. This lethal product, called sulfanilamide elixir, caused the deaths of over 100 people before the Federal Food, Drug, and Cosmetic Act of 1938 intervened. This new act made it mandatory for drugs to demonstrate their safety before they could be marketed, marking a significant turning point in drug regulation. The sulfanilamide disaster served as a wake-up call for the need for more rigorous testing and safety standards in the pharmaceutical industry, ultimately leading to improved public health outcomes.

Building upon the foundation of drug safety, the Kefauver-Harris Amendments were enacted in 1962, mandating that new drugs not only be safe but also demonstrated effectiveness. This was a critical step in evaluating the efficacy of new drugs and the emergence of controlled clinical trials as a gold standard for drug testing.

In 1977, the FDA Modernization Act streamlined the drug approval process by introducing mechanisms to expedite the review times for certain types of drugs, ensuring timely access to potentially life-saving treatments for patients in need. Additionally, the Food and Drug Administration Modernization Act of 1997 expanded patient access to experimental drugs, enabling patients with serious or life-threatening conditions to access investigational treatments under specific circumstances.

Recognizing the importance of pediatric drug testing, the Best Pharmaceuticals for Children Act was passed in 2002, providing incentives for drug companies to conduct clinical trials specifically designed for children, ensuring that pediatric patients received appropriate and evidence-based treatments. In 2007, the FDA Amendments Act emphasized the importance of post-marketing safety studies, requiring drug companies to conduct studies to assess the safety of certain drugs after they had been approved and made available to the public.

These legislative acts have played a vital role in shaping the drug development landscape, ensuring patient safety, and advancing the medical industry. Controlled clinical trials have become a cornerstone of the drug testing process, enabling researchers to rigorously evaluate the efficacy of new therapies. Although challenges remain, such as participant recruitment and generalizability of results, these milestones have paved the way for patients to receive safe and effective treatments.

It is remarkable to see how far the pharmaceutical industry has come since its early days of drug regulation.The interplay of scientific advancements, regulatory fortitude, and unwavering ethics stands as a testament to the relentless pursuit of safer and more effective medicines. With each passing year, novel procedures and cutting-edge technologies enhance productivity and precision, allowing us to explore the remarkable world of pharmaceuticals together

As we trace the remarkable progress of the pharmaceutical industry over time, it becomes clear that rigorous drug testing has been an essential driving force behind the development of safe and effective medicines. The process of bringing a new drug to market is a complex journey that involves multiple stages, each with its own set of challenges and opportunities. In the next section, let’s explore the different phases of drug testing and how they contribute to advancing medical science.

Steps in Drug Testing:

When it comes to finding out the effectiveness of a drug, there are a few critical factors we need to bear in mind. We’re talking about safety and ethical considerations, optimization of trial design, predictive analysis, cost, and time savings. But here’s the thing — if we want to avoid making any futile errors, we need to update and enhance our methods constantly. After all, no one wants to waste their time and money on a trial that doesn’t give us the results we’re looking for. So, let’s work together to ensure that we’re always pushing the boundaries of what’s possible when it comes to testing new treatments.

1. Early Stages:

Target Identification:

• Isolating the function of a potential therapeutic target (gene/nucleic acid/protein) and its significance in the illness is the first step in target discovery.
• Following the identification of the target, the molecular processes targeted by the target are characterized.
• A good target should be effective, safe, fulfill clinical and commercial objectives, and be druggable.Target can be identified using the following.
• Data mining using bioinformatics — identifying, selecting optimizing potential disease targets.
• Genetic association — genetic polymorphism and their relation with the disease.
• Expression profile — examining the levels of mrna and proteins.
• Pathway and phenotypic analysis — In vitro cell-based mechanistic studies.
• Functional screening — knockdown using target specific tools.

Target Validation:

Target validation is the process of certifying the intended molecular target of a tiny molecule(gene).

The following steps are involved in target validation:

• Determining the structure activity relationship (SAR) of small molecule analogues
• Creating a drug-resistant mutant of the presumed target
• Knocking down or overexpressing the presumed target
• Monitoring the known signalling systems downstream of the presumed target.

The process of showing the functional relevance of an identified target in the illness phenotype is known as target validation.

Lead Identification:

• Screening tests are used to select hit compounds that exhibit the required activity.
• Lead compounds are selected from hits using revised criteria that take into account off-target effects and pharmacological features.

Identification Techniques:

• High-throughput screening, affinity selection, fragment-based approaches, and biotechnology are all methods for identifying hits. To increase potency and physicochemical qualities, the structure-activity interactions of hit mimics are established.
• High Throughput Screening (HTS) employs robotics, data processing/control software, liquid handling equipment, and sensitive detectors to perform millions of pharmacological, chemical, and genetic tests in a matter of minutes, saving scientists hours of labour.
• Small molecule hits from an HTS are reviewed and optimised in a restricted fashion into lead compounds during the Hit to Lead (H2L) process. These compounds are subsequently subjected to the lead optimisation procedure.

Lead optimisation:

• After identifying an initial lead molecule, the process of designing a drug candidate is known as lead optimisation.
• Preclinical investigations of lead compounds include pharmacokinetic and safety assessments. Absorption, distribution, metabolism, excretion, safety investigations, formulation, administration, synthesis feasibility, and large-scale manufacture are all factors to consider. These factors influence drug development at every step.
• When a new drug molecule demonstrates promising therapeutic activity, it is defined by its size, shape, strength, weakness, use, toxicity, and biological activity.

Pharmaceutical Formulation:

Pharmaceutical formulation is a stage of medication research in which the physicochemical properties of active pharmaceutical ingredients (APIs) are studied in order to create a bioavailable, stable, and appropriate dose form for a certain delivery route.

2. Pre-Clinical Phase:

The compounds identified are refined, optimized, and thoroughly tested in the laboratory as well as in animal or alternative models.The primary goal is to collect considerable evidence regarding the safety and efficacy of these drugs prior to performing human Clinical Trials. It is also critical to determine the optimal dosage levels for human testing. They are done by 2 methods:

• Pharmacology Testing:

Pharmacokinetic studies are critical for determining the safety and efficacy parameters for absorption, distribution, metabolism, and excretion(ADME). These studies provide information on absorption rates for various routes of administration, which aids in the selection of dose form, distribution, rate of metabolism, and elimination; all of which affect the drug’s half-life.

• Toxicity Testing:

These studies can be carried out in vitro to investigate direct impacts on cell proliferation and phenotypic. To evaluate qualitative and quantitative toxicological effects, in vivo investigations are conducted using appropriate animal species. Because many medications have species-specific effects, choosing the appropriate animal model for toxicity investigations is critical. In vivo studies are also used to analyse the pharmacological and toxicological properties of the medicine, including the mechanism of action, which supports the drug’s suggested usage in clinical research.

3. Clinical Trials:

Clinical testing is divided into four stages that aim to assess the safety, effectiveness, and dose of a proposed medicine in human beings.

Phases of Clinical Trials:

• A small sample of healthy volunteers is used in Phase 1 to test the drug’s safety, dose range, and potential side effects.
• The study is expanded to a broader sample of individuals with the target ailment in Phase 2 to further evaluate the drug’s effectiveness and negative effects.
• Larger-scale research with a more diverse patient group is planned for Phase 3 to validate efficacy, evaluate side effects, and compare the new medicine to conventional treatments.
• Phase 4 incorporates post-market surveillance to examine long-term safety and effectiveness in real-world settings after regulatory approval.

Importance of Clinical Trials:

• Clinical trials are critical in the discovery of new disease therapies, diagnostic procedures, and preventative measures.
• They reveal human-specific reactions that cannot be recreated in the laboratory or on animals. Clinical trials help healthcare professionals make educated decisions by testing the efficacy and tolerability of novel medicines.
• Although there have been cases where patients have had harmful effects, it is critical to recognise that prior volunteers’ involvement in trials has resulted in the creation of improved and more efficient medicines, benefiting millions of people.

4. Regulatory Approvals:

The data obtained is gathered and analyzed before being submitted to the appropriate authorities for evaluation.

• When the FDA receives a complete New Drug Application (NDA), the FDA review team normally takes 6 to 10 months to decide whether to approve the NDA. If the FDA receives an incomplete NDA, however, the review panel will reject it.
• If the FDA believes that a drug is safe and effective for its intended use, it must work with the drug manufacturer to update the prescribing information, often known as labelling. The labelling contains specific information regarding the basis for approval as well as instructions on how to take the medication. However, there may be some difficulties that must be addressed before the medicine may be licenced for marketing.

Only one chemical, out of the many that go through clinical testing phases and regulatory assessments, makes it through this demanding process. As a result, only one molecule is approved as a medicine or vaccine.

5. Post-Marketing Monitoring:

Postmarketing surveillance, also known as pharmacovigilance, is the monitoring of drug safety after a treatment has been licensed for market usage after clinical studies have been completed successfully. The primary purpose of this surveillance is to uncover any previously unknown bad or positive side effects of the newly licensed medicine. Important components of postmarketing surveillance might also include tracking the use of off-label medications, resolving orphan drug concerns, and addressing issues particular to performing clinical studies in the pediatric population. A significant increase in the number of patients who take the drug yields a substantial amount of data and enables comparisons with existing treatments. These studies are specifically designed to evaluate the prolonged impact of a drug.

Even though many risks were avoided with the stringent rules, still steps had to be taken to protect the personnel working for the Drug discovery and Development. Many limitations and obstacles had to be reduced, this was when the emergence of different innovations in each phase of Drug Testing came to play. The innovations not only played a major role in eradicating of the risks but also in vastly increasing the success rates, accelerating the timeline for the drug development, improving the therapeutic options, and approaches towards the drug development were enabled to be more cost-effective.

Innovations in Drug Delivery and Testing

One of the major challenges in drug discovery is finding a safe and effective way to get drugs to their intended targets in the body. Innovations in drug delivery and testing have significantly advanced the field, making it easier to develop new drugs and to ensure their safety and efficacy. In this blog post, we will discuss some of the latest innovations in drug delivery and testing.

Computational Modeling:

Basically, here Computer-based models and simulations are induced to test out the pharmacokinetics, pharmacodynamics, and safety profiles of potential drugs or interventions. These models help researchers analyze study parameters, such as dosages, treatment durations, and study endpoints. This is also known as In Silico Modeling, which is a powerful tool used in drug discovery. It helps us to explain the drug-target interaction and drug properties. This tool aids in accelerating drug development.

Computational modeling allows us to briefly understand the biological pathway, in which the prescribed drug interacts. It promotes us to work on the binding process of the drug on the target using molecular docking. It provides us with insights onbinding affinity and mode of interaction.

The prediction of ADME properties is done with ease, the ADME refers to Absorption, Distribution, Metabolism, and Excretion. These factors let us estimate the bioavailability, metabolic stability, drug-drug interactions, and potential toxicity risks, which makes us come up with suitable compounds with favorable pharmacokinetic profiles and reduced safety concerns.

High-throughput Screening:

It is a method that is very less time-consuming that is used in drug discovery, as it is rapid and efficient at the same time and moreover it tests a large number of chemical compounds for their biological activity against a target of interest. HTS allows researchers to scout through the vast chemical libraries available and identify potential lead compounds for further development.This is a quite enhanced way of learning through automation and robotics, allowing researchers to examine the potential candidates for further testing. It steps up the identification of potential drug candidates, uplifts the probability of finding compounds with required activity, and aids in prioritization of the compounds for further escalation and development.

High density screening formats are feasible with HTS as it miniatures assays that accommodate it. Assays run on a hundred to thousand well microplates are one such example. As HTS is in an automated form, handling with precision doesn’t affect it . it is cost effective as it uses compound libraries and the process is done rapidly

Tissue Engineering: Tissue engineering techniques eases preclinical testing in many levels; it is achieved by creating artificial tissues or organ-like structures that closely mimic human physiology. These engineered tissues provide a more precise representation of human responses compared to old cell culture methods, improving the predictive value of preclinical testing. In other words, tissue engineering in drug discovery provides more physiologically relevant and predictive models for evaluating drug efficacy, toxicity, and ADME properties. These tissue-engineered systems enhance the capability and precision of drug development

With our advanced Tissue Engineering platform we at BIODIMENSION TECHNOLOGIES PVT LTD are determined to back the pharmaceutical companies to rationalize and accelerate the Drug development, and we integrate with the Research lab, as our tissue models mirror the human tissues and organs granting better and efficient Drug Testing.

Organ-on-a-Chip Technology: Organ-on-a-chip devices replicate the structure and function of specific organs by integrating living cells, microfluidic systems, and sensors. These systems enable behavioral studies of organs easier by including organ-level responses, interactions, and drug effects, enhancing the purpose and reliability of preclinical testing.

One of the main aspects of the Organ-on-a-chip is to enact the functions of the Organ, Organ-on-chip devices are structured in a way to replicate the complex architecture and functionality of organs present in the human body. By planting the device with appropriate cells and creating the microenvironment for it to work such as providing oxygen and nutrients through microfluidic channels, the OOC systems aim to understand the key aspects of organ function, including tissue-tissue interfaces, fluid flow, and cellular responses.

One of the remarkable advantages of the Organ-on-a-chip is that it has the capability to combine multiple organs models on a single chip, which could be more of a “body-on-a-chip” or “multiple-organ-on-a-chip” system this enables us with the information on organ-organ interaction the systemic effects of drugs or interventions. They could activate interconnections that are seen in the human body, aiding us to come up with better statements on drug response to the particular organ and its toxicity.

Pharmacogenomics and Personalized Medicine: The main objective is to understand the genetic makeup and influence it using the Drug, It involves evaluating genetic variations, such as single nucleotide polymorphisms (SNPs), and their impact on drug metabolism, drug targets, and drug transporter. It encourages the interpretation of drug metabolism, Drug Targets, Adverse Drug Reactions (ADRs), Drug Development and Clinical Trials.

In conclusion, a mocktail of innovations and effective testing procedures can lead to the unprecedented discovery of drugs.Tissue engineering furthermore enhances the process by providing a simulation of the human model to check the direct effects of the drug.