ICH E6(R3) in Plain English: What Changes for Sponsors Running Trials in India

The biggest change to Good Clinical Practice in nearly a decade is here. ICH adopted the E6(R3) Principles and Annex 1 on 6 January 2025. The EU made it effective in July 2025 and the US FDA published it as final guidance later that year. Regulators worldwide, including in India, are aligning with it.

If you sponsor trials in India – especially trials whose data will be used abroad – E6(R3) is now the standard your study will be judged against. Here is what it means in plain English.

1. Quality by design, not quality by inspection

E6(R2) introduced risk-based monitoring. E6(R3) goes further: quality must be built into the protocol from the start. Sponsors are expected to identify what is critical to quality – the data and processes that truly affect participant safety and the reliability of results – and focus effort there.

What to do: run a documented risk assessment at protocol stage, and revisit it as the study progresses.

2. Proportionality everywhere

The guideline repeatedly asks for approaches that are proportionate to risk. A low-risk nutraceutical study does not need the same level of monitoring as a first-in-human oncology trial. That is good news for smaller sponsors – but only if the reasoning is written down.

What to do: document why your monitoring, data checks and audit plan are right-sized for your trial.

3. Stronger sponsor oversight

E6(R3) makes it clear that sponsors must oversee every service provider – CROs, labs, technology vendors. Signing a contract is not oversight.

What to do: define oversight activities (meetings, metrics, audits) in an oversight plan and keep evidence that you did them.

4. Technology-neutral and data-focused

The new text is written to work for paper, electronic and hybrid trials. It gives detailed attention to data governance: audit trails, access control, system validation and the integrity of data across its whole life cycle.

What to do: ask your vendors for validation evidence, and make sure audit trails are reviewed, not just switched on.

5. Participant-centred conduct

E6(R3) puts more weight on the participant experience – clear consent information, reduced burden and flexibility such as remote consent or visits where appropriate and permitted locally.

What to do: review consent documents and visit schedules from the participant's point of view.

6. Essential records, not just essential documents

The focus shifts from a fixed list of documents to records that allow the trial to be reconstructed and evaluated. Your TMF must tell the story of the study.

What this means in India

Indian trials are governed by the New Drugs and Clinical Trials Rules, 2019 and Indian GCP guidance, and CDSCO has been moving its guidance in line with E6(R3) themes. For global sponsors, sites in India will be inspected against E6(R3) expectations by foreign regulators too.

The practical gap I see most often: sites and smaller CROs are still working with E6(R2)-era SOPs and training. A short gap assessment now can prevent findings later.

Quick E6(R3) readiness checklist

• Is there a documented risk assessment for each study?
• Is the monitoring plan clearly risk-based and justified?
• Is there a written vendor oversight plan with evidence of execution?
• Are computerised systems validated and audit trails reviewed?
• Have site and sponsor staff been trained on E6(R3)?

If you answered "no" or "not sure" to any of these, now is the right time to act.

Need an E6(R3) gap assessment or training for your team or sites? Write to me at anup.cra@gmail.com.

– Anup Kumar, Independent Clinical Research Auditor & Consultant, New Delhi

Why Every Sponsor Needs an Independent Auditor – Even If Your CRO Is Excellent

Many sponsors tell me the same thing: "Our CRO is very good. Why would we need an independent auditor?"

It is a fair question. Most CROs in India work hard and have experienced teams. But a good CRO and independent assurance are two different things – and regulators expect sponsors to have both.

The sponsor is always responsible

Under ICH GCP, a sponsor can transfer tasks to a CRO, but never responsibility. If an inspector finds that consent was taken incorrectly, data was changed without an audit trail, or safety reports were late, the finding lands on the sponsor. "Our CRO was handling it" is not a defence.

That is why ICH E6(R3) places strong emphasis on sponsor oversight of service providers. Oversight means you need your own evidence that the work is being done correctly – not just the CRO's reports telling you it is.

Why a CRO cannot audit itself

A CRO's internal QA team is valuable, but it has natural limits:

• Conflict of interest. Internal auditors report to the same management that is delivering your study. Even with the best intentions, there is pressure to soften findings.
• Shared blind spots. If the CRO's SOPs have a gap, internal QA trained on those same SOPs may not see it.
• Different priorities. The CRO's QA protects the CRO's quality system. An independent auditor protects your study, your data and your submission.

What an independent auditor actually gives you

1. An unbiased view. Findings are reported directly to the sponsor, graded by risk, with no filter.
2. Early warning. Problems found at month two cost far less to fix than problems found at database lock – or by an inspector.
3. Evidence of oversight. Audit reports and CAPA records show regulators that you actively supervised your trial.
4. Confidence for partners and buyers. If you plan to license your product, raise funds or file abroad, an independent audit trail strengthens due diligence.
5. Local knowledge. For overseas sponsors, an India-based auditor understands how sites, Ethics Committees and CDSCO processes really work on the ground.

When should you bring in an auditor?

You do not need to audit everything. A risk-based plan works best:

• Before the study: CRO and vendor qualification audits.
• Early in recruitment: an audit of the highest-enrolling or newest site.
• For cause: when you see unusual data patterns, frequent deviations or staff turnover.
• Before submission: TMF and Clinical Study Report audits.

For small and nutraceutical sponsors, even one or two well-timed audits can transform the credibility of a study.

The bottom line

A strong CRO and an independent auditor are not competitors – they are partners in quality. The CRO delivers the study; the auditor gives you proof that it was delivered right.

If your data will be judged by a regulator, a partner or the market, independent assurance is not a cost. It is insurance.

Planning or running a trial in India? I provide independent GCP audits, independent monitoring and GCP consulting for pharma, biotech and nutraceutical sponsors. Write to me at anup.cra@gmail.com for a free, confidential discussion.

– Anup Kumar, Independent Clinical Research Auditor & Consultant, New Delhi

Navigating Risk-Based Quality Management (RBQM) in Clinical Trials

The clinical research industry is undergoing a monumental paradigm shift. For decades, trial monitoring relied heavily on exhaustive, 100% Source Data Verification (SDV)—a method that consumed immense resources while offering diminishing returns on patient safety and data integrity.

Enter Risk-Based Quality Management (RBQM).

Driven by evolving regulatory expectations and the increasing complexity of clinical trials, sponsors and Contract Research Organizations (CROs) are moving away from rigid, one-size-fits-all monitoring. Instead, the industry is pivoting toward a proactive, targeted approach that focuses efforts where they matter most: protecting participant safety and safeguarding critical trial data.

What is Risk-Based Quality Management (RBQM)?

RBQM is a systematic, prioritized approach to managing quality throughout the lifecycle of a clinical trial. Rather than treating all data points and site processes with equal weight, RBQM identifies critical-to-quality factors right from the protocol design stage.

The framework encourages clinical teams to ask:

• What are the most significant risks to patient safety and study reliability?

• Where are errors most likely to occur?

• What mitigation strategies can we put in place proactively?

Core Pillars of RBQM

A robust RBQM framework rests on several interconnected components:

1. Risk Assessment and Categorization (RAC)

Before a single patient is enrolled, cross-functional teams (clinical operations, data management, medical safety, and biostatistics) collaborate to build a Risk Assessment Categorization Tool (RACT). This helps pinpoint protocol-specific risks, such as complex endpoint evaluations or specific patient population vulnerabilities.

2. Centralized Monitoring

While on-site monitoring remains essential, centralized monitoring leverages technology and data analytics to review incoming data streams in real-time. Central monitors look for anomalies, missing data trends, and site-to-site variances across all participating centers, allowing teams to spot signals of non-compliance or systemic error early.

3. Key Risk Indicators (KRIs) and Quality Tolerance Limits (QTLs)

• KRIs act as early warning systems, tracking metrics like high query rates, protocol deviations, or delayed safety reporting.

• QTLs define thresholds of systematic quality that, if crossed, could impact the overall credibility of the trial results, triggering immediate root-cause analysis and corrective action.

Impact on CRAs and Clinical Auditors

For Clinical Research Associates (CRAs), RBQM transforms the role from a mechanical checklist-ticker to an analytical problem-solver. Instead of spending days verifying every single data field on a Case Report Form (CRF), CRAs can focus on high-value tasks: engaging with site staff, investigating root causes of deviations, and evaluating site processes.

For Clinical Trial Auditors, RBQM changes how inspection readiness is evaluated. Auditors no longer just look for whether 100% SDV was completed; they evaluate:

• Was the risk assessment documented early and updated regularly?

• Did the sponsor act on the signals generated by centralized monitoring?

• Are the documented mitigations proportional to the risks identified?

The Future Outlook: Preparing for ICH E6(R3)

Regulatory modernization—exemplified by the draft and final updates to the ICH GCP E6(R3) guidelines—solidifies RBQM not just as a "best practice," but as a regulatory expectation. Sponsors are expected to embrace governance models where quality is built into the protocol rather than inspected into the results at the end.

As we move forward, mastering RBQM will no longer be optional for clinical operations professionals. It is the definitive key to running faster, leaner, and fundamentally safer clinical trials.

What are your thoughts on implementing RBQM in your current trials? Share your experiences in the comments below!

Need of Audio / video recording of informed consent in clinical trial

The Indian health ministry will soon amend the Schedule Y of Drugs and Cosmetics (D&C) Rules to make a provision for audio and video recording of the informed consent in clinical trials. Once the necessary amendments are done by the ministry in this regard, the audio and video recording of informed consent will become mandatory in the country.

It is proposed that the investigator should make audio / video recording of the procedure of obtaining informed consent of the individual subject and maintain it for record. This will authenticate that at the time of enrollment proper care was taken to inform the subject about the pros and cons of the clinical trial and his participation was voluntary. A provision in this regard was proposed to be introduced under sub-para (4) related to ‘Informed Consent’, under para ‘2. Clinical Trials’ under Schedule Y.

DCGI further stated that it was also proposed that the trial subject should also be made aware during informed consent process, that there may be a possibility of failure of investigational product to provide intended therapeutic effect and in the case of placebo controlled trial, the placebo administered would not have therapeutic effect.

Once the ministry makes the necessary amendments in this regard, the audio/video recording of informed consent will become mandatory in the country. Besides, the audio/video recording of the informed consent process of individual subject, including procedure of providing information to the subject and his understood consent, should be maintained by the investigator for record.

The purpose behind this provision is that it will authenticate that at the time of enrolment, proper care is taken to inform the subject about the pros and cons of the clinical trial and to ensure his participation is voluntary.

The Drugs Technical Advisory Board (DTAB), the highest authority in the union health ministry on technical matters, has already given its approval to the proposal of the CDSCO to amend Schedule Y of the D&C Act to insert a clause, “An audio/video recording of the informed consent process of individual subject including procedure of providing information to the subject and his understood consent shall be maintained by the investigator for record.”

Even though it is mandatory under Schedule Y of the Drugs and Cosmetics Rules to obtain a freely given informed, written consent from each study subject before he is enrolled in a clinical trial, in the absence of audio/video proof, there have been complaints of misuse of this provision by the companies who are engaged in clinical trial business. There were reports that many a time the informed consent was taken from the participating subjects without informing them the pros and cons of the trial.

The feeling among the ministry officials is that it is the duty of the investigators to adequately inform the trial subjects about the essential elements of the study and that of the drug to be administered. The trial subjects should be made aware that the drug is a new drug and is first time being administered; its therapeutic efficacy and serious adverse reactions have not yet been well documented. The research subject should also give his consent stating that he has understood the information provided by the investigator in respect of the study and his participation in the trial is voluntary.

The officials feel that the audio and video recording of this procedure of individual subject will act as a proof of a well informed consent.

Source : http://www.cdsco.nic.in