New Drug Development and Approval

New Drug Development and Approval Process

• The new drug development process involves a new chemical entity's journey from discovery through preclinical and clinical trials, FDA review via New Drug Application, and post-marketing activities.

Process and Time from Drug Discovery to Approval for Marketing

• A new chemical entity can be sourced via organic synthesis, molecular modification, or isolation from plants.
• Preclinical studies involve chemistry, physical properties, biological aspects, pharmacology, ADME (absorption, distribution, metabolism, excretion), toxicology, and preformulation assessments.
• An Investigational New Drug Application (IND) needs to be submitted and reviewed by the FDA before further trials.
• Clinical trials consist of Phase I, Phase II, and Phase III to assess safety and efficacy in humans.
• Preclinical studies also include long-term animal toxicity studies, product formulation, manufacturing and controls, and package & label design.
• After clinical trials, the drug sponsor submits a New Drug Application (NDA) that contains all the data and information gathered during the drug development process.
• If the FDA approves the NDA, the drug can be marketed.
• Post-marketing entails Phase IV clinical studies to gather more info about side effects and long-term risks.
• The time from initial synthesis to FDA approval averages approximately 15 years.

Time Course for The Development of A New Drug

• An Investigational New Drug (IND) application is filed with the FDA for initial human testing only after preclinical studies demonstrate the new agent's adequate safety and promise as a useful drug.
• If initial studies demonstrate adequate safety, progressive human trials through Phases 2 & 3 assess safety and efficacy.
• Lab work continues during clinical trials to define basic & clinical pharmacology & toxicology, product design & development, manufacturing scale-up & process controls, analytical methods development, proposed labeling & package design, and initial marketing plans.
• At the completion of preclinical and clinical trials, the drug's sponsor files a New Drug Application (NDA) for approval to market it.
• FDA approval indicates the submitted scientific evidence sufficiently demonstrates drug safety and effectiveness for proposed clinical use and that there's assurance of proper manufacture, control, and accurate labeling.
• Some products have been approved then later removed from the market because of safety reasons.

Drug Discovery and Drug Design

• The combined efforts of chemists, biologists, pharmacologists, engineers, etc. participate in drug discovery and development.
• An example of drug development is penicillin which became commercially available in 1944 after it was discovered in England 15 years prior.

Sources of New Drugs

• New drugs are discovered in laboratories, whether accidentally or after years of work, or from plants using biotechnology.
• New drugs can be found from plants (approx. 270,000), animals, or genetic engineering.

Sources of New Drugs - Plant Examples

• Plant material can be used directly, such as Rauwolfia serpentina, synthesizing reserpine (a tranquilizer).
• Natural chemicals from plants can serve as starting material to create semisynthetic drugs.

Sources of New Drugs - Animal Examples

• Knowledge of hormonal structural architecture led to various synthetic & semisynthetic compounds with hormone-like activity, such as oral contraceptives.
• Poliomyelitis vaccine is prepared in cultures of renal monkey tissue.
• Mumps and influenza vaccines are developed in fluids of the chick (chicken) embryo.
• Rubella vaccines are made in duck embryos.
• Smallpox vaccine is extracted from the skin of bovine calves inoculated with vaccinia virus.

Sources of New Drugs - Genetic Engineering

• Biologic drugs like monoclonal antibodies, therapeutic proteins, immunotherapies, and vaccines are results of genetic engineering.
• Recombinant DNA (rDNA) and monoclonal antibody (mAb) production are key technologies in the genetic field.
• The ability to manipulate & produce proteins is a common property of both rDNA & mAb.

Genetic Engineering - Recombinant DNA (rDNA)

• Recombinant DNA (rDNA) consists of techniques to influence a cell's ability to produce proteins and has the ability to manufacture "any" protein.
• Genetic material is transplanted from higher species such as humans into a lower bacterium and called gene splicing; it can induce lower organisms to make proteins.
• Human insulin, human growth hormone, hepatitis B vaccine, epoetin alfa, and interferon are made this way.
• Human insulin was the first recombinant biopharmaceutical approved in the US in 1982.

Genetic Engineering - Monoclonal Antibody (mAB)

• Unlike rDNA techniques which involve protein manipulation within cells of lower animals, monoclonal antibody (mAb) production is conducted entirely within higher animal cells, including patients.
• This technique stimulates an unending stream of pure antibody production and these antibodies combat a specific target.
• The first FDA-approved therapeutic mAb was muromonab, a transplant rejection drug approved in 1986.

Genetic Engineering - Human Gene Therapy

• Used to prevent, treat, cure, and diagnose human diseases caused by genetic disorders.
• It involves insertion of new genetic material into a patient's cells with a genetic disease.
• The human body has up to 100,000 genes.
• Genes aligned on a double strand of DNA in the nucleus of every cell control bodily functions.
• Only genes necessary for a specific cell's function are active or expressed.
• When a gene is expressed, a specific type of protein is produced.
• In genetic diseases, gene expression is altered and sequences can be mismatched, partly missing, or repeated too many times, causing cellular malfunction and disease.
• Cells can be modified outside the body (ex vivo), or modified within the body (in vivo) by direct delivery of gene therapy products.
• Genetic material (usually cloned DNA) transfers into patient's cells physically (via microinjection), chemically, or via disabled retroviral gene transfer systems that integrate genetic material directly within host cell chromosomes.
• The first human gene therapy treated adenosine deaminase (ADA) deficiency consisting of genetically modified cells capable of producing ADA.
• The FDA has established guidelines for cellular and gene therapy.

A Goal Drug

• In theory, a goal drug produces the desired effect when administered via desired route at minimal dosage and dosing frequency, has optimal onset and duration, no side effects, is eliminated efficiently, has low cost, is pharmaceutically elegant, and is physically and chemically stable.

Method of Drug Discovery

• Some drug discoveries are accidental, but most result from carefully designed research including combinatorial chemistry, molecular modification, and mechanism-based drug design.
• Combinatorial chemistry (High Throughput Screening) involves testing numerous synthetic organic compounds or natural substances for biological activity using biological assays.
• Initial bioassays may be in vitro using cell cultures, while subsequent ones are in vivo using animal models.
• Newer techniques can examine 15,000 chemical compounds weekly using 10-20 biological assays.

Method of Drug Discovery - Molecular Modification

• It involves altering a known organic compound's chemical structure to enhance its usefulness as a drug.
• This can enhance specificity for a target, increase potency, improve absorption, modify time course, reduce toxicity, or change physical/chemical properties for desired features.
• Molecular modifications can be slight or substantial and involve changes in functional groups, ring structures, or configuration.
• Knowledge of chemical structure-pharmacologic activity relationships (SAR) helps design new drug molecules, resulting in new chemical entities/improved therapeutic agents.

Method of Drug Discovery - Mechanism-based drug design

• Involves molecular modification to design a drug that interferes specifically with a known/suspected biochemical pathway or disease mechanism.
• The goal is to change the parent compound's structure, resulting in blocking, disruption, or reversal of the disease process.
• It is a useful complementary tool in drug molecule design as Molecular Graphics uses computer graphics to represent the drug molecule's structure to fit the simulated receptor site shape.
• Enalaprilat, the active metabolite of enalapril, inhibits angiotensin-converting enzyme (ACE) and decreases plasma angiotensin II, leading to decreased vasopressor effects.
• Ranitidine (Zantac®) inhibits histamine at H2-receptors which inhibits gastric acid secretion and is effective in gastric ulcer treatment.
• Sertraline (Zoloft®) inhibits the neuronal uptake of serotonin and is useful for treating depression.

A Lead Compound

• A lead compound is a prototype chemical compound with the desired biological or pharmacologic activity.
• While active, it might lack desired features (potency, solubility, low toxicity).
• Medicinal chemists modify the lead compound's chemical structure to achieve desired features while reducing undesired ones via analogs and chemical modifications.
• Synthesis of prototype chemical derivatives leads to successive generations of new compounds, such as cephalosporin antibiotics, H2-antagonists, or antianxiety drugs like chlordiazepoxide (Librium).

Prodrugs

• Prodrugs require metabolic biotransformation after administration to produce active compounds, where enzymes present in the body enable conversion from inactive to active through enzymatic cleavage.
• The action of a prodrug is to alter solubility, improve absorption, enhance biostability, and promote prolonged release.
• Enalapril maleate is a prodrug, which, after oral administration, is bioactivated into enalaprilat, an ACE inhibitor to treat hypertension.
• Altering a drug's solubility allows for specifically desired dosage forms/routes of administration.
• If an active drug lacks sufficient water solubility for an IV injection, a water-soluble prodrug like hydrocortisone sodium succinate can be prepared through adding a functional group.
• Drugs can be made more water or lipid-soluble for facilitating absorption via the intended route.

Prodrugs - Biostability and Prolonged Release

• If a drug is destroyed by biochemical/enzymatic processes, designing a prodrug protects it during body transport such as the instance of Valacyclovir which is is a prodrug of acyclovir.
• Liver esterases convert valacyclovir to acyclovir via first-pass metabolism resulting in increased bioavailability.
• Since Dopamine cannot cross the blood-brain barrier to treat Parkinson's, its prodrug levodopa is used; it can cross the barrier and convert to dopamine.
• Depending on the rate by which a prodrug metabolically converts to an active drug, it has the ability to provide prolonged drug release and extended therapeutic activity.

FDA's Definition of A New Drug

• Any drug not recognized by qualified experts as safe and effective under the conditions recommended for its use.
• A change formulation or manufacture constitutes newness because such changes can alter both therapeutic efficacy and/or safety.
• A combination of 2+ old drugs or changed drug proportions can constitute newness if a question of safety or efficacy arises.
• Proposing a new use for an established drug, plus/minus new dosage schedule, administration route, or dosage form can also make a drug product new and triggers reconsideration for its safety/efficacy.

Biologic Characterization

• Assesses the potential of drug substances as therapeutic agents via preclinical testing.
• Studies encompass pharmacology, drug metabolism, and toxicology.
• Work is done by biologists, microbiologists, molecular biologists, geneticists, pharmacologists, toxicologists, statisticians etc.
• It leads to the determination of safety & usefulness of new drugs.
• Judging drug safety and effectiveness requires information on drug absorption, distribution, storage, metabolism, and excretion.
• Outside-the-body (in vitro) studies via cell/tissue cultures & computer programs simulate human and animal systems.
• Cell cultures are increasingly used to screen for toxicity before animal testing.
• Computer models help predict properties/actions of substances in living systems.

Biologic Characterization - Pharmacology

• It is the science concerned with drugs and their sources, appearance, chemistry, actions, and uses.
• It includes properties, biochemical & physiological effects, action mechanisms, & ADME.
• Pharmacodynamics: study of biochemical/physiological effects of drugs & mechanisms of action.
• Pharmacokinetics (ADME): study of absorption, distribution, metabolism, and excretion.
• Clinical pharmacology applies pharmacologic principles when studying the effects/actions of drugs on humans.

Biologic Characterization: Pharmacology - Receptors

• Different drugs produce differing effects due to specific interactions happening between a drug's chemical structure and cell components called receptors.
• Receptors (like enzyme active centers) contain reactive groups oriented within the cell complimentary to drug compounds.
• Drug receptor binding is accomplished by ionic, covalent, or reversible bonds, but covalent bonding causes the drug effect to slowly reverse.
• There's a relationship between the drug molecules for available interaction and capacity of the specific receptor site.
• Maximized effects of specific interaction arise when receptors are saturated.
• Circulation of additional, non-participating drug will serve as a reservoirs to later replace the complex drug.
• Two drugs in a biological system will compete with each other to bind at the same site, so the drug having the stronger bonding attraction will prevail at the site.
• Already bound molecules of the more weakly bound drug will then be displaced and freely circulate.
• Some body cells are capable of drug binding without the effect, and act as carriers important to drug biotransformation and relocation.
• Evaluating chemical compounds' biological activity and determining their action mechanism is the responsibility of the pharmacologist.

Biologic Characterization: Pharmacology - Study Examples

• The pharmacological profile is defined using in-vitro cell cultures and enzyme systems plus in-vivo animal models.
• Such studies determine a compound's selectivity for receptors and its activity against enzyme systems.
• Cell function effect studies determine efficacy and whether it's an agonist/antagonist.
• Studies with isolated animal tissues indicate activity selectively, while whole-animal studies evaluate the agent's pharmacological effects on specific organ systems.
• Animal models of disease lead into candidate drugs.
• Small animals are usually tested (rodents, mice, rats) due to reasons like cost, availability, and that only a small amount of drug is needed for the study.
• FDA requires two or more animal species in final trials including a rodent and an animal from another order.
• Animals are studied at different dose levels for effect, potency, and toxicity.
• Animal study's chief objective is obtaining basic information on the drug's possible effects on humans regarding safety and effective use.
• Rodents (rats and mice), dogs, guinea pigs, and rabbits are all tested on for their different effects on human functions.

Biologic Characterization: Drug Metabolism

• The proposed ADME (absorption, distribution, metabolism, and excretion) sequence is measured via animal studies to determine what routes the compound can be prescribed.
• A minimum of 2 animal species are used; usually, a rodent plus a dog.
• Drugs are metabolized by drugs means to transform Nonpolar drugs into polar ones allowing for their elimination to become more readily available.
• Enzymes are the biggest participating molecules in drug metabolism in the Liver, Kidneys, Lungs and GIT.
• Since drugs produce materials causing safety issues, whether the metabolites are toxic must be determined.

Biologic Characterization: Toxicology

• Toxicology studies deals with the diverse adverse effects of drugs.
• Drug toxicity studies are needed to to determine substance's toxicity, organ toxicity, the intensity of toxicity, dose-response relationships, teratogenicity, and carcinogenicity.
• Studies are done on cells and in animals like rodents and dogs at various levels of strength to evaluate short-term, sub-chronic, and chronic effects.
• Acute toxicity studies involve test compounds administered in single and multiple doses across a day.
• Testing involves administering test compounds and observing for onset, progression, severity, mortality etc.
• Animal studies are undertaken.

Toxicology: Testing Guidelines

• Testing begins by ranging doses in the following order: find the largest single test that doesn't produce toxic effect, determine the severe toxicity presence and follow up with levels for intermediates.
• Also monitored are: eating/drinking habits, weight, psychomotor changes, and other atypical signs typically across a 30-pay post dose period.
• Animal specimens are taken and tested in the lab for any indications/clinical changes suggesting toxicity.
• All animal deaths are recorded, analyzed for histology/pathology, dose-response effects, gender, findings on intra and inter specific species, age, as well as existing lab controls.
• Sub-acute toxicity studies are designed to determine the initial toxicity studies in humans prior to the first doses.
• Two weeks with daily drug administration for three levels are needed for both dogs and rodents.
• The initial human dose is 1/10 the highest non-toxic dose in units of mg / subject's weight shown in animal studies.
• Performing is dependent upon being directed by the FDA and testing for: 90-180 day periods/3-6 months for animals.
• Carcinogenicity studies use limited numbers of rats and mice to test tumors for cases of high, intermediate, and levels.
• Testing is performed in a long-term design, at least one to two years.
• Surviving animals are killed and studied for defined weeks during the test period as well as animal deaths and neoplasic instances.
• These studies use mammalian reproduction.

Toxicology: Reproduction and Stability

• They include embryonic cases, and are multigenerational.
• In reproduction studies, various embryotoxic animals are used in conjunction.
• Genotoxicity or mutagenicity studies determine effects on genes, mutate, chromosomes or DNA.
• These require constant and sustained doses as well as accurate, consistent readings.
• Salmonella Typhimurium strands are routinely for detecting mutations.
• Preformulation studies involve looking at drug solubility, partition coefficient, dissolution, form and ultimately the stability.
• Formulations are a must look at property for any drug or substance to have a systemic therapeutic response for effective absorption.
• Poor drugs inhibit consistent absorption.

Early Formulation Studies

• Low solubility of materials is enhanced from their derivative preparations and micronization that increases dissolution.
• To produce a pharmacologic response, a drug molecule must cross biological protein and lipid membranes and have its solubility determined in this regard.
• The partition coefficient is measured to distribute between multi-phase lipophilic and hydrophilic systems to observe ability to penetrate the membrane.
• Drug solubility dictates the rate for the drug to be properly distributed such that it properly dissolves.
• To examine a chemical's solubility as either base, salt, acid etc. all lead to differing variations in dissolution rate.
• The crystal or amorphous forms or the physical size can affect rate extent during the drug's total time in the body.
• Reducing a molecule's size will increase solubility in the gut.
• Stability is examined based on both the physical properties of the formula alone but also when it's in conjunction with active ingredient for long-term protection.
• Drugs susceptible to decomposition may need antioxidants, while drugs that may become destroyed will need protection from moisture during processing and preservation.
• Stability testing helps develop product longevity and label instructions and should be stored correctly for a longer shelf life.

Initial Product Formulation and Clinical Trial Materials

• Phase 1 studies evaluate safety in healthy people taking active ingredients alone.
• 20-100 are tested for several months where dosages are around 1/10 the typical effect of animal studies.
• Phase 2 studies examine both effectiveness and safety in patients and ADME is studied in phases.
• Excipients are included in phase 2 trails where many people are selected to be tested/evaluated.
• Throughout this phase, the intended drug's formula is selected and several 100 or 1000 are tested, lasting for years total.
• FDA approval is based on phase 3 and studies safety, effectiveness, and correct dosage.

Drug Dosage and Terminology

• Dosage depends on both the drug's substance, the dosage form, its route, patient conditions etc.
• Low dose of drugs will cause sedation and large doses could cause potentially long-term effects.
• Age is relevant during neonatal and geriatric times where hepatic and renal functions become naturally more sensitive and fragile.
• Pediatric dosing is based on the patient's weight and body area.
• Pharmacogenetics involves effects and common polymorphisms, therefore requiring individual-patient treatment planning.
• Drug dosage adjustment is important for those with higher than average weight, with many drugs using the units of mg / kg.
• Weight in conjunction with age helps further plan in pediatric cases with drugs utilizing the same mg / kg scale.
• Other factors such as height with weight can cause variations body surface area (BSA values) and is represented across straight axis nomograms.
• Sex, gender, and differences are influential in planning, especially if a drug has small therapeutic ratings.
• Similar cautions apply to pregnant women and new mothers too.
• The effects of drugs are modified patients already known to have other existing conditions from renal, heart, lung conditions due to impaired conditions from over-medication and high toxicity amounts.
• Patients being monitored/ tested, must have their blood samples analyzed routinely to mitigate or prevent further toxicity.
• Tolerance can either be the ability for the human system to endure it with continued sustenance or tolerance due to drug intake.
• It can be commonly known with antibiotics and narcotics.

Drug Tolerances: Dosage, and Other Guidelines

• Re-introduction of specific pharmaceuticals from their normal route is achieved by suspending administration.
• Concomitant ingestion has great effect since it raises risk and can cause significant amounts of interaction and side-effects.
• The administered influence of time varies dosage; the greater amount of time a molecule is distributed, the lower the concentration it requires for a more effective does.
• Drug interactions affect the body greatly.
• Drug dosage must be determined by degrees of absorption depending on the route in which its prescribed from, mouth, rectum, throat, or skin for the drug to be effective for what it is recommended.
• Must be evaluated individually through clinical trials by the FDA.

Drug Product Labeling

• Includes but is not necessarily limited to: Packaging of the substance in the insert, and any promotional literature.
• Labeling must contain: The description, clinical information, usage, contra-indications, warnings, precautions, negative effects, dependence, the appropriate dosage.

FDA Review and Action Letters

• Completed NDA is reviewed by the FDA and decides market allowance for the company or the drug altogether.
• After the action letters has been made, any failed report that is necessary has the strong possibility of causing market approval withdrawals.
• If the market is authorized or FDA approved: Post market reporting and annual reviews are required.
• Lastly with SNAD: Sponsoring approved products may require new manufacturing formulas, different facilities, different closure systems, extra length on experimentation and more.