Good Clinical Practice (GCP) audits sit at an uncomfortable intersection: they are simultaneously the least visible and most consequential quality activity in a clinical trial’s lifecycle. A sponsor’s internal audit program rarely makes headlines, but its absence — or its shallowness — tends to surface unmistakably the moment a regulatory inspector walks in. Between 2017 and 2023, the FDA completed 2,836 review-based routine GCP inspections in support of Center for Drug Evaluation and Research (CDER) marketing applications alone, with 81.2% resulting in a final No Action Indicated (NAI) classification, 18.5% Voluntary Action Indicated (VAI), and 0.3% Official Action Indicated (OAI).

Encouragingly, the proportion of inspected establishments that were issued a Form FDA 483 fell steadily over that period — from 23.5% in 2017 to 10.4% in 2023 [1]. That downward trend tracks with an industry that is auditing itself more rigorously before regulators arrive, rather than treating inspection readiness as a fire drill. This piece sets out what a GCP audit actually examines, where audits and inspections most often surface trouble, and a practical, checklist-driven approach to preparation — updated for the ICH E6(R3) guideline that came into effect through 2025 and 2026.

Audit vs. Inspection: A Distinction Worth Keeping Straight

The terms get used loosely, but the mechanics differ. A GCP audit is a systematic, independent review conducted by or on behalf of the sponsor — typically by a dedicated quality assurance (QA) function or a specialist CRO partner — to verify that trial-related activities and documentation comply with the protocol, applicable standard operating procedures (SOPs), GCP, and regulatory requirements. It is a sponsor-controlled, proactive exercise. A regulatory inspection, by contrast, is conducted by a competent authority — the FDA’s Bioresearch Monitoring (BIMO) program, the EMA and its member-state inspectorates, MHRA, PMDA, Health Canada, or others — and its findings carry direct regulatory consequences for a marketing application or an ongoing trial.

Monitoring is a third, related but distinct activity: it is the ongoing, trial-level oversight of site conduct and data, usually performed continuously rather than as a periodic systems check. Audits sample across monitoring, site, vendor, and TMF performance to test whether the oversight system itself is working — which is precisely what an inspector will also be testing, just with more at stake.

The Regulatory Backbone Behind GCP Audits

ICH E6(R2) has functioned as the baseline international standard for GCP since 2016, and most current SOPs, audit checklists, and CRO quality systems are still built on its structure. That baseline has now been substantially updated. The ICH adopted the revised guideline, ICH E6(R3), in January 2025; the EU’s overarching principles and Annex 1 came into effect on 23 July 2025 following CHMP adoption, and the FDA issued its final Level 1 guidance implementing E6(R3) on 9 September 2025.

A second component, Annex 2 — covering pragmatic and decentralized trial designs and the use of real-world data — reached ICH Step 4 in June 2026 and CHMP adoption later that month, with an EU effective date of 15 January 2027 [2]. For sponsors and CROs running multi-region trials, that staggered timeline means audit programs need to accommodate two overlapping GCP frameworks for some time yet.

The E6(R3) revision does not replace the core GCP principles so much as re-weight how compliance is demonstrated. It formalizes a proportionate, risk-based approach to quality management — often shorthanded as “Critical-to-Quality” (CtQ) factors — and puts new emphasis on documented rationale: sponsors are expected to keep clear records of the decisions, risk assessments, and reasoning behind their oversight approach, not just evidence that oversight happened. Training requirements now explicitly extend to personnel at CROs, sites, and other service providers, not solely sponsor staff. Auditors should expect these expectations to appear in inspection checklists well before every annex is finalized, on a region-by-region basis.

Cross-agency collaboration also shapes what “audit-ready” means in practice. FDA and EMA have jointly conducted GCP inspections since 2009, and the two agencies’ inspection programs continue to feed a shared body of findings through mechanisms such as the GCP Inspectors Working Group (GCP IWG). Sponsors preparing for a single-agency inspection are, in effect, preparing against a broader, harmonized set of expectations.

Where Audits and Inspections Actually Find Trouble

Preparation is most effective when it targets where deficiencies actually cluster, not where an audit program assumes they will. A comparative analysis of 49 concurrent FDA and EMA inspections found that for FDA, the most common findings were Protocol Compliance issues at clinical investigator sites and Trial Management issues at sponsors and CROs; for EMA, Documentation deficiencies — including Trial Master File (TMF) gaps — were the leading finding category at both site and sponsor/CRO level.

Concordance between the two agencies was high: roughly 90% agreement on Protocol Compliance and Trial Management findings, and about 70% agreement on Documentation findings [3]. More recent data reinforces the same pattern. An analysis of the 2025 GCP IWG report found that inspections concentrated in the EU/EEA (34%), Asia (28%), and North America (18%), with investigator sites accounting for 69% of inspections and sponsors 25%; General, Trial Management, and Investigational Site findings were the top three categories, with recurring gaps in documented delegation of duties to service providers and in direct-access provisions for source records [4]. At the site level, failure to follow the investigational plan or protocol remains the most-cited category across FDA clinical-investigator inspections, followed closely by inadequate source documentation and informed consent deficiencies [5].

Deficiency category	Most common at FDA inspections	Most common at EMA inspections
Protocol compliance	Leading finding — clinical investigator (CI) sites	High concordance with FDA (~90%) but secondary to documentation
Trial management	Leading finding — sponsor/CRO inspections	High concordance with FDA (~90%)
Documentation / TMF	Present, ~70% concordance with EMA	Leading finding — both CI and sponsor/CRO inspections
Source documentation & informed consent	Second and third most cited at CI sites	Consistently among leading critical/major findings

A Practical GCP Audit Preparation Checklist

The checklist below is organized by the domains in which FDA and EMA data show findings are concentrated. It is written as a pre-audit self-verification tool — the questions a sponsor’s QA function, or an outsourced audit partner, should be able to answer with documented evidence before scheduling either an internal audit or anticipating a regulatory inspection.

Domain	Verify before the audit	Evidence to have on hand
Trial Master File	The TMF structure follows the TMF Reference Model; essential documents are complete, dated, and version-controlled; and the TMF is reconciled against the trial timeline, not just a filing checklist.	TMF completeness/health-check reports; open-item log with owners and target dates.
Protocol compliance	Protocol deviations are logged, categorized by severity, and supported by evidence of root cause analysis and CAPA — not just recording.	Deviation log with trending; CAPA tracker; amendment history.
Informed consent & source documentation	Current IRB/EC-approved consent versions are in use at every site; source data is attributable, legible, contemporaneous, original, and accurate (ALCOA); source-to-CRF traceability spot-checked.	Site-level consent version tracker; source data verification (SDV) sample results.
Trial management & oversight	Sponsor oversight of delegated tasks is documented with a clear rationale, not assumed; risk assessments that drive monitoring frequency are current and align with the CtQ approach under E6(R3).	Risk assessment and monitoring plan; oversight meeting minutes; escalation records.
Vendor & delegation contracts	Written agreements specify exactly which duties are delegated to each CRO/vendor and confirm the sponsor retains ultimate legal responsibility; direct-access-to-source clauses are present.	Signed task-delegation logs; vendor qualification and oversight files.
Computerized systems & data integrity	Electronic systems are validated per applicable guidance; audit trails are complete and reviewed; access controls and e-signature workflows are current.	System validation summary; audit-trail review logs; access-control records.
Training & GCP currency	Training records cover sponsor, CRO, site, and service provider personnel — not sponsor staff alone — and reflect the current ICH E6(R3) content.	Training matrix with completion dates and course versions.

What ICH E6(R3) Changes About Audit Readiness Going Into 2027

Three shifts under E6(R3) are worth building directly into 2026 audit programs rather than treating as a future compliance project:

• Proportionality has to be documented, not just applied. Auditors and inspectors alike will look for a written record of why a given level of monitoring, data verification, or oversight was chosen for a given trial element — the CtQ rationale itself becomes an auditable artifact.
• Training obligations extend across the outsourcing chain. Sponsors are expected to ensure GCP, protocol, and role-specific training for personnel at CROs, sites, and service providers, which shifts training records from a nice-to-have vendor-file item to a core audit checkpoint.
• The framework will remain a two-track system for a while. With Annex 2 not taking EU effect until 15 January 2027, audit checklists covering decentralized elements, pragmatic designs, and real-world data sources need to satisfy both the current baseline and the incoming annex, particularly for trials that will still be active when it lands.

None of this replaces the fundamentals. Protocol compliance, source documentation, informed consent, and TMF completeness remain — by a wide margin — where both FDA and EMA findings concentrate. E6(R3) changes how sponsors are expected to justify and evidence their oversight decisions around those fundamentals, not the fundamentals themselves.

Where Specialist Oversight Fits

The global clinical trial support services market — encompassing the monitoring, quality, and operational functions that audits ultimately test — is projected to grow from roughly USD 28.1 billion in 2025 to USD 42.0 billion by 2031 [6], a trajectory that reflects sponsors’ increasing reliance on outsourced partners for exactly the oversight functions inspectors scrutinize most. That makes the choice of CRO partner and the rigor of its quality system inseparable from a sponsor’s audit readiness. A CRO whose SOPs are already mapped to ICH E6(R3), whose TMF practices follow the TMF Reference Model, and whose delegation contracts are audit-tested in advance shortens the distance between an internal audit finding and a closed CAPA — and, ultimately, between a routine inspection and a clean one.

Frequently Asked Questions

How often should a sponsor conduct GCP audits during an active trial?

There is no single mandated frequency — ICH E6(R3) calls for a proportionate, risk-based approach. In practice, most sponsors schedule at least one system-level audit (of the TMF, vendor oversight, and data management) early in a trial, plus periodic site and vendor audits keyed to enrolment milestones, risk indicators, or protocol amendments, rather than a fixed calendar.

What is the difference between a critical, major, and minor audit finding?

Severity classifications vary slightly by framework, but broadly: critical findings indicate a direct risk to participant safety, data integrity, or regulatory compliance and typically require immediate corrective action; major findings reflect a significant deviation from GCP or the protocol that could affect trial conduct or data reliability; minor findings are isolated, low-impact deviations that still warrant correction and trending.

Does a sponsor audit replace the need to prepare for a regulatory inspection?

No. A well-run audit program reduces the likelihood and severity of inspection findings by catching and correcting issues in advance, but it does not substitute for inspection-specific readiness activities such as mock inspections, inspection response planning, and designated spokesperson training.

How does the TMF Reference Model relate to GCP audit findings?

Because Documentation and TMF completeness are consistently among the top deficiency categories — the leading category at EMA inspections specifically — structuring the TMF around the TMF Reference Model gives auditors and inspectors a predictable, navigable filing structure and makes gaps easier to identify and close before they become findings.

Who should conduct a GCP audit — an internal QA team or an external partner?

Either can be appropriate, and many sponsors use both. Internal QA teams bring institutional context; independent external auditors bring a perspective closer to what a regulatory inspector will apply and are especially valuable for sponsors without a large in-house quality function or for auditing a CRO partner’s own performance.

About AICROS

The Association of International CROs (AICROS) is a global alliance of specialist, small- to midsize contract research organizations headquartered in Bremen, Germany. AICROS member CROs deliver specialist-led service with multinational reach across six core service lines: biostatistics, clinical operations, data management, medical writing, pharmacovigilance, and regulatory affairs — giving sponsors access to focused expertise without sacrificing the coordinated, multi-region delivery larger CROs offer.

To discuss GCP audit readiness, quality system design, or clinical operations support for an upcoming trial, contact the AICROS team at info@aicros.org.

References

[1] A 7-Year Analysis of the U.S. FDA Good Clinical Practice Inspection Outcomes for Marketing Applications — NCBI/PMC

[2] ICH E6 Good Clinical Practice — Scientific Guideline, European Medicines Agency

[3] Descriptive Analysis of GCP Inspection Findings from FDA and EMA — NCBI/PMC

[4] New Insight into Risk Mitigation in 2025: An Analysis of the GCP IWG Report — Florence Healthcare

[5] Common GCP Violations & How to Avoid Them — CASRAI

[6] Clinical Trials Support Services Market Size & Share — Mordor Intelligence

Additional guidance referenced: E6(R3) Good Clinical Practice — FDA Guidance for Industry

If you’ve spent any time around drug development, medical device programs, or clinical trials, you’ve probably heard the term “CRO” thrown around as if everyone already knows what it means. For sponsors evaluating outsourcing for the first time, though, the term can hide a lot of important nuances — and the decision of whether and how to bring one on board can shape a program’s timeline, budget, and regulatory standing for years.

A contract research organization (CRO) is a company that provides research, clinical trial management, and related services to pharmaceutical, biotechnology, and medical device companies on a contracted basis. Rather than an in-house sponsor team handling every function of drug development itself — from statistical design to regulatory filings to safety monitoring — sponsors engage a CRO to execute some or all of that work. The global CRO services market reflects just how central this outsourcing model has become: it’s projected to reach roughly US$93–100 billion in 2026, expanding at a compound annual growth rate of about 8–9% through the early 2030s.

Why the CRO Model Exists

Drug development is expensive, slow, and unforgiving of mistakes. The Tufts Center for the Study of Drug Development estimates the average out-of-pocket and time cost of bringing one new prescription drug through approval at roughly US$2.6 billion, and only about 12% of drug candidates that enter clinical trials ultimately win approval. Against that backdrop, few sponsors — especially small and midsize biotech and device companies — can justify building and maintaining full in-house teams for every specialized function a trial requires.

CROs solve this by pooling expertise across multiple sponsor programs simultaneously. A biostatistician, a pharmacovigilance officer, or a regulatory affairs specialist working inside a CRO builds depth of experience — across therapeutic areas, geographies, and regulatory frameworks — that would be difficult and costly for any single sponsor to replicate internally. That specialization is a major reason the full-service/integrated CRO model held roughly 62% of market share in 2025, even as functional service provider (FSP) arrangements — where sponsors contract for specific functions rather than a whole program — are growing faster.

What Services Does a CRO Actually Provide?

The scope of CRO services varies by provider, but most cluster around a similar core set of functions across the drug and device development lifecycle:

• Clinical operations — trial design support, site selection and management, patient recruitment, and multinational study coordination.
• Biostatistics — statistical analysis plans, sample size and power calculations, and interim and final analyses.
• Data management — electronic data capture, CDISC-standard data mapping, and database lock and validation.
• Medical writing — protocols, clinical study reports, investigator brochures, and regulatory submission documents.
• Pharmacovigilance — adverse event monitoring and reporting aligned to frameworks such as ICH E2B(R3)/E2C(R2) and EMA GVP Modules.
• Regulatory affairs — submission strategy, agency correspondence, and compliance with frameworks like GCP, GVP, and device standards such as ISO 13485.

Some sponsors need all of these under one roof for a single program; others need targeted support in just one or two areas while their internal team handles the rest. Both are legitimate ways to use a CRO — which is part of why choosing the right model matters as much as choosing the right provider.

CRO by the Numbers

A snapshot of the data shaping outsourcing decisions across the industry in 2026:

Metric	Figure
Global CRO services market, 2026	~US$93–100 billion¹²
Projected market by 2031–2034	US$138–199 billion¹²ⁱ⁰
Market CAGR through early 2030s	8–9%¹²
Full-service/integrated CRO share, 2025	62.2%¹
North America share of global market	38.9%–50.1%¹¹⁰
Average cost to develop one approved drug	US$2.6 billion (out-of-pocket + time costs)¹¹
Share of clinical-trial candidates ultimately approved	~12%¹¹
Retention improvement from decentralized/hybrid trial models	Up to 30%¹

Full-Service Giants vs. Specialized Alliances: Two Ways to Outsource

Large, full-service CROs offer scale: global site networks, in-house laboratories, and the infrastructure to run the most complex multi-region programs. That scale carries a trade-off, though. Sponsors are often one account among thousands, and functional service provider and unbundled sourcing arrangements have been shown to compress traditional full-service margins by 15–20%, a sign of how much pricing pressure and negotiating friction exists at that end of the market.

An alternative model — the one that alliances of small- to midsize CROs are built around — pairs specialized, hands-on teams with the flexibility to scale across borders when a program needs it. Sponsors get direct access to experienced biostatisticians, data managers, and regulatory specialists without routing every decision through multiple layers of account management, while still gaining the multinational reach a single boutique CRO couldn’t offer alone.

Do You Need a CRO? Questions Worth Asking

Not every program needs full outsourcing, and not every sponsor needs the same type of CRO relationship. A few questions tend to clarify the decision:

• Does your team have in-house depth in every function the trial requires — biostatistics, data management, medical writing, pharmacovigilance, and regulatory affairs — or only some of them?
• Will the trial run in multiple countries, each with its own regulatory pathway and language requirements?
• Is your program subject to complex safety reporting obligations, such as EU QPPV requirements or FAERS/EudraVigilance submission?
• Would a large, full-service CRO’s scale outweigh the cost premium and reduced flexibility it typically entails, or would a specialized alliance model better fit your program’s size?

For small and midsize pharmaceutical, biotech, and device companies in particular, the honest answer is usually not “build everything in-house” nor “hand the whole program to the biggest name available” — it’s finding a partner sized and structured to match the program’s actual complexity.

The Bottom Line

A contract research organization exists to enable sponsors to access specialized expertise — in biostatistics, clinical operations, data management, medical writing, pharmacovigilance, and regulatory affairs — without building all of those capabilities internally. Whether you need one, and what kind, depends less on your company’s size than on the complexity of what you’re trying to get approved, and how many regulatory frameworks you’ll need to satisfy along the way.

Frequently Asked Questions

What’s the difference between a CRO and a CMO?

A CRO focuses on research and clinical trial services— including trial design, data management, regulatory submissions, and related functions. A contract manufacturing organization (CMO) focuses on producing the drug or device itself. Sponsors often work with both, but they serve different stages of the product lifecycle.

How much does it cost to work with a CRO?

Costs vary widely based on trial phase, therapeutic area, number of sites and countries, and which services are outsourced versus handled in-house. Sponsors typically request detailed proposals scoped to their specific protocol rather than relying on industry-wide averages, since per-program costs can differ substantially even within the same therapeutic area.

Are small or midsize CROs less capable than large, global CROs?

Not necessarily. Size affects scale and geographic reach, not clinical or regulatory expertise. Alliances of small- to midsize CROs are often formed specifically so member organizations can offer the multinational coordination of a large CRO while preserving the hands-on, specialist-led service model that smaller organizations are known for.

What is a functional service provider (FSP) model?

Instead of outsourcing an entire trial to a single CRO, a sponsor contracts for specific functions — for example, only data management or only pharmacovigilance — potentially across multiple providers. FSP engagements are one of the fastest-growing segments of the CRO market as sponsors look for more granular control over cost and quality.

Do CROs need to be GCP- or GVP-compliant?

Yes. Any CRO conducting clinical trials is expected to operate under ICH Good Clinical Practice (GCP) standards, and any CRO handling drug safety monitoring is expected to follow Good Pharmacovigilance Practice (GVP) frameworks, such as those set by the EMA. Sponsors should confirm a CRO’s compliance history and audit record before engagement.

About AICROS

The Association of International CROs (AICROS), headquartered in Bremen, Germany, is a global alliance of small- to midsize contract research organizations working together across biostatistics, clinical operations, data management, medical writing, pharmacovigilance, and regulatory affairs. By connecting independent, specialist-led CROs across borders, AICROS gives sponsors the multinational reach of a large CRO network alongside the direct, experienced-led service that smaller organizations are known for. For more information about AICROS member services, contact info@aicros.org.

Sources

1. Mordor Intelligence — Contract Research Organization Market Size Report, 2026
2. MarketsandMarkets — Contract Research Organization Services Market Report, 2026–2031
3. Coherent Market Insights — Contract Research Organization Market Forecast, 2026–2033
4. International Council for Harmonisation (ICH) — Good Clinical Practice (E6) Guideline
5. European Medicines Agency — Good Pharmacovigilance Practices (GVP) Modules
6. Mordor Intelligence — North America Contract Research Organization Market Report, 2026
7. AICROS member survey and internal project data, 2025–2026
8. Fortune Business Insights — Contract Research Organization (CRO) Services Market, 2034
9. Tufts Center for the Study of Drug Development — Cost to Develop and Win Marketing Approval for a New Drug

There will always be patients requiring innovative treatment solutions, which at times may not be able to wait for COVID-19 to subside. For those cases, we would like to see clinical research continuing as best as possible at a normal pace, which is not always easy, of course.

CROs are key in this process and we think our perspective will help to have a better picture of how COVID-19 is affecting and will affect Clinical studies.

The main challenges we have faced as CROs

In Ongoing trials:

We have lived in a very dynamic environment. There has been an increase in the use of online communication tools and an uptick in virtual team meeting to make sure that everyone is on the same page.

We were used to remote practices on operational tasks, but we have had to adapt all our business activities to a remote model.

Patient participation in the studies. The lack of patients was an issue for some trials and recruitment was directly on hold for many others.

It has been also a challenge for patients and our people to comply with COVID-19 regulations that, moreover, were constantly changing.

Responsiveness and availability of site staff has been rather limited for a lot of our trial sites, limiting traditional data verification options and delaying clinical trial progress. Most of this could be counteracted by increasing the amount of remote and centralized monitoring.

In those cases where onsite was preferable, like close out visits, travel to sites was subject to restrictions and had to be rescheduled.

Regarding new trials:

Fundraising for new research projects has been limited worldwide.

Many sponsors were hesitant to start new clinical trials, mainly because it was unclear how COVID-19 might impact ongoing trials.

Travel to sites has been limited for study start-up, site assessment and site initiation visits. Many of them have been cancelled or postponed due to lockdowns.

The information was changing so instruction from local regulatory bodies and sponsors has been unclear.

Some of the measures we have introduced in our procedures for running clinical trials in the context of the pandemic

Business Contingency Plans for clinical trials, that covered all facets of impacts that COVID-19 could have on clinical trials from availability of RA/EC for approval processes, to IMP/IMD shipments, availability of sites for on-site visits, how to handle patients that are on medication but cannot see the study site, to the need to adjust the statistical analysis or submit a protocol amendment to deal with the changes. It is very important that all this information is available for both our Project Management team and the Sponsor’s team.

Working with sites and clinics to implement virtual monitoring visits using electronic medical records and CRFs

CRA safety precautions, COVID-19 test before visiting a site.

Much more remote communication and increasing the number of remote visits.

Changes we have lived that are here to stay:

A lot of traditional monitoring techniques have not been conducted during the crisis, and remote and centralized monitoring techniques have played a much bigger role. On-site monitoring will be combined with remote monitoring as well as conducting virtual monitoring visits to minimize the cost of travel.

We remain hopeful that this change will persist, and that more and more authorities approve these procedures and more sponsors decide to move in this direction. Studies have shown that this results in improved data quality, and it can end up saving time and money that is otherwise spent on travel to the sites and performing Source Data Verification (SDV).

Additionally, we have seen home-sampling of laboratory samples employed – which can greatly improve the satisfaction of the patient. However, it may only be useful in niche trials and will likely remain irrelevant for the majority of clinical trials. Lastly, we have lived a more frequent use of e-signatures, opened up conversations with Regulatory bodies and e-Consent.

Digitalization of most of our activities was being completed before this situation started, and now it has been accelerated and we are pretty sure that, in a very near future, complete e-trials will be developed and we will find that results will be equally valid and patients will benefit from the results of that research.

Our experience with COVID studies

At the moment there are almost 4.000 studies related to COVID-19 on clinicaltrial.gov database and as CROs we have had the opportunity to be part of some of them.

If you want to know more about global clinical investigation on Coronavirus and its evolution , you can read our in depth analysis that is updated every month in our Coronavirus research post.

We highlight also that they have been conducted in a very wide range of geographic areas.

Although we have made use of the shortened regulatory paths that have been put in place by the regulatory authorities of many countries, we have so far seen limited impact on the studies we tried to conduct, and other trials going into the submission process have not been impacted. You can see more about this in this post.

How do we see the future of clinical trials?

We have all heard that crisis can also bring opportunities. In this case, COVID has helped us to glimpse possible trends in the future of outsourcing clinical trials.

Global clinical trials

COVID-19 has shed a light on the need to centralize clinical trials throughout the world and share this information to work together in order to advance together.

Remote monitoring

The coronavirus crisis has just speed up the trend and on-site monitoring will be reduced in the future

Patients’ visits remotely

Much more reliability on technologies that make people open to run not only monitoring but also Patients’ visits remotely.

Digital solutions on Monitoring

The use of electronic solutions not only on traditional activities such as Source Data Verification (SDV), but also Trial Master File (TMF), Site management, Investigator Site File (ISF) and even the consent procedure and Patient Reported Outcome (PRO) have shifted into focus for potential available electronic solutions.

Some of them can be seen as rather wide-spread but there is a lot of room for growth and development in the clinical research world.

We strongly believe that this is the right path to take, and that COVID-19 has accelerated change in this direction by forcing Sponsors, Sites and CROs alike to adapt.

In recent years, Israel has morphed into an emerging and preferred destination for clinical trials, offering high-standard research and medical expertise, a diversified population and short, simple regulatory approval pathways, and relatively low administrative costs.

Bigrange of geographical regions and climates

The country’s 22K km² covers a broad range of geographical regions and climates, with three densely populated central metropolitan areas.

Its 9 million-large, demographically diverse population, includes a spectrum of ethnicities and sociocultures, immigration histories and living settings.

The accumulated knowledge and experience in familial genetic disorders unique to the region and/or ethnic groups serves as fertile ground for a variety of personalized medicine-oriented programs.

Recruitment potential is further enhanced by high patient awareness of the importance of medical research and motivation to contribute.

Healthcare services are provided through a compulsory medical insurance plan, implemented by four, non-for-profit Sick Funds, and 11 publically owned hospitals, seven of which are Joint Commission-accredited. Its public clinics, and hospital and infant-care facilities are equipped with state-of-the-art, advanced technologies and professional personnel trained at internationally renown local or foreign medical institutions.

The comprehensive, high-quality and efficient medical databases managed by each institution, contain critical data of highest value for epidemiological studies and retrospective chart analyses, and ensure accurate and tight monitoring during prospective trials.

The country’s clinical trials legislation is harmonized with EU standards

All ethics committees demand well-controlled trials, on par with all of the most updated international policies (ICH, GCP), which undoubtedly stands at the root of its long-standing history of satisfactory FDA audits.

Clinical trial players, such as start-up companies and clinical research organizations, nurture close ties with the Israeli Ministry of Health, and are well versed in the local and international regulations and policies.

Supported by physicians and researchers

The clinical trial infrastructure is supported by physicians and researchers with extensive experience with multi-center, multi-national studies, alongside highly skilled and designated study coordinators, regulatory specialists and sub-investigators.

Overall, the highly competitive local arena, drives clinical trial professionals to commit to the highest standards and to regularly participate in continued education enrichment courses.

Patient recruitment is generally smooth and well organized, and is often supported by highly active rare disease societies and non-for-profit organizations, which keep abreast with ongoing research and trials.

Moreover, the relatively small geographical area, generally requiring no more than a two-hour drive to collaborating facilities, simplifies monitoring and sample shipping procedures, while minimizing administrative costs.

Regulatory approval paths are relatively short, with the option of parallel submission to the institutional Helsinki Committee (IRB) and Regulatory Authority, the Israeli MOH.

In addition, contract-related negotiations can be initiated in parallel to Helsinki submission, further shortening time to trial initiation.

As a country with ongoing international collaborations in all disciplines, most professionals are well versed in the English language and all trial-related documents can be prepared and submitted in English, with only patient-facing documents requiring translation to the three leading spoken languages (Hebrew, Russian and Arabic).

AICROS, the alliance of International CROs, is a network of local & well established CROs businesses providing full range clinical research services on a global scale. If you are planning your Clinical Trial in Israel or need local help, AICROS team is here to help. Call +972 52 4532325  or email us on info@aicros.com

We are living in a transition period in relation to the data collection for clinical trials. The trend is that paper-based data collection is replaced more and more by Electronic Data Capture (EDC).

In this article we will point out the advantages of EDC and what to take into account when selecting an EDC system.

EDC systems growth

According to Thomas Kirssner, an expert on data management, using an electronic data capture system is similar to online banking.

Not that long ago, it was normal to spend the whole morning queueing at your bank office, and without smartphones to keep us entertained!

Nowadays, most bank transactions can be completed directly from your smartphone in only minutes. It was scary at the beginning and most people were reluctant to do it, but more and more we are now trusting online banking.

The same can be said for EDC systems, we are getting used to them but there is still a long way to go.

Proof of this is that there is still around 25% of paper based CRFs and many people have reservations with regard to the electronic model.

eCRF versus Paper CRF

When comparing paper based CRF with eCRF, the differences are huge:

Paper CRFs have a lower learning curve, however, they require more investment in the data treatment and monitoring.

eCRFs have a higher learning curve and also a higher investment when starting a clinical study (mainly licenses and training), however in the mid and long term, they save time and money as a result of the improved of data quality.

Another advantage is that the slope of the curve is decreasing as EDC systems are becoming more competitive and investigators are becoming more used to them, so the learning time is also reduced.

Types of EDC systems

There are some basic features that all EDC systems have: data storage, open patient records and audit trails.

EDC systems also add value by:

• Offering the ability to remotely review and clean data.

• Enabling the identification of risk such as serious adverse events to the project manager or to any other party involved.

• Having a system that can interconnect all the different electronic data sources: eCRF, electronic randomization tools, drug supply management, central labs and ePRO (usually data is stored separately and is unified manually with the risk that data errors can be caused by manual data handling).

How to choose an EDC system

Your EDC system should serve you. If you need to take care of it, you should probably change it.

As there is a wide range of prices for EDC systems, the first thing you should do is evaluate what you need at a trial level and the allocated budget.

Next, list what do you expect and see what systems can provide your needs. After that, you just select a reliable service provider as a partner. And remember, the goal is to conduct the study the best way possible, not to have the best EDC system.

The new Medical Devices Regulation 2017/745 (MDR) was supposed to take full effect in Europe by mid-2020, being a fundamental revision of existing Medical Device Directive 93/42 EEC (MDD) and Active Implantable Medical Devices Directive 90/385/EEC (AIMD); following the SARS-CoV-2 outbreak in Europe, on April 23rd 2020, the EU legislator published an amendment to the EU MDR (Amending Regulation), postponing the application of most of its provisions by one year, until May 26th, 2021.

The aim of the MDR is to establish a robust, transparent, predictable and sustainable regulatory framework for Medical Devices (MDs) including combinations of MDs with In Vitro Diagnostic (IVDs) Medical Devices and/or Medicinal Products across EU member states.

All new MDs deemed to be placed in the EU member states market will have to conform to the requirements of the MDR by the end of May 2021 on.

There are 15 key major changes in the MDR versus the previous regulatory framework defined by the MDD:

• The MDR, as a regulation, carries mandatory jurisdiction that is directly applicable and enforceable in all EU Member States, while the directives are just legislative frames that set out the rules which must then be transposed into national legislation in order to become effective.

• The new regulation is four times outstretched in number of pages and number of articles and has five more annexes than its predecessor, the MDD.

• There is a big emphasis on patient’s health and safety outlined in the MDR, the word "safety" appears 290 times in the MDR, while the MDD uses it only 40 times, moreover the MDR introduces provisions for transparency and MD traceability in order to improve health and safety.

• MDR requires MDs manufacturers to rationalize their portfolios and perform a global impact assessment in order to implement the necessary compliance changes.

• Outlines new conditions that will need to be addressed for most CE marked MDs under the MDD. Devices which were lawfully placed on the EU market pursuant to MDD or AIMD prior to MDR date of application may continue to be made available until end of May 2025 – if the manufacturer fulfils the specific requirements drawn in the MDR; this means that MD Companies subject to transition will need to review their processes including the quality assurance, risk management and post-market product outlook. This requires a conscientious planning, implementation and review in strict compliance with the MDR.

• The MDR sets out the regulatory obligations of economic operators as it require most MD companies to update their technical documentation, clinical data and labeling ( for instance the Unique Device Identification (UDI) has to be implemented in order to to enable global device traceability throughout the entire MD manufacturer supply chain , UDI should be shown on all labels).

• The scope of medical device is broadened, covering both devices for specific medical purposes alongside devices without medical purpose such as non-medical and cosmetic devices (which previously were not regulated). For instance products for cleaning, disinfection or sterilization of devices as well as devices for the purpose of control or support or conception, hair removal lasers, liposuction equipment and contact lenses are regulated throughout the MDR.

• The MDR provides new classification rules for software (classified into classes I, IIa, IIb or III depending on the intended use of the software and a risk profile) while the software itself is considered an active medical device; also regarding software the MDR introduces the concept of interoperability to devices including software, as the ability to exchange information and use the information that has been exchanged for correct execution of specified function without changing the content of the data, and/or communicate with each other, and/or work together as intended.

• Manufacturers will need to generate and provide more in-depth clinical data to prove safety and performance claims including tighter equivalence standards. MDR provides a new understanding of clinical evaluation as being a systematic and planned process to continuously generate, collect, analyze and assess the clinical data to verify the safety and performance of a device when used as intended by the manufacturer, moreover the clinical evaluation report is required for all classes of devices and throughout the product life cycle process.

• The MDR details with greater emphasis the Quality Management System responsibilities: the Legal Manufacturer must provide a person responsible for regulatory compliance (which is a new provision explicitly defined), qualification requirements (specific education, training and experience), Provision for ability to make decision (“shall suffer no disadvantage in relation to the proper fulfilment of his duties …”) and covers responsibilities (conformity of device verified before product release, technical documentation are kept up-to-date, PMS obligations are complied with, etc)

• The MDR sets explicit provisions on manufacturers’ responsibilities for the follow-up of the quality, performance and safety of devices placed on the market. Manufacturers of all devices classes will need to report all incidents, injuries and deaths into an EU portal (Centralized Post Market Surveillance System -PMS) that will centralize data so the and user will have access to safety-related information. The timelines for serious incidents reports is shortened to 15 days from previous 30 days, while field safety corrective actions should be submitted through an electronic system.

• The MDR contains a new centralized database (EUDAMED) for Device registration, Conformity Assessment, Vigilance (incidents and recalls), Universal Device Identifier (UDI), Surveillance Reports, Clinical Investigations, Notified Bodies. MDR/IVDR UDI and device data sets provide for their registration in EUDAMED.

• MDR provides a strict set of general obligations to verify compliance with requirements of Economic Operators which includes the Legal Manufacturer, the EC Authorized Representative, the Importer, the Distributor and the Person who puts together [refer to Article 22 [1] or sterilizes [refer to Article 22[3] system or procedure packs.

• MDR involves also key changes as regards the NBs: as current NB designations will expire with the date of application of the MDR, all NB applicants for MDR accreditation must go through a re-designation process (observing organizational, quality management, resource and processes matters); as a result of re-designation, only few selected NBs will have a scope covering Class III high-risk devices.

• Through the MDR the NB oversight must be observed for reclassification of many medical devices to a higher risk class (for instance a new classification for reusable surgical devices is observed).

The MDs manufacturers should be advised on the onward movement towards the MDR. The MD Manufacturers of already CE certified devices under either MDD or AIMD are strongly recommended to consult their respective NBs in order to evaluate possible compliance issues, to develop a plan for a timely transition towards the MDR and also to perform an assessment of how their current MD portfolio may be impacted by the MDR. This is extremely important as not all MD design changes are anticipated or expected while this fact could likely lead to re-certification under the MDR. Let’s give a practical example: a MD manufacturer receives a new report on adverse event which will trigger a label update; as a consequence the Competent Authority (CA) may request corrective action related to the label change, this CA request will suddenly push the manufacturer forward into the MDR transition.

If you are planning your EU MDR transition or need help on MDR requirements AICROS team is here to help. Call us on: +4917621065564 or email us at: info@aicros.com

Bibliography:

1. Regulation (EU) 2017/745 of the European Parliament and of the Council , April 2017
2. Regulation (EU) 2020/561 of the European Parliament and of the Council of 23 April 2020 amending Regulation (EU) 2017/745 on medical devices, as regards the dates of application of certain of its provisions
3. Factsheet for Manufacturers of in vitro Diagnostic Medical Devices, European Union, Nov 2018
4. WHO Global Model Regulatory Framework for Medical Devices, WHO Technical Report Series, No. 1003, 2017
5. Guide for Clinical Evaluation Under EU-MDR, The FDA group, Mar 2018
6. The New European MDR Harmonization Effort with International Regulatory Requirements for Medical Devices, Stephan Buttron, Mar 2016

Conducting Clinical Studies in Romania and Bulgaria

Why choose Romania and Bulgaria?

Romania and Bulgaria are home to highly competitive cost solutions per patient in clinical research, a unique epidemiological profile leading to a wide range of therapeutic indications, a wide availability of naïve patients, experienced researchers and highly educated health professionals working under regulatory and protocol compliance with good-quality data proved by audits and regulatory inspections, highly concentrated and specialized healthcare service, smooth regulatory pathways following EU regulations and supportive infrastructure.

Population ( potential patient pool )

According to Eurostat1, together the two countries share a population of 27.5 million people, the largest country being Romania with almost 20 million inhabitants, followed by Bulgaria with 7.5 million residents.

Regional economy &  health care system opportunities

 Both countries belong to the EU and NATO, have stable and fast-developing economies, enjoying some of the highest GDP growth rates in the EU:

What makes both countries extremely cost-attractive for clinical trials is that their labor costs are just a fraction of those in Western European countries, which have the lowest GDP per capita rates in the EU.

In terms of the healthcare system, both countries follow a similar path; their healthcare systems are critically underbudgeted while patients have to share an important burden of local healthcare expenditure directly out of their pockets, leading to poor availability of curative means and a high percentage of treatment-naïvepatients:

• Health Spending per capita is the lowest among EU countries:

• In terms of health coverage, Romania and Bulgaria have a large coverage gap versus the Western European countries:

• Direct out-of-pocket payments represent a large stake of the health spending, especially in Bulgaria:

Therefore, all Clinical Trial Programs in Romania and Bulgaria are offering ethical therapeutic means to local patients, while also representing an alternative (sometimes the only) option for patients to access innovative, new-generation molecules and medical devices.

The epidemiological profile of both countries shares similar challenges and offers a direct input regarding the clinical trial opportunities within a wide range of therapeutic indications:

• Smoking among Bulgarian adults is way above the EU average :

• One out of three adolescents across Romania and Bulgaria report having been drunk at least twice in their life:

• Regular heavy alcohol drinking is a big problem in both countries :

• Obesity among the juvenile population has grown significantly over a decade:

• Too many antibiotics are prescribed, particularly in Romania:

Regulatory Environment

Regulatory and legislative reforms follow EU accession; both Romania and Bulgaria have adopted and fully implemented the EU Clinical Trials Directives. Trial start-up times and requirements are comparable with other EU countries: it takes, on average, 60 days since submission to obtain CA and CEC approvals, the regulatory environment being one of the principal reasons behind the important figures of completed and active studies in both countries in 2018 2.

CECs’ work is slightly different in Romania and Bulgaria:

• Romania: For IMP studies with multiple sites, there is a centralized EC to be addressed, yet if a single site is involved, only LEC approval could be obtained.  For MD studies only LECs could be involved.
• Bulgaria: IMPs and MDs follow the same path, meaning a centralized EC is designated for study submission

 In both countries, some (but not all) sites ask for LEC approval, which is much more formal.

The start-up process depends on the duration of contract negotiation between sponsor and study sites and the process is slightly different in the two countries:

• Bulgaria: CEC/CA asks for contract drafts, but the management of some sites need to see the contract drafts first in order to release some documents for CA so , depending on site, contracts are not a burden, but it is good to have them ready upfront at least 45 days prior to CEC/CA submission

• Romania: a single fully executed CTA is needed (out of all the sites subject to CEC submission) while the remaining CTAs should be submitted fully executed forms no later than 45 days post NEC submission; therefore, contracts should be ready for site negotiations 30 days prior to NEC  submission in order to speed up the approval process

Quality:

There is an abundance of high-quality investigational sites in Romania and Bulgaria because the number of teaching hospitals, university clinics and postgraduate medical schools is high. There is a well-established, very high standard of medical education; there are 17 medical university schools in Romania and 5 medical schools in Bulgaria, while the number of university clinics stands at 39 units in Romania and 15 in Bulgaria, with similar infrastructure and state-of-the-art diagnostic capabilities meeting Western standards. More practitioners are employed by teaching hospitals and university clinics compared to the Western European average. GCP guidelines are fully implemented, the GCP training of the investigators is compulsory required by the regulatory authorities in both countries, while GCP refresher is required every second year for all study team members. Overall good regulatory and protocol compliance, with good-quality data (comparable to Western Europe and the US), is certified by audits and inspections.

High recruitment rate:

There are several particularities of the healthcare system that constantly translate into high recruitment rates throughout the region:

• Shortage of available therapy as the national therapy and reimbursement programs  are not able to meet the local needs 
• The insufficient availability (sometimes the total lack) of preventive medicine
• A wide availability of naive patients
• A large heterogeneous patient population
• Availability of multi-specialty medical institutions with highly educated medical personnel and specialized healthcare services
• Patient willingness to participate in clinical trials sponsored by Western companies, patient retention if very good
• Investigators are motivated to take part in clinical trials and perform well, as they largely acknowledge that cooperating with Western pharmaceutical companies in scientific research is a sign of academic distinction, merit, and prestige, while the investigator fees comfortably round up their earnings
• Over 90% of site staff speak English, including study nurses

Logistics and communication:

Our synergistic operations and local know-how covering Romania and Bulgaria facilitate your access to highly specialized & fully trained ICH-GCP investigators that have vast experience in running clinical trials.The site staff (English-speaking investigators in a dense network of healthcare facilities) makes a great deal of efforts to ensure the studies are run according to the protocol and in line with local and international regulations. The guidance provided by CRO’s and sponsors is largely accepted and there is a refreshing willingness to learn and improve practice. 

AICROS, the alliance of International CROs, is a network of local & well-established CRO businesses providing a full range of clinical research services on a global scale. If you are planning your Clinical Trial in Romania and Bulgaria or need local help AICROS team is here to help. Call +4917621065564  or email us at info@aicros.com

REFERENCES:

^1. https://ec.europa.eu/CensusHub2/query.do?step=selectHyperCube&qhc=false

^2. https://clinicaltrials.gov/ct2/search/map?map=EU, data source 30 September 2019

DISCLAIMER:

 This document reflects the opinion of AICROS on the date of publication and subject to the available information, and may be modified at any time. The information, analyses and opinions presented are drawn from multiple sources that were judged reliable and credible. However, AICROS does not guarantee the accuracy, completeness or representativeness of the data contained in this document. The information, analyses and opinions are provided for information only and should be used in conjunction with other information the reader might already possess. AICROS is not bound by an obligation of results but by an obligation of means and shall not be held responsible for any losses incurred by the reader arising from the use of the information, analyses and opinions contained in this document. This document, and likewise, the analyses and opinions which are expressed are the sole property of AICROS. The reader may consult or reproduce them for internal use only and subject to mentioning AICROS as the source; the data may not be altered or modified in any way. The information may not be used, extracted or reproduced for public or commercial purposes without prior permission from AICROS.

30 September 2019                                                                                                 Copyright © AICROS. All rights reserved.

The Association of International Contract Research Organizations (AICROS) is delighted to announce the acceptance of Asymchem Clinical as its newest associate partner. Asymchem Clinical, a leading full-service Contract Research Organization (CRO) with a rapidly expanding global presence, joins our consortium of established, regional CROs dedicated to providing top-tier clinical research services worldwide.

About AICROS

AICROS is a prestigious global consortium of small and mid-sized CROs, committed to delivering personalized, high-quality clinical trial management services across the pharmaceutical, biotech, and medical device sectors. By bringing together experts from CROs around the world, AICROS ensures that our members adhere to the highest international standards while offering tailored solutions that address the unique needs of specialized and emerging markets.

AICROS is uniquely positioned as a worldwide partner in clinical research, with each member committing to a joint quality standard, undergoing regular trainings and members exchanging continuously on experiences with local regulators and how to improve speed of trial execution. Our consortium is built on the principles of collaboration and resource-sharing, enabling smaller and mid-sized CROs to compete with larger global players. Through our collective expertise and international partnerships, AICROS helps members streamline clinical research processes, mitigate risks, and accelerate development timelines, all while maintaining the highest standards of quality and compliance.

Asymchem Clinical: A New Strategic Partner

Asymchem Clinical has earned a stellar reputation for its innovative and comprehensive clinical research solutions, which span early-phase trials to post-market surveillance. With a focus on biopharmaceutical companies, Asymchem Clinical excels in developing unique clinical development strategies, managing complex trials, and integrating cutting-edge technologies, all while navigating diverse regulatory environments across the globe.

As an AICROS associate member, Asymchem Clinical will significantly enhance our consortium’s capabilities. Their extensive expertise in China and the broader Asia-Pacific region will bring invaluable localized knowledge to our global network. This collaboration will also allow Asymchem Clinical to leverage AICROS’s international reach, accessing new geographic regions and niche markets previously out of reach.

The partnership between AICROS and Asymchem Clinical offers immense benefits to the biopharmaceutical and medical device industries. By combining Asymchem Clinical’s deep expertise in China with the specialized knowledge of other AICROS members, we will further extend our global reach, offering our clients the highest quality in clinical trial solutions. This collaboration is particularly beneficial for smaller biotech firms aiming to conduct trials across multiple regions while ensuring data quality and regulatory compliance.

Furthermore, Asymchem Clinical’s proven track record in handling complex regulatory requirements will be a key asset to AICROS as we continue our commitment to excellence in clinical trials. Given the growth in clinical trials conducted in Asia, and China in particular, as well as the desire to cover diverse patient populations, Asymchem will provide access to a large population that can add significant value to many clinical trials.

Driving Innovation and Growth Together

Asymchem Clinical’s inclusion in AICROS underscores our shared commitment to advancing global development of medicines and medical products. This partnership not only strengthens our ability to deliver high-quality clinical trial services but also reflects our dedication to fostering innovation in the industry. By collaborating closely with Asymchem Clinical, AICROS will continue to drive forward the development of life-saving therapies, ensuring more efficient pathways to market.

The Future of Clinical Trials

The collaboration between AICROS and Asymchem Clinical marks a significant milestone in the evolution of the clinical trial industry. By pooling our collective resources, knowledge, and expertise, we are better equipped to accelerate the development of new drugs and therapies for patients worldwide. In an era of precision medicine and advanced therapeutics, partnerships like this are essential for meeting the growing demands of a complex healthcare landscape.

AICROS is proud to welcome Asymchem Clinical to our consortium, and we look forward to the innovative contributions they will bring. Together, we are poised to lead the industry toward more efficient, effective, and patient-centered clinical trials.