The Clinical Trial Has Changed

Looking back at Cybermed 1999

My Cybermed page on ICH-GCP carries a writing date of 17 July 1999 and an update date of 25 April 2008. It brings together the research resources of that period, including Malaysia’s first GCP guideline. It is an archive, and its present wording includes later updates. Cybermed archive.

Twenty-seven years after that original column, Malaysia has reached its Fifth Edition. The question is worth revisiting: what changed in Good Clinical Practice along the way?

Why GCP was needed

Ethical intentions alone cannot establish whether a medicine works. Research also needs sound methods, reliable records and responsibility for what happens to the people taking part.

International drug development added another problem: data generated in one country needed to be acceptable to regulators elsewhere. Harmonisation sought to reduce unnecessary duplication while preserving public-health safeguards. This was a central rationale explained in the old Cybermed column.

GCP connected the ethical obligation to the practical conduct of a trial. Consent, safety review, recording and reporting became parts of one accountable system.

ICH E6 establishes a common standard

ICH E6 reached Step 4 on 1 May 1996; editorial corrections followed in June as E6(R1). These were international harmonisation milestones, rather than one universal national commencement date. ICH document history.

The original framework set out the responsibilities of ethics committees, investigators and sponsors, alongside the protocol, investigator’s brochure and essential documents. Those foundations are visible in Malaysia’s First Edition.

Its two purposes were inseparable: protect research participants and produce evidence that could be trusted. Poor science can expose people to risk without answering the question that justified their participation.

Malaysia establishes its GCP framework

Malaysia’s First Edition was published in 1999. Its foreword is dated October, and the archived Cybermed page records the launch that month. The guideline adapted ICH standards to local requirements. Malaysian GCP First Edition.

The original document names the Steering Committee for Clinical Research in the Ministry of Health. Its chairman, Dato’ Dr Ismail Merican, highlighted concerns about awareness and adherence among researchers. It also records that the Malaysian Liver Foundation had been conducting GCP training since 1997.

I was involved in those early efforts. The First Edition lists me, representing the Pharmaceutical Association of Malaysia, on the Subcommittee of Malaysian Consensus Guideline on Good Clinical Practice.

The task was broader than publishing a booklet. Malaysia was establishing shared expectations about how clinical research should be conducted.

When compliance became complicated

Documentation has a purpose. Without it, an investigator cannot demonstrate what happened, a monitor cannot verify it, and a regulator cannot assess it.

The difficulty is deciding how much process helps, and when process begins to obscure the important work.

ICH’s 2019 concept paper for R3 documented increasing complexity in trial design, technology, data volume and service-provider involvement. It proposed a full rewrite and reorganisation, with guidance adaptable to different trial designs.

That supports a measured criticism: GCP systems must keep pace with research, and their application must be proportionate. It does not establish that every additional form or monitoring visit was unnecessary.

My concern is simpler. A well-filled file is evidence of documentation. It is not, by itself, evidence of a well-conducted trial.

E6 R2 brings risk into focus

Adopted on 9 November 2016, E6(R2) was an integrated addendum to the existing guideline.

Section 5.0 required a quality-management system throughout the trial. Sponsors were to identify critical processes and data, assess the risks, introduce controls, review them and report the approach.

It already called for methods proportionate to risk and the importance of the information collected. It also warned against unnecessary complexity, procedures and data collection. Electronic systems and oversight of outsourced activities received further attention.

Risk-based GCP therefore did not begin with R3. R2 had already made the case. The later challenge was to embed that thinking more consistently into trial design and conduct.

E6 R3 builds quality into research

ICH adopted the E6(R3) Principles and Annex 1 on 6 January 2025. The redesign was deliberate: the 2019 concept paper had proposed an overarching framework of principles, supported by annexes, and further development of R2’s proportionate approach.

Another important bridge was ICH E8(R1), adopted in 2021. It described quality as fitness for purpose and promoted designing quality into the protocol and processes. It encouraged early attention to factors that could undermine participant protection or the usefulness of the answer.

This is practical. Before a trial begins, ask whether its research question is clear, whether its endpoint answers that question, whether the procedures are feasible, and whether participants can manage what is being asked of them.

Good monitoring cannot fully rescue a poorly conceived study. Preventing an avoidable design problem is preferable to documenting its consequences.

E6(R3) embeds quality by design, proportionality and avoidance of unnecessary burden in its principles. Its Annex 1 includes a dedicated data-governance section. Essential records, traceability and accountability remain necessary.

What proportionality means in practice

Consider an illustrative example. A minor transcription error in a non-critical administrative field and a missed assessment needed to recognise a serious safety problem both require appropriate handling. Their consequences are different.

Neither should be dismissed without assessment. But the safety failure warrants urgent attention, investigation and action to protect participants.

R3 section 3.9.3 requires trial-specific criteria for important protocol deviations: those that may significantly affect participant rights, safety or well-being, or the completeness, accuracy or reliability of trial data.

The judgement must be justified and documented. Proportionality is a reason to allocate attention intelligently, while meeting applicable requirements.

Malaysia reaches its Fifth Edition

The Malaysian Fifth Edition, 2026 records the national sequence below and explicitly adapts ICH E6(R3). Its foreword reports that more than 30,000 individuals have obtained GCP certification.

Edition dates: Fifth Edition publication history. R2 alignment: Fourth Edition.

The new edition combines international expectations with Malaysian practices and sensitivities. The educational task now is to help investigators apply the principles to the studies they actually conduct.

What has never changed

For Malaysian researchers, I would ask a practical question: can we explain why a requirement matters to this trial, and what might happen if it fails?

A certificate records training. Applying that training requires judgement, appropriate supervision and the willingness to raise a concern.

Looking back at the First Edition, the enduring purpose is easy to recognise. Protect the person who volunteers. Make sure the answer can be trusted.

GCP has evolved by strengthening how those obligations are met. R3 offers a clearer framework; whether it improves research will depend on how we use it.

Good Clinical Practice was never meant to mean more paperwork. It was meant to mean better research.

Sources and further reading

1. Vadivale M. — ICH–GCP Guidelines for Clinical Trials, Cybermed — Writing date 17 July 1999; updated 25 April 2008. Historical archive; present wording includes later updates.
2. Ministry of Health Malaysia — Malaysian Guideline for Good Clinical Practice, First Edition, 1999 — Subcommittee list, foreword and chairman’s message; PDF.
3. ICH — Integrated Addendum to ICH E6(R1): E6(R2) — 9 November 2016. See document history and section 5.0; PDF.
4. ICH — Final Concept Paper: E6(R3) — 17 November 2019; endorsed 18 November 2019; PDF.
5. ICH — E8(R1) General Considerations for Clinical Studies — 6 October 2021. See sections 2.2 and 3; PDF.
6. ICH — E6(R3) Guideline for Good Clinical Practice — Principles and Annex 1, adopted 6 January 2025. See principles 6–9 and Annex 1 section 3.9.3; PDF.
7. Ministry of Health Malaysia — Malaysian Guideline for Good Clinical Practice, Fourth Edition, 2018 — Foreword dated January 2018; adapted from the integrated addendum E6(R2); PDF.
8. Ministry of Health Malaysia — Malaysian Guideline for Good Clinical Practice, Fifth Edition, 2026 — Publication history, foreword and introduction; adapts ICH E6(R3); PDF.

Note: This article provides general information and does not replace individual medical advice. The views expressed are the author’s own and do not represent those of any employer or organisation. Guidelines and regulatory requirements change; consult the current official text for any study.