The Caribbean Regulatory System (CRS)

The Caribbean Regulatory System (CRS) is an initiative of the Caribbean Community and Common Market (CARICOM) and is managed as a regulatory unit within CARICOM’s regional public health body, the Caribbean Public Health Agency (CARPHA). It is supported by a number of partners, including the Pan American Health Organization/World Health Organization (PAHO/WHO), PAHO designated National Regulatory Authorities of Regional Reference (NRA/RR) (Argentina, Brazil, Canada, Chile, Colombia, Cuba, Mexico, United States), and the Bill and Melinda Gates Foundation (BMGF).

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LEGAL AUTHORITY:  

The CRS derives its legal authority from CARPHA’s public health mandate , the Caribbean Pharmaceutical Policy , and various other Ministerial health frameworks  and decisions.

CARICOM’s Technical Advisory Committee on Pharmaceutical Policy (TECHPHARM), made up of representatives from CARICOM Member States and institutions, advises the CRS on policy and technical matters.
 
The CARPHA Drug Testing Laboratory plays an integral role as well.

PURPOSE: 

The main purpose of the CRS is to strengthen regulatory capacity in CARICOM Member States in support of improved access to safe, quality, efficacious, and affordable medicines and health technologies. The CRS strengthens regulatory capacities through the provision of registration and pharmacovigilance support to Member States, using efficiencies, such as reliance on reference authorities, to enable a sustainable enterprise in the resource-constrained environment of small states. This contributes to CARPHA’s mandate to prevent diseases, promote health and respond to public health emergencies.

FOCUS ACTIVITIES:  

Very broadly, the CRS carries out the following regulatory focus activities: 

  • *Reviews safety, quality, and efficacy of generic (multisource) finished medicine products that meet specific CRS eligibility criteria, including:
    • 1) the product has a current marketing authorization from a CRS-designated “reference authority, ” or products prequalified by WHO; and
    • 2) the product is named in the periodically issued CRS “Expression of Interest,” (click Eligibility Criteria tab for list) or is a priority medicine (e.g. medicine on WHO Essential Medicine List or PAHO Strategic Fund (see Expression of interest/Priority medicine tab)."
  • *Conducts abbreviated reviews of product dossiers that conform to international standards, including PAHO/WHO and International Conference on Harmonization (ICH) standards,
  • *Recommends all medicines reviewed  favourably to CARICOM Member States,  and requests completion of in-country processes to grant marketing authorization/import permit within 60 calendar days,,
  • *Carries out pharmacovigilance of medicines registered by CRS.

OPERATIONAL POLICIES: 

The operational policies of the CRS, including links to guidance on dossier submission requirements for registration, are laid out in the “CRS Operational Policy.”

BENEFITS TO INDUSTRY:  

The CRS benefits industry in a variety of ways. It offers a central portal for access to CARICOM’s markets of over 17 million people.

  • *These Member States are:
    • Antigua and Barbuda, Bahamas, Barbados, Belize, Dominica, Grenada, Guyana, Haiti, Jamaica, Montserrat, Saint Lucia, St. Kitts and Nevis, St. Vincent and the Grenadines, Suriname, and Trinidad and Tobago
  • *Associate Member States are:
    • Anguilla, Bermuda, British Virgin Islands, Cayman Islands, and Turks and Caicos Islands
  • *Because these countries are diverse and have different regulatory requirements and timelines for processing, the CRS will benefit companies by giving them one streamlined set of requirements and a known and accelerated timeline for processing compared to what currently exists.
  • *The requirements are based on an abbreviated and accelerated procedure WHO uses for Prequalification when a product has already been registered by a reference authority.
  • *The CRS also participates in the WHO Collaborative Procedure, whereby sponsors that hold a prequalified product can authorize the release of that dossier, and corresponding assessments, to the CRS for review. If reviewed favourably, the CRS would recommend the product to countries for marketing authorization within 60 calendar days, per its usual procedure.

MORE INFORMATION

For more background and context, please see the recent article “Regionalization as an approach to regulatory systems strengthening: a case study in CARICOM Member States” published in the Pan American Journal of Public Health. 

CONTACT

For more information or submission inquiries, please contact: CRSRegistration@carpha.org

Operational Policy

Introduction
Glossary of key terms
CRS operational policies
Accountability, confidentiality, conflict of interest, and transparency
Eligibility Criteria
Expression of interest/Priority medicines
Submitting a dossier
Screening of dossiers submitted
Dossier assessment
Site inspection
Meetings with sponsors
Issuance of recommendation for marketing authorization/import permit
Marketing authorization in CARICOM Member States
Maintenance of registration status
Variations
Suspension, revocation, recall, withdrawal
Timelines
Appeals and complaints
User fees

 

This section outlines the major operational policies of the CARIBBEAN REGULATORY SYSTEM (CRS)

Glossary of key terms

Applicant/sponsor/application/dossier
  • An applicant or sponsor is the person or company who submits an application or dossier for marketing authorization of a new medicine, an update to an existing marketing authorization, or a variation to an existing marketing authorization.
  •  

    Finished product
    • A product that has undergone all stages of manufacture, including packaging in its final container and labelling.
    Marketing authorization and registration

    • Marketing authorization is an official document issued by the competent national medicines regulatory authority for the purpose of marketing a product after evaluation for safety, efficacy, and quality. Once a product has been given marketing authorization, it is included in a list of authorized products—the register—and is often said to be “registered” or have a “registration."
    • The CRS uses the term “registration” instead of “marketing authorization” in that both terms imply the same regulatory review, but only a sovereign country can authorize products for sale in their market.
    •  

      Medicine
      • Any substance or pharmaceutical product for human use that is intended to modify or explore physiological systems or pathological states for the benefit of the recipient

     

Operational Policies

Accountability, confidentiality, conflict of interest, and transparency

  • CRS staff obey a code of conduct including observe guidelines on confidentiality and conflict of interest.
  • Consultants such as expert advisors obey guidelines on confidentiality and conflict of interest and are required to make a confidentiality undertaking and declaration of conflict of interest known as an “Agreement for Performance of Work” or “APW”.
  • CRS registration recommendations are made public on the CARPHA website.
  • The CRS publishes other relevant regulatory information on the CARPHA website. Relevant information may include key policies, guidelines, decisions, and performance metrics.

Eligibility criteria

  • The CRS currently accepts dossiers for generic (multisource) medicine finished products already given at least one marketing authorization by the following Pan American Health Organization (PAHO)  designated National Regulatory Authorities of Regional Reference (NRA/RR). These authorities have been assessed by PAHO to meet reference standards in accordance with PAHO Directing Council Resolution CD50.R9 ; NRAs/RR also provide capacity building support to other regulatory authorities in the region. NRAs/RR include the countries:
    • Argentina, Brazil, Canada, Chile, Colombia, Cuba, Mexico, and United States
    • The CRS also accepts dossiers for generic medicines already given marketing authorization in the European Union. This is because of the close historical and cultural ties to countries in the Caribbean.
  • Together, these authorities are referred to as “Reference Authorities” or “RAs”.
    • The CRS reserves the right to modify the list of RAs in the future, including for example, factor in new assessment results by PAHO for NRA/RR.
    • The CRS also accepts dossiers for generic medicine finished products prequalified by the World Health Organization (WHO)

Expression of interest/Priority medicines

  • The CRS periodically publishes a list of products it wishes sponsors to submit dossiers for on its website. This list is called an expression of interest (EOI) and is similar to the WHO prequalification program’s EOI. Any sponsor’s product that meets eligibility criteria and the EOI is invited to submit a dossier.  In responding to the EOI, the sponsor should refer to the dossier submission requirements and send the documentation to the CRS at CRSRegistration@CARPHA.org  
    • The current EOI is as follows:
      • WHO Essential Medicines List and/or PAHO Strategic Fund dosages and dosage forms for the following, in priority order: Metformin; Amlodipine; Amoxicillin; Metronidazole; Ciprofloxacin; Losartan; Digoxin; Haloperidol; Ibuprofen; Omeprazole
      • If the product is not on the Expression of Interest but is on World Health Organization's Essential Medicine List or the Pan American Health Organization's Strategic Fund,  the sponsor is invited to make an inquiry with the CRS as to whether the CRS can agree to a dossier submission of that product. 
      • All documents should be submitted in English. When the original language is not English, translation is needed, but sponsors are encouraged to proactively consult CRS staff about requirements.
      • For particular requirements, more than one language may be requested, in consultation with the sponsor.
      • The CRS may request original documentation which may be in a regional language

Submitting a dossier

Screening of dossiers submitted

  • Each product dossier submitted by a sponsor is screened for completeness against the list of required documentation before being assessed.
  • The CRS conducts two screenings of dossiers. The first is a preliminary or pre-screening of the dossier to check that all required documentation is submitted. This may be done with the sponsor present. If documentation is missing at this stage, the CRS will send a communication to the applicant and request a 10 business day turnaround time. The second is a more in depth screening to check that the submitted material is sufficiently comprehensive and of high quality for the CRS to proceed to assessment.
  • Dossiers that are considered complete as the result of screening processes are retained for assessment by the CRS.
  • If the dossier is accepted for assessment, the sponsor is informed of this by written communication. This serves as an agreement between the CRS and the sponsor for the participation in the CRS review and a commitment to comply with the provisions of the CRS review process.

Dossiers Assessment

  • The product information submitted in the dossiers is assessed by a multidisciplinary team of experts
  • The assessors must comply with conditions of appointment, as well as confidentiality and conflict of interest rules of the CRS.
  • The CRS may ask questions of the sponsor during the assessment stage.
  • The CRS provides an assessment report to the sponsor following the assessment.
  • The CRS reserves the right to share the assessment report and relevant documentation, including the product summary characteristics, with any interested authorized CARICOM member state.

Site Inspection

  • The CRS expects that sponsors comply with Good Manufacturing Practices (GMP) and this is assessed through correspondence and verification of GMP with RAs. The CRS reserves the right to conduct site inspections.

Meeting with sponsors

  • The CRS reserves the right to request meetings with sponsors at any time.
  • Meetings requested by sponsors are granted at the discretion of the CRS.

Issuance of registration

  • The CRS issues a registration to the sponsor if the dossier is reviewed favorably.
  • The conditions of the registration include:
  • That no changes will be made to pharmaceutical aspects of the product without prior conforming to the CRS policy on variations.
  • All information must be consistent with the approved product information.
  • The CRS publishes recommended products on its website, including, but not limited to, the following information:
  • Generic name, dosage form, and strength;
  • Brand name, if applicable;
  • Registration holder;
  • Registration number;
  • Each sponsor receives a written communication from the CRS informing it of the outcome of the assessment.

Marketing authorization in CARICOM Member States

  • If a dossier is recommended, the CRS contacts focal points in each Member State to initiate the marketing authorization process.
  • It shares relevant dossier documentation, including assessment reports, and if requested, makes the full dossier available.
  • It the Member State has a user fee, it will request it at this stage.
  • The goal is to turn the CRS recommendation into a lawful marketing authorization in CARICOM countries within 60 calendar days.
  • The  CRS uses Memorandums of Understanding between CARPHA and the individual Member States to facilitate this process.

 

Maintenance of recommendation status

  • Sponsors achieving CRS registration for a given product keep that registration for 5 years, provided they notify the CRS of any changes or variations in manufacture and control that may have an impact on the safety, efficacy and quality of the product (see “variations” section.
  • The renewal process will be abbreviated in comparison to the first registration but will include showing proof of marketing of products in CARICOM markets.

Variations

  • The CRS requests that sponsors notify the CRS of variations, including provide notifications of variations to dossiers when notifying and receiving decisions from the RA on which the product’s eligibility is based.
  • Some types of changes are so significant that the sponsor must re-register the product. These include:
  • A change of the API to a different API.
  • Inclusion or removal of an API.
  • A change in the dose of an API.
  • A change in the dosage form.
  • A change in the route of administration.
  • A change in manufacturing site.
  • Please consult with the CRS as to the appropriate action regarding a variation if there is any uncertainty about the right path.

Suspension, revocation, recall, withdrawal

  • The sponsor must notify the CRS of any suspensions, revocations, recalls, and/or withdrawals of the sponsor’s products on the CRS registry—including in markets beyond those of the RA.
  • The CRS reserves the right to suspend or revoke a product registration, including, but not limited to, the following situations:
  • The quantitative or qualitative composition is not as agreed in the registration.
  • The product is found not to be in compliance with the conditions of the registration.
  • The product is a danger to public health.

Timelines

  • The CRS reviews sponsor dossiers and issues a decision within 180 calendar days from the date of accepting the dossier for review, not including time that additional information or clarification is needed from the sponsor after accepting the dossier.

Appeals and complaints

  • The CRS accepts any request for appeal or filing of a complaint, provided that the sponsor makes the request or filing in writing. 
  • The CRS addresses appeals and complaints within 30 business days in a written response.

 

User fees

  • The CRS  is currently in its pilot phase to test the system.  All CRS fees will be waived in the pilot
  •  In the future, the CRS will charge fees for the regulatory work it conducts.  This will enable a sustainable system.
  • Note that the Member States may charge its own fees in the marketing authorization phase.  It is important to keep these fees in place as they are a meaningful source of revenue.
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CARPHA/CRS recommended medicines

CARPHA/CRS recommends the medicines listed in this document to CARICOM member states for granting marketing authorization/import permit.

Stakeholder Information

FREQUENTLY ASKED QUESTIONS
FOR INDUSTRY

 

Question: Can I submit the dossier and/or packaging/labelling in another language besides English?

Answer: No, at this time, all dossier/packaging/labelling materials must be submitted in English.

Question: What climate zone do I need to submit stability data for? And if this differs from the Reference Authority zone, what do I do?

Answer: WHO’s prequalification program has guidance on this (http://apps.who.int/prequal/info_general/documents/guidelines/Storage_June2015.pdf) and the CRS follows this approach. Generally, zone IVb stability data (data generated at 302C/75 5%RH) on the primary or production batches of the product in the same packaging as approved for marketing of the finished product in the Reference Authority (RA) country, should be provided.

If these zone IVb data are not available at the time of submission, applicants should initiate as soon as possible long-term stability testing at these conditions in the same packaging as approved by the RA. When complete, the full long term data (at minimum 12 months) should be submitted to the CRS team. Questions regarding this matter can be directed to CRSregistration@CARPHA.org 

The CRS team has compiled procurement data for select priority medicines from sample Member States and procurers in the region. It can be downloaded here
Question: What happens if my product is recommended by the CRS?

Answer: A positive CRS review is posted on the CARPHA/CRS website, and triggers a process whereby the CRS notifies CARICOM Member States and Associate Member States, as well as regional and national procurers, of the recommendation. Pertinent dossier information, such as the assessment report compiled by the CRS, is then shared with focal points in each of these entities, and the clock begins to tick for sovereign countries to turn the recommendation into a marketing authorization. The goal is 90 calendar days.

 

Trinidad and Tobago’s 2016 procurement list can be found under “New pharmaceutical pricelist booklet”.  Click here 
The CRS team has compiled procurement data for select priority medicines from sample Member States and procurers in the region. It can be downloaded here.

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FOR GOVERNMENTS AND CRS FOCAL POINTS

The CRS has requested countries/territories to provide officially nominated government focal points to engage with the CRS. The following are terms of reference for focal point responsibilities. Click here to read terms of reference.

CARICOM Member state engagement

CARICOM Ministers of Health issues a decision to implement the CRS in 2014 and have reaffirmed that decision in subsequent years

The CRS has also begun to pursue Memorandums of Understanding with individual states to further cement engagement. The below graphic shows the present state of this engagement

Note that the OECS Pharmaceutical Procurement Service signed an MOU so those participating countries are colored in.

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