Planning for a clinical trial application

In recent years, global clinical trials have become standard, and for a good reason. In broad terms, expanding clinical trials across the world provides a better opportunity for demonstrating the true impact of an investigational drug. Global clinical trials offer key advantages to patients and industry, but smaller companies may be hesitant to participate in global trials, wondering if the inevitable challenges outweigh the benefits. The key considerations in designing a global clinical trial are selecting the most appropriate trial sites with a representative patient population, choosing to work with the right partners and staying stay up-to-date with the changing regulatory and clinical landscape. In this article, the author discusses planning global clinical trials, from choosing the countries through to preparation of a global dossier and submission of clinical trial application.
 
Introduction
Clinical trials are prospective, organized, systematic exposures of patients to interventions of some kind (e.g., drug, surgical procedure, dietary change). Clinical trials advance through four phases to test a treatment, find the appropriate dosage, and look for side effects. The health authority typically requires phase 1, 2, and 3 clinical trials to be conducted to determine whether the intervention can be approved for use. It is important for clinical trials to have participants of different ages, sexes, races, and ethnicities to have much wider applicability when the drug is in market.¹ Over the past two decades, globalization of clinical trials has increased steadily for a number of reasons, for example: investigators have access to a greater number of willing, well-characterized, and often treatment-naïve participants, resulting in expedited enrollment; the availability of qualified local investigators eager to conduct trials; enhanced capacity of international sites; and the lower costs of conducting trials in developing countries.
 
Economic incentives to site trials in developing economies also stem from the significant increase in clinical trial costs in developed countries. such as the US and EU member states. In addition, national regulations increasingly require local, in-country study data to demonstrate a medicinal product or device is efficacious and safe in that country and thus across racial and ethnic groups. These regulations propel multinational pharmaceutical companies to consider involving these multiregional sites early in any drug development program.^2,3
 
Despite the rise in clinical trials globally, conduct of such trials is particularly challenging in developing countries because of the relative scarcity of healthcare resources, the unavailability of appropriate medical care, and an inadequate infrastructure. Globalization attracts resources to participating countries, to provide standardized clinical trial conduct and procedures and to train investigators and their teams.³
 
Choosing the countries
Many factors should be taken into account when selecting countries in which to conduct clinical trials, including:

• The ease of recruiting patients;
• The ease of recruiting qualified medical staff;
• Applicability of data (e.g., ethnic heritage might be a consideration);
• Regulatory requirements (e.g., a country may refuse to import a drug essential to the trial);
• The efficiency of the approval process;
• The resources already available (e.g., a regional hospital providing specialized equipment and a pool of physicians/patients);
• The market potential of the country (i.e., whether individuals will be able to access the medication or treatment after it is approved); and
• The standards of care acceptable for the study in regard to integrity and consistency of data.

 
Prior regional experience by the clinical research organization and/or research team is essential in finding a site because a network of former relationships can help ease every step of the clinical trial process, including recruitment, validation of physician credentials, and regulatory approvals.⁴
 
In choosing the countries in which to conduct global clinical trials, the regulatory professional should bear in mind that a global trial’s costs grow as the number of participant countries increases. Thus, it is important to establish the right balance between having a larger number of participant countries to enhance recruitment and facilitate approval and controlling the research costs.
 
Global dossier
Most clinical trial application (CTA) requirements, around the world, are based on requirements of the US Food and Drug Administration (FDA) or European Medicines Agency (EMA). Once those requirements are understood, applications in other countries can be similar, taking individual country-specific documentation into account (e.g., notarized copies of business licenses, draft case report forms, etc.).
 
The first step is to assemble a global dossier. A global dossier is not too different from the US investigational new drug (IND) application, because most commercial CTAs use the common technical document format preferred by the FDA. In addition to the IND, investigational medicinal product dossier, or CTA, completing the global submission will require collecting and making available the following:^5,6

• Cover sheet (Form FDA 1571), including, but not limited to, sponsor contact information, investigational product name, application date, clinical investigation phase(s) to be conducted, and commitment that the ethics committee (EC) will conduct initial and continuing review and approval of each study proposed in the investigation.
• Table of contents
• Introductory statement and general investigational plan
• Master informed consent form (typically, if a country follows the International Council for Harmonisation [ICH], the same global requirements apply)
• Investigator’s brochure (IB)
• Protocol
• Protocol signature page
• Chemistry, manufacturing, and control data
• Pharmacology and toxicology data
• Previous human experience with the investigational drug
• Financial disclosure
• Letter of delegation of responsibilities/power of attorney
• Advertising
• Qualified person review and sign off (EU only)
• Data protection declaration (EU only)
• Case report forms (typically, draft acceptable)
• Data Safety Monitoring Board charter/Independent Data Monitoring Committee (typically, draft acceptable)
• Clinical supply labels in country-specific language
• Letter of acceptance of study from another country (if available), or letter or rejection from an EC (if applicable)

 
Ethics committee
The primary scope of information assessed by the EC (referred to as an institutional review board [IRB] in the US) relates to maintaining and protecting the research participants’ dignity and rights and ensuring their safety throughout their participation in a clinical trial. The EC must also pay special attention to reviewing informed consent and protecting the welfare of certain participant classes deemed to be vulnerable. In addition, the EC is responsible for ensuring a competent review of the research protocol, evaluating the possible participant risks and expected benefits, and verifying the adequacy of confidentiality safeguards.⁵
 
Clinical supply labels
Clinical supply products must be appropriately labeled in accordance with the following principles:

• Ensuring protection of the participant and traceability,
• Enabling identification of the product and the clinical trial,
• Facilitating proper use and storage of the product, and
• Ensuring the reliability and robustness of data generated in the clinical trial.⁷

 
Determining clinical supply label requirements and translations can be very time consuming. The regulatory professional must first develop a table of what each country requires on the outer and inner packaging (bottle or vial) for both active study drugs and placebo (alternatively, Tarius or Cortellis cross-country tables can be used to help plan and manage this task). Then, the regulatory professional needs to determine requirements for a final label template, in each country’s language. The label text must be translated, back-translated, and certified. The labels then are printed, checked against the certified translation for quality assurance, and the drug finally can be labeled. This entire process can take 3 to 6 months, depending on a range of factors, including time taken to compile initial requirements, translation time, printing, quality assurance, and time taken to schedule investigational material labeling. Any error on the final printed label (which can happen with a variety of languages and their unique characters) can set back a clinical program by several months.
 
The investigational product must be coded and labeled in a way that protects the blinding, if applicable, and also must be suitably packaged to prevent contamination and unacceptable deterioration during transport and storage.
 
Further, innovative approaches and technology have been implemented to manage clinical trial investigational product and auxiliary product traceability and accountability. For example, computerized technologies, such as interactive voice response systems or interactive web response systems, have been used to manage randomization, investigational product accountability at trial sites, dose titration, emergency unblinding and expiry date updating for clinical trials. Therefore, a measured degree of flexibility has been included in the regulations to allow alternative approaches to the labeling requirements, provided the labeling principles are not compromised.
 
Document translations
Once a company decides to conduct clinical trials in a country other than its home market, key clinical documents often require translation. Most documents will need to be certified translations (translated into another language, translated back, and reviewed against original documents to ensure the original intent has not been lost). A certified translation will be accompanied by signed and dated documentation from the translator, identifying the document translated (stating the original language). Documents typically needing translation include:
 
Before trial initiation

• Protocol synopsis
• Protocol (typically in countries where a formal IND is not submitted)
• IB (typically in countries where a formal IND is not submitted)
• Informed consent form
• Patient diary or questionnaires
• Clinical supply labels
• Questions from regulators/answers from sponsors
• Ministry of health approval letters
• EC approval letters
• Investigators’ Form 1572s and curriculum vitae (CV)
• Instructions for automatic randomization

 
After trial initiation

• Serious adverse events
• Annual reports
• Notice of study discontinuation or close-out
• Additional ministry of health or EC communication – for protocol amendments or IB

 
Maintaining the submission
After all of the above documents have been created, collected, and notarized, and the initial submission has been made, the work has just begun from a regulatory perspective. The submission now needs to be maintained. Here are the types of submissions required to support the submission:
 
Serious adverse events
Serious adverse events (SAEs) need to be reported in every country, meeting ICH or local ministry of health requirements. Some of the reporting challenges are:

• Different forms in different countries. In the US, SAEs need to be reported on MedWatch FDA Form 3500A,⁸ whereas the rest of the world uses the Council for International Organizations of Medical Sciences (CIOMS) form⁹ (except Canada, which uses the adverse drug reaction form¹⁰).
• Distribution. Some countries and sites require paper SAEs, whereas other sites, ECs, and countries require electronic SAEs, which means converting the CIOMS form into XML and obtaining email addresses.
• Timelines. All SAE reporting timelines need to be met, even though there are different forms, timelines, and submission standards.

 
Annual and quarterly reports
Annual reports or development safety update reports are required in all major countries; the due date depends on the IND effective date and the EudraCT registration date, respectively. The IND effective date or date of first EU approval typically is known as the international birthdate, which establishes the date for annual report submission. For European countries that are not part of the EU, the annual report is due on the anniversary of the first site’s approval. Sometimes, countries allow sponsors to coordinate an annual report with only one or two data cuts needed to prepare the reports, but that is not always the case. This means the sponsor has to coordinate data analysis on an almost monthly basis to write annual reports for multiple countries. In addition, some EU and Eastern European countries require both quarterly safety reports and annual reports.
 
Final report
An investigator must provide the sponsor with an adequate report shortly after completing participation in the investigation. There is no specific timeframe stipulated for report completion.
 
The investigator or institution should provide the EC with a summary of the trial’s outcome and supply the FDA or the health authority with any additional report(s) required.
 
The sponsor or its principal investigator must submit results for applicable investigational product clinical trials to ClinicalTrials.gov no later than 1 year after the study’s completion date.
 
Submitting a CTA
The sponsor is responsible for submitting a CTA or IND application. Institutional EC review of the clinical investigation may be conducted concurrently with the FDA’s IND or health authority CTA review. However, EC approval must be obtained before the sponsor is allowed to initiate the clinical trial.⁵
 
To complete the IND application package, the sponsor must provide the following information in paper format or electronically:

• Cover sheet (Form FDA 1571), including, but not limited to: sponsor contact information, investigational product name, application date, clinical investigation phase(s) to be conducted, and commitment that the EC will conduct initial and continuing review and approval of each study proposed in the investigation.
• Protocols
• Chemistry, manufacturing, and control data
• Pharmacology and toxicology data
• Previous human experience with the investigational drug

 
Multicenter, or cooperative research, studies
In regard to multicenter clinical studies, which were required to comply with the revised Common Rule, all federally funded or sponsored institutions located in the US and engaged in multicenter research must use a single EC to review that study, known as the EC policy. This policy will streamline the review process and eliminate duplicative reviews. Exceptions to the requirement include when multiple EC review is required by law (including tribal law) or for research in which any federal department or agency supporting or conducting the research determines that the use of a single EC is not appropriate.
 
The National Institutes of Health (NIH) issued a final policy, effective 21 January 2019, that was designed to complement the revised Common Rule. The final policy required all institute-funded multicenter clinical trials conducted in the US to be overseen by a single EC, unless prohibited by any federal, tribal, or state law, regulation or policy.
 
Data safety and monitoring boards are also specifically required for NIH-funded multisite clinical trials, including interventions that involve potential participant risk.⁶
 
Protocol amendments, IB updates, and informed consent modifications
Each time a protocol amendment is made, the updated protocol and master informed consent form has to be sent to both the ministry of health and the EC, and the site will need to wait for an opinion from both before implementing the amendment. Whether the protocol is a substantial or administrative amendment will determine the review timeline.
 
IBs need to be reviewed on an annual basis for updates. If an update is made, it must be submitted to the sites, ministries of health, and ECs.
 
Shelf-life extension
If an investigational product expires during trial conduct, a shelf-life extension has to be filed. This submission can include: extended release statement, stability tables with stability data, and an extension justification memo stating the material will be good for another 3, 6, or 12 months, or a new study drug will need to be exchanged for the old material. Either way, this information will need to be submitted to countries requiring this update, and there often is a period of 28-60 days for reviewing this information before the material with the new expiry date or the new material can be used. If the shelf-life extension or information on the new lot is not submitted or reviewed in a timely manner, enrollment in the study could be halted until this has been resolved.
 
In addition, new expiration date labels will need to be printed and the drug packages over-labeled at the site. The over-labeling process will need to be tracked to ensure all sites have received the updated labeling.
 
Form 1572 and financial disclosure updates
Assuming the study is going to be conducted under a US IND, if investigational site information changes, then Form 1572 needs to be updated and submitted to the sponsor in a timely manner. Some clinical research associates prefer to update Form 1572 at the end of the study. However, that is not acceptable, because the information can change many times during the study, and those changes need to be captured. In addition, any changes in financial disclosure information will need to be captured on a new financial disclosure form and evaluated to see if it affects the final study analysis (an additional, separate efficacy analysis might need to be conducted for investigator(s) who have exceeded financial disclosure limits). In addition, a final financial disclosure form will need to be submitted no later than a year after the study ends.
 
Maintaining the US IND – paperwork required
As with most investigator submissions, the sponsor needs to submit Form 1572 and the physician’s CV. (For some products, the IRB approval letter and informed consent form also need to be submitted, depending on the product and FDA reviewing division.) For studies conducted under a US IND outside the US, the following should be submitted:

• Form 1572 (in English)
• Investigator CV (in English)
• EC letter (if required) in native language, English translation, and a certified translation certificate
• Approved informed consent form (if required) in English and a certified translation certificate

 
Gathering the documentation
Collection of all the documentation, either paper or electronic, from a global clinical trial can sometimes be daunting. The required documentation includes:

• Regulatory authority approval, all submissions, correspondence (including emails), and certified translations
• Ethics (central, local, hospital, etc.) approvals, correspondence, and certified translations
• Annual report submissions and regulatory authorities’ acknowledgment receipts
• SAE submissions and acknowledgments
• Investigators’ Form 1572s, CVs, and financial disclosure forms

 
IND/investigational product supply, storage, and handling requirements
The sponsor also must supply the investigator(s)/institution(s) with the investigational product, including the comparator(s) and placebo, if applicable. The sponsor must ensure the following:

• Investigational product quality and stability over the period of use
• Investigational product manufactured according to any applicable good manufacturing practices
• Proper coding, packaging and labeling of the investigational product
• Records maintained for investigational product document shipment, receipt, disposition, return and destruction
• Acceptable storage temperatures, conditions and times for the investigational product
• Timely delivery of the investigational product

 
Record requirements
The sponsor and the investigator(s) must retain the clinical investigation records and reports for 2 years after a marketing application (known as a new drug application) is approved for the investigational product; or, if a new drug application is not approved, until 2 years after shipment and delivery of the investigational product is discontinued for investigational use, and FDA has been so notified.
 
Conclusion
Conducting clinical trials in multiple countries is no small feat for the clinical or regulatory team, which not only supports ongoing maintenance but acts as the gatekeeper for initiating trials. Planning is essential not only to the trial initiation, but also maintenance. Mapping out all the required documentation, through the regulatory professional’s own knowledge, with help from a contract research organization, or by using Tarius or Cortellis cross-country tables early, will help navigate the global clinical trial process with minimal delays to first patient enrolled.^11,12
 
Abbreviations
CIOMS,Council for International Organizations of Medical Sciences; CTA, clinical trial application; CV, curriculum vitae; EC, ethics committee; EMA, European Medicines Agency; FDA, [US] Food and Drug Administration; IB, investigator’s brochure; ICH, International Council for Harmonisation; IMPD, investigational medicinal product dossier; IND, investigational new drug; IRB, institutional review board; NIH, National Institutes of Health; SAEs, serious adverse events.
 
About the author
Sharry Arora, MPharm, is clinical and marketed regulatory project lead with around 14 years of experience and expertise in providing global regulatory support for submission strategy and planning of all stages of product development including conceptualization, development, filing, approval and commercialization. She can be contacted at sharry.arora@novartis.com.
 
Acknowledgment
This article is based on a chapter in the second edition of Global Pharmaceutical and Biologics Regulatory Strategy. The reference for the chapter is: Arora S. Clinical trial application planning [Chapter 9]. In: Sietsema WK, Meacham MM, eds. Global pharmaceutical and biologics regulatory strategy. 2nd ed. Rockville, MD: Regulatory Affairs Professionals Society; 2020:99-106.
 
Citation Arora S. Planning for a clinical trial application planning. RF Quarterly. March 2021;1(1);33-9.
 
References

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5. Electronic Code of Federal Regulations. Title 21 CFR Part 312: Investigational new drug application. https://www.ecfr.gov/cgi-bin/text-idx?tpl=/ecfrbrowse/Title21/21cfr312_main_02.tpl. Current as of 4 February 2021. Accessed 7 February 2021.
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8. Food and Drug Administration. MedWatch forms for FDA safety reporting [MedWatch for industry FDA Form 3500A pdf]. https://www.fda.gov/safety/medical-product-safety-information/medwatch-forms-fda-safety-reporting. Current as of 26 February 2020. Accessed 7 February 2021.
9. Council for International Organizations of Medical Sciences. Suspect Adverse Reaction Report Form. https://cioms.ch/wp-content/uploads/2017/05/cioms-form1.pdf. Not dated. Accessed 7 February 2021.
10. Health Canada. Mandatory adverse reporting form for industry. http://hc-sc.gc.ca/dhp-mps/alt_formats/pdf/medeff/report-declaration/ar-ei_indus-form-eng.pdf. Dated January 2011. Accessed 7 February 2021.
11. Tarius website. Cross-country tables (CGTs). http://www.tarius.com/?page_id=29. Last date of revision not given. Accessed 22 February 2021.
12. Cortellis website. https://www.cortellis.com/intelligence/report/ri/globalregcomparison/DB/112. Last date of revision not given. Accessed 22 February 2021.