This quarterly eNewsletter will keep you informed of regulatory news and trends as it relates to the clinical development industry and insights from PRA's Global Regulatory Clinical Services team.
Project Orbis – A Global Collaboration
As organizations go increasingly global, the Food and Drug Administration (FDA) is not one to be left behind.
On 17 September 2019, the FDA's Oncology Center of Excellence (OCE) launched Project Orbis, in initiative providing the framework for concurrent submission and simultaneous review of oncology drugs by participating international health authorities. The project leverages the FDA’s longstanding communication and collaboration with international regulators for clinical trials in cancer.
Collaborative regulatory authority interaction in accelerating product approvals worldwide is good news for both patients and the pharmaceutical industry. It opens up the possibility of allowing cancer patients to receive earlier access to drugs in other countries where there may be significant delays in regulatory submission, regardless of whether the drug has FDA approval.
Project Orbis is a model set up by the Australia-Canada-Singapore-Switzerland (ACSS) Consortium, a joint review program among the regulatory authorities of the four countries. Under ACSS, each country takes the lead in evaluating different parts of a regulatory submission.
The streamlined model for collaborative review was tested by inviting Eisai and Merck to participate in Project Orbis by submitting simultaneous applications to the US, Canada and Australia for the Lenvima-Keytruda combination. Although in this case, each country conducted its own regulatory review, there were no major points of disagreement.
Under Project Orbis, consensus amongst participating countries is not required - if a country's regulator views any aspect of the application differently, it would not be bound to the accept the decision of the other countries. The product in that country would have different labeling to account for this. The Lenvima-Keytruda combination for use in advanced endometrial carcinoma, for example, received approval from all three regulatory bodies (FDA, Health Canada and Therapeutic Goods Administration (TGA)). Canada approved a slightly different indication from the US and Australia with regard to prior chemotherapy. The collaboration proved fruitful for Health Canada, whose approval process was accelerated to 90 days compared to a 200 day review period for a new indication. Most recently the three regulatory bodies also approved a new indication for acalabrutinib for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), four months ahead of the FDA’s goal date.
As Project Orbis expands, partnering with additional international health authorities, there is the possibility of opening up the initiative to cover new molecular entities and novel biologics. This presents its own challenges though concerning proprietary information, inspections and review by multiple disciplines.
One burning question is the likelihood of this coordination being used for initial marketing applications in a therapeutic indication other than oncology. For now though, the FDA is ploughing ahead, looking for pharmaceutical companies to submit supplemental applications serving unmet medical needs where approvals could have a major impact on disease.
Therapeutic Goods Administration (TGA), Project Orbis, and International Cooperation
The Lenvima-Keytruda combination, and Acalabrutinib approvals by the TGA late last year, represent one of the latest achievements in a consistent and developing strategy by the Australian regulator developing of greater international collaboration.
This is especially true in Oncology, where there continues to be exciting new developments – such as checkpoint inhibitors and CAR-T cell therapy. There is a large focus on removing delays in the regulatory system. This is magnified by well-educated patients and patient advocacy groups creating significant political pressure to keep the country on the cutting edge of available treatment options. Participation in initiatives such as Project Orbis keep Australia there.
In looking at how and why Australia/the Therapeutic Goods Administration (TGA) contribute to such initiatives, it can be instructive to look at some of the characteristics of the TGA itself.
Two particularly notable characteristics would be:
1 – Size
Relative to other regulators in English speaking countries, the TGA is relatively small—meaning how and where they deploy their resources takes on an additional importance.
This is one of the reasons the TGA has a “light touch” in terms of regulation of clinical trials – relying heavily on ethics committees, and also part of the reason they want to share the burden of regulatory review among like-minded regulators.
This was also one of the driving factors behind the now abandoned attempts to merge the TGA with New Zealand’s regulator MedSafe.
2 - Expertise/Reputation and Regional Experience
The TGA’s scientific expertise would be well-regarded globally, with regulatory standards meeting or exceeding those of most other countries. It would also be valued for its experience cooperating across the APAC region.
The TGA leverages this reputation to take a significant role in a large number of international collaborations, a list of which can be found here.
While the aim of Project Orbis is to allow the FDA, TGA and Health Canada to share responsibility of regulatory review when extending the registered indication of oncology medications, there are currently still limitations to how much responsibility can be shared for initial registration of new drugs.
Australia does designate certain regulators such as the FDA and Health Canada as Comparable Overseas Regulators (CORS) and will make use of previous assessments by COR’s in order to reduce duplication of review within Australia. This is most extensively used with regards to medical device assessments that have occurred in Europe providing a head start in Australia, but it does also extend to some drug evaluation, with the hope being that as Projects such as Orbis succeed, the cooperation can become increasingly extensive.
The same regulators alongside Japan and the European agency have also recently been cooperating in a pilot program to cooperate on GMP inspections of manufacturing facilities in countries not participating in the program.
As regulators across the globe cooperate to work smarter, not harder through such collaborations, treatments will be brough to patients faster and at lower costs, improving outcomes for all.
Swissmedic Contribution to the Orbis Project
The Orbis project provides a fast track review process of oncology products among leading international regulatory agencies. This international collaboration among different regulatory authorities offers a way of delivering a faster patient access to innovative cancer treatments.
In February 2020, Swissmedic representatives and an FDA delegation headed by Dr Richard Pazdur, Director of the OCE, discussed how Swissmedic can be involved in the Orbis project.
The main goal of this international collaboration is to allow review applications for innovative first authorizations or indication extensions for oncology products in parallel, so that these medicinal products can be made available sooner to patients outside the USA.
Swissmedic collaborates with Australian Therapeutic Goods Agency (TGA), Health Canada (HC), and the Health Sciences Authority (HSA) in Singapore, and supports the initiative in the form of a first pilot trial conducted during 2019-2022. After the pilot phase, detailed evaluation will help to decide whether Swissmedic can continue this collaboration permanently.
On May 7, 2020, Swissmedic announced a first approval issued based on a ORBIS project cooperation. The authorization application (Seattle Genetics, Inc) of tucatinib for the treatment of patients with HER2-positive metastatic breast cancer (TUKYSA film-coated tablets) was submitted to the US Food and Drug Administration (FDA) on December 20, 2019. Shortly after, Swissmedic received the application on January 6, 2020. The FDA approved tucatinib on April 17, 2020, while Swissmedic authorized it for Switzerland on May 7, 2020.
Swissmedic met the very short process deadline of only 123 days in total by combining phases I and II and sending rolling questions to the applicant. The approval is based on results from the pivotal trial HER2CLIMB, a randomized (2:1), double-blind, placebo-controlled trial that enrolled 612 patients with HER2-positive unresectable locally advanced or metastatic breast cancer who had previously received trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1), either separately or in combination. The results of the study were published in The New England Journal of Medicine in December 2019.
This approval of a new active substance is a great example of bringing new targeted therapies to patients within extremely short time periods.
International Coalition of Medicines Regulatory Authorities (ICMRA) – A Global Collaboration
The ICMRA is not a new global collaboration. Indeed, it was back in 2012 when more than 30 medicines regulatory authorities came together to discuss ways of improving global dialogue between regulators in order to strengthen information sharing, leverage resources and work together on common activities. The ultimate goal of course was and still is to improve the quality, safety and efficacy of medicinal products globally.
These discussions continued to take place at further meetings until the decision was made to establish the ICMRA. The ICMRA is a voluntary, executive-level group including the following participating regulatory authorities. Learn more here.
The ICMRA holds regular meetings throughout the year and an annual ICMRA Summit which is held sequentially in each of the three global parts of the world (the Americas, Europe and ROW including Africa, Asia, Australia and New Zealand). Key outcomes from some of the meetings can be found on the ICMRA website. Learn more here.
As an example, the 2019 ICMRA Summit in Rome, included delegates from 28 different countries (representing more than 35 medicines regulatory authorities globally, as well as experts from the World Health Organisation (WHO), the European Commission (EC) and the European Medicines Agency (EMA)) and was hosted by the Italian Medicines Agency (AIFA). Topics discussed at this meeting included digitalized healthcare and patient-centered clinical trials, big data and real world evidence, and increased medical use of cannabis.
The rapidly changing scientific and technological environment is a challenge and an inspiration for us, as regulatory authorities from across the world shape the future of our strategic collaboration and develop common policies that bridge different national legislative frameworks. They help us use our resources and expertise most wisely.
Guido Rasi, ICMRA Chair and Executive Director of the European Medicines Agency (EMA)
Part of the ICMRA’s mandate is to cooperate on shared current regulatory issues and challenges. Nothing seems more fitting here than the COVID-19 pandemic. During this challenging time, the ICMRA has been holding strategic meetings every 2 weeks and regular regulatory workshops, with a focus on international alignment on the COVID-19 response in terms of pragmatic approaches, regulatory flexibility, regulatory considerations for clinical trial management and preventing supply issues.
In June this year, the ICMRA committed to ramp up the global collaboration and focus on COVID-19 clinical trials, in order to speed-up the development of COVID-19 treatments and vaccines worldwide. Meetings and workshops held in June looked at Phase 3 COVID-19 vaccine trials. It is expected that increased regulatory convergence in terms of Phase 3 trial design will help developers generate the evidence needed to meet the regulators’ requirements across the world. Per the WHO landscape document of COVID-19 Candidate Vaccines – September 9, 2020, there are 145 candidate vaccines in preclinical evaluation and 35 candidate vaccines in clinical evaluation. Of the 35 in clinical evaluation, 9 are at the Phase 3 stage.
Key topics discussed at the ICMRA SARS-CoV-2 Vaccine Workshop on June 22, 2020 included clinical and pre-clinical data requirements for Phase 3 clinical trials and trial design for Phase 3 studies in terms of trial population, endpoints and statistical considerations. The ICMRA emphasized the need for large randomized, double-blind, controlled Phase 3 studies enrolling many thousands of people, including those with underlying medical conditions in order to generate the most relevant data for the target populations.
Following the workshop, generally agreed positions among global regulators were released. Some examples of these included postvaccination challenge data using non-human primates to assess the potential for enhanced respiratory disease (ERD). Despite acknowledging that this would be valuable data to support proceeding to Phase 3 clinical trials, ICMRA also acknowledged that this data may not be available at the time of Phase 3 initiation. Thus, a case-by-case approach would be applied taking into consideration the particular SARS-CoV-2 vaccine construct and the overall data available (preclinical and clinical) for this construct. It was also suggested that other challenge models such as ferrets, hamsters, and transgenic mice could provide valuable supportive data. Another discussion point was the requirement for evaluation of immune markers of potential ERD outcomes to be included as part of the nonclinical data looking at the immune response in animal models vaccinated with doses of the SARS-CoV-2 vaccine and also as part of the clinical data.
In terms of the study design for Phase 3 vaccine trials, the importance of looking at vaccine safety and efficacy in SARS-CoV-2 naïve individuals was noted, but it was acknowledged that in reality, pre-vaccination screening for previous infection was unlikely to happen with the licensed vaccine. Thus, data should also be collected in individuals with prior infection. It was also noted that it was important to include older adults (e.g. over 55 years of age), including those with co-morbidities. Inclusion of older adults would be supported by safety and immunogenicity data collected from younger adults and healthy older adults who had taken part in Phase 1 and Phase 2 clinical trials. Also, there was an acknowledgment of the relevance of assessing safety and efficacy in subjects older than 75 years. The ICMRA agreed that pediatric assessments of safety and effectiveness of SARS-CoV-2 vaccines should be planned, however it was noted that the initial SARS-CoV-2 vaccines to go on the market would likely be in adults. Inclusion of pregnant women would be a case-by-case decision based on the overall data available for the vaccine construct including developmental and reproductive toxicology studies. It was agreed that follow up of subjects post-vaccination should be long enough (suggested one year or more) to assess safety and the duration of the immune response.
Further discussion points and details on the topic of Phase 3 vaccine trials can be found on the ICMRA website.
In addition, information can be found on previous and later (pre and post-June 2020) ICMRA meetings/workshops in relation to COVID-19 focusing on topics such as improved information sharing globally with regards to research and development of treatments and vaccines against COVID-19, cooperation on observational studies of real world data in the context of COVID-19, and the acceptability of different end points used as primary endpoints in clinical trials for the treatment of COVID-19.
The ICMRA truly represents global collaboration and the importance of this collaboration has only been heightened during the ongoing COVD-19 pandemic. It is hoped that the synergy between the heads of national regulatory authorities around the world, leveraging knowledge and expertise as well as global alignment will bring safe and effective COVID-19 vaccines and treatments to the market as quickly as possible.
Real World Data Covid-19 Tracking
PRA collects, manages, and analyzes large volumes of research and health data. Through patient activity observed for diagnosis, testing, exposure of COVID-19 infection, PRA is currently (September 2020) tracking longitudinal insights into over 13 million patients overall and 1.35 million diagnosed patients.
PRA leverages our US medical, hospital, and prescription claims data assets to provide information and insights into patients tested, diagnosed, or suspected, with or without symptoms.
PRA’s Medical Informatics Team and the Symphony Health COVID-19 Rapid Response team developed several patient activity trackers to rapidly disseminate insights to broader PRA teams. One of the trackers is a data platform to provide COVID-19 infected, tested, or exposed patient diagnosis trends, patient demographics, physician profiles, top places of service by age, chronic comorbidities (1 year prior to diagnosis), acute symptoms and manifestations (30 days prior to diagnosis and same day as diagnosis) via a tableau dashboard. The underlying claims data is refreshed on a weekly basis to provide insight on COVID-19 diagnosis and testing trends across the United States.
Did You Know?
The European Court of Justice invalidated the US data Privacy Shield, making the transfer of data from EU to US “invalidated”. The Court considered that the requirements of U.S. domestic law, and in particular certain programs enabling access by U.S. public authorities to personal data transferred from the EU to the U.S. for national security purposes, result in limitations on the protection of personal data which are not circumscribed in a way that satisfies requirements that are essentially equivalent to those required under EU law1. This legislation does not grant data subjects actionable rights before the courts against the U.S. authorities. As a consequence of such a degree of interference with the fundamental rights of persons whose data are transferred to that third country, the Court declared the Privacy Shield Adequacy Decision invalid.
Key Insights from PRA’s Real World Data
Key Insights from PRA’s Real World Data amongst Covid-19 diagnosed patients:
- At the start of the pandemic, a higher proportion of diagnosed COVID-19 patients were male. Recently more diagnosed COVID-19 patients have been female. However, amongst hospitalized patients, male patients were a higher proportion.
- Diagnosed patient age has been trending younger since the beginning of the pandemic. Recently, patients under 30 were 27% of the total volume. These patients have been mostly diagnosed at outpatient hospital, ER, and office locations.
- At the start of the pandemic, patients mainly received a diagnosis at an inpatient hospital setting. Recently patients have been receiving their Covid-19 diagnosis across multiple places of service, most notably outpatient, office, and telehealth settings.
- Hypertension (37%), Hyperlipidemia (26%), T2DM (22%), Anemia (15%), and Obesity (14%) continue to be the most common chronic comorbidities observed in patients diagnosed with COVID-19 infections.
Key Insights from PRA’s Real World Data amongst Covid-19 hospitalized patients:
Of the 1.2 Million diagnosed COVID-19 Patients through August, PRA evaluated that 29% of these patients had inpatient hospital care.
- The median length of stay was 10 days shorter for hospitalizations without ventilator use (5 days) compared to those with ventilator use (15 days)
- The shortest length of hospitalization stay was for patients under 30 who were discharged alive (3 days median length of stay)
- 8% of patients expired during hospitalization and were on average 10 years older than those patients who were discharged alive
- 10% of hospitalized patients had ventilator use. Of the hospitalizations with ventilator use, 45% of those patients died.
Impacts on Healthcare Trends
As the COVID-19 pandemic continues, researchers are starting to get a clearer picture of patient demographics and how this impacts healthcare trends for the non-COVID-19 related care of patients.
- Patient office visits continue to increase from their low point in the week of March 27 for all specialties.
- While being higher than 2019 trends, weekly updates show some fluctuations in telemedicine visits; likely sharp highs and lows as medical offices and hospital networks frequently update their patient visit guidelines. PRA’s real world evidence teams will continue to bring key insights in this significant trend of telemedicine visits across all facets of care – patients, physicians, indications, billing.
- Total prescription activity continues to report under prior year thresholds as August comes to a close. New prescription uptick continues to display even slower recovery rates
- Despite a 0.9% lift in retail activity with week ending 8/28/2020, overall trends continue to report under regular thresholds. Mail Order continues to stay just above normal reporting levels
COVID-19 Patient Cohort tracking was enabled through collaboration between the PRA Medical Informatics team and PRA’s Symphony Health Division. Big data management and analytics is core to Symphony Health’s mission. We use data to create solutions for virtually any business that needs to answer questions about the various aspects of a patient health journey. Symphony’s data is also frequently leveraged to show the impact or influence of any constituent on that journey, including payers, providers, labs, hospitals, medical offices, advertising, and pricing.
Symphony maintains one of the largest integrated repositories of healthcare data, known as the Integrated Dataverse (IDV®). Then, analytics teams make that data work for our clients. The Integrated Dataverse (IDV®) is a foundational component of PRA’s Big Data capabilities as the most comprehensive longitudinal source of healthcare data in the industry. Medical, hospital, and prescription claims across all payment types come together with point-of-sale prescription data and non-retail invoice data as a comprehensive base, which is enhanced with diagnostic, lab and registry data, demographic and affiliation data, and electronic health record data to build a complete health picture of each de-identified patient.
IDV offers a consistent market view across prescriber, payer, and patient dimensions. With specific views and tools, and exclusive adjustments for products that are abandoned at the pharmacy, IDV® answers key questions and facilitates critical insights into healthcare transactions to enable outcomes research, commercial strategies, and managed markets planning. A hallmark of this data platform is its always on, instant access to over 80 therapeutic areas covering the most important classes for pharmaceutical manufacturers. IDV® combines different facets of information to build a complete picture of any given health event, offering true integration across all dimensions to enable critical insights for the PRA organization and the clients we support.
Brexit and Clinical Trial Applications
The United Kingdom (UK) formally left the European Union (EU) on 31st January 2020. There is currently a transition period until 31st December 2020, which no longer has the possibility of being extended. During the ongoing transition period, the UK is following EU rules. At the end of the transition period, the UK will no longer be part of the customs union or EU single market in its current form. Perhaps coverage of Brexit in 2020 has been quieter than anticipated due to COVID-19, but it is important that preparations continue with the aim of limiting the impact of Brexit on clinical trial activities.
Rules for the future relationship and a trade deal are under discussion, but it is still uncertain whether or not there will be a deal between the UK and EU. Again, it is not possible to wait until EU-UK talks are concluded to take action. PRA’s Brexit taskforce has been leading a team of functional area leads in preparing for a ‘no deal’ Brexit scenario, and PRA’s GRCS team has supported activities for many Sponsors who are making changes and submitting amendments in preparation for the end of the transition period.
In this article, we will focus on Brexit-related clinical trial application considerations for the EU and UK. Those working in the field of clinical trials are reminded to consider the impact and risks of Brexit at the study level and take any final required measures as the end of the transition period approaches.
Clinical Trials in EU
There are several potential impacts of Brexit on clinical trials in the EU, and a pertinent reference will be summarised here:
The European Commission issued a revision to the notice titled ‘Withdrawal of the UK and EU rules in the field of clinical trials’, on 7 May 2020. The notice reiterates that after the transition period ends, EU rules in the field of clinical trials (and in particular Directive 2001/20/EC) no longer apply to the UK, and as such several actions may be required for trials ongoing in the EU.
In summary, the advice is to:
Ensure establishment of the Sponsor or the legal representative in the EU
The Sponsor of a clinical trial or a legal representative (LR) must be established in the EU. After the end of the transition period, a Sponsor established in the UK or outside the EU, and conducting a clinical trial in the EU has to ensure that a Sponsor or a legal representative is established in the EU. The change of the Sponsor or of the Sponsor's legal representative is typically a substantial amendment, which requires submission to RAs and ECs and should be planned accordingly. Failure to meet this requirement of having Sponsor or LR in the EU would be a breach of Directive 2001/20/EC and could trigger a request for corrective actions by RAs.
Adapt distribution channels, to take importation requirements into account
Import of investigational medicinal product (IMP) into the EU requires the holding of an importer’s authorization, which is also required even if only part of the manufacturing is performed in a third country (i.e. a country that is not a member of the EU). The holder of this authorization must have at least one Qualified Person (QP) located in the EU. After the end of the transition period, these rules will apply to IMPs imported from the UK into the EU. Sponsors of all ongoing trials need to establish a QP in the EU, and failure to do so could in the worst case result in discontinuation of trial treatment and thus jeopardise trial participants’ safety. Therefore, for any trials that include EU countries and may still have QP release in UK, follow up action should be taken now.
The European Commission’s notice also includes information on changes to protocol-related and results-related information being submitted to the EU clinical trials database EudraCT, which should be taken into account when working on these activities.
Relevant separation provisions in the UK-EU Withdrawal Agreement (a 600-page legal document) are also outlined, and this document points out that ‘an existing and individually identifiable good lawfully placed on the market in the EU or the UK before the end of the transition period may be further made available on the market of the EU or of the United Kingdom and circulate between these two markets until it reaches its end-user.’ “Placing on the market” means the first supply of a good for distribution, consumption or use on the market in the course of a commercial activity, and there may be studies in which this provision comes into play (e.g for IMP supply from the UK to an EU country).
Two complicating factors in Brexit have been in the geography of the UK and the island of Ireland. Because Ireland (IE) is an EU member state and has a land-border with Northern Ireland (NI) (which is part of the UK), there has been a separate Protocol on Ireland/Northern Ireland prepared, which is initially in place for four years. The IE/NI protocol means that certain parts of EU law will be applicable in NI, and the EU and the UK have agreed that insofar as EU rules apply to and in the UK in respect of NI, NI is treated as if it were an EU Member State. This means that in NI Article 13 of the Clinical Trials Directive 2001/20/EC applies and as such:
- EU rules for Good Manufacturing Practice of IMPs apply in NI
- IMP manufactured in NI and shipped to EU is not considered an imported IMP
- An IMP shipped from Great Britain (the UK minus NI) to NI is considered an imported IMP
- The QP for EU may be established in NI.
The IE/NI Protocol excludes the possibility for NI to participate in the decision-making and decision-shaping of the EU, or invoke the country of origin principle or mutual recognition, meaning an official IMP batch released in NI is not recognised in the EU; however, the batch release by a QP of an importer/manufacturer established in NI is recognized in the EU.
Lastly, the notice points out that other topics for consideration in relation to clinical trials are covered in other notices, and whilst not an exhaustive list, the below references may be of further interest:
- EU rules on personal data protection
- Medicinal products that are not investigational medicinal products
- Substances of human origin (blood, tissues and cells, organs)
Clinical Trials in UK after The Transition Period (i.e. from 1 January 2021)
The UK Regulatory Authority, the MHRA, issued new guidance on 1 September 2020 on clinical trial authorisations from 1 January 2021. The UK, at least initially, will be continuing to recognise activities conducted within the EU, and some key UK considerations are outlined below.
The UK will require the sponsor or legal representative of a clinical trial to be in the UK or country on an approved country list, which would initially include EU/European Economic Area (EEA) countries. Separate registration of a UK contact point, which was initially requested, is understood to not be required.
Manufacturing / QP-Certification
The MHRA previously confirmed that the UK will recognise QP certification done in an approved country (which would initially include all EU/EEA countries). The IMP supply chain from a country on the approved country list (initially including EU/EEA countries), will allow direct supply to clinical investigator sites.
If there are changes (addition/replacement) of any IMP manufacturing, importation or certification site relevant for supply of IMP to an ongoing UK trial, a substantial amendment will be required. However, if an existing UK IMP release site is maintained for an ongoing UK trial but an additional EU/EEA site is needed for trials ongoing in EU/ EEA only, then a substantial amendment would not need to be submitted to the MHRA (but to the concerned EU member states).
Informed Consent Forms (ICFs)
The UK Health Research Authority (HRA) had confirmed that ICFs do not need to be updated to remove reference to EU Law or to revise terminology related to the General Data Protection Regulation (GDPR).
Voluntary Harmonisation Procedure (VHP)
The UK can no-longer participate in VHP.
The MHRA has issued guidance on 1st September 2020 on Importing Investigational Medicinal Products (IMP) from countries on a list to Great Britain which should be referenced by those involved in this process. Of interest, there will be a one-year transition period from 1 January 2021 to implement some of the requirements outlined in the guidance.
There is information published at the EU level and by individual Member States on planning for the end of the transition period. Various EU Regulatory Agencies continue to include reminders on Brexit preparedness in their communications and publish information on their websites. With less than four months to go until the end of the transition period, now is the time to have a final push on Brexit preparations at the study level and ensure that appropriate planning is in place.