Preventing Fraud—3.Pre-Clinical Research and Development

3. Pre-Clinical Research and Development: Building a Foundation of Integrity

Pre-clinical research and development encompasses all the research activities that occur before a drug candidate is tested in humans. This includes:

·         Drug Discovery: Identifying potential drug targets and developing new molecules or compounds that interact with those targets.

·         In Vitro Studies: Testing the drug candidate in cells or tissues in a laboratory setting.

·         In Vivo Studies: Testing the drug candidate in animals.

·         Formulation Development: Developing a stable and effective formulation of the drug.

·         Pharmacokinetic/Pharmacodynamic (PK/PD) Studies: Studying how the drug is absorbed, distributed, metabolized, and excreted by the body (PK), and how it affects the body (PD).

·         Toxicology Studies: Assessing the potential toxicity of the drug.

·         Process Development: Developing scalable methods to produce the compound.

The integrity of pre-clinical research is paramount because it forms the basis for all subsequent clinical development and, ultimately, for the approval and use of the drug.

3.A. Data Integrity and Reproducibility :

·         Definition (Revisited):

o    Data Integrity: The accuracy, completeness, consistency, and reliability of data throughout its lifecycle. (ALCOA+ principles, detailed previously, are central here).

o    Reproducibility: The ability of another researcher, using the same methods and materials, to obtain similar results. This is a cornerstone of the scientific method.

·         Importance in Pre-Clinical Research:

o    Foundation for Clinical Trials: Pre-clinical data provides the justification for testing a drug in humans. If the pre-clinical data is flawed or fabricated, the clinical trials may be based on false premises, putting patients at unnecessary risk.

o    Investment Decisions: Companies make significant investment decisions based on pre-clinical data.

o    Scientific Progress: Reproducibility is essential for scientific progress. If other researchers cannot reproduce the findings of a study, it undermines the credibility of the research.

o    Regulatory Submissions: Pre-clinical data is a crucial part of regulatory submissions (e.g., IND applications).

·         Challenges to Data Integrity and Reproducibility:

o    Complexity of Biological Systems: Biological systems are inherently complex and variable, making it challenging to obtain consistent and reproducible results.

o    Pressure to Publish: Researchers are under pressure to publish positive results, which can create an incentive to manipulate data or selectively report findings.

o    Lack of Standardization: There can be a lack of standardization in research methods and protocols, making it difficult to compare results across different studies.

o    Inadequate Training: Researchers may not be adequately trained in data management, statistical analysis, or research ethics.

o    Poor Record Keeping: Inadequate documentation of research methods and data can make it difficult to reproduce results.

o    Publication Bias: The tendency for studies with positive results to be more likely to be published than studies with negative or inconclusive results.

o    “File Drawer Effect”: Studies with negative or inconclusive results may never be submitted for publication, remaining hidden in researchers’ “file drawers.”

o    Lack of Access to Raw Data: Researchers may be reluctant to share their raw data, making it difficult for others to verify their findings.

·         Best Practices for Ensuring Data Integrity and Reproducibility:

o    Detailed Protocols: Develop clear, detailed, and written experimental protocols before starting the research. These protocols should specify:

§  The research question.

§  The hypothesis.

§  The experimental design.

§  The materials and methods to be used.

§  The data collection procedures.

§  The data analysis plan.

§  The criteria for determining whether the results support or refute the hypothesis.

o    Calibration and Validation: Regularly calibrate and validate all equipment and instruments used in the research.

o    Data Recording: Accurate and contemporaneous recording of all data, including raw data, intermediate data, and any deviations from the protocol.

§  Electronic Lab Notebooks (ELNs): Using ELNs to improve data management, traceability, and security. ELNs provide:

§  Date and time stamps.

§  Audit trails.

§  Version control.

§  Secure storage.

§  Direct Data Capture: Where possible, capture data directly from instruments into electronic systems to minimize manual transcription errors.

o    Data Storage and Security: Secure storage of data to prevent loss, corruption, or unauthorized access.

§  Regular Backups: Regularly back up data to multiple locations.

§  Access Controls: Restrict access to data to authorized personnel.

§  Data Encryption: Encrypt sensitive data.

o    Data Analysis:

§  Appropriate Statistical Analysis: Use appropriate statistical methods to analyze data and interpret results.

§  Blinding: Where possible, blind researchers to the treatment being administered to reduce bias.

§  Pre-specified Analysis Plan: Develop a pre-specified data analysis plan before data collection begins to avoid “p-hacking” and other forms of data manipulation.

§  Consultation with Statisticians: Consult with statisticians during the design and analysis phases of the research.

o    Data Audits: Regular internal audits of data to ensure integrity and compliance.

o    Replication Studies: Encourage independent replication of key findings.

o    Data Sharing: Promote the sharing of pre-clinical data, where appropriate, to facilitate reproducibility and collaboration.

§  Data Repositories: Deposit data in publicly accessible data repositories.

§  Data Use Agreements: Establish clear agreements for the use of shared data.

o    Training: Provide training to researchers on data integrity, reproducibility, and responsible conduct of research.

o    Standard Operating Procedures (SOPs): Develop and follow SOPs for all research activities.

o    Metadata: Thoroughly document all metadata (data about the data), including experimental conditions, instrument settings, and analysis parameters.

3.B. Animal Welfare and Ethical Research Practices :

·         Ethical Imperative: The use of animals in research carries a significant ethical responsibility to minimize any pain, suffering, or distress experienced by the animals.

·         The “3Rs”: The guiding principles for ethical animal research (widely accepted internationally):

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

o    Reduction: Using the minimum number of animals necessary to obtain valid results.

§  Statistical Power Calculations: Performing power calculations to determine the appropriate sample size.

§  Pilot Studies: Conducting pilot studies to optimize experimental procedures and reduce the number of animals needed in the main study.

§  Sharing of Animals and Tissues: Sharing animals or tissues between researchers to reduce the overall number of animals used.

o    Refinement: Minimizing any pain, suffering, or distress experienced by the animals.

§  Pain Management: Using appropriate analgesics and anesthetics to minimize pain.

§  Humane Endpoints: Establishing clear criteria for when animals should be euthanized to prevent unnecessary suffering.

§  Environmental Enrichment: Providing animals with a stimulating and enriching environment.

§  Proper Housing and Care: Providing appropriate housing, nutrition, and veterinary care.

§  Minimally Invasive Procedures: Using minimally invasive techniques whenever possible.

§  Training of Personnel: Ensuring that all personnel involved in animal handling and procedures are adequately trained.

·         Regulatory Frameworks:

o    Animal Welfare Act (AWA) (US): Regulates the care and use of certain animals in research.

o    Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals (US): Applies to all research funded by the US Public Health Service.

o    Guide for the Care and Use of Laboratory Animals (US): A widely accepted set of guidelines for animal care and use.

o    EU Directive 2010/63/EU: On the protection of animals used for scientific purposes.

o    Other National and International Regulations: Many other countries have their own regulations governing animal research.

·         Institutional Animal Care and Use Committees (IACUCs) / Animal Ethics Committees:

o    Role: IACUCs (or equivalent committees in other countries) review and approve all research protocols involving animals to ensure that they are ethically sound and comply with all applicable regulations and guidelines.

o    Composition: IACUCs typically include:

§  Scientists

§  Veterinarians

§  Non-scientists

§  Community members

o    Responsibilities:

§  Reviewing and approving research protocols.

§  Monitoring animal care and use.

§  Investigating concerns about animal welfare.

§  Ensuring compliance with regulations.

§  Providing training on animal care and use.

·         Transparency and Reporting:

o    ARRIVE Guidelines (Animal Research: Reporting of In Vivo Experiments): Guidelines for reporting animal research to improve transparency and reproducibility.

o    Public Disclosure: Increasingly, there is a push for greater public disclosure of information about animal research.

·         Alternatives to Animal Testing:

o    In Vitro Methods: Using cells or tissues grown in a laboratory.

o    Computer Modeling: Using computer simulations to predict the effects of drugs.

o    Human Volunteers: Using human volunteers in early-stage clinical trials (when ethically permissible and scientifically justified).

o    Organ-on-a-Chip Technology: Microfluidic devices that mimic the function of human organs.

o    In Silico Methods: Computational methods to predict toxicity and other properties of drugs.

3.C. Conflict of Interest Management :

·         Definition: A conflict of interest (COI) exists when an individual’s personal interests (e.g., financial, professional, personal relationships) could potentially bias their judgment or actions in their professional role.

·         Types of Conflicts of Interest:

o    Financial Conflicts: The most common type of COI, involving financial relationships with companies or organizations that could be affected by the research.

§  Consulting Fees: Receiving payments from a pharmaceutical company for consulting services.

§  Stock Ownership: Owning stock in a pharmaceutical company.

§  Research Funding: Receiving research funding from a pharmaceutical company.

§  Patent Ownership: Holding patents related to the research.

§  Speaking Fees: Receiving payments for speaking engagements.

o    Non-Financial Conflicts:

§  Professional Conflicts: Conflicts that arise from an individual’s professional roles or responsibilities.

§  Personal Conflicts: Conflicts that arise from personal relationships or beliefs.

§  Intellectual Conflicts: Conflicts that arise from an individual’s prior work or publications.

·         Importance of Managing Conflicts of Interest:

o    Protecting Research Integrity: COIs can bias research findings, leading to inaccurate or misleading results.

o    Maintaining Public Trust: COIs can erode public trust in research.

o    Ensuring Objectivity: Managing COIs helps to ensure that research is conducted objectively.

o    Compliance with Regulations: Many regulations and guidelines require the disclosure and management of COIs.

·         Strategies for Managing Conflicts of Interest:

o    Disclosure: Researchers must fully disclose any financial or other relationships that could potentially bias their research. This is the foundation of COI management.

§  To Institutions: Disclosing COIs to their institution (e.g., university, research institute).

§  To Funding Agencies: Disclosing COIs to funding agencies.

§  In Publications: Disclosing COIs in publications and presentations.

§  To Research Participants: Disclosing COIs to research participants (in clinical trials).

o    Management Plans: Developing and implementing plans to manage or mitigate any identified COIs. This may involve:

§  Recusal: Recusing oneself from decisions related to the research (e.g., data analysis, manuscript review).

§  Independent Oversight: Having an independent committee or individual oversee the research.

§  Divestment: Divesting oneself of financial interests that create a conflict.

§  Limiting Involvement: Limiting one’s involvement in certain aspects of the research.

o    Elimination: In some cases, the only way to manage a COI is to eliminate it (e.g., by divesting a financial interest).

o    Institutional Policies: Institutions should have clear and comprehensive policies on COIs that are regularly reviewed and updated.

o    Training: Providing training to researchers on COI policies and procedures.

o    Monitoring and Enforcement: Monitoring compliance with COI policies and taking appropriate action when violations occur.

o    Transparency: Making COI disclosures publicly available.

3.D. Documentation and Record Keeping :

·         Importance: Meticulous documentation and record keeping are essential for ensuring data integrity, reproducibility, and regulatory compliance. “If it wasn’t documented, it didn’t happen.”

·         Key Principles:

o    Contemporaneous Recording: Data should be recorded at the time it is generated, not later.

o    Accuracy and Completeness: All records should be accurate, complete, and legible.

o    Attributable: It should be clear who recorded the data and when.

o    Original: Original records should be retained.

o    Audit Trails: Any changes to data should be tracked with an audit trail.

o    Secure Storage: Records should be stored securely to prevent loss, damage, or unauthorized access.

o    Retention Policies: Clear policies should be in place for how long records must be retained.

·         Types of Records:

o    Experimental Protocols: Detailed descriptions of research methods.

o    Raw Data: The original data collected during the research (e.g., instrument readings, images, observations).

o    Data Analysis: Records of all data analysis procedures.

o    Animal Care Records: Records of animal housing, care, and use.

o    Personnel Training Records: Records of training for all personnel involved in the research.

o    Equipment Maintenance Logs: Records of equipment maintenance and calibration.

o    Standard Operating Procedures (SOPs): Written procedures for all research activities.

o    Correspondence: Records of any correspondence related to the research.

o    Deviations and Amendments: Records of any deviations from the protocol and any amendments to the protocol.

·         Electronic Records: Increasingly, electronic records are used in pre-clinical research.

o    Electronic Lab Notebooks (ELNs): (Detailed previously)

o    Compliance with Regulations: Electronic records must comply with relevant regulations, such as 21 CFR Part 11 in the US (for electronic records and electronic signatures).

o    Validation: Electronic systems used to generate or store data must be validated.

3.E. Independent Review and Oversight :

·         Importance: Independent review and oversight can help to ensure the quality, integrity, and ethical conduct of pre-clinical research.

·         Forms of Oversight:

o    Peer Review: Having research protocols and findings reviewed by independent experts before publication. This is a cornerstone of the scientific process.

§  Limitations of Peer Review: Peer review is not perfect and can be subject to bias.

o    Internal Audits: Conducting regular internal audits of research practices to ensure compliance with regulations and company policies.

o    External Audits: Allowing external audits by regulatory agencies or other independent organizations.

o    Data Monitoring Committees (DMCs): (More common in clinical trials, but can also be used in pre-clinical research, particularly for large or complex studies).

o    Institutional Review Boards (IRBs): (Primarily for clinical research, but may also review pre-clinical research that has implications for human health).

o    Institutional Animal Care and Use Committees (IACUCs): (Detailed previously)

o    Scientific Advisory Boards: Independent groups of experts who provide advice to companies or research institutions.

·         Benefits of Oversight:

o    Improved Quality: Can help to improve the quality and rigor of research.

o    Early Detection of Problems: Can help to identify potential problems early, before they escalate.

o    Enhanced Credibility: Can enhance the credibility of research findings.

o    Compliance with Regulations: Can help to ensure compliance with regulations and ethical guidelines.

o    Protection of Animals and Human Subjects: Ensuring ethical treatment.

3.F. Promoting a Culture of Scientific Integrity :

·         Beyond Policies: Creating a culture of scientific integrity goes beyond simply having policies and procedures in place. It requires a fundamental commitment to ethical conduct at all levels of the organization.

·         Key Elements:

o    Leadership Commitment (“Tone at the Top”): Senior management must demonstrate a strong commitment to scientific integrity.

o    Ethical Training: Providing regular training on research ethics, data integrity, and responsible conduct of research.

o    Mentorship: Pairing junior researchers with experienced mentors who can provide guidance on ethical research practices.

o    Open Communication: Encouraging open communication about research challenges and potential errors.

o    Reporting Mechanisms: Establishing clear mechanisms for reporting suspected misconduct.

o    Protection for Whistleblowers: Protecting researchers who report misconduct from retaliation.

o    Recognition and Rewards: Recognizing and rewarding researchers who demonstrate ethical conduct and high-quality research.

o    Accountability: Holding researchers accountable for their conduct.

o    Transparency: Promoting transparency in research methods and data.

o    Reproducibility: Encouraging researchers to make their data and methods available so that others can reproduce their findings.

o    Addressing Conflicts of Interest: (Detailed previously)

o    Promoting Collaboration: Fostering a collaborative research environment.

o    Continuous Improvement: Continuously monitoring and improving the research environment to promote scientific integrity.

The pre-clinical research and development phase is the bedrock upon which all subsequent drug development activities are built. Ensuring the integrity of this phase is not just a scientific imperative, but an ethical one, with profound implications for patient safety and public health. The detailed strategies outlined above are essential for building a foundation of trust and ensuring that the drugs that eventually reach patients are based on sound science and ethical conduct. This requires a multi-faceted approach, encompassing rigorous methodology, ethical oversight, transparency, and a commitment to continuous improvement.