Category Archives: Clinical Trials

Clinical Study Reports: A Detailed Guide

Clinical study, Clinical Trials

In clinical research, documenting results and findings is as important as conducting the study. The Clinical Study Report (CSR) is crucial in this process. It is essential to evaluate the safety and effectiveness of new drugs and therapies, whether you are a healthcare professional, part of the pharmaceutical industry, or a regulatory agency. This blog will explore what a CSR is, its components, its importance, and its role in the regulatory approval process.

What is a Clinical Study Report?

A CSR is a detailed document presenting a clinical trial’s methodology, results, and conclusions. It is designed to provide a comprehensive account of the trial, ensuring that the data generated is transparent, replicable, and accessible. Regulatory authorities primarily use CSR to make informed decisions regarding approving a drug or therapy for market release.

Structure of CSR

The format and content of a CSR are generally guided by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), precisely ICH E3 guidelines. These guidelines help standardize the reports across different trials and pharmaceutical companies, facilitating more accessible reviews by regulatory bodies. A typical CSR includes the following key sections:

  • Title Page and Synopsis: This section provides basic information about the study, including its title, phase, and summary of the trial and its outcomes.
  • Table of Contents: Lists the major and minor sections of the document for easy navigation.
  • List of Abbreviations and Definitions: Clarifies terms and abbreviations used throughout the report.
  • Trial Protocol and Amendments: This section includes the original study protocol and any amendments made during the study. It outlines the study objectives, design, population, treatments, procedures, and statistical considerations.
  • Trial Participants: Detailed information about trial participants, including inclusion and exclusion criteria, demographic data, and the number of participants who completed or withdrew from the trial.
  • Efficacy and Safety Results: This is often the most scrutinized section of the report. It details the trial’s outcomes, including primary and secondary endpoints, statistical analyses, and efficacy and safety data.
  • Discussion and Conclusion: The authors interpret the results and discuss the implications for future research and clinical practice. The conclusions must be supported by the data presented in the report.
  • Appendices: These may include raw data tables, sample case report forms, and details of the statistical analysis methods.

Types of CSR

CSR can be categorized based on the trial stage, the report’s purpose, and its audience.

  • Full Reports: These are the most comprehensive type of CSR and include complete details about the trial’s design, methodology, statistical analysis, results, and conclusions. Complete reports are necessary for regulatory submission and are scrutinized by regulatory authorities as part of the drug approval process.
  • These reports are shorter and include summarized data. They are often used for internal Abbreviated Reports: documentation and preliminary discussions with regulatory authorities to give an overview of the trial outcomes without going into the depth typically required for final approval.
  • Interim Reports: During ongoing trials, interim reports provide a snapshot of the trial’s progress. They are crucial for long-term studies and are often used to make decisions about the continuation or modification of the trial. Interim reports can be critical in adaptive clinical trials, where the data from these reports can influence future trial phases.
  • Safety Reports: Focused specifically on the safety outcomes of a clinical trial, safety reports detail adverse events, serious adverse events, and other safety data collected during the study. They are crucial for ongoing safety evaluations by regulatory bodies and ethics committees.
  • Integrated Reports: These reports compile data from multiple studies of a single drug or therapeutic approach. Integrated reports are helpful for regulatory submissions when a comprehensive view of a drug’s efficacy and safety is required across various populations, dosages, or comparators.
  • Pharmacokinetic/Pharmacodynamic (PK/PD) Reports: Specialized reports that focus on pharmacokinetics (how the drug moves through the body) and pharmacodynamics (the drug’s effects on the body) are crucial for understanding the dosing and mechanism of action of a drug.
  • Statistical Reports: These provide detailed statistical analyses and interpretations separate from the main body of clinical findings. They are essential for specialists assessing the statistical validity of the trial results.
  • Patient Reports: Sometimes required by regulatory authorities, these reports provide a summary of the clinical trial and its results in a format that is accessible to patients and the general public. This type is becoming increasingly important as patient advocacy groups call for greater transparency in clinical research.

Importance of CSRs

CSRs play a critical role in the pharmaceutical and medical fields for several reasons:

Regulatory Review and Drug Approval: CSRs are fundamental in drug approval. Regulatory bodies like the FDA in the United States and the EMA in Europe rely heavily on the information provided in CSRs to assess a drug’s safety and efficacy.

Transparency and Accountability: By detailing every aspect of the clinical trial, CSRs ensure transparency in clinical research. This helps maintain trust in the pharmaceutical industry and among the general public.

Scientific Communication: CSRs are often used as a basis for publications in scientific journals. They provide a detailed account of the research that other scientists can replicate or build upon.

Legal Documentation: In cases of legal scrutiny, CSRs serve as an essential document to verify that a trial was conducted according to regulatory standards and ethical guidelines.Challenges and Considerations in CSR Preparation

  • Data Integrity: Ensuring that the data presented in the CSR accurately reflects the findings from the trial is paramount. Any discrepancies can lead to regulatory sanctions and damage the company’s reputation.
  • Compliance with Regulations: Adhering to the specific regulatory guidelines of different countries can be complex, especially for multinational trials.
  • Clarity and Detail: The CSR must strike a balance between comprehensive detail and clarity, making the data accessible not just to experts but also to those who may not be specialists in the field.

The Future of CSR

With advancements in digital technology, the future of CSRs may include more interactive and dynamic formats. Regulatory agencies are also moving towards greater transparency, with some requiring the publication of full CSRs online to facilitate public access and scrutiny.

In conclusion, Clinical Study Reports are not just documents but the backbone of clinical research transparency, regulatory review, and scientific communication. They ensure that the medical and patient communities can trust the results and safety of new therapies. As clinical research continues to evolve, so will the standards and practices surrounding CSRs, enhancing their role in advancing healthcare and treatment options globally.

For those interested in taking their first steps into medical writing or enhancing their expertise to meet the challenges of omnichannel communication in healthcare, we invite you to explore the opportunities available through our training programs. Contact us at [email protected] to learn more about how you can join the ranks of medical writers making a significant impact in healthcare communication. Together, let’s shape a future where accurate, accessible, and actionable health information reaches every corner of the globe, empowering individuals and transforming healthcare outcomes.

PMCF Planning as per EU MDR

Clinical Trials

As the Medical Device Regulation (MDR) deadlines are approaching for re-certification and/or introduction of new products, manufacturers are also working to start or fulfil the Post-market Clinical Follow-up (PMCF) activities as per requirements set out in Annex XIV, part B of the MDR.

The Annex states “PMCF shall be understood to be a continuous process that updates the clinical evaluation referred to in Article 61 and Part A of this Annex and shall be addressed in the manufacturer’s post-market surveillance plan”.

The purpose of PMCF is:

a) to gather information regarding:

  • rare complications
  • clinical observations only seen in a larger user/patient population
  • clinical observations only seen after long-term use of the device

b)  verification of clinical risk-benefit analysis conclusions

PMCF requirements as per EU MDR

A successful PMCF plan ensures that safety and performance results are continuously available to the market. PMCF should be carried out to proactively collect and evaluate clinical data per the method laid out in the PMCF plan which aims at:

  • confirming the safety and performance throughout the product lifecycle
  • identifying risks and previously unknown side-effects while continually monitoring already identified side-effects and contraindications,
  • ensuring the continued acceptability of the benefit-risk ratio, and
  • identifying off-label uses of the device, while ensuring the intended purpose is correct in the environment it is supposed to be used.

If through PMCF, the need for preventive and/or corrective measures has been identified, the manufacturer must implement them and update the post market surveillance report accordingly.

Therefore, PMCF plan specifies the methods and procedures that will be used to proactively collect and evaluate clinical data in relation to the product’s safety as well as clinical performance.

PMCF Planning Pitfalls

Some of the most common pitfalls in planning a prospective clinical PMCF plan are: 

a) Time-consuming ethical approval

Overall delay in planning a PMCF study might happen due to requirement of approval from ethical committees, which can be a time-consuming task as requirements may vary from country to country.

b) GDPR Compliance

The GDPR is a comprehensive regulation which can help identify the safety, performance, and risk profile specific to your device. The key to compliance lies in selecting systems that guarantee the correct security and safety measures and obtaining clear informed consent from respondents/patients. 

c) Key Opinion Leaders

It is important to collaborate with a network of key opinion leaders in the region you are seeking approval as conducting as planning a PMCF study requires correct and relevant data reported to ensure the safety and performance profile of the device is rightly captured. Clinical experts in the region can help assess and guide these requirements as they have expertise in the filed due to their exposure to working with such devices.

 

Good Clinical Practice Guidelines by WHO

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Good Clinical Research Practice (GCP) is an established international ethical and scientific quality standard process for the design, conduct, performance, auditing, monitoring, recording, analysis, and reporting of clinical studies. GCP ensures that the reported data and results are credible and accurate, and the rights integrity and confidentiality of study subjects are respected and protected. All the stakeholders must adhere to the GCP standards including research subjects, sponsors, investigators, contract research organizations (CROs), site staff, ethics committees, and regulatory authorities.

Goals of Good Clinical Practice

The GCP is established with the following aims:

  • To protect the rights,safety, and wellbeing of humans involved in research
  • To assure the accuracy, reliability, quality and integrity of data collected
  • To provide standards and guidelines for a well-conducted clinical research
  • To speed up the marketing and promotion of new products
  • To ensure benefit to both sponsors and consumers by reducing the cost of trial and investigation products.

Figure 1: Goals of GCP

Compliance of GCP assures public that the safety,rights and well-being of human subjects involved in research are protected and are consistent with the principles stated in the Declaration of Helsinki and other internationally recognized ethical guidelines.

Foundations for Ethical Conduct

Declaration of Helsinki

Declaration of Helsinki (1964) was developed as a statement of ethical principles to guide physicians and other participants in medical research involving human subjects.

The other foundations for the ethical conduct of clinical research include:

  • The Nuremberg Code (1947): After the second world war, Nuremberg trials of war criminals resulted into introduction of 10 elements of medical ethics, known as ‘Nuremberg Code’, in August 1947, to protect human subjects from cruelty and exploitation while conducting human experiments.
  • The Belmont Report (1979): As a result of National Research Act of 1974, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research had written ‘The Belmont Report’. It was created to identify the basic ethical principles for the conduct of biomedical and behavioral research involving humans and develop guidelines to make sure that the research is conducted in accordance with the principles.
  • International Conference on Harmonization (ICH-GCP): ICH provided the international quality standard to harmonize technical procedures and standards, enhance quality and accelerate time to market.
  • International Standards Organization (ISO): ISO 14155:2011 developed international standards to protect the rights, wellbeing and safety of human subjects, ensure the accuracy and reliability of results, define the responsibilities of sponsorsand clinical investigators, and assist sponsors, investigators, regulatory authorities, ethics committees, and others involved in the conformity assessment of medical devices.
  • Code of Federal Regulations (CFR): CFR is the codification rules and regulations published in the Federal Register by the federal government of the United States. The CFR includes FDA regulations on human subject protection and the conduct of clinical studies.

Background

WHO organized a ‘Scientific Group on Principles for Clinical Evaluation of Drugs’ in 1968 and then in 1975 to review and formulate principles and guidelines for clinical evaluation of drugs, new indications or dosage forms for marketed drug products and new combination products, and covering all aspects of drug development.In 1995,the WHO published ‘Guidelines for good clinical practice for trials on pharmaceutical products’ based on these reports.

WHO Principles of GCP

There are 14 principles of WHO GCP and are summarized as follows:

Principle 1 –Ethical Conduct: All clinical trials must adhere to basic ethical principles which have their origin in the Declaration of Helsinki, namely equal importance for persons, beneficence, and justice, permeate all other GCP principles.

Principle 2 –Protocol: A detailed, clear protocol including background, rationale, objective(s), design, methodology, statistical considerations, information, and organization of a trial should be laid out for every clinical research involving human subjects and comply with scientific standards.

Principle 3 – Risk Identification: Beforea study/trial is initiated, all foreseeable inconveniences and risks should be assessed against the estimated benefit(s)for the individual trial subject and society. A proposed clinical trial should be supported by sufficient non-clinical and clinical information for source of information, knowledge of literature, and on adequate lab, and where applicable, animal experimentation.

Principle 4: Benefit-Risk Assessment: Trial with human subjects should be initiated and continued only if the predicted benefits outweigh the risks for the individual and society. The safety and well being of the trial subjects should be considered most important over the interest of science and society.

Principle 5 – Review By IEC/IRB:A protocol review of a clinical trial involving humans,should be submitted for consideration, guidance, evaluation, comments, and approval by specially appointed independent ethics committee/institutional review board (IEC/IRB).

Principle 6 – Protocol Compliance: Research with humans should be well-conducted in compliance with the protocol after approval by IEC/IRB. Any deviation or changes of the protocol shouldn’t be applied by the investigator without the sponsor’s agreement and documented approval/favorable opinion by IEC/IRB.

PRINCIPLE 7 – Informed Consent: A freely provided informed consent from each human subject before participation in any clinical trial should be obtained in compliance with the national culture(s) and requirements. The subjects should volunteer as informed participants. If giving informed consent is not possible for any subject, a legally authorized representative should give permission,by applicable law.

Principle 8 – Continuing Review/Ongoing Benefit-Risk Assessment: Clinical trials having humans as research subjects should be continued only if the benefit-risk assessment remains favorable. The sponsors should ensure a process to assess and evaluate the drug development continuously during the clinical trial. The ethics committee should conduct reviews during the research and monitor its progress.

Principle 9 – Investigator Qualifications: On behalf of the trial subjects, the decisions and medical care should be made by a qualified and duly licensed medical professional, i.e., physician or, when appropriate, a dentist.

Principle 10 – Staff Qualifications: Every individual who is involved in directing a trial must be qualified by training, education, and experience to perform their respective task. This includes the investigator and his/her supporting staff to assist him.

Principle 11 – Records: All the information during the clinical trial should be recorded, handled, and stored in a way to allows accuracy in its interpretation, reporting, maintenance, and verification.

Principle 12 –Confidentiality/Privacy: The confidentiality of records that could identify subjects must be protected, respecting the privacy and confidentiality rules in compliance with the applicable regulations This is done to safeguard the integrity of subjects.

Principle 13 – Good Manufacturing Practice (GMP): Manufacturing, handling, and storage of investigational product(s) should be in accordance with applicable GMP and should be used in accordance with the approved protocol.

Principle 14 – Quality Systems: Systems with procedures that assure the control assure and improve the quality of every aspect of the clinical trial must be implemented.

Turacoz Healthcare Solutions understands and abides by the GCP. We aim to deliver the best of the information about clinical research. Turacoz is a medical communications company, which offers services to healthcare professionals in clinical research, regulatory writing, publication writing, medico-marketing writing, and support for conducting medical advisory board meetings.

If you have any queries, email us at [email protected].

References

  1. World Health Organization. Handbook for Good Clinical Research Practice (GCP), 2002. Available at https://www.fda.gov/files/medical%20devices/published/Presentation–Good-Clinical-Practice-101–An-Introduction-%28PDF-Version%29.pdf. As accessed Apr 14, 2020.
  2. Vijayananthan A, Nawawi O. The importance of Good Clinical Practice guidelines and its role in clinical trials. Biomed Imaging Interv J. 2008;4(1):e5.
  3. S. Food and Drug Administration. Good Clinical Practice 101: An Introduction. Available at https://www.fda.gov/files/medical%20devices/published/Presentation–Good-Clinical-Practice-101–An-Introduction-%28PDF-Version%29.pdf. As accessed Apr 14, 2020.
  4. Permissible Medical Experiments. Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10: Nuremberg October 1946–April 1949. Washington: U.S. Government Printing Office (n.d.), 2,181-182.
  5. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research (1979).
  6. International Organization for Standardization. ISO 14155:2011: Clinical investigation of medical devices for human subjects — Good clinical practice (2011). Available at https://www.iso.org/standard/45557.html.As accessed Apr 14, 2020.
  7. S. Food and Drug Administration: FDA Regulations Relating to Good Clinical Practice and Clinical Trials (2015). Available at https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/fda-regulations-relating-good-clinical-practice-and-clinical-trials.As accessed Apr 14, 2020.

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New Drug and Clinical Trial Rules 2019, INDIA What they bring to the table!

Clinical Trials, , , , ,

Effective from March 19, 2019, The New Drug and Clinical Trial Rules released by the Ministry of Health and Family Welfare have met with mixed reviews by the industry. These rules which apply to Investigational new drugs for humans, clinical trials, bioequivalence and bioavailability studies, except the chapter on ethics, were much awaited by the healthcare industry in order to bring a change in the clinical research sector in India.

These new rules have brought quite a few changes to the previously published Drugs and Cosmetics Rules, 1945, the name itself, being the first.

Reduced Timelines

The drug approval regulatory body- the Central Drugs Standard Control Organisation (CDSCO) will have 30 days to respond to a clinical trial in India and 90 days for global trials with India as one of the site. Failing to respond within these timelines, the trials will be deemed as approved. Earlier, these approval timelines were a major challenge as these could take anywhere from six months to one year.

This, however, would add on to the pressure for CDSCO to approve trials within the stipulated timeline.

Hello phase IV

These rules state that the drugs and indications approved by the regulatory authorities like Food and Drug Administration, European Medicines Agency, etc, would not require a phase III to test the efficacy and safety in India and can directly skip these to a phase IV, to be promoted to the Indian population.

This rule would also apply to Orphan drugs which are used for treatment of rare diseases affecting less than five lakh Indians. With this rule, the accessibility of drugs for the Indian population is believed to increase and will help them in getting better treatment options. Whether these drugs be effective for the Indian population who differ from their counterparts, is still an unanswered question.

Free Post-trial drug access

Trial participants enrolled in clinical trials did not have access to the drugs under study until they were marketed after completing the necessary steps involved. This, however, has been revised in the new rules. Participants will have access to the trial drugs post-trial if and only if there is no other alternative available. Also, the trial participants would have to submit a written waiver to the sponsor, relieving them of the responsibility of any post-trial complications caused by the drug under study. 

Clinical Trial Approval Validity

The approved clinical trials would have a validity of two years which is extendable by one year. This is aimed at fast-tracking the trials and in turn, would help patients to get faster access to drugs.

Welcoming equality

The New Drug and Clinical Trial Rules would now apply to bioequivalence and bioavailability studies and consider them at par with clinical trials. This would help in understanding these studies in terms of their conduct, analysis, and reporting. It has also been mentioned to acknowledge the centers conducting these studies.

Compensatory vows

It has been stated that the compensation for death or permanent disability of the trial participants would be decided by the Drug Controller General of India. Also, free compensation for trial-related disability or injury would be extended until the injury subsides or is no longer related to the trial or drug under study. There is, however, a catch in this clause. This extended compensation would be provided under the guidance of the trial investigator. So, if the investigator feels that the injury is not trial related or is no longer associated with the trial, his opinion would be deemed final. This does put the trial participant at a bit of disadvantage.

These rules aim to promote clinical trials and studies in India, which has a very high disease burden, yet only 1.2% of Global clinical trials are conducted here. Hopefully, these rules would help India be taken seriously as a country which supports ethical Clinical trials and studies, providing opportunities for various Global leaders to see India in a different light.

Turacoz Healthcare Solutions aims to provide information regarding the latest trend and updates in the clinical trial industry. Turacoz is a medical communications company, which offers services to healthcare professionals in clinical research, regulatory writing, publication writing, medico-marketing writing, and support for conducting medical advisory board meetings.

You can write to us at [email protected] to know more about us and avail our services.

Moving to Virtual Clinical Trials

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In the clinical trials industry, 80% of trials do not meet enrolment timelines, leading to a loss of $8 million per day. Delayed enrolment not only impacts trial timelines, but more trials are being cancelled because of it, preventing investigators from determining the safety and efficacy of what could be promising new therapies for patients who need them the most.  This loss can be dealt through incorporation of virtual clinical trials. Unlike traditional site based clinical trials, virtual clinical trials do not require multiple study sites. Though some research space will be required for management of a virtual clinical trial, it can generally be organized from a single facility. Also, patients need not be in proximity to sites, and the data collection requirements fit more easily into their everyday routines, improving compliance and patient engagement. Greenlight insights reported that virtual industry will reach $7.2 billion by the end of 2017, and is expected to touch $74.8 billion by 2021.

Virtual clinical trial is a new method of collecting safety and efficacy data from trial participants, from scratch of the study through execution to follow-up. The participant does not have to travel to the trial site and can make use of simple mobile applications to report general information and adverse events. Body temperature and other vital signs are send directly to the electronic data capture records via wearable sensors.

What are the benefits of virtual clinical trials?

The advantages of virtual clinical trials compared to the traditional trials are mentioned below.


Figure 1: Benefits of virtual clinical trials
  1. Maximizes patient availability and enrolment: The patient recruitment phase is longest in clinical trials and almost 80% of the study fails to reach the initial target.
  2. Overcome of mobility issues: As the patient is not required to travel to the trial site or doctor’s office, it is convenient for elderly participants residing in remote area.
  3. Keep subjects engaged with the study: Almost 40% of the phase III clinical trials subjects drop out from the study due to many factors such as inconvenience in travelling, complexity of trial design and data collection procedure. However, virtual clinical trials does not require patient to travel to clinical study sites. Also, the data collection procedure is automated which increases the patient engagement and reduces the dropout rates.
  4. Better data collection: Data collection is made easy by electronic data capture records hence; the timelines can be achieved at a faster rate.
  5. Benefits to research team: With notifications, scheduling and reporting functions, researchers are freed from performing tedious administrative duties.
  6. Reduce risk in drug development process: Real-time data analysis and data cleaning can be carried out simultaneously. Based on the real time clinical trial data, decisions to terminate drugs development can be made faster.
  7. Cost effectiveness: The reduced number of sites involved in the study leads to reduction of the cost. While trial staff will likely still be based at a single site or a reduced number of sites in multi-site trials, the operating costs will be significantly lower.

Key challenges of virtual clinical trials

  1. Sometimes
    technology may fail:     When everything
    relies on technology, challenge arises if it won’t operate optimally.
  2. Data accuracy
    problems:     As the patients will not face the
    doctor directly, doubts exist whether ideal standard treatment care is provided
    for the patient.
  3. Conservative in
    approach:     Corporate conservatism is another
    major challenge as it is difficult for the sponsors to move on from traditional
    method and trust the data generated from virtual clinical trials.
  4. Challenges in
    device selection:      There are concerns that the device model, the position at which the
    trial participants wear it and other factors could introduce variability into
    the trial results.

Pioneers in virtual clinical trials

REMOTE (Research on Electronic Monitoring of Overactive Bladder Treatment Experience) trial by Pfizer in 2011 was the first virtual clinical trial. Though, the trial faced many challenges, it was the first trial to use web and smartphone based patient recruitment. Also, the patients were not required to visit the study site.

Turacoz Healthcare Solutions aims to provide information regarding the latest trend in clinical trial industry. Turacoz is a medical communications company, which offers services to healthcare professionals in clinical research, regulatory writing, publication writing, medico-marketing writing, and support for conducting medical advisory board meetings.

To know more about us and our services, write to us at [email protected]