regulation of drug products: role of the fda

Republic of the Philippines Department of Health

Food and Drug Administration

Regulation of Drug Products: Role of the FDA

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Center For Drug Regulation and Research FDA Philippines

I. Legal Bases for Regulation

II. The Food and Drug Administration

III. Regulatory Framework A. Licensing and Inspection of establishments

B. Pre-marketing assessment

C. Post-marketing surveillance

D. Communication, Coordination, and Collaboration

IV. The Way Forward

Presentation Outline

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I. LEGAL BASES FOR REGULATION

Republic Act No. 3720 (as amended) – Foods, Drugs and Devices, and Cosmetics Act

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Legal Bases

• Republic Act No. 6675 – The Generics Act of 1988

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Legal Bases

• Republic Act No. 7394 – Consumer Act of the Philippines

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Legal Bases

• Republic Act No. 8203 – Special Law on Counterfeit Drugs

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Legal Bases

• Republic Act No. 9502 – Universally Accessible Cheaper Quality Medicines Act of 2008

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Legal Bases

• Republic Act No. 9711 – Food and Drug Administration (FDA) Act of 2009

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Legal Bases

• Republic Act No. 10354 – The Responsible Parenthood and Reproductive Health Act of 2013

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Legal Bases

• Republic Act No. 10918 – Philippine Pharmacy Act

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Legal Bases

• Republic Act No. 7277 (as amended) – Magna Carta for Disabled Persons

• Republic Act No. 9165 – Comprehensive Dangerous Drugs Act of 2002

• Republic Act No. 9994 – Expanded Senior Citizens Act of 2010

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Legal Bases

• Republic Act No. 10532 – Philippine National Health Research System Act of 2013

• Republic Act No. 10747 – Rare Diseases Act of the Philippines

• Republic Act No. 10767 – Comprehensive Tuberculosis Elimination Plan Act

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Legal Bases



II. The Food and Drug Administration

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The Food and Drug Administration

• Office under the Department of Health

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The Food and Drug Administration

• Office under the Department of Health

• Created in 1963 by virtue of Republic Act 3720 as amended by Executive Order No. 175, and subsequently Republic Act No. 9711

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• To ensure the safety, efficacy, and quality of health products

– Food, drugs, cosmetics, devices, biologicals, vaccines, in-vitro diagnostic reagents, and household/urban hazardous substances and/or a combination of and/or a derivative thereof

Mandate 17

Drug

1. any article recognized in the official USP-NF, official HPUS, PP, PNDF, BP, EP, JP, IP, any national compendium or any

supplement to any of them;

2. any article intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease in humans or

animals;

Drug

3. any article other than food intended to affect the structure or any function of the human

body or animals;

4. any article intended for use as a component of any articles specified in clauses (1), (2) and

(3) not including devices or their components, parts or accessories;

Drug 5. herbal and/or traditional drugs

which are articles of plant or animal origin used in folk medicine which are:

i. recognized in PNDF

ii. intended for use in the treatment or cure or mitigation of disease symptoms, injury or body defects

in humans

Drug 5. herbal and/or traditional drugs

which are articles of plant or animal origin used in folk medicine which are:

iii. other than food, intended to affect the structure or any function of the human body

iv. in finished or ready-to-use dosage form; and

v. intended for use as a component of any of the articles specified in clauses (i), (ii), (iii) and (iv)

• Drug Products include:

Mandate 22

1. New chemical entities 2. Generic products 3. Biological products

(including biosimilars and vaccines)

4. Household remedies 5. Over-the-counter products

6. Traditionally-used herbal products

7. Herbal medicines 8. Medical gases 9. Veterinary Drugs 10. Stem Cell Products

To ensure the safety, efficacy, purity, and quality of products we regulate through effective implementation of the national regulatory framework consistent with international best practice

MISSION 23

VISION

To be an internationally recognized center of regulatory excellence safeguarding the health of the Filipinos

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QUALITY POLICY

Our highest commitment is to ensure the safety, efficacy and quality of health products.

Toward this end, we commit to maintain and establish science-based policies based on national and international standards as basis for regulatory policies, to continually improve and maintain our competencies in relation to our regulatory function, and to deliver quality public service with integrity and efficiency.

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Four centers according

to product jurisdiction

Inspection

Laboratory

analyses



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III. Regulatory Framework

A. Licensing and Inspection of establishments

B. Pre-marketing assessment

C. Post-marketing surveillance

D. Communication, Coordination, and Collaboration

Regulatory Framework Elements

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III. Regulatory Framework: A. Licensing and Inspection of

Establishments

Establishments must comply with the requirements of different good practices:

• Good Manufacturing Practice

• Good Distribution Practice

• Good Storage Practice

• Good Laboratory Practice

• Good Clinical Practice

• Good Tissue Practice

Licensing and Inspection of Establishments

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AO 2012-0008

AO 2013-0027

FC 2013-018

AO 2013-0012

Administrative Order No. 2016-0003

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FDA Circular No. 2016-004

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I. Drug Manufacturer II. Drug Distributor III. Drugstore/Pharmacy/Botica IV. Retail Outlet for Non-prescription

Drug (RONPD) V. Sponsor VI. Contract Research Organization

(CRO)

Classification

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engaged in any or all operations involved in the production of drug products including preparatory processing, compounding, formulating, filling, packaging, repackaging, altering, ornamenting, finishing and labeling with the end in view of its storage, sale or distribution; provided, that the term shall not apply to the compounding and filling of prescriptions in drugstores and hospital pharmacies.

Drug Manufacturer 35

Procures raw materials, active ingredients and/or finished products to other drug establishment whether through import, export, or local wholesale

Drug Distributor 36

Drugstore/ Pharmacy/Botica

including hospital pharmacy and institutional pharmacy shall refer to drug establishment where registered drugs, chemical products, dental, medicinal and household remedies are dispensed directly to the general public on a retail basis.

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RONPD

drug establishment such as a supermarket, convenient store and other similar retail establishment authorized to sell only Over-the-Counter (OTC) and household remedy products directly to the general public on a retail basis.

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an individual, company, institution, organization or an entity which takes the responsibility for the initiation, management, and/or financing of a clinical trial.

Sponsor 39

a person or an organization (commercial, academic, or other) contracted by the sponsor to perform one or more of the sponsor’s trial-related duties and functions.

CRO 40

General Rule (1)

All establishments shall first secure an LTO from FDA prior to engaging in the manufacture, import, export, sell, offer for sale, distribute, transfer, promote, advertise and/or sponsor of any activity that involves drug product

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General Rule (2)

Likewise, no CRO and/or Sponsor shall be involved in the conduct of clinical trial without a license from FDA.

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All establishments must continuously comply with the existing requirements, regulations and standards, otherwise the they may be ordered closed or their licenses suspended or revoked motu proprio or upon petition by any person. A violation with any of the terms and conditions of the LTO may result in the suspension, revocation, or cancellation of the LTO, or disapproval of its application for renewal.

General Rule (3) 43

All establishments must continuously comply with the existing requirements, regulations and standards, otherwise the they may be ordered closed or their licenses suspended or revoked motu proprio or upon petition by any person. A violation with any of the terms and conditions of the LTO may result in the suspension, revocation, or cancellation of the LTO, or disapproval of its application for renewal.

General Rule (3) 44

GMP

GDP

GSP

GCP

General Rule (4)

The FDA shall have the authority to enter any establishment for (1) inspection and/or (2) verification of documents submitted in support of its application for license.

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The responsibility of ensuring the safety, quality, efficacy, and/or purity of any drug product shall rest upon all the establishments or persons involved in the production, sale, handling, transport, distribution, trading and storage thereof

General Rule (5) 50

General Rule (6)

All drug establishments engaged with vaccines, biologics, and other temperature-sensitive drug products shall comply with the cold chain management requirements.

Cold Chain Management Requirements

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All drug establishments shall be under the supervision of a registered pharmacist as required by pertinent rules and regulations.

General Rule (7) 54

All FDA-required information, education and communication campaign material shall be displayed in the establishment’s conspicuous area.

General Rule (8) 57

General Rule (9)

All foreign manufacturers must prove compliance to GMP.

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Foreign GMP Clearance

• Previously, FDA relies solely on the documentary evidence from DRA of the country of origin for GMP evaluation of foreign manufacturers

• New policy – empowers FDA to inspect foreign manufacturers

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Foreign GMP Clearance

• Foreign manufacturers inspected by PIC/S – GMP Clearance

• Foreign manufacturers not inspected by PIC/S – requires inspection

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III. Regulatory Framework: B. Pre-Marketing Assessment

• Product Type 1. New Chemical Entities

Not previously authorized for marketing for any pharmaceutical use

2. Biotechnological Products (including biosimilars and vaccines) Any product of biological origin, prepared with biological

processes, derived from human blood and plasma, or manufactured by biotechnology consisting of substances of high MW whose purity, potency, and composition cannot readily be determined by chemical or physicochemical analysis

3. Generic Drugs Intended to be interchangeable with the innovator product

Drug Class

• Formally adopting the ASEAN Common Technical Dossier (ACTD) and Requirements (ACTR) for the registration of new chemical entities, biotechnological products, and prescription generic products

• 4 parts: Administrative, Quality, Nonclinical, Clinical document with RMP

• With consideration for ICH CTD

ACTD/ACTR

• Product Type 4. Traditionally-used Herbal Products

preparations from plant materials whose claimed application/s is/are based only on traditional experience of long usage which should be at least five (5) or more decades as documented in medical, historical and ethnological literature

5. Herbal Medicines finished, products that contain as active ingredient(s) aerial or

underground part(s) of plants or any other plant material, or combination thereof, whether in the crude state or as plant preparations

have specific therapeutic claim(s) intended for use in the diagnosis, alleviation, cure or treatment of disease, promotion of health or intended to affect or modify the structure or any function of the body of humans or animals

Drug Class

Traditionally-used Herbal Products

Herbal Medicines

• Product Type 6. Household Remedies

containing pharmaceutical substances of common or ordinary use to relieve common physical ailments which may be dispensed without a medical prescription in original packages, bottles or containers, the nomenclature of which has been duly approved by FDA in the process of registration. A household remedy preparation should have no history of or recognized adverse reaction after being marketed and used for at least twenty (20) years according to its indication

7. Over-the-Counter Preparations drug products or preparations that can be dispensed even

without the written order of a licensed physician or dentist

Drug Class

Household Remedies

Over-the-Counter Preparations



Registration Requirements

I. Administrative Requirements

II. Quality Data

III.Non-clinical Data

IV.Clinical Data

Registration Requirements

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• Labeling materials and product information

• GMP Certificate of foreign manufacturer(s)

• Certificate of Pharmaceutical Product (or Certificate of Free Sale)

• Site Master File

Major Administrative Data

Labeling Requirements

• GMP Clearance issued by FDA after review of foreign GMP application,

• Or as issued by FDA for local manufacturers

GMP Certificate

• Establishes:

– Product is manufactured compliant to GMP

– Product is freely sold either in the country of origin or another country

– Product is

Certificate of Pharmaceutical Product

Major Quality Documents

• API: Manufacturing process and controls

• API: Process validation and process development

• API: Characterization

• API: Specifications, procedures, analytical validation

• API: Batch analyses

• API: stability

New Chemical Entities and Biotech Products

Major Quality Documents • FP: Pharmaceutical development – formulation

development, physicochemical and biological properties

• FP: Manufacturing process development, • FP: microbiological attributes • FP: batch formula • FP: manufacturing procedure and process control • FP: process validation


Major Quality Documents

• FP: control of excipients – specifications and procedures

• FP: Specifications, procedures, analytical validation

• FP: Batch analyses

• FP: Characterization of impurities

• FP: Stability


Major Safety and Efficacy Documents

• Pharmacodynamics (effects, mode of action)

• Safety pharmacology (potential side effects)

• Drug interactions

• Pharmacokinetics (ADME)

• Toxicology (single/repeat-dose, genotoxicity, carcinogenicity, reproductive and developmental toxicity, tolerance) (onset, severity, and duration)


Major Safety and Efficacy Documents

• Biopharmaceutic studies (bioavailability, bioanalytical studies)

• Clinical pharmacology studies (protein binding, hepatic metabolism, health and patient subjects)

• Clinical Efficacy and Safety (controlled and uncontrolled studies)

• Post-marketing experience


• In lieu of clinical trials to prove safety and efficacy, product interchangeability

Generic Products

Prior to the marketing of products:

1. The conduct of clinical trials must comply with ICH GCP

2. Proof of safety, efficacy, and quality must pass the requirements of FDA • For innovative drugs – full quality, safety, and efficacy review,

compliant with ASEAN reqts

• For generic drugs – full quality plus proof of interchangeability

Pre-marketing Assessment 87

Also included:

• Sample submission and evaluation

• Labeling review

• Review and imposition of post marketing commitments (where applicable)




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III. Regulatory Framework: C. Post-marketing surveillance

Post-Marketing Surveillance

1. Pharmacovigilance

Safety monitoring of drugs on the market for unexpected health risks and informing the public of risks posed by specific drugs and other health products;

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2. Monitoring, collecting, sampling and testing of drugs

3. Audits and inspection of manufacturers/ distributors/ retail outlets

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4. Advertisements and claims monitoring

Monitor of advertisements, promotions, sponsorship and other marketing activities on health products to protect consumer against misleading, deceptive, false, and erroneous impressions

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Administrative Order No. 65 s. 1989

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5. Product recall / Labeling revision/ restrictions on use

6. Other administrative sanctions

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III. Regulatory Framework: D. Communication, Coordination, and

Collaboration

Communication, Coordination, and

Collaboration

1. International Collaboration

• World Health Organization (WHO)

• United States Pharmacopeia – Promoting the Quality of Medicines (USP-PQM)

• European Union

• Asia Pacific Economic Cooperation (APEC)

• International Council for Harmonization (ICH)

• Other Drug Regulatory Authorities (DRAs) such as Taiwan FDA, MFDS Korea, HSA Singapore, US FDA 104


Collaboration

2. Alignment with other government agencies

• DOH offices such: Pharmaceutical Division

Health Facilities and Services Regulatory Bureau (HFSRB)

Disease Prevention and Control Bureau (DCPB; formerly NCDPC)

Epidemiology Bureau (EB; formerly NEC/EPI)

Philippine Health Insurance Corporation (PhilHealth)

Philippine Institute of Traditional and Alternative Health Care (PITAHC) 105


Collaboration


• Philippine Drug Enforcement Agency (PDEA) and the Dangerous Drug Board (DDB)

• Professional Regulation Commission (PRC) and Professional Regulatory Boards such as: Board of Pharmacy

Board of Medicine

• Technical Education and Skills Development Authority (TESDA)

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Collaboration


• Department of Trade and Industry (DTI) offices, such as: Philippine Economic Zone Authority (PEZA) and Board of

Investments (BOI)

Bureau of Product Standards (BPS)

Philippine International Trading Corporation (PITC)

Intellectual Property Office of the Philippines (IPOPHL)

Philippine Accreditation Bureau (PAB)

• Bureau of Customs (BOC) 107


Collaboration


• Department of Agriculture offices, such as: Bureau of Animal Industry (BAI)

Bureau of Fisheries and Aquatic Resources (BFAR)

• Department of Science and Technology (DOST), such as: Philippine Council for Health Research and Development

(PCHRD)

Philippine Health Research Ethics Board (PHREB)

Philippine Health Research Registry (PHRR) 108


Collaboration


• Other enforcement partners, such as: National Bureau of Investigation (NBI)

Philippine National Police (PNP)

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Collaboration

3. Partnerships with professional associations and private institutions

• Philippine Pharmacists Association

• Philippine Medical Association

• Ad Standards Council

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IV. THE WAY FORWARD

• Electronic Processing of applications for registration

• Introduction of risk-based processing from bench-mark countries

• Shift from pre-market to post-market, with emphasis on public health

• Regulatory convergence

The Way Forward

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