Drug Discovery and Development

Part 1: Drug Discovery and Development

The initial phase of bringing a new drug to market, drug discovery and development, is a complex, lengthy, and highly regulated process. It’s a high-risk, high-reward endeavor, with the vast majority of potential drug candidates failing along the way. Regulations are designed to ensure patient safety, scientific rigor, and ethical conduct throughout this crucial phase.

1.1 Preclinical Studies:

• Purpose: Before a potential drug can be tested in humans, it must undergo extensive preclinical testing. This phase aims to:

  • Establish a reasonable expectation of safety: Identify potential toxicities, determine safe dosage ranges, and understand how the drug is absorbed, distributed, metabolized, and excreted (ADME) by the body.

  • Demonstrate preliminary efficacy: Show that the drug has the desired biological effect in relevant in vitro (cell-based) and in vivo (animal) models of the disease.

  • Develop a formulation: Determine the best way to deliver the drug (e.g., pill, injection, topical cream) and ensure its stability.

• Types of Studies:

  •  Studies: These are conducted in a controlled laboratory setting, using cells, tissues, or isolated organs. They help researchers understand the drug’s mechanism of action, its effects on specific cell types, and its potential interactions with other substances.

  •  Studies: These involve testing the drug in live animals. Animal models are chosen to mimic the human disease as closely as possible. Common animal models include mice, rats, rabbits, dogs, and non-human primates. The choice of animal model depends on the disease being studied and the drug’s characteristics.

    • Pharmacology Studies: Assess the drug’s effects on the body’s systems (e.g., cardiovascular, respiratory, nervous).

    • Toxicology Studies: Determine the drug’s potential to cause harm. These studies involve administering different doses of the drug to animals over varying periods (acute, sub-chronic, and chronic toxicity studies). They look for signs of organ damage, adverse effects, and carcinogenicity (cancer-causing potential).

    • Pharmacokinetic (PK) Studies: Investigate how the drug is absorbed, distributed, metabolized, and excreted (ADME) by the body. This information is crucial for determining the appropriate dosage and dosing regimen.

    • Pharmacodynamic (PD) Studies: Examine the drug’s biochemical and physiological effects and its mechanism of action.

• Regulatory Guidelines:

  • Good Laboratory Practice (GLP): GLP is a set of principles that ensures the quality, reliability, and integrity of non-clinical laboratory studies. It covers all aspects of the study, from planning and execution to data recording and reporting. GLP regulations are enforced by regulatory agencies like the FDA (in the US), EMA (in Europe), and similar bodies worldwide. GLP compliance is essential for the acceptance of preclinical data by regulatory authorities.

  • Animal Welfare Regulations: Strict regulations govern the use of animals in research. These regulations aim to minimize animal suffering and ensure humane treatment. They cover aspects such as housing, feeding, veterinary care, and the use of anesthesia and analgesia. Institutional Animal Care and Use Committees (IACUCs) review and approve all research protocols involving animals to ensure compliance with these regulations. The “3Rs” principle (Replacement, Reduction, Refinement) is a cornerstone of ethical animal research:

    • Replacement: Using non-animal methods whenever possible (e.g., in vitro studies, computer modeling).

    • Reduction: Using the fewest number of animals necessary to obtain valid results.

    • Refinement: Improving procedures to minimize pain and distress.

  • Specific Guidelines for Different Types of Studies: Regulatory agencies provide detailed guidance on the specific requirements for different types of preclinical studies (e.g., carcinogenicity studies, reproductive toxicity studies).

• Data Requirements:

  • Detailed study protocols, raw data, statistical analyses, and comprehensive reports must be submitted to regulatory agencies.

  • Data must be accurate, reliable, and traceable.

  • Any deviations from the protocol must be documented and justified.

• Investigational New Drug (IND) Application (US) / Clinical Trial Authorisation (CTA) (EU and other regions):

  • Before starting clinical trials in humans, the pharmaceutical company must submit an IND application (in the US) or a CTA (in the EU and other regions) to the relevant regulatory agency.

  • The IND/CTA includes all the preclinical data, manufacturing information, and the proposed clinical trial protocol.

  • The regulatory agency reviews the IND/CTA to ensure that the proposed clinical trial is safe and scientifically sound. They may request additional information or modifications to the protocol.

  • Only after the IND/CTA is approved can clinical trials begin.

1.2 Clinical Trials:

• Purpose: Clinical trials are research studies conducted in human volunteers to evaluate the safety and efficacy of a new drug or a new use of an existing drug. They are the cornerstone of drug development and are essential for obtaining regulatory approval.

• Phases of Clinical Trials: Clinical trials are typically conducted in a series of phases, each with a specific purpose:

  • Phase 1:

    • Focus: Safety and tolerability.

    • Participants: Small number (typically 20-80) of healthy volunteers (sometimes patients with the disease, especially in oncology).

    • Objectives: Determine the safe dosage range, identify side effects, and study how the drug is absorbed, distributed, metabolized, and excreted (ADME) in humans.

    • Design: Often open-label (both researchers and participants know which treatment is being given) and dose-escalation studies (starting with a low dose and gradually increasing it).

  • Phase 2:

    • Focus: Efficacy and side effects.

    • Participants: Larger number (typically 100-300) of patients with the disease being treated.

    • Objectives: Assess the drug’s effectiveness in treating the disease, further evaluate safety, and determine the optimal dose and dosing regimen.

    • Design: Often randomized, controlled trials (participants are randomly assigned to receive either the new drug or a standard treatment or placebo). May be blinded (participants and/or researchers don’t know which treatment is being given).

  • Phase 3:

    • Focus: Confirm efficacy, monitor side effects, and compare to commonly used treatments.

    • Participants: Large number (typically 1,000-3,000) of patients with the disease.

    • Objectives: Confirm the drug’s effectiveness, monitor side effects in a larger and more diverse population, and compare it to existing treatments. Gather information that will allow the drug to be used safely and effectively.

    • Design: Usually randomized, double-blinded, controlled trials (neither participants nor researchers know which treatment is being given). Often multi-center trials (conducted at multiple research sites).

  • Phase 4 (Post-Marketing Surveillance):

    • Focus: Long-term safety and effectiveness.

    • Participants: Patients who are prescribed the drug after it has been approved for marketing.

    • Objectives: Monitor the drug’s long-term effects, identify rare side effects, and collect information on its use in different populations and with other medications.

    • Design: Observational studies, registries, and other data collection methods. This is a crucial part of pharmacovigilance (discussed later).

• Regulatory Guidelines:

  • Good Clinical Practice (GCP): GCP is an international ethical and scientific quality standard for designing, conducting, recording, and reporting clinical trials that involve human participants. GCP ensures the protection of the rights, safety, and well-being of trial participants and the credibility of the clinical trial data. Key principles of GCP include:

    • Ethical Conduct: Trials must be conducted ethically, with respect for the rights and dignity of participants.

    • Informed Consent: Participants must be fully informed about the purpose, procedures, risks, and benefits of the trial before agreeing to participate. They must provide written informed consent.

    • Data Integrity: Data must be accurate, complete, and verifiable.

    • Trial Monitoring: Trials must be monitored to ensure compliance with the protocol and GCP guidelines.

    • Investigator Responsibilities: Investigators (the physicians conducting the trial) have specific responsibilities for ensuring the safety of participants and the integrity of the trial.

    • Sponsor Responsibilities: Sponsors (usually pharmaceutical companies) are responsible for initiating, managing, and financing the trial.

    • Institutional Review Board (IRB) / Ethics Committee (EC) Approval: All clinical trials must be reviewed and approved by an IRB (in the US) or an EC (in other regions) before they can begin. The IRB/EC is an independent committee that reviews the research protocol to ensure that it is ethical and that the rights and welfare of participants are protected.

  • Specific Regulations: Countries have specific regulations governing clinical trials, often based on GCP principles but with local variations. These regulations cover aspects such as:

    • Clinical trial application and approval process.

    • Requirements for informed consent.

    • Reporting of adverse events.

    • Data management and monitoring.

    • Inspections of clinical trial sites.

• Data Requirements:

  • Detailed clinical trial protocol (including objectives, design, participant selection criteria, treatment procedures, and statistical analysis plan).

  • Informed consent forms.

  • Case report forms (CRFs) for each participant, documenting all relevant data.

  • Serious adverse event (SAE) reports.

  • Interim and final clinical study reports.

  • Statistical analyses of the data.

• Challenges in Clinical Trials:

  • Recruitment and Retention: Finding and retaining enough eligible participants can be a major challenge.

  • Cost: Clinical trials are extremely expensive, often costing hundreds of millions or even billions of dollars.

  • Complexity: Managing large, multi-center trials can be logistically complex.

  • Ethical Considerations: Balancing the need for scientific rigor with the protection of participant rights and safety is a constant challenge.

  • Regulatory Compliance: Navigating the complex regulatory landscape can be time-consuming and demanding.

  • Diversity and Inclusion: Ensuring that clinical trials include a diverse population that is representative of the patients who will ultimately use the drug is crucial, but often challenging to achieve. This is particularly important for diseases that disproportionately affect certain racial or ethnic groups.