Regulatory Class - Nov 28 Flashcards
General Requirements for Exporting Drugs (801)
Drug, device, or biologic for export will not be considered to be adulterated or misbranded if:
Meets specifications of foreign purchaser (dose, strength, purity, quality)
Not in conflict with laws of the country (need letter from government agency saying this doesn’t conflict with laws or has marketing approval)
Labeled on outside of shipping package “intended for export” (needs to be clearly identifiable and segregated from products intended for sale in US)
Not sold or offered in domestic (U.S.) commerce
Unapproved drug requirements for export (802f)
Be in “substantial conformity” with cGMPs
Not contain a substance or have been prepared in conditions where it could be contaminated or injurious to health
Not have a container composed of a substance that could render the contents injurious to health
Have strength, purity and quality it is represented to possess
Not be prohibited from export by FDA
Not be an imminent hazard to public health of the importing country
Labeled in accordance with the requirements of a listed country where it has marketing authorization and the importing country
Exporting Unapproved drugs (802)
The product complies with the laws of the importing country, and
It has valid marketing authorization by the appropriate authority in a “listed country”
Listed Country
EU, EEA, Australia, Canada, Israel, Japan, New Zealand, Switzerland and South Africa
Simple Notification for Export
Must submit Simple Notification to FDA at time of initial export
Contents:
Product’s trade name and established name
Strength, dosage form, model number
Import country if not a listed country (FDA recommends identifying listed country)
Exporting Unapproved Drugs and Biologics to Unlisted Countries (N/A to devices) (802b)
Happens when drug is not approved in a list country. (only Russia has been approved, need approval for country not drug)
The drug complies with the laws of the importing country
Has valid marketing authorization by the appropriate
authority
FDA has determined that the importing country has laws and regulations:
For review of safety and effectiveness by a government entity
Requiring cGMPs
For reporting adverse events and removing unsafe or ineffective drugs from the market
Requiring labeling and promotion consistent with the drug’s approval
Petition to Authorize Export of an Unapproved drug (802b3)
Firm can petition FDA to authorize export of an unapproved drug or biologic to an unlisted country:
Must certify drug would not meet conditions for FDA approval or approval in a listed country, and
Provide “credible scientific evidence” to FDA to show that drug would be safe and effective under conditions of use in the import country
Health authority in import country requests approval of exportation, and
Certifies understanding that drug is not approved by FDA or listed country, and
Concurs that scientific evidence provided to FDA is credible scientific evidence
New petition for each drug, not each country; more common than 802b
FDA has 60 days to act on petition, but can’t export until FDA responds
Unapproved drug exported for investigational use in a listed country (802c)
Don’t need prior FDA approval or an IDE (must send simple notification)
Must be exported in accordance with the laws of the import country
Must comply with drug export requirements (802f)
All records for exported drugs must be kept.
Unapproved drug exported for investigational use in an unlisted country
Trial is covered by an IND
Drug has marketing authorization in any listed country (Prior FDA approval or IND not required, but Must notify FDA of export)
Drug is to be used in a clinical trial in a listed country (Prior FDA approval, IND and notification are not required)
Certify that export meets conditions of the “312 program”
312 program
Drug is intended for export for investigational use in a foreign country
Drug meets foreign purchaser’s specifications
Drug is not in conflict with foreign country’s laws
Outer shipping label identifies drug is intended for export from the U.S.
Drug is not sold in U.S.
Clinical investigation will be conducted in accordance with 21 CFR 312.120 (FDA acceptance of foreign clinical studies not under an IND)
Drug is manufactured in substantial conformity with cGMPs
Drug is not adulterated
Drug does not present an imminent hazard to public health (in the U.S. or the import country)
Drug is labeled in accordance with import country’s laws
European Authority
European Commission - FDA and FHS
European Medicines Agency (EMA) - CDER
Member state = country in the EU
National Competent Authorities - responsible for national regulations (under Ministry of Health)
Notified Bodies
Review submissions for devices, do inspections and provide information to competent bodies
Accredited by the member state (must prove technical competence and independence to be objective)
When submitting, sponsor must pick a notified body with expertise for that device. Sponsor pays the notified body.
Pharmaceutical Inspection Cooperation Scheme (PICS)
Develop harmonized GMP requirements and inspections techniques. So if one of these countries does an inspection, the others can accept the results
International regulatory authorities: Most EU countries, U.S., Israel, Australia, Singapore, Argentina, Switzerland, Norway, Iceland, Malaysia, South Africa
EU Clinical Study Requirements
Manufacture of all investigational medicinal products intended for clinical trial must be authorized and conducted in accordance with GMPs (including Placebo)
Import authorization required for products from outside EU
Obtain EudraCT number from centralized EudraCT database
Clinical Trial Application submitted to Competent Authority of each country
Clinical Trial Application Contents
General information including EudraCT number, cover letter, application form, list of Competent Authority responses
Informed consent and patient information
Ethics Committee opinions
Protocol, summary of protocol in national language, ethical assessment of principal (coordinating) investigator
Investigator’s brochure, Investigational Medicinal Product Dossier, manufacturing information
Copy of labeling
Some also require: Insurance or indemnification information Compensation for investigators Compensation for subjects Investigator agreements
Clinical Trial Application Review
Competent Authority has 60 days to review clinical trial application (sponsor can start if no objections are raised in that time) [within the first 10 days, CB must tell sponsor if CTA is not valid]
CTAs also undergo 60 day review with Ethics Committees
Amendment Notification
Competent Authority is responsible for all inspections
Sponsor must notify Competent Authority (changes to scientific value) and/or Ethics Committees (impact of safety of trial subjects) of clinical trial amendments
Submit a Amendment Notification Form and there is a 35 day review
If urgent safety measures are needed, that can be performed without prior notification, but must notify ASAP
Study Completion
Sponsor must notify the Competent Authority and Ethics Committees within 90 days of study completion
Sponsor must submit a summary report to the Competent Authority and Ethics Committees within 1 year of study completion
Sponsor and investigators must retain essential documents for at least 5 years after study completion
Medical Device Regulations
Medical Devices Directive (MDD) and Active Implantable Medical Devices Directive (AIMD)
Key elements of essential requirements require that devices are designed and manufactured:
So that when used as intended they do not compromise safety of patients or users
They will deliver intended performance
To adhere to safety principles:
Eliminate or reduce risks as much as possible
Adequately protect patients and users from risks that cannot be eliminated
Inform users of residual risks
Retain performance characteristics over claimed lifetime – including during transport and storage
Medical Device Clinical Trials
No standard application form – sponsor notifies the relevant Competent Authorities of the proposed study, including:
Information identifying the device
Investigational protocol/plan
Investigator’s brochure, case report forms, confirmation of insurance, informed consent documents
Ethics committee approvals
Investigator and institution information
Starting date and duration of study
Statement that device conforms to applicable essential requirements and precautions have been taken to protect health and safety of subjects
Competent Authority reviews application and responds within 60 days (letter of no objection may be sent immediately if device is low-risk)
Contents of IMP Dossier
Quality data
Nonclinical pharmacology and toxicology data
Previous clinical trial and human experience
Overall risk and benefit assessment
