Identifying the Right Investigators and Patients for your Study – Mini Podcast Biosimilar Development Capabilities – Watch Now Vaccine Development Capabilities - Brochure Check out our latest Validated PK & ADA Methods List Read about Veeda's partnership with Ahammune Biosciences for first in human studies Check out our Assay List (Method Library)

Advancement in medical sciences has benefited humanity in many ways. However, in the process of conducting clinical trials, incidences of scientific, moral, and ethical misconduct have been unearthed that have shaken up the scientific community and public. This led to the formation of a formal organization in 1979 by the United States (US) namely the “International Ethical Guidelines for Biomedical Research Involving Human Subjects” to protect and safeguard the interests of trial subjects. Following this, many countries drafted their own guidelines for Good Clinical Practices (GCP). However, with increasing number of clinical trials being conducted at sites in multiple countries, it was necessary to have a uniform guideline for conducting clinical trials. This gave rise to the International Conference on Harmonization (ICH)-GCP guidelines in 1996 with the objective of providing a uniform standard that facilitates the acceptance of clinical trial data by the regulatory authorities of the respective countries. Over the course of time, many countries adapted the ICH-GCP guidelines to frame their own guidelines. India too followed suit with the Indian Council of Medical Research (ICMR) introducing the “Ethical Guidelines for Biomedical Research on Human Subjects” that is continuously revised and amended to ensure that clinical trials are conducted with utmost quality, giving priority to the welfare of the subjects involved.1

India – A global destination

India is emerging to be a favorite destination for clinical trials for many international companies due to several factors:

☉  Conducive Regulatory Environment: Internationally harmonized and favorable regulatory processes such as fast track approval of investigational new drugs making the Indian clinical research environment more amenable to conducting clinical trial. Market trends show a compound annual growth rate (CAGR) of approximately 12% (US dollars 987 million) in the Indian clinical trials industry from US dollars 500 million in 2017.1,2,3,4,5

☉  Trained Manpower: Availability of skilled healthcare professionals who are specialists in different therapy areas, well-versed in the English language and who ensure compliance to ICH-GCP guidelines.1,2,3

☉  Technology Infrastructure: World-class technologies in data management and information technology and related services.1,2,3

☉  Patient Pool: Large population who are treatment naïve and have a diverse genetic and ethnic makeup. With India becoming increasingly urbanized and with greater connectivity between the urban and rural areas, it becomes convenient to recruit patients from different geographical areas. In addition, there is a high incidence and prevalence of acute and chronic diseases due to lifestyle changes leading to diseases such as diabetes, cancer, and so on. Such lifestyle-related disorders open up the possibility of conducting more clinical trials in these disease areas.1,2,3,6

☉  Ease of recruitment: In countries such as the US, approximately 86% of the clinical trials fail to recruit the required number of subjects leading to delay of almost a year. This delay costs the sponsor company several million dollars. Some of the reasons for delayed recruitment are unwillingness of patient to participate, stringent safety requirements, and hefty compensation packages. India provides the possibility of recruitment of patients with relative ease with due to increased trial compliance and transparency especially with the recent release of the New Drugs and Clinical Trial Rules 2019 that consists of updated rules and regulations for fast tracking approval of clinical trials. Among countries with fast growing economies, it has been noted that India has a growth rate in recruitment sites of approximately 22.6% with the highest growth rate seen in China (≈36%).1,2,7,8

☉  Competitive costs – Cost effectiveness is a pushing factor for many trials being shifted to India. The cost to develop a new drug is estimated to be almost 50% less than what would be required in the US or in the European Union. 1,2,3

Future of clinical research in India

Specific guidelines are being worked upon by the Central Drugs Standard Control Organization (CDSCO) for stem cell research, biosimilars, and medical devices to protect patients as well as to encourage clinical research and development in the country. After a lull period in the Indian clinical industry before 2015 due to ethical and quality concerns, open communication between sponsor representatives and the regulatory team of CDSCO has helped in reconsidering India once again as a potential global destination for enrolling a diverse population in clinical trials that adhere strictly to ICH-GCP guidelines.6

Disclaimer:

The information contained on this article is intended solely to provide general guidance on matters of interest for the personal use of the reader, who accepts full responsibility for its use. Accordingly, the information on this article is provided with the understanding that the author(s) and publisher(s) are not herein engaged in rendering professional advice or services. As such, it should not be used as a substitute for consultation with a competent adviser. Before making any decision or taking any action, the reader should always consult a professional adviser relating to the relevant article posting.

While every attempt has been made to ensure that the information contained on this article has been obtained from reliable sources, Veeda Clinical Research is not responsible for any errors or omissions, or for the results obtained from the use of this information. All information on this article is provided “as is”, with no guarantee of completeness, accuracy, timeliness or of the results obtained from the use of this information, and without warranty of any kind, express or implied, including, but not limited to warranties of performance, merchantability and fitness for a particular purpose. Nothing herein shall to any extent substitute for the independent investigations and the sound technical and business judgment of the reader. In no event will Veeda Clinical Research, or its partners, employees or agents, be liable to the reader or anyone else for any decision made or action taken in reliance on the information on this article or for any consequential, special or similar damages, even if advised of the possibility of such damages. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, mechanical, electronic, photocopying, recording or otherwise without the prior written permission of the publisher.

For information, contact us at:

Veeda Clinical Research Private Limited

Vedant Complex, Beside YMCA Club, S. G. Highway,

Vejalpur, Ahmedabad – 380 051,

Gujarat India.

Phone: +91-79-3001-3000

Fax: +91-79-3001-3010

Email: info@veedacr.com

Biosimilar or bio generics are bio therapeutic products with large and complex structures that are similar to their innovator product in all aspects including their safety, efficacy, and quality.

There is a palpable sense of urge among researchers and pharmaceutical industries to develop biosimilar for treatment, with its popularity expected to rise in the forthcoming years especially in developing low-cost biosimilar that are easily accessible and affordable for patients.

Market trends show that North America continues to dominate the global oncology biosimilar market followed by Europe, Asia Pacific, Latin America, Middle East, and Africa. The market is purported to reach approximately USD 45 Billion in the year 2026 from the current market of approximately USD 6 Billion.

Understanding the local and global market demand is necessary for companies, research institutes, and investors to study the changing dynamics in the biosimilar market. Segmentation of biosimilar by product, type of cancer, as well as targeted end-user such as hospital/online/retail pharmacies is particularly useful in empowering industries to make informed business decisions. Product segmentation also helps gauge the project’s feasibility so that the pharmaceutical industry can focus on developing safe and commercially viable products. Comprehensive analyses, robust legal and regulatory frameworks, continuing medical education for health care professionals and increased awareness among the public will undoubtedly increase the uptake of biosimilar and help the biosimilar market move ahead competitively.

Data Integrity in Clinical Research

Importance of Data Integrity

The scientific community has been a witness to some of the worst tragedies in the history of clinical trials data integrity. From the year 2015 till date, The Journal of the American Medical Association (JAMA) and the JAMA Network journals have published at least 18 notices citing concern over data error and/or falsification of data.

1 For instance, the trials conducted by a Japanese anesthesiologist and researcher to treat post-operative nausea and vomiting were reviewed by the Japanese Society of Anesthesiologists (JSA) in the year 2012 to find startling revelations.

The data obtained from the trials were either totally fabricated or fraudulent, and approximately 210 papers published by the anesthesiologist had falsified data.

2 Lapses in data integrity caused a significant loss of revenue, with the direct costs estimated to be close to 525,000 US dollars while indirect costs amounting to approximately 1.3 million US dollars.3

Such scientific misconduct served as a wake-up call to tighten regulations and laws to monitor drug development and drug use.

Scientists acknowledged the need for data integrity at every stage to safeguard human subjects, starting from pre-clinical development to pharmacovigilance.

What is Data Integrity?

Data integrity is defined as paper-based or electronic data that is complete, accurate, consistent, and reliable through its lifecycle from the time of data creation, archival, scanning, retention, and destruction.

4 The updated International Council for Harmonization Guideline for Good Clinical Practice (ICH GCP E6[R2]) reiterates the need for data integrity as well as the importance of monitoring clinical data throughout the study.

The United States Food and Drug Administration (FDA) uses the ALCOA acronym to define expectations with respect to data integrity.4

Data Compliance Issues

The FDA issued Good manufacturing practices (GMP) warning letters to various countries outside the United States (US), citing compliance issues over data integrity. Figure 1 shows China to have received the maximum GMP warning letters, followed by India and Europe.5

Figure 1 GMP warning letters issues outside US5

Chart of Gmp Warning Letters Issues Outside US

Data Integrity Checkposts

Data integrity can be monitored by keeping a check on the following areas:6

  • ►Source Data Verification (SDV)
  • ►Data access and control
  • ►Training of personnel involved in data collection
    such as investigators, data processors, analysts, site staff, and report writers
  • ►Data monitoring: On-site, centralized, and risk-based monitoring
  • ►Clinical trial quality assurance units (QAU): Some sponsors set up internal QAUs or external QAUs with a contract research organization (CRO) to ascertain trial compliance with standard operating procedures (SOPs) and FDA regulations. QAUs also eliminates the risk of internal bias. Regulatory laws, however, do not mandate the need of a QAU.7
  • ►Clinical trial audits

SDV

Strict adherence to good documentation practices (GDP) in clinical trial records is a way to ensure data integrity. GDP should be followed for paper records as well as electronic records and signatures.

Equally important is the need to retain and organize essential documents required before the start of a clinical trial, during the trial, and after the completion or termination of a trial.

The collection of essential documents that is kept at the sponsor site and investigator site is called the clinical trial master file (TMF). TMF plays a major role in facilitating trial conduct and management, thereby allowing for data integrity and GCP compliance at all stages of the clinical trial. The TMF is the document that is reviewed during an audit or inspection.8

Many pharmaceutical companies are now moving towards electronic TMF (e-TMF) for easier management of large and complex clinical trials that involve numerous departments or CROs.

Data Access and Control

It is necessary to exercise caution while handling data from clinical trials. Confidentiality of data should be maintained during all the phases of a clinical trial, including interim data results.

9 The ability to tamper with data, such as changing, deleting, or falsifying data, should be restricted by clearly demarcating roles. This also prevents potential conflicts of interest between similar roles that may hamper data integrity.4

The National Institute of Health (NIH) states that only voting members of the Data and Safety Monitoring Board (DSMB) should be permitted to look at the interim analyses results unless circumstances makes it necessary to share data, such as in the case of serious adverse events.

9In addition, the DMC members should not have any conflict of interest that would influence the outcome data. The FDA has also recommended the use of an “independent statistician” model to analyze interim data who is independent of the principal investigator and trial sponsor and reports unbiased results to the DMC.10

Data Monitoring

It is necessary to set up an independent data monitoring committee (DMC) that prioritizes the safety and interests of enrolled subjects and scrutinizes the authenticity of data as well as the clinical trial conduct.9

On-site Monitoring: is carried out to trace any discrepancy between the source data and data entered. It is also particularly useful to see if the site staff is familiar with the study document and if the staff has demonstrated accountability to carry out the trial ethically and responsibly.11

Centralized Risk-Based Approach: ICH GCP E6(R2) emphasizes the need for centralized monitoring to reduce the number of trial visits by the clinical monitor and to allow for remote spotting of reliable and unreliable data by statisticians or other data management staff.4,11

Risk-based Monitoring: The sponsor company is required to develop a robust risk management plan to prevent or mitigate any risk to human subjects by overseeing trial conduct and monitoring data quality across trial sites.11

Data Integrity Audits12

  • Specific audits look out for any data or metadata that previously went unnoticed, such as deleted or unchecked, misused, orphaned, or reprocessed data.
  • The entire data lifecycle should be subjected to scrutiny by all departments involved in the trial, such as but not limited to data management, safety, quality risk management, and statisticians for compliance issues in areas of data management and data access control.4,8
  • Unnecessary incentivization for speedy results or data from high-risk phase II trials should be closely monitored for unscrupulous activities.
  • Weightage should be given to raw data, and not summary reports and results should be backtracked for any compliance issues.

Conclusion

To avoid huge financial repercussions and loss of business, sponsor companies and CROs should lay sufficient emphasis on maintaining data integrity at every step of the clinical study for its completeness, accuracy, and consistency.

Sources

1. Bauchner H, Fontanarosa Phil B, Flanagin A et al. Scientific Misconduct and Medical Journals. 2018;320(19):1985-1987 https://jamanetwork.com/journals/jama/fullarticle/2708590

2. George SL and Buyse M. Data fraud in clinical trials. Clin Investig (Lond). 2015; 5(2): 161–173.

3. Michalek AM, Hutson AD, Wicher CP et al. The Costs and Underappreciated Consequences of Research Misconduct: A Case Study. PLoS Med. 2018;7(8):e1000318. https://doi.org/10.1371/journal.pmed.1000318

4. Rutherford M. ICH E6(R2) and Data Integrity: Four Key Principles. Clinical Researcher. 2018 April;32(4):doi:10.14524/CR-18-4021. https://acrpnet.org/2018/04/17/ich-e6r2-data-integrity-four-key-principles/

5. https://www.pharmaceuticalonline.com/doc/an-analysis-of-fda-fy-drug-gmp-warning-letters-0003 Accessed on April 26, 2019

6. Moody LE and McMillan S. Maintaining data integrity in randomized clinical trials. Nur Res. 2002 Mar-Apr;51(2):129-33. https://www.ncbi.nlm.nih.gov/pubmed/11984384

7. http://firstclinical.com/fda-gcp/?show=MonitoringvAuditing&search=compliance&type=&page=1 Accessed on April 26, 2019

8. https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-good-clinical-practice-compliance-relation-trial-master-file-paper/electronic-content-management-archiving-audit-inspection-clinical-trials_en.pdf Accessed on April 26, 2019

9. Fleming TR, Sharples K, McCall J et al. Maintaining confidentiality of interim data to enhance trial integrity and credibility. Clin Trials. 2008;5(2):157-67. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2703711/

10. Ellenberg SS. Protecting Clinical Trial Participants and Protecting Data Integrity: Are We Meeting the Challenges? PLoS Med. 2012 Jun;9(6):e1001234.

11. https://www.thefdagroup.com/thefdgroup-blog/conducting-data-integrity-audits-a-quick-guide Accessed on April 26, 2019.

Disclaimer:

The information contained on this article is intended solely to provide general guidance on matters of interest for the personal use of the reader, who accepts full responsibility for its use. Accordingly, the information on this article is provided with the understanding that the author(s) and publisher(s) are not herein engaged in rendering professional advice or services. As such, it should not be used as a substitute for consultation with a competent adviser. Before making any decision or taking any action, the reader should always consult a professional adviser relating to the relevant article posting.

While every attempt has been made to ensure that the information contained on this article has been obtained from reliable sources, Veeda Clinical Research is not responsible for any errors or omissions or for the results obtained from the use of this information.

All information in this article is provided “as is,” with no guarantee of completeness, accuracy, timeliness, or of the results obtained from the use of this information, and without warranty of any kind, express or implied, including, but not limited to warranties of performance, merchantability, and fitness for a particular purpose.

Nothing herein shall, to any extent, substitute for the independent investigations and the sound technical and business judgment of the reader. In no event will Veeda Clinical Research, or its partners, employees, or agents, be liable to the reader or anyone else for any decision made or action taken in reliance on the information in this article or for any consequential, special, or similar damages, even if advised of the possibility of such damages.

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of the publisher.

For information, contact us at:

Veeda Clinical Research Private Limited
Vedant Complex, Beside YMCA Club, S. G. Highway,
Vejalpur, Ahmedabad – 380 051,
Gujarat India.
Phone: +91-79-3001-3000
Fax: +91-79-3001-3010
Email: info@veedacr.com