Quality (Q) Guidelines focus on the chemical, pharmaceutical, and biological quality standards, including stability testing protocols to ensure the longevity and consistency of drug products.
Safety (S) Guidelines address non-clinical and preclinical safety evaluations, guiding the toxicological assessments necessary to protect patients’ health.
Efficacy (E) Guidelines cover the clinical aspects of pharmaceutical development, providing standards for designing, conducting, and analyzing clinical trials to ensure therapeutic benefits.
Multidisciplinary (M) Guidelines encompass guidelines that do not fit neatly into the other categories, dealing with genomics, terminologies, and technical aspects of drug registration.
Any Q document is instantly and rightly viewed as a GMP guideline. This includes the quality trio, which, while they have a good philosophy, are still written specifically for GMP purposes. So, if you write your paper, good practice guide, standard, article, or what-have-you and refer heavily to the Q trio, you are either writing a GMP-centered piece or losing most of your audience.
The frustrating thing is that quality-by-design (Q8), risk management (Q9), and quality system management (Q10) are core concepts that apply across the pharmaceutical lifecycle, and there are best practices across all three that can and should be universal, especially Q9(r1), which can really better define risk management as defined in E6, and Q10, which can really shore up parts of E8.
What I would love to see the ICH do is write a technical reference document on risk management. Then, E6 and Q9 would have specific implementation aspects related to their focus. Put all the shared approaches in one place and build on them. The amusing thing is that they are already doing that. For example, Q13 applies the Q trio to continuous manufacturing, and Q14 applies it to the analytical lifecycle.
But for now, if you are writing and just referring to Q9 and Q10 don’t be surprised when all your clinical and safety colleagues tune you out.
The ICH, ICMRA, and PIC/S are three important international organizations in the pharmaceutical regulatory space that folks should pay attention to and understand how they shape our profession’s future.
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is a global initiative that brings together regulatory authorities and the pharmaceutical industry to discuss and establish common guidelines and standards for developing, registering, and post-approval pharmaceutical products.
History and Evolution
Establishment: ICH was established in 1990 by the regulatory authorities and pharmaceutical industry associations from Europe, Japan, and the United States. The goal was to harmonize the regulatory requirements for pharmaceutical product registration across these regions.
Reformation: In 2015, ICH was reformed and became a legal entity under Swiss law, transforming from the International Conference on Harmonisation to the International Council for Harmonisation. This change aimed to create a more robust and transparent governance structure and to expand its global reach.
Objectives and Goals
Harmonization: The primary goal of ICH is to achieve greater harmonization worldwide to ensure that safe, effective, and high-quality medicines are developed and registered in the most resource-efficient manner.
Efficiency: By harmonizing technical requirements, ICH aims to improve the efficiency of the drug development and registration process, reduce duplication of clinical trials, and minimize the use of animal testing without compromising safety and effectiveness.
Structure and Governance
ICH Assembly: This is the overarching governing body, which includes all members and observers. It adopts decisions on guidelines, membership, work plans, and budgets.
ICH Management Committee: This committee oversees the operational aspects, including administrative and financial matters and working group activities.
MedDRA Management Committee: This committee manages the Medical Dictionary for Regulatory Activities (MedDRA), standardizing medical terminology for adverse event reporting and clinical trial data.
ICH Secretariat: Handles the day-to-day management and coordination of ICH activities.
Guidelines and Categories
ICH guidelines are categorized into four main areas:
Quality: Covers topics such as stability testing, analytical validation, and good manufacturing practices (GMP).
Safety: Includes guidelines on genotoxicity, reproductive toxicity, and other safety evaluations.
Efficacy: Focuses on the design, conduct, safety, and reporting of clinical trials, including novel drug classes and pharmacogenetics.
Multidisciplinary: Encompasses cross-cutting topics like the Common Technical Document (CTD) and electronic standards for regulatory information transfer.
Global Impact and Implementation
Membership: ICH includes regulatory authorities and industry associations from around the world. It currently has 20 members and 36 observers.
Implementation: Regulatory members are committed to adopting and implementing ICH guidelines within their jurisdictions, ensuring consistent regulatory standards globally.
Key Activities
Guideline Development: ICH develops harmonized guidelines through a consensus-based process involving regulatory and industry experts.
Training and Support: Provide training materials and support to facilitate the consistent implementation of guidelines across different regions.
The ICH plays a crucial role in the global pharmaceutical regulatory landscape by promoting harmonized standards, improving the efficiency of drug development, and ensuring the safety and efficacy of medicines worldwide.
International Coalition of Medicines Regulatory Authorities (ICMRA)
The International Coalition of Medicines Regulatory Authorities (ICMRA) is a voluntary, executive-level, strategic coordinating, advocacy, and leadership entity. It brings together heads of national and regional medicines regulatory authorities worldwide to address global and emerging human medicine regulatory and safety challenges.
Objectives and Goals
Global Coordination: ICMRA provides a global architecture to support enhanced communication, information sharing, crisis response, and addressing regulatory science issues.
Strategic Direction: It offers direction for areas and activities common to many regulatory authorities’ missions and identifies areas for potential synergies.
Leveraging Resources: ICMRA leverages existing initiatives, enablers, and resources to maximize the global regulatory impact wherever possible.
Membership
Voluntary Participation: Membership is voluntary and open to all medicines regulatory authorities. It includes prominent entities such as the European Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA), and many others worldwide.
Global Representation: The coalition includes regulatory authorities from various regions, with the World Health Organization (WHO) participating as an observer.
Key Activities and Projects
Antimicrobial Resistance (AMR): Developing a coordinated global approach to tackle AMR.
COVID-19 Response: During the COVID-19 pandemic, ICMRA has been pivotal in expediting and streamlining the development, authorization, and availability of COVID-19 treatments and vaccines worldwide.
Innovation and Pharmacovigilance: Ongoing investigations and case studies relating to emerging regulatory challenges and working on real-world evidence, adverse event reporting, and vaccine confidence.
Supply Chain Integrity: Ensuring the integrity of the global supply chain for medicines.
Strategic Importance
Enhanced Collaboration: ICMRA fosters international collaboration among medicine regulatory authorities to ensure the safety, quality, and efficacy of medicinal products globally.
Regulatory Agility: The coalition promotes regulatory agility and rapid response to global health emergencies, ensuring patients have timely access to safe and effective medical products.
The ICMRA plays a crucial role in the global regulatory landscape by enhancing communication and cooperation among medicines regulatory authorities, addressing shared challenges, and promoting the safety and efficacy of medicinal products worldwide.
Pharmaceutical Inspection Co-operation Scheme.
PIC/S stands for the Pharmaceutical Inspection Co-operation Scheme, a non-binding, informal co-operative arrangement between regulatory authorities in Good Manufacturing Practice (GMP) of medicinal products for human or veterinary use. Its main purpose is to lead the international development, implementation, and maintenance of harmonized GMP standards and quality systems of inspectorates in the pharmaceutical field.
History: PIC/S was established in 1995 as an extension to the Pharmaceutical Inspection Convention (PIC) of 1970. It was created to overcome legal limitations that prevented new countries from joining the original PIC due to incompatibilities with European law.
Membership: PIC/S is open to any regulatory authority with a comparable GMP inspection system. As of 2023, it comprises 56 participating authorities worldwide, including Europe, Africa, America, Asia, and Australasia.
Structure: PIC/S operates as an association under Swiss law, registered in Geneva, Switzerland. It has a committee, an executive bureau, and various working groups.
Relationship with Other Organizations: PIC/S works closely with other international bodies, including the European Medicines Agency (EMA), to promote GMP harmonization and share resources.
Objectives
Harmonizing inspection procedures worldwide
Providing training opportunities for inspectors
Developing common standards in GMP
Facilitating cooperation between competent authorities and international organizations
Activities
Developing and promoting harmonized GMP standards and guidance documents
Training competent authorities, particularly inspectors
Assessing and reassessing inspectorates
Facilitating networking among regulatory authorities
Benefits
Ensures high standards among members
Provides training and networking opportunities
May facilitate pharmaceutical exports indirectly
Increases confidence in medicines manufactured in member countries
PIC/S plays a crucial role in global pharmaceutical regulation by promoting harmonized standards, facilitating cooperation between regulatory authorities, and working towards ensuring the quality and safety of medicinal products worldwide.
The Three in Overview
Aspect
ICH
ICMRA
PIC/S
Full Name
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
International Coalition of Medicines Regulatory Authorities
Pharmaceutical Inspection Co-operation Scheme
Established
1990 (reformed in 2015)
2013
1995
Primary Focus
Harmonization of technical requirements for drug development and registration
Strategic coordination and leadership in global human medicine regulation
Harmonization of Good Manufacturing Practice (GMP) standards and inspections
Main Objectives
Develop harmonized guidelines for drug development, registration, and post-approval
Enhance communication, information sharing, and crisis response among regulators
Develop common GMP standards and train inspectors
Membership
20 members, 36 observers (regulatory authorities and industry associations)
Heads of medicines regulatory authorities worldwide
Guideline development, training, and implementation support
Scope
Global, with emphasis on technical aspects of drug development
Global, focusing on high-level strategic issues
Global, concentrating on GMP and quality systems
Key Activities
Guideline development, training, implementation support
Strategic initiatives, position papers, statements
GMP guidelines, inspection reports, training programs
This table highlights the distinct roles and focuses of these three important international pharmaceutical regulatory organizations. While they all contribute to global harmonization and cooperation in pharmaceutical regulation, each has a unique emphasis:
ICH primarily develops technical guidelines for drug development and registration.
ICMRA focuses on high-level strategic coordination among regulatory authorities.
PIC/S concentrates on harmonizing GMP standards and inspection practices.
Their complementary roles contribute to a more cohesive global regulatory environment for pharmaceuticals.
How to Monitor
Organization
What to Monitor
How to Monitor
Frequency
ICMRA
– COVID-19 updates and guidance – Statements on regulatory issues – Reports on emerging topics (e.g., AI, RWE) – Strategic meetings and workshops
– Check ICMRA website regularly – Subscribe to ICMRA newsletter – Follow ICMRA on social media – Attend public workshops when possible
Monthly
ICH
– New and updated guidelines – Ongoing harmonization efforts – Implementation status of guidelines – Training materials and events
– Monitor ICH website for updates – Subscribe to ICH news alerts – Participate in public consultations – Attend ICH training programs
Bi-weekly
PIC/S
– GMP guide updates – New guidance documents – Training events and seminars – Inspection trends and focus areas
– Check PIC/S website regularly – Subscribe to PIC/S newsletter – Review annual reports – Participate in PIC/S seminars if eligible
Monthly
Key points for monitoring:
Set up automated alerts or RSS feeds where available
Create a calendar reminder for regular check-ins on each organization’s website
Collaborate with regulatory affairs colleagues to share insights and updates
Implement a system to disseminate relevant information within your organization
Consider joining industry associations that actively engage with these organizations
The 2024 U.S. Supreme Court decisions have had significant impacts on the Food and Drug Administration (FDA) and other federal agencies. I don’t think we will truly understand the impact for years as matters move through the courts. This increased uncertainty has led to new questions arising as we assess risk.
Overturning the Chevron Doctrine
A significant decision was made to overturn the Chevron doctrine, a longstanding precedent that mandated courts to defer to federal agencies’ expertise when interpreting unclear statutes. This doctrine has played a crucial role in enabling agencies such as the FDA to establish and enforce regulations based on their specialized knowledge.
Reduced Authority: With the Chevron doctrine overturned, the FDA’s ability to interpret and enforce regulations without judicial interference is significantly curtailed. This change makes it easier for regulations to be challenged in court, potentially leading to increased litigation and uncertainty in regulatory enforcement.
Challenges to Regulatory Actions
The decisions made by the Supreme Court have made it harder for federal agencies to effectively carry out their regulatory functions. The court’s rulings have extended the time frames for challenging agency actions, leading to delays in implementing new regulations and enforcement actions. This could particularly affect the FDA’s ability to respond promptly to emerging public health issues.
Specific Cases Affecting the FDA
Several other cases have also directly impacted the scope of FDA regulations:
Environmental and Safety Regulations: Recent court decisions have impacted the FDA’s ability to enforce regulations concerning food safety and environmental protection. For example, the decision to block certain EPA regulations on cross-state pollution indirectly affects the FDA’s responsibility to ensure the safety of food and drugs that might be affected by environmental factors. It’s still uncertain how significant this impact will be, but I am more concerned about this issue than I am about the weakening of the Chevron defense.
The Supreme Court’s decision to protect access to the abortion medication mifepristone is an important exception. The court upheld the FDA’s regulatory decision, which ensures that the FDA can continue to regulate and approve medications important to public health. However, it’s worth noting that this ruling was specifically about the legal standing of the case, so it’s not an entirely straightforward situation.
Broader Implications
The recent decisions signal a change in the balance of power between the judiciary and federal agencies. The Supreme Court’s decision to limit the deference typically given to agencies such as the FDA has altered the federal regulatory landscape. This change could result in a more restricted and litigious regulatory environment.
Laboratory diagnostic testing regulations
The recent Supreme Court rulings, especially the overturning of the Chevron doctrine in Loper Bright Enterprises v. Raimondo, will first impact the FDA’s new laboratory diagnostic testing regulations.
Increased Legal Challenges: The removal of Chevron deference means that courts will no longer automatically defer to the FDA’s interpretation of ambiguous statutes. This change might result in more legal disputes regarding the FDA’s power to regulate laboratory-developed tests (LDTs) as medical devices. The American Clinical Laboratory Association (ACLA) has already filed a lawsuit against the FDA over the new LDT rule, and this Supreme Court decision could strengthen their case.
Uncertainty in Regulatory Framework: The FDA’s final rule, published on May 6, 2024, regulates Laboratory Developed Tests (LDTs) as medical devices, similar to in vitro diagnostics. However, due to a new Supreme Court ruling, the FDA’s authority to regulate LDTs may face greater scrutiny by the courts. This could lead to uncertainty in the regulatory framework for clinical laboratories.
Potential Delays in Implementation: The Supreme Court’s decision in Corner Post v. Board of Governors extends the timeframe for challenging agency rules. This could lead to delays in the implementation of the FDA’s LDT regulations because stakeholders may now have more time to challenge the rules in court.
Stricter Scrutiny of FDA Decisions: The new ruling emphasizes that courts should exercise independent judgment in deciding whether an agency has acted within its statutory authority. This could lead to stricter scrutiny of FDA decisions regarding LDT approvals and regulations.
Keep in mind that although these potential impacts are meaningful, the complete effects of the Supreme Court’s rulings on FDA regulations will likely become more apparent over time as cases are presented in court and as the agency adjusts its approach. The situation is still evolving, and those of us involved in FDA regulated industries should be prepared for significant changes ahead.
The FDA’s reorganization has been unveiled and will be implemented on October 1st. As a total wonk, this is exciting.
There are two major changes:
Forming a Human Food Program (HFP) to consolidate a preventive approach will not have much impact on me professionally, but I’m hoping that as a consumer, we see significant dividends from this refocus.
ORA is being renamed the Office of Inspections and Investigations (OII) and will focus on inspections, investigations, and imports as its core mission. If nothing else, this will make explaining the structure of the FDA a heck of a lot easier.
Everything else seems to be mostly a lot of shuffling of the deck chairs that will have little impact.
Investigations of a Dog 