Drug Development Process Overview
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Questions and Answers

What are the two phases of drug development?

Pre-clinical and clinical.

What is the primary focus of pre-clinical development?

Assessing safety, toxicity, pharmacokinetics, and metabolism of new chemical entities.

What are new chemical entities (NCEs)?

NCEs are compounds with promising activity against a biological target important in disease.

What does CMC stand for in drug development?

<p>Chemistry, Manufacturing, and Control.</p> Signup and view all the answers

Why is an assessment of major organ toxicity important in drug development?

<p>It is legally required to determine the drug's effects on critical organs before human trials.</p> Signup and view all the answers

How are tests for drug toxicity increasingly being conducted?

<p>Using in vitro methods with isolated cells.</p> Signup and view all the answers

What must manufacturers consider regarding the physicochemical properties of an NCE?

<p>Chemical makeup, stability, and solubility.</p> Signup and view all the answers

What is the role of investigational new drug (IND) application in the drug development process?

<p>It allows for the initiation of clinical trials in humans.</p> Signup and view all the answers

What is the main purpose of preclinical trials?

<p>To test the efficacy and safety of a new drug or medical device on animal subjects before human testing.</p> Signup and view all the answers

How does selectivity testing contribute to drug safety?

<p>It assesses a compound's affinity for its molecular target to minimize unwanted side effects.</p> Signup and view all the answers

What are binding assays designed to measure?

<p>They measure the dissociation constant of a test compound to assess its affinity for a specific receptor.</p> Signup and view all the answers

What is the focus of pharmacological profiling?

<p>It determines the pharmacodynamic effects of a new compound both in vitro and in vivo.</p> Signup and view all the answers

What are two models used in pharmacological profiling?

<p>In vitro models (cell lines or isolated tissues) and in vivo models (normal animals or disease models).</p> Signup and view all the answers

Why is it important to correlate drug potency across different levels?

<p>To ensure that the effects observed in molecular tests match outcomes in tissues and whole organisms.</p> Signup and view all the answers

What is the significance of determining the duration of action of a drug in vivo?

<p>It helps relate the pharmacokinetic properties of the drug to its therapeutic effectiveness over time.</p> Signup and view all the answers

What potential problem does selectivity testing aim to prevent?

<p>It aims to prevent the compound from causing unwanted side effects due to binding to unrelated molecular targets.</p> Signup and view all the answers

What potential effects might occur with the continuous administration of a drug over time?

<p>The drug may lose its effectiveness or reveal previously unseen effects, and there might be rebound effects upon cessation.</p> Signup and view all the answers

What is the primary function of in vitro profiling in pharmacological studies?

<p>In vitro profiling allows for accurate measurement of concentration-effect relationships using isolated tissues.</p> Signup and view all the answers

What are some limitations of in vitro studies?

<p>In vitro studies typically use tissues from small laboratory animals and preparations rarely survive beyond a day, limiting experimental time.</p> Signup and view all the answers

How does in vivo profiling differ from in vitro profiling?

<p>In vivo profiling involves testing in normal animal models within a living organism, allowing for long-term effects to be evaluated.</p> Signup and view all the answers

Why is it important to consider species differences in pharmacological profiling?

<p>Species differences can affect pharmacological specificity, meaning the same target may respond differently across species.</p> Signup and view all the answers

What is the significance of using animal models with human diseases during drug testing?

<p>Animal models help determine whether physiological effects lead to therapeutic benefits, bridging the gap between preclinical and clinical research.</p> Signup and view all the answers

What characterizes acute physiological and pharmacological models?

<p>These models aim to mimic specific aspects of a clinical disorder to study the immediate drug effects.</p> Signup and view all the answers

What are the broad classifications of animal models of disease?

<p>Animal models of disease can be classified into acute, chronic, and genetic models.</p> Signup and view all the answers

What are supplementary tests in the context of drug evaluation?

<p>Supplementary tests are additional evaluations that assess potential impacts of a drug on non-vital organ systems or specific safety concerns related to the drug's use.</p> Signup and view all the answers

Under what conditions are safety pharmacology studies not necessary?

<p>Safety pharmacology studies are not required for locally applied agents, when the pharmacology is well known, or for new derivatives with similar pharmacokinetics and pharmacodynamics.</p> Signup and view all the answers

What factors influence the need for supplementary tests in drug evaluation?

<p>The need for supplementary tests depends on the therapeutic area, expected drug exposure, and regulatory authority requirements for specific drug classes.</p> Signup and view all the answers

Which common physiological tests are included in renal function assessments?

<p>Common physiological tests for renal function include urine volume, osmolality, pH, and the presence of proteinuria.</p> Signup and view all the answers

What does the evaluation of ventricular contractility primarily gauge?

<p>The evaluation of ventricular contractility primarily gauges the heart's pumping efficiency and overall cardiac function.</p> Signup and view all the answers

Why are acute toxicity studies important in animal toxicology?

<p>Acute toxicity studies are important because they help assess the potential harmful effects of a drug in at least two species before human testing.</p> Signup and view all the answers

What parameters are evaluated in gastrointestinal system assessments?

<p>Parameters evaluated include gastric secretion, gastric pH, intestinal motility, and gastrointestinal transit time.</p> Signup and view all the answers

How do supplementary tests contribute to drug safety evaluations?

<p>Supplementary tests provide more detailed mechanistic insights into the safety signals observed in the core battery of tests.</p> Signup and view all the answers

What significant change was introduced in the 4th revision regarding placebo-controlled trials?

<p>The 4th revision allowed for placebo-controlled trials only in cases where no proven diagnostic or therapeutic method existed.</p> Signup and view all the answers

How did the 5th revision differ from earlier revisions in terms of research benefit to participants?

<p>The 5th revision made no references to research that had no potential benefit to participants.</p> Signup and view all the answers

What was one of the ethical standards CIOMS stated regarding research in developing countries?

<p>CIOMS stated that ethical standards in developing countries should be no less exacting than those adopted in the country initiating research.</p> Signup and view all the answers

What was a notable concern regarding the ethical strength of the 6th revision?

<p>The ethical strength of the Declaration of Helsinki (DoH) was perceived to be weakened following the 6th revision.</p> Signup and view all the answers

What provisions were introduced in the 7th revision related to participants harmed during research?

<p>The 7th revision introduced provisions for compensation and treatment for those harmed in research.</p> Signup and view all the answers

What outcome did the 4th revision have on the stance of the FDA compared to the EU?

<p>The FDA ignored the 4th revision and continued to refer to the 1989 version, while the EU cited the 4th revision in its clinical trial directive.</p> Signup and view all the answers

Why was the 3rd revision significant in terms of informed consent for minors?

<p>The 3rd revision included guidelines on obtaining informed consent from minors for participation in research.</p> Signup and view all the answers

What was one of the outcomes of the extensive debates held prior to the 5th revision?

<p>The debates led to an extensive revision of the structure of the document, enhancing clarity and ethical standards.</p> Signup and view all the answers

What conditions allow for the use of a placebo in clinical trials according to Article 29?

<p>Placebos can be used when no proven intervention exists or when scientifically sound reasons justify their use without risking serious harm.</p> Signup and view all the answers

What must happen at the conclusion of a clinical study according to Article 30?

<p>Patients must be informed about the study's outcome and should have access to any beneficial interventions identified.</p> Signup and view all the answers

What ethical concerns arise with placebo-controlled trials in emerging countries?

<p>Ethical concerns include the risk of inadequate standard care and the potential exploitation of vulnerable populations.</p> Signup and view all the answers

Why is the Declaration of Helsinki (DoH) considered morally binding but not legally enforceable?

<p>The DoH provides ethical guidance to physicians but lacks legal authority, relying on moral obligation rather than legal enforcement.</p> Signup and view all the answers

What argument is made for the relevance of the DoH despite its lack of legal enforceability?

<p>The DoH carries significant moral weight similar to the Hippocratic oath, guiding ethical research practices.</p> Signup and view all the answers

What does the WMA encourage in relation to the DoH?

<p>The WMA encourages all participants in medical research involving human subjects to adopt the principles of the DoH.</p> Signup and view all the answers

What financial incentives can create potential ethical issues in medical research?

<p>Financial incentives for pharmaceutical companies may lead to conflicts of interest and influence the conduct of clinical trials.</p> Signup and view all the answers

What additional factors should physicians consider when conducting research involving human subjects?

<p>Physicians should consider the ethical, legal, and regulatory norms specific to their countries in addition to applicable international standards.</p> Signup and view all the answers

Flashcards

New Chemical Entities (NCEs)

Compounds discovered during drug discovery with potential activity against diseases.

Drug Discovery Approaches

Methods used to identify and develop new drugs, including pharmacological, toxicological, and application processes.

Preclinical Development

The assessment of new drug compounds (NCEs) before human clinical trials.

Clinical Trials

Human testing phases of drug development, building on preclinical data.

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Chemistry, Manufacturing, and Control (CMC)

The process of optimizing the method to create medication for clinical trials and beyond.

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Investigational New Drug (IND) application

Formal submission to regulatory authorities for permission to conduct human trials.

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Major Organ Toxicity

Assessment of effects of a compound on major organs like heart, lungs, brain, kidney, liver, and digestive system.

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Drug Characterization

Determining the chemical makeup, stability, and solubility of a new drug compound

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Preclinical Trial

A lab test on animals to check if a new drug or medical device works and is safe for human testing.

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Pharmacology

The study of how drugs affect living organisms.

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Selectivity Testing (in drug discovery)

Testing to see if a new drug targets only the intended molecule in the body, minimizing unwanted side effects.

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Binding Assay

A lab test to measure how strongly a drug binds to its intended target (receptor).

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Pharmacological Profiling

Examining the different effects of a new drug in various settings, from isolated cells to whole animals.

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In vitro Models

Using cells or tissues outside of a living organism to study drug effects.

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In vivo Models

Using living animals to test how drugs work and their effects.

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Questions Answered by Pharmacological Profiling

Understanding if the drug acts as expected in tissues and animals, if it has unintended effects, and if its potency matches across different levels.

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In Vitro Profiling

Testing on isolated tissues, like muscle or brain slices, to study drug effects. It's versatile and fast but limited to short-term studies and uses tissues from animals, not humans.

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Concentration-Effect Relationship

How the effect of a drug changes as the amount given (concentration) increases. This can be measured accurately in in vitro tests.

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In Vivo Profiling

Testing on whole living animals to see how a drug affects the entire organism. It's more complex and expensive, but reveals long-term effects.

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Species Differences

Drugs can act differently in different species, even if the same target exists. This is important to consider in drug development.

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Transgenic Animals

Animals with genes modified to mimic human diseases, used for drug testing. This provides more relevant data but raises ethical concerns.

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Animal Models of Disease

Animals with diseases similar to humans, used to test the effectiveness of potential drug treatments.

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Acute Physiological Model

Animal models that mimic a short-term, sudden aspect of a disease, like an allergic reaction.

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Chronic Physiological Model

Animal models that mimic a long-term, ongoing aspect of a disease, like arthritis.

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Safety Pharmacology

Studies that evaluate the potential effects of a drug on vital organ systems and safety concerns, beyond its intended therapeutic effect.

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Core Battery Tests

Standard tests conducted during safety pharmacology studies to assess the potential effects of a drug on vital organ systems like cardiovascular, respiratory, and central nervous systems.

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Supplementary Tests

Additional evaluations performed in safety pharmacology studies to investigate specific safety concerns or the impact of a drug on non-vital organ systems.

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Ventricular Contractility

The strength and force with which the ventricles of the heart contract, a key indicator of heart function.

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Vascular Resistance

The opposition the blood vessels present to the flow of blood, regulating blood pressure and distribution.

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Airway Resistance & Compliance

The ease with which air flows through the airways and how readily the lungs expand and contract, essential for breathing.

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Acute Toxicity

The harmful effects of a drug or substance observed shortly after a single or multiple doses, usually assessed in animals.

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Animal Toxicology

Studies performed in animal models to evaluate the safety and potential toxicity of a drug or substance before human testing.

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IRB

An independent committee that reviews and approves research involving human subjects.

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IEC

An independent ethics committee, often used in regions outside of the US, with a similar role as an IRB.

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Informed Consent

A process where potential research participants are provided with information about the research and their rights, and then voluntarily agree to participate.

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CIOMS

Council for International Organizations of Medical Sciences: Develops international ethical guidelines for research involving humans.

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What is the key difference between the 4th and 5th revisions of the ethical guidelines for biomedical research?

The 4th revision allowed for placebo-controlled trials in certain circumstances, while the 5th revision removed this reference, emphasizing the importance of potential benefit to participants.

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What is the significance of the 6th revision?

It followed a general review and included minor revisions, but raised concerns about the ethical strength of the Declaration.

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What were the key changes introduced in the 7th revision?

The 7th revision included new provisions for compensation and treatment for research participants who were harmed in the study.

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What are the main challenges in using placebo-controlled trials in developing countries?

The ethical challenge of providing a placebo while a proven treatment exists, particularly in developing countries where access to healthcare might be limited.

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Article 29 of the Declaration of Helsinki

This article states that new interventions must be tested against existing proven treatments unless there's no existing treatment or a compelling reason to use placebo. It emphasizes using placebo only for safety and efficacy testing, and ensuring patients aren't at serious risk.

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Article 30 of the Declaration of Helsinki

This article outlines the rights of patients involved in research, stating they should be informed about the study outcome and benefit from any positive findings, such as access to new treatments.

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Placebo-Controlled Trials in Emerging Countries

This presents a concern about the ethics of using placebo in countries where access to standard treatments is limited. Critics argue that it might exploit vulnerable populations and deny them potentially beneficial treatments.

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Ethical Hypocrisy

This refers to the perceived inconsistency in applying ethical standards to different populations. It highlights the concerns about using placebo-controlled trials in emerging countries while not doing so in developed countries.

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Moral Weight of the Declaration of Helsinki

Although not legally enforceable, the Declaration carries moral weight and strongly encourages adherence to its principles, particularly by physicians.

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Ethical, Legal, and Regulatory Norms in Research

Researchers should consider the ethical, legal, and regulatory norms of their own countries as well as international norms to ensure ethical and compliant research practices.

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DoH's Applicability Beyond Physicians

While primarily directed at physicians, the Declaration also encourages everyone involved in human research to adhere to its principles.

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Subsequent Guidelines

While the Declaration of Helsinki serves as a primary reference, future guidelines and updates are likely to further develop and refine ethical principles for human research.

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Study Notes

Drug Development Process

  • The process involves bringing a new pharmaceutical drug to market following drug discovery
  • Includes preclinical research (microorganisms and animals), filing for regulatory status (e.g., NPRA), clinical trials on humans, and regulatory approval for marketing.

Preclinical Approaches to Drug Discovery

  • Pharmacological Approach:
    • Selectivity testing (evaluates a compound's preference for a specific target)
    • Pharmacological profiling (determines the compound's pharmacodynamic effects on cells & tissues)
    • Testing in animal models of disease (evaluates drug effects in relevant disease models)
    • Safety pharmacology (assesses potentially dangerous effects unrelated to the desired therapeutic effect)
  • Toxicological Approaches:
    • Animal toxicology (examines potential adverse effects on animals)
    • Reproduction studies (evaluate potential effects on fertility and pregnancy)

Clinical Approaches to Drug Discovery

  • Drug Characterization:
    • Important steps to characterize the drug, including its physicochemical properties such as solubility, stability, and crystallinity
  • Dosage Form:
    • Choosing the appropriate dosage form (e.g., tablets, capsules, injections) based on factors such as the drug's properties, route of administration, and intended use.
  • Biopharmaceutics:
    • Examination of drug's absorption, distribution, metabolism and excretion (ADME) to understand how it interacts with the body and ultimately the site of reaction

Ethical Codes for Clinical Trial

  • Nuremberg Code: A set of ethical guidelines for research involving human subjects, established in 1947.
  • Belmont Report: A foundational document in research ethics, published in 1979. Developed by the U.S. National Commission.
  • Declaration of Helsinki: A set of ethical principles for research involving human subjects, established in 1964 by the World Medical Association (WMA).

Testing in Animal Models of Disease

  • Animals models, used to mimic human diseases
  • This is used to understand how physiological effects in the animal translate to a potential therapeutic effect on humans
  • Classifications of Models:
    • Acute physiological and pharmacological models
    • Chronic physiological and pharmacological models
    • Genetic models.

Acute Physiological And Pharmacological Models

  • Mimic aspects of clinical disorders like epilepsy or asthma
  • Examples:
    • Seizures induced by electrical brain stimulation (epilepsy)
    • The hot plate test (pain)
    • Histamine-induced bronchoconstriction (asthma)

Chronic Physiological Models

  • Studies use drugs and physical interventions to establish ongoing abnormalities that mimic clinical conditions
  • Examples:
    • Use of alloxan to inhibit insulin secretion (type I diabetes mellitus)
    • Self-administration of opiates, nicotine, or other drugs (drug dependence)

Genetic Models

  • Using transgenic animals
  • Gene manipulations to mimic human genetic disorders.

Safety Pharmacology

  • Evaluation of potentially life-threatening effects that are not related to the desired therapeutic effect
  • Testing uses doses that aren't excessive compared to possible clinical use
  • It identifies secondary or unanticipated effects
  • Based on single-dose administration
  • Guidelines by the International Conference on Harmonization (ICH) S7A

Physiological Systems and Tests

  • Central Nervous System: Motor activity, behavioral changes, coordination, reflex responses, body temperature on conscious and anaesthetized animals

  • Cardiovascular System: Blood pressure, heart rate, ECG changes, delayed ventricular repolarisation (on anaesthetized animals)

  • Respiratory System: Respiratory rate, tidal volume, arterial oxygen saturation (on anaesthetized and conscious animals)

  • Follow-up Tests: Learning and speech tests, complex behavioral and motor functions, tests on vision and auditory function, cardiac output, ventricular contractility, and vascular resistance(for all systems.)

Supplementary Tests

  • Renal function (urine volume, osmolality, pH, proteinuria, blood urea/creatinine, fluid/electrolyte balance)
  • Autonomic Nervous System (cardiovascular and respiratory system responses to agonists and stimulation of autonomic nerves.)
  • Gastrointestinal System (gastric secretion, gastric pH, intestinal motility, and gastrointestinal transit time)

Conditions Where Safety Studies Aren't Necessary

  • Locally applied drugs (e.g., dermal or ocular)
  • When the pharmacology of the drug is well-known
  • With low systemic absorption

Acute Toxicity

  • Toxicity studies on at least 2 species (mice and rats), using the same route of administration as intended for humans.
  • Must consider different administration routes to fully assess absorption
  • Monitoring mortality and signs of toxicity for up to 72 hours for parenteral routes and up to 7 days for oral routes
  • Reporting macroscopic and microscopic findings.
  • LD50 (lethal dose in 50% of the test population) quantification with 95% confidence.

Long-term Toxicity

  • Studies should run on at least 2 mammal species (one of which isn't a rodent)
  • Duration of study length depends on application and/or phase of clinical trials
  • Administration of the drug is continuous and done 7 days a week to match the intended clinical route
  • Minimum number of animals for study data
  • Inclusion of a control group receiving a vehicle/placebo
  • Three graded doses of the drug; higher dose produces toxicity, intermediate dose demonstrates symptoms with no gross toxicity/death, lower dose shows no observable toxicity and is comparable to a proposed therapeutic human dose

Reproduction Studies

  • Performed only if the drug is intended for use by or in women of childbearing age.
  • Two species (one non-rodent, if possible)
  • Fertility studies: Administer drug prior to mating to both males and females.
  • Teratogenicity studies: Administer drug throughout organogenesis.
  • Prenatal studies: Administer drug during the last trimester of pregnancy and throughout lactation.
  • Local Toxicity: Important if drug absorption happens at the admin site. Animals are used for that

Drug Characterisation

  • Pre-formulation: Includes spectroscopic, solubility, melting point, assay, stability, microscopy, powder flow and compression properties and excipient compatibility analysis to characterize essential drug properties.

Dosage Forms

  • Different forms for different delivery applications
  • Each form has advantages and disadvantages to consider
  • Delivery and administration considerations are important, such as if it is administered orally, topically or intravenously.

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