Pharmacy Research & Ethical Considerations

Pharmacy Research & Ethical Considerations

This topic provides a comprehensive overview of the principles and practice of research, the critical evaluation of scientific literature, and the ethical responsibilities inherent in clinical investigations.

1. Research in Clinical Pharmacy

Pharmacist’s Role and Purpose of Research The main purpose of clinical research is to generate new knowledge for improving the health of individuals and populations. This includes providing information for disease prevention and treatment to enhance health outcomes and quality of life. Pharmacists, equipped with a unique educational background in medicinal chemistry, pharmaceutics, pharmacology, pharmacotherapy, and clinical experience, are ideally positioned to conceive research ideas, design and conduct studies, analyse data, and disseminate findings. Pharmacists should not only participate in research but also lead projects as principal investigators. In India, there is an urgent need for skilled clinical research pharmacists due to limited knowledge about epidemiological and clinical aspects of drug use in the Indian population.

Types of Clinical Research Pharmacists can contribute to various types of clinical research:

• Pharmacokinetics: Characterises drug absorption, distribution, metabolism, and elimination in humans to estimate doses and administration frequency.
• Pharmacodynamics: Investigates the relationship between drug concentration and its pharmacological and toxicological responses.
• Efficacy or Effectiveness Studies: Determines the therapeutic or clinical response to drug therapy in patients, using objective or subjective endpoints.
• Adverse Effects or Safety Studies: Assesses potential risks of drug therapy.
• Drug Interactions: Examines drug-drug, drug-disease, and drug-food interactions.
• Pharmacogenetic/Genomic Studies: Investigates the influence of genetics on drug response, including efficacy and safety.
• Pharmacoeconomics: Evaluates the costs and outcomes (clinical, economic, or humanistic) of pharmaceutical products, programs, and services.
• Health Outcomes/Quality of Life Studies: Assesses the impact of interventions on patient-related outcomes.
• Drug Utilisation Studies: Researches patterns and determinants of drug use in institutions or communities, covering benefits, risks, ADRs, hospitalisations, adherence, and quality of use.
• Drug Use Evaluation (DUE) or Review: A quality improvement process to ensure appropriate drug use against predetermined standards, measuring the effectiveness of corrective actions.
• Stability Studies: Assures that a modified dosage form (e.g., suspension) retains at least 90% of the drug.
• Compatibility Studies: Ensures chemical and physical stability when multiple drugs are co-administered from the same delivery system.
• Pharmacoepidemiology: Applies epidemiological methods to study the uses and effects (beneficial and adverse) of drugs in human populations.

Knowledge and Skills for Conducting Clinical Research The successful completion of clinical research involves a logical progression of steps:

1. Identify a clinical problem based on observation and confirm the need for research through literature review and colleague discussions.
2. Formulate a research question, hypotheses, and specific objectives.
3. Assess feasibility, considering patient availability, collaborators, and funding.
4. Design the study with appropriate methods to address objectives and test hypotheses.
5. Submit the proposal to a Human Subjects Research (Ethics) Committee and for funding.
6. Assign responsibilities, perform the study, and analyse results for statistical and clinical significance.
7. Discuss results with collaborators and prepare an abstract for presentation and a manuscript for publication in a refereed journal.

Guidelines for Conducting Clinical Research

• Pharmacokinetic studies require collecting demographic data, accurately recording drug administration times, and collecting multiple blood samples to characterise absorption, distribution, metabolism, and elimination. For renally excreted drugs, timed urine volume collection is also needed. For drugs treating meningitis, cerebrospinal fluid samples are collected.
• Efficacy and Safety studies (Clinical Trials) should be conducted with appropriate controls, such as randomised, double-blind, or single-blind designs. New drugs can be compared to accepted drugs or placebo if no established therapy exists. Drug development typically proceeds through phases:
  • Phase I: Determines pharmacokinetics and safety in 20–100 healthy volunteers.
  • Phase II: Performed in 100–300 patients with the disease to evaluate the drug’s effect in a small population.

Transition from Research Project to Program Pharmacy administration should emphasize clinical research as an essential part of its mission, fostering a multidisciplinary research culture. Pharmacists should initiate with a single, high-impact research project, taking it from conception to publication. Sustaining research efforts by identifying additional clinical problems and securing support from physician collaborators and the Department of Pharmacy is crucial for success and funding. In India, training in research methodology, biostatistics, epidemiology, public health, pharmacoeconomics, and grant writing is needed to support this potential.

2. Critical Appraisal: How to Read a Research Paper

Definition and Importance Critical appraisal is the ability to read original research papers to judge their scientific value and consider how the results can be applied in practice. This is an essential skill for clinical pharmacists to independently evaluate the significance of research findings for their patients. It helps pharmacists avoid being swayed by selective advertising from the pharmaceutical industry. The main aim is to determine if a paper should change clinical practice when considered alongside other literature and clinical experience. Critical appraisal is also essential for the practice of Evidence-Based Medicine (EBM), which integrates the best research evidence with clinical expertise and patient values.

Types of Drug Therapy Research Papers Research papers relevant to clinical pharmacists focus on clinical efficacy, short- and/or long-term drug toxicity, drug pharmacokinetics, dose-response relationships, and drug therapy monitoring. Other important types include systematic reviews/meta-analyses, therapeutic guidelines, population studies, economic analyses, qualitative research, drug utilisation evaluations, and case series. Meta-analysis is a statistical technique that summarises the results of several studies into a single estimate, giving more weight to larger studies.

Choosing a Paper for Critical Appraisal Hundreds of biomedical journals publish thousands of papers annually, but only a few warrant critical appraisal. When selecting a paper, consider if it addresses an important or controversial therapeutic issue relevant to patients, if it is the first evidence for a new drug class, if it involves more patients or longer duration than previous studies, if the studied population is different, or if its methodology addresses prior problems. Studies with stronger designs, such as randomised controlled trials (RCTs), are generally more important.

Critical Appraisal of Primary Research Papers Primary research papers typically follow the IMRAD structure: Introduction, Methods, Results, and Discussion. It is advisable to identify the study’s aims first, then read the methods and results sections to draw your own conclusions before reviewing the authors’ discussion.

• The Methods Section (Study Design): This section should describe the study design, specific interventions, outcomes measured, subject recruitment (inclusion/exclusion criteria), bias avoidance, duration and completeness of follow-up, and statistical methods. Examples of study designs include prospective, retrospective, multi-centre, case-control, and cross-over studies.
• Bias: It is crucial to look for potential biases that can affect interpretation, such as selection bias, performance bias, exclusion bias, and detection bias. The gold standard for RCTs is double-blinding, where patients, doctors, and assessors are unaware of treatment allocation, to minimise bias. “Open-label” trials have a greater potential for bias.
• Intervention Details: The drug treatment or intervention should be fully described, including names, formulations, doses, administration, duration, and details of placebo or comparator treatments. Compliance measures (e.g., tablet counts) should also be included.
• Outcomes: All outcomes, whether objective (e.g., blood pressure, mortality) or subjective (e.g., patient diary entries), should be identified and clearly defined, including how they were assessed. Composite endpoints, which combine multiple outcomes, should have components of similar importance and expected relative risk reductions.
• Evaluating Results:
  • Randomisation: Check for proper randomisation to balance confounders.
  • Subgroup Analysis: If present, verify it was pre-specified and appropriately powered.
  • Confidence Intervals (CI): Provide a range for the true effect.
  • Absolute Risk Reduction (ARR) and Number Needed to Treat (NNT): These are preferred over relative risk reduction for clinical relevance.
  • Statistical vs. Clinical Significance: Statistical significance is not the same as clinical significance.
• Discussion and Other Parts: The introduction explains the research need. Author affiliations and acknowledgments should be examined for potential conflicts of interest (e.g., sponsorship, consultancy, share ownership), as these may influence research or result presentation.

3. Ethical Issues in Clinical Research

Definition and Basic Principles Clinical research is defined as a systematic investigation in humans designed to discover or contribute to a body of generalisable knowledge. Researchers are legally and ethically obligated to protect human participants. Unlike clinical practice, where interventions aim for individual well-being, research tests hypotheses, meaning participants may not receive the best known treatment, thus increasing obligations on researchers.

The three fundamental principles of ethical research are:

1. Autonomy (Respect for Persons): A rational individual’s capacity to make informed, un-coerced decisions. It requires acknowledging independence and protecting those with diminished autonomy.
2. Beneficence: The obligation to minimize harm and maximize potential benefits. This is achieved through best research design, competent researchers, prohibiting research with an unfavourable risk-benefit ratio, and appropriate ethical review.
3. Justice: Ensures fairness in who bears the burden and who receives the benefits of research, preventing exploitation of vulnerable populations.

Informed Consent Informed consent is a central and fundamental requirement for ethical research. It means a competent individual voluntarily agrees to participate after receiving and understanding necessary information, and making a decision without coercion or undue influence. If a subject cannot consent (e.g., a child or unconscious patient), consent must be obtained from a legally acceptable representative (LAR).

• Elements of an Informed Consent Document: Must include the study’s purpose, interventions, procedures, risks, benefits, alternative treatments, compensation or treatment for injury, subject responsibilities, payment, confidentiality of data, and contact details for the study and the Ethics Committee (EC).
• Revisions: If important new information arises during the study, the informed consent form must be revised, approved by the EC, and subjects re-consented.
• Therapeutic Misconception: ECs should assess the degree of therapeutic misconception, where participants may confuse research interventions with personal medical care.
• Barriers in India: The consent process in India faces challenges due to lengthy, technical documents. Vernacular translations are difficult and may lose meaning (e.g., ECG, placebo). For illiterate participants, the form must be provided in a language they understand and read by a witness. Issues like confidentiality in HIV studies, individual vs. community consent, and cultural influences also pose challenges.

Roles and Responsibilities of Ethics Committees (ECs) as per Indian Guidelines ECs are mandated to review all proposals on biomedical research involving human subjects to protect subjects’ well-being, rights, and confidentiality. This is in line with international guidelines like the Declaration of Helsinki and Indian guidelines from the Indian Council for Medical Research (ICMR).

• Composition: ECs are typically multidisciplinary, with members qualified to review scientific, medical, and ethical aspects, and aware of local, social, and cultural norms.
• Review Process: An EC must provide independent, competent, and timely review. Key aspects reviewed include:
  • Scientific design and conduct: Assessing the appropriateness of study design, statistical methodology, and potential for sound conclusions. Poor science is poor ethics.
  • Risk-benefit ratio: Justification for predictable risks weighed against anticipated benefits. ECs should not approve research where risks are unreasonable.
  • Recruitment: Characteristics of the population, recruitment methods, and information provided to potential participants.
  • Standard therapies: Justification for withdrawing or withholding standard therapies.
  • Medical care and post-trial access: Adequacy of medical supervision, psychosocial support, and plans for post-trial access to the study product.
  • Financial aspects: Costs to participants, rewards, and provisions for compensation/treatment in case of injury/disability/death.
  • Confidentiality: Plans to protect patient information.
  • Informed consent process: Adequacy, completeness, and understandability of information (including vernacular forms), and justification for using vulnerable populations.
• Indian Context: The ICMR Ethical Guidelines for Biomedical Research on Human Subjects (2000, revised 2006) address various ethical issues including the role of ECs, informed consent, compensation, conflict of interest, vulnerable groups, and post-trial access. The Indian Good Clinical Practice (GCP) guidelines (2001, current Schedule Y 2005) provide legal support, with investigators responsible for ensuring EC compliance.

Special Challenges in India Specific ethical challenges in Indian research include:

• The Consent Process: Difficulties with vernacular translations, literacy, and cultural influences can impede true understanding and voluntary participation.
• Standard of Care: Debates on whether the control arm should be the global best treatment, locally available best care, or placebo, as universal standards can be impractical or create undue inducement.
• Post-Trial Access: Questions about whether post-trial access to the study drug should always be provided, if it constitutes undue inducement, and who is responsible for providing it, especially if the drug is not registered in India.

Pharmacists, as essential members of the healthcare team involved in clinical research, must internalize the principles of autonomy, beneficence, and justice, and adhere to national and international guidelines and regulatory supervision to ensure robust participant protection and contribute ethically to new knowledge.