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Getting in Tune: The ICH Process of Harmonizing Guidelines

August 16, 2018 | Cheryl Ainslie, PhD, Clinical Research Scientist II  │ Regulatory Affairs Services

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“The only constant is change,” commonly attributed to the Ancient Greek philosopher Heraclitus, is as true today as it was in 500 BCE.  In the global industry of drug development, the conduct and reporting of clinical trials may change to a small degree with every new study proposed.  But what happens when there is growth or momentum for change that could impact the industry as a whole?

The Role of ICH

In a previous post, Ilana discussed the International Council for Harmonisation (ICH, previously called the International Conference on Harmonisation) guideline for clinical study report authoring, Efficacy Guideline 3 (E3).  The goal of the post you are reading is to take a step backward and explain how ICH guidelines are proposed, evaluated, and (possibly) adopted.  This process is key to understanding the function and operation of ICH to ensure that drug development is highly efficient and scientifically sound.

Created in 1990, the ICH of Technical Requirements for Pharmaceuticals for Human Use comprises experts from regulatory authorities and the pharmaceutical industry in the EU, US, and Japan.

The mission of ICH is “to achieve greater harmonisation worldwide to ensure that safe, effective, and high quality medicines are developed and registered in the most resource-efficient manner.”  According to ICH, “harmonisation is achieved through the development of ICH Guidelines via a process of scientific consensus with regulatory and industry experts working side-by-side.”

ICH Guidelines

The ICH may adopt a guideline in 1 of 4 categories:

  1. Quality (Q) – addressing chemistry, manufacturing, and controls
  2. Safety (S) – addressing nonclinical studies
  3. Efficacy (E) – addressing both clinical efficacy and safety studies
  4. Multidisciplinary (M)

Once adopted, the ICH guidelines are endorsed by the US Food and Drug Administration, European Medicines Agency, Japanese Pharmaceuticals and Medical Devices Agency, and Health Canada.

Among the ICH efficacy guidelines currently endorsed are:

  • E3 for authoring clinical study reports
  • E5 for analyzing and reporting of clinical data collected in one geographical region to support drug applications in another geographical region, ie, ethnic factors in the acceptability of foreign clinical data
  • E6 for designing, conducting, analyzing, and reporting trials with human subjects using the principles of Good Clinical Practice
  • E7 for the design and conduct of clinical trials for drugs that will be used by elderly patients
  • E10 for the choice of appropriate control groups in clinical trials

As Ilana stated in her post, ICH guidelines may have aspects that are ambiguous and open to clinical or scientific interpretation and discretion by the Sponsor.  This is intentional because the fields of drug delivery, biological therapies, genomics/epigenetics, and metabolomics (to name a few) are continually evolving, and strict or highly specific guidelines may not always apply to certain drug products or biologics, patient populations, or study designs or programs.  This flexibility is essential to promote drug development that proceeds as efficiently as possible while also securing the protection of patients’ health and privacy as well as the integrity of clinical trial data.

How are ICH Guidelines Composed and Harmonized?

To meet its mission of achieving harmonization, the ICH has an iterative process to generate new guidelines or revise existing guidelines.  Both consist of the same 5 separate and clearly defined steps.

Prior to Step 1, any ICH Member introduces a Concept Paper, which outlines the objectives of the new or revised guideline and may or may not have an attached business plan.  If they elect to move forward with the proposal, the ICH Assembly endorses the Concept Paper and creates an Expert Working Group (EWG).

Step 1: Consensus Building

In Step 1, the EWG prepares a draft of the full Technical Document based on the objectives described in the Concept Paper.  When the members of the EWG reach consensus on the draft, the Technical Document is submitted to the ICH Assembly.

Step 2: Draft Guideline

Step 2 is broken into 2 parts.

Step 2a occurs when the ICH Assembly agrees that the EWG has reached consensus on the draft of the Technical Document.

Next, Step 2b consists of the Regulatory Members of the ICH Assembly revising the draft Technical Guide Document as needed to develop a draft guideline, and then providing their endorsement.

Once both of these parts are completed, the Technical Document is considered a Step 2 draft guideline.

Step 3: Regulatory Consultation and Discussion

Step 3 is broken into 3 stages.

Stage I is the regional regulatory consultation, wherein the draft guideline is subjected to regulatory review in ICH regions.  During this stage, regulators may provide comments to the ICH Secretariat for consideration.

After the comment period has ended, Stage II commences with the discussion of the regional regulatory consultation comments by the EWG.

Once the EWG has addressed all of the comments and revised the draft guideline (if needed), Stage III comprises the adoption of the revised draft guideline by the Regulatory Members of the ICH Assembly.  A proposed guideline that reaches this stage is considered a Step 3 Expert Draft Guideline.

Step 4: Adoption of an ICH Harmonized Guideline

During Step 4, the Regulatory Members of the ICH Assembly may agree that there is adequate consensus on the Step 3 Expert Draft Guideline and adopt it as an ICH Harmonized Guideline.

Step 5: Implementation

Immediately after adoption of the new or revised ICH Harmonized Guideline, Step 5 entails the regulatory implementation of the Guideline in accordance with the national and local procedures of the ICH regions.

What about Minor Updates or Clarifications to Guidelines?

In addition to the 5-step process for new or revised Harmonized Guidelines, there are also established procedures to produce a Questions and Answers (Q&A) document when an existing guideline requires clarification and to maintain existing guidelines to add or update scientific and technical content only.

Both of these procedures (Q&A and maintenance) are similar to the 5-step process outlined above, but the Q&A procedure may not involve Step 3.  The Q&A document can be adopted after either Step 2b or Step 4.  For examples of current Q&A documents, click here.

How to Add Your Notes to the Harmony

As of 16 Aug 2018, there are 5 draft Step 2b documents open for public comment here.

These guidelines address the use of Biopharmaceutics Classification System-based biowaivers for applicable drugs (M9); the calculation method of the permitted daily exposure level for cadmium by inhalation (Q3D[R1]); the management of postapproval Chemistry, Manufacturing, and Controls changes (Q12); the use of estimands and sensitivity analyses in clinical trials (E9[R1]) (to be covered in a future blog post); and the measurement of reproductive toxicity (S5[R3]).

Do you have any comments on these issues or want to see the ICH harmonization process in action?  Visit the link above or to comment in the US.

In Need of Regulatory Advice?

The experienced medical writers and regulatory affairs group at IMPACT are continually striving to produce high quality regulatory documents incorporating the most up-to-date ICH Harmonized Guidelines.  If you have any questions about the ICH process or would like to work with us on any regulatory documents, please do not hesitate to contact us.

Category: Regulatory Affairs Services
Keywords:  ICH; Clinical trial transparency; Harmonization; Regulation; Clinical Study Report; Clinical trials

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