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International Regulatory Processes

Beyond the existing (complex) system for regulation of Nanomedicines in Europe, Nanomedicine providers may address further international markets and therefore need to dispose of basic information on regulatory issues in significant markets. ENATRANS provides on this page a quick overviews, relevant documents and contacts for major countries: USA, China.

International Regulatory Processes

Beyond the existing (complex) system for regulation of Nanomedicines in Europe, Nanomedicine providers may address further international markets and therefore need to dispose of basic information on regulatory issues in significant markets. ENATRANS provides on this page quick overviews, relevant documents and contacts for major countries:

 

Regulatory Processes in the USA

In contrast to the European regulatory systems with many different agencies and approval processes in the US only the Food and Drug Administration (FDA or USFDA) is responsible for the evaluation and approval of both medicinal products and medical devices. FDA is a Federal Agency of the United States Department of Health and Human Services, responsible for protecting and promoting public health through the regulation and supervision of areas ranging from food safety, vaccines, medicinal products, medical devices, cosmetics, animal foods & feed  and veterinary products, to name a few.
Accordingly, FDA represents the entry portal for approval of all drug and medical devices. The main criteria for approval are safety, efficacy, and quality. Along these three pillars all products including nano-based products are evaluated.
FDA is organised in several centers dedicated to a specific area. All centers dealing with medicine are grouped in the “Office for Medical Products and Tobacco”. The Center for Drug Evaluation and Research (CDER) is dealing with the approval of drugs while the Center for Devices and Radiological Health (CDRH) is handling medical devices and IVD products.
FDA published three Guidance Papers related to Nanotechnology Applications which also deal with nanomedicine. For a further overview, please check as well the following relevant information and guidelines for drugs.

  • Medicinal Products

After having completed the preclinical testing phase, the sponsor files an Investigational New Drug Application (IND) to the FDA seeking permission to start clinical trials in humans. On approval by FDA and by an Institutional Review Board, the manufacturer may start the first phase of Clinical Trials.
During Phase I, II and III of these trials, safety, dosing, efficacy and side effects are being tested. As soon as Phase III is completed, the manufacturer submits a New Drug Application (NDA) to the FDA which is the request to manufacture and to sell the drug in the USA.
At this stage, the drug undergoes a detailed evaluation. In order to obtain sufficient data on drug safety, effectiveness, adverse events and other criteria, FDA consults advisory committees prior to granting approval.
In order to obtain approval of Generic Drugs, a sponsor is not requested to repeat clinical studies which have been conducted for the original product. He may submit an Abbreviated New Drug Application (ANDA).
In case of an urgent medical need or breakthrough therapy, FDA offers an accelerated approval process (Fast Track) in order to expedite review and approval of drugs.
One should be aware of the fact that a product classified as a drug in Europe can be regarded as a medical device by FDA or vice versa. Example is NBTXR3, lead NanoXray product of company Nanobiotix which is classified as a drug in the USA by the FDA, while this product is regarded as a medical device in Europe.

  • Medical Devices

The Medical Device Amendments of 1976 to the Federal Food, Drug and Cosmetic Act define three regulatory classes for medical devices with an increasing degree of control to assure safety and effectiveness of devices:

Class I – These devices present minimal potential for harm to the user, e. g.: dental floss, elastic bandages. They do not require premarket approval but are subject to general control requirements such as records and reports provided by the manufacturer (= 47% of all medical devices).
Class II – Medium-risk devices that require the 510(k) Premarket Notification, e. g.: Diagnostic tests, cardiac catheters, hearing aids (= 43% of all medical devices).
Class III – These devices usually sustain or support life, e.g. implantable pacemakers, breast implants and automated external defibrillators. These high-risk devices are approved by the Premarket Approval (PMA) process (= 10% of all medical devices).
As a first step of the regulatory pathway, the MD has to be classified either by consulting the FDA classification database or the FDA device classification panel which indicates medical specialties.
If clinical trials are required (innovative class II and class III), studies have to be conducted and a clinical trial protocol has to be submitted. Moreover, facility inspections of all major suppliers of class III devices will be executed.
A company which is not locally represented in the USA has to appoint an FDA US Agent representative as a direct contact to the FDA. Among other functions, the agent is responsible for assisting the FDA in communication with the applicant and in scheduling FDA inspections of the facilities.
In case of approval, FDA issues a 510(k) clearance letter for class II MDs and a PMA approval letter for class III MDs and publishes them online. Company authorization for marketing the device in the USA remains valid as long as no changes are made to the intended use, design etc.
For additional information, please follow the links regarding FDA medical device approvals and on the different submission methods.

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Regulatory Processes in China

The China Food and Drug Administration (CFDA), until 2013 called State Food Drug Administration (SFDA), is responsible, amongst other functions, for the implementation of pharmaceutical legislation and the regulation, approval and inspection of drugs and medical devices in China. It is therefore the central entry portal for the approval of drugs and medical devices and subject to the Ministry of Health (MOH).

Relevant approval procedures are conducted by the CFDA Department of Drug and Cosmetics Registration and, accordingly, by the CFDA Department of Medical Device Registration.

  • Medicinal products

Important regulations and provisions which should be considered are:

Drug Administration Law of the People's Republic of ChinaRegulations for Implementation of the Drug Administration Law of the People's Republic of China;

Provisions for Drug Registration (2007)Special Review and Approval Procedure for Drug Registration of the China Food and Drug Administration.

CFDA regulation for a new drug development is similar to the US FDA pathway. CFDA requires a clinical trial application (CTA), similar to the US FDA investigational new drug application (IND). This is followed by a clinical evaluation programme. As next step, the manufacturer presents a new drug application (NDA).

The application and approval procedure for clinical trials is described on the CFDA website; as well as the application and approval procedure for imported drugs.

  • Medical Devices

First step in the regulation of medical devices (MD) is to define their risk classification. Three classes exist and are comparable to the European guidelines. However, there is no distinction between class Ila and Ilb which means that CFDA decides how to evaluate the risk potential and allocates the regulation procedure based on three classes.

Class I MDs do not require, in most cases, product tests or clinical studies whereas class II MDs have to ensure their safety and efficacy by means of product tests; some of them additionally have to pass through clinical trials. For class III MDs, product tests and clinical trials are mandatory.

Manufacturers have to check if, in addition, a CCC certification (China Compulsory Certificate, a compulsory safety mark for many products) is required for their product. The China Quality Certification Center (CQC) conducts CCC mark applications and determines if the products needs the CCC. Certification procedure involves additional specific product tests and factory audits.

On receipt of the applicant’s documents, CFDA confirms or corrects the risk classification, potentially requests additional information, determines the necessity of product tests and clinical trials and accepts or refuses admission of the MD.

The assistance of a professional service provider in this process is recommended due to the fact that the documentation for CFDA’s evaluation often requires translation into the Chinese language. Moreover, an intransparent situation in view of Notified Bodies in China which are not always publicly known requires very good contacts to Chinese public authorities.

On approval of the MD for the Chinese market, a CFDA certificate with a five-year validity period is issued and registered in the CFDA database. At the end of this period, a comprehensive re-assessment is required.

  • Current Situation and Prospects

China, the second largest pharma market in the world with a constant growth in a double-digit percent range, is characterized by an ageing population, increasing living standards, health-consciousness and a high interest in adequate medical provision as well as by a fast-growing share of health insured individuals.

At the same time, profits of pharmaceutical enterprises in China are under pressure because of the expenses in public health sector. In this field, China is in a backlog in comparison with international compliance guidelines and in slow processing of numerous approval applications.

In view of this situation, the Chinese Government is planning comprehensive changes: More experts for approvals have already been employed and an electronic system has been installed for the follow up of medicinal developments. A new classification of pharmaceuticals is being envisaged. Innovative drugs covering an urgent medical need shall be approved by means of „Fast Track“.

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Regulatory Processes in Japan

The Pharmaceuticals and Medical Devices Agency (PMDA) is an independent administrative legal authority. It provides, among other functions, the advice for clinical trials; the scientific review of market authorisation applications including the evaluation of quality, efficacy and safety of drugs, medical devices, cellular and tissue-based products; the inspection and assessment of Good Clinical Practice (GCP), Good Laboratory Practice (GLP) and Good Practice Systems and Programs (GPSP) as well as the auditing of manufacturers. It is the entry portal for the approval of drugs and medical devices and collaborates with the Ministry of Health, Labour and Welfare (MHLW). According to the PMDA’s review results, the MHLW formally approves or rejects the relevant drug or MD. Various laws and regulations provide the basis for pharmaceutical administration in Japan, among them are the Pharmaceutical Affairs Law (PAL), the Law Concerning the Establishment for Pharmaceuticals and Medical Devices Organization, and the Law Concerning Securing Stable Supply of Blood Products. As of 25th Nov. 2014, the Pharmaceutical and Medical Device Act (PMD Act) has been launched. It is entitled „Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products and Cosmetics“ and replaces the former Pharmaceutical Affairs Law  (PAL). In addition to the PAL, the PMD Act includes regenerative and cellular therapy products and gene therapy products.

  • Medicinal Products

Only a Marketing Authorization Holder (MAH) which can be a distributor with a MAH license, a regulatory consulting firm or a licensed manufacturer can submit an approval application to the PMDA. On receipt of the application form, review teams of the PMDA undertake a compliance review of the data, a GCP on-site inspection and a detailed review. The teams prepare a report; and important problems will be discussed with external experts. On completion of the review report, it will be sent to the Ministry of Health, Labour and Welfare. The Pharmaceutical Affairs and Food Sanitation Council (PAFSC) is then consulted for additional advice. The MHLW finally grants the new drug manufacturing approval.

  • Medical Devices

First step of the regulatory pathway of an MD in Japan is the selection of a Marketing Authorization Holder (MAH) i.e. the company which manages the device approval process and is responsible for all aspects of the product, including quality and compliance with the conditions of the marketing authorisation. Then the MD has to be classified. Four classes exist: General MDs (Class I) with an extremely low risk such as X-Ray films for which a self declaration is sufficient. Controlled MDs (Class II) with a low risk, e. g. MRI Magnetic Resonance Imaging which need a third party certification of a Registered Certified Body (RCB). Specially controlled MDs: Class III, e. g. Dialyzers, Artificial bones and Class IV, e. g. pacemaker, artificial heart valves which require PDMA’s review and Minister’s approval. All documents have to be submitted in Japanese language. The manufacturer must obtain registration of their facilities from the PMDA and has to establish a Quality Management System (QMS) in accordance with MHLW Ordinance #169, which is comparable to ISO 13485. Depending on the classification, a QMS conformity assessment or audit, either by PMDA or by an RCB, is required. In case of a positive review, a QMS conformance certificate will be issued by RCB or PMDA. On receipt of MD’s approval, the Marketing Authorization Holder must submit Import Notification to the Regional Bureau of Health and Welfare. From now on, he can start marketing the device in Japan.

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Regulatory Processes in India

The Central Drugs Standard Control Organization (CDSCO) is the national regulatory body and entry portal for regulation and approval of pharmaceuticals and medical devices in India. It is linked to the Ministry of Health and Family Welfare and holds six zonal offices, four sub-zonal offices, several port offices and laboratories. Among other functions, it approves clinical trials, controlls drug imports and supervises Drugs Consultative Committee and Drugs Technical Advisory Board meetings. Within the CDSCO, the Drug Controller General of India (DCGI) is the main licensing authority which directly issues permission for new drugs and specific medical devices and for the manufacturing of certain drugs (vaccines, blood-products, r-DNA derived).

  • Medicinal Products

The Drugs & Cosmetic Act 1940 and Rules 1945 regulate the manufacturing, import, sale and distribution of Drugs and Medical Devices as well as clinical trials. The drug manufacturer has to submit his request on Form 44 under the provisions of this Act in order to obtain permission to import or manufacture a new drug or to undertake clinical trials. A Common Technical Document - covering administrative and legal information, a product summary, quality, nonclinical and clinical issues - has to be presented as well. In addition, the manufacturing site has to be registered for import activities.
According to Rule 122-A of the Drugs and Cosmetics Act, already existing international clinical trial data or other information can replace an additional clinical trials procedure in India. The same applies to drugs that have been approved and marketed in other countries for a long time.
Currently, 14 medical devices, among them cardiac stents, catheters, heart valves and orthopedic implants, have been notified as drugs.

  • Medical Devices

Important regulations and provisions which should be considered are:

A first step of the regulatory pathway of a MD in India is the appointment of a local agent as license holder. Then the MD has to be classified. Although a formal classification scheme does not exist, draft regulations propose four classes with an ascending risk as follows: Class A, Low Risk, e. g.: thermometers, tongue depressors; Class B, Low-moderate Risk, e. g.: hypodermic needles, suction equipment; Class C, Moderate-high risk, e.g.: lung ventilator, bone fixation; Class D, High Risk, e. g.: heart valves, implantable devices.
If the MD does not require registration, the local agent/manufacturer should obtain a No Objection Certificate (NOC) from the Drug Controller General of India which states that the MD does not require registration and can be directly imported into India.
If it requires registration, a Device Master File and a Plant Master File have to be compiled, together with the Application Form and corresponding documents. Documents and fees have to be sent to the DCGI for review. The DCGI reviews, sends back an inquiry letter and may additionally ask for a technical presentation. Clinical data may not be necessarily requested if foreign clinical data are available and acceptable. In case of a positive documentation review, MD approval is granted. In January 2017, India’s Ministry of Health and Family Welfare released the Medical Device Rules, 2017 which will take effect on January 1, 2018 and will replace the former Drugs and Cosmetics Act. The new rules provide a regulation of medical devices based on international standards and on the principals of the Global Harmonisation Task Force (GHTF). In the meantime, the GHTF has been replaced by the International Medical Device Regulators Forum (IMDRF).

Integral parts of the new Medical Device Rules:

  • Classification of MDs into four classes (Class A - D) as described above;
  • Quality Management System (QMS) for all manufacturing sites will be aligned with ISO 13485;
  • A structure of Notified Bodies, accredited by the National Accreditation Board for Certification Bodies (NABCB), will be implemented;
  • Manufacturing and import licences will remain valid until they are cancelled-  with no periodic renewal of licences in future
  • Complete procedure from submission of documents to grant of licence will be handled via an online electronic platform with defined timelines.

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Regulatory Processes in Brazil

The Agência Nacional de Vigilância Sanitária or National Sanitary Surveillance Agency (ANVISA), created in 1999, is an independently administered and financially autonomous regulatory body of the Brazilian government. The agency which is the entry portal for the regulation and approval of drugs and medical devices is managed by a collegiate board of directors and linked to the Ministry of Health.
Among other functions, it is responsible for establishing of regulations for clinical trials and drug prices, the monitoring of drug and MD prices and the inspection of factories in order to supervise the quality of drugs. Moreover, it analyses patent requests regarding pharmaceutical products and processes, in cooperation with the Brazilian Patent Office, Instituto Nacional da Propriedade Industrial (INPI).

  • Medicinal Products

Important laws and resolutions to be known are:
Law 5991/73, regulated by Decree 54170/74 setting the sanitary control of the drug trade, drugs and active pharmaceutical ingredients; Law 6360/76, regulated by Decree 74170/77, controlling the production of medicines; Resolution 136/2003 for the registration of new medicines. The ANVISA website which is primarily in Portuguese does not contain all updated laws and, accordingly, their complete version - as in some cases, part of the law is repealed, and part remains in force. For these reasons, an applicant for approval should seek the assistance of a professional regulatory expert.
Documents which have to be submitted for the registration procedure of a new drug are: Protocols of the clinical studies as well as registration petition forms, a proof of payment of Sanitary Surveillance Inspection, a copy of the company’s Operation License, and a Technical Responsibility Certificate. Moreover, a Good Manufacturing Practices certificate (GMP) is required of each importer of a product into Brazil, a process which can take up to 3-4 years to receive.

  • Medical Devices

Brazil’s medical device classification schemes are similar to those outlined in the European MDD 93/42/EEC.
The MD has to be classified according to ANVISA Resolution RDC 185/2001. Four classes I – IV with an increasing risk exist. The Cadastro registration applies for Class I + II which is a simplified pathway requesting the Brazil Good Manufacturing Practice certification (BGMP) but no audit. Class III + IV follow the Registro pathway which is more time-consuming and additionally stipulates an audit according to ANVISA resolution RDC 16/2013.
Class I + II require a Technical Dossier. For class III + IV, a Technical File including clinical data, clinical studies and additional device information has to be presented. In general, devices registered through the Cadastro pathway can be licensed within 4-6 months and, through the Registro pathway, within 12-18 months.
Some electro-medical devices subject to IEC 60601 as well as other MDs additionally need a certification by The National Institute of Metrology, Standardization and Industrial Quality (INMETRO). INMETRO usually accepts electrical safety certifications which already exist if they had been carried out by International Laboratory Accreditation Cooperation certified laboratories (ILAC).
As an important step in the regulatory process, a Brazil Registration Holder (BRH) has to be defined who holds a Company Working Allowance.
The Brazil Registration Holder prepares and submits the application - for all classes - to ANVISA which reviews the application. In case of approval, class I and II registrations do not expire; class III and IV registrations will be valid for 5 years.

  • Market Situation and Prospects

Brazil, Latin America’s largest healthcare market, currently the world’s eighth largest prescription drug market and the seventh largest economy in Medical Devices worldwide, expects a huge potential for further growth. In recent years, Brazil spent 9.5% of its Gross Domestic Product (GDP) on healthcare; and the significant medical device manufacturing sector benefits from government policy support.
However, Brazilian registration processes are characterized by ANVISA’s bureaucratic, overcharged system and long delays, a lot of them can be attributed to a time-consuming GMP certification procedure of up to 3-4 years. Manufacturers should seek the assistance of a professional regulatory expert in Brazil in order to meet with the complex processes, accelerate approval and reduce regulatory costs.
In view of this situation, Brazil has started to reform and improve its system, e. g. by means of allowing manufacturers to commence their application process before the GMP certificate has been obtained. A pilot programme exists which allows mutual recognition of GMP certificates between Brazil, USA, Canada and Australia.

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Regulatory Processes in South Korea

The Ministry of Food and Drug Safety (MFDS), previously known as Korea Food and Drug Administration, is the South Korean regulatory authority and the entry portal for the approval of drugs and medical devices. Moreover, it is responsible for the establishment and revision of drug laws, the GMP inspection and evaluation of drugs and post-marketing safety control. It establishes and revises standards of medical devices, provides technical support for GMP management and re-evaluates safety and efficacy of MDs.
It co-operates with the Ministry of Health and Welfare (MoHW) which takes the final decision of covering, coding and pricing of medical devices.
Important laws to be known are the: Pharmaceutical Affairs Act and the Medical Device Act.
The National Law Information Center as the Korean representative legal information web site is helpful for the research and identification of additional relevant law titles.

  • Medicinal Products

For new medicinal products, an Investigational New Drug Application (IND) has to be submitted to the MFDS. In case of a positive review by MFDS, the applicant may present a New Drug Application (NDA). As soon as the NDA is approved, the application dossier for drug approval can be prepared and adressed to the Drug Approval & Review Management Division.
On receipt of this documentation, the MFDS carries out an assessment of the application and generates a report. A review is then conducted by the Drug Evaluation Department, including technology, safety & efficacy data, clinical trial data, GMP data, Drug Master File data and the results of the initital assessment. In case of a positive result, the certificate of approval is being issued and the result of the drug approval is being released.

  • Medical Devices

Manufacturers and distributors who intend to market their MD in South Korea have to be approved by the MFDS. Companies without a registered office in South Korea must appoint a Korea License Holder as legal representative who is located in the country and coordinates the MD registration application to the MFDS. If a subsidiary exists, the subsidiary will be the license holder, and a consultant conducts the registration.
As next step, the MD has to be classified. Four classes (I – IV) according to an increasing risk for human health exist. According to recently implemented changes in 2015/2016, the regulatory pathway is as follows:
Prior to the medical device registration by MFDS, Classes II – IV require a Korea Good Manufacturing Practices (KGMP) audit and certification. For Class II devices, an on-site audit is carried out by a Third Party Auditor (TPA). Classes III – IV will be audited by a TPA and the MFDS. The certificate will be valid for three years.
Classes and Risks: Class I: low risk (e. g.: scissors, mechanical stethoscope) for which a pre-market notification is sufficient. It contains basic information and is sent to the Medical Device Information & Technology Assistance Center (MDITAC), a new MFDS unit dealing with low risk MDs. A pre-market notification for Class I does not expire.
Class II: low/medium risk (e. g.: infusion pumps); Class III medium serious /moderate risk (e. g.: spinal cage), Class IV: high risk (e. g.: coronary stent, cardiac pacemaker).
If the MD (Classes II-IV) has a substantial equivalent already sold in Korea, the submission of a General Technical File (GTF), similar to a US FDA 510 (k) submission, is expected by the MFDS. For Class II, third parties approved by the MFDS can evaluate the technical documentation.
Manufacturers of Class II - IV MDs without substantial equivalence have to prepare a SER Technical File (Safety and Effectiveness review)  submission which is comparable to a US Premarket Notification submission. Clinical data have to be included in the SER submission. In general, proven clinical trial data from OECD member countries will be accepted.
On approval of the medical device by MFDS, the applicant is authorized to market his device. Validity periods for device registrations (classes II-IV) do not expire as long as the MD and its usage remain unmodified.

 

Ecosystem of Nanomedicine:

EU Regulatory Process >> International Regulatory Processes >> Clinical trials >> Pricing and Reimbursement

Contact:

Should you have any question or require further information related to the ecosystem of Nanomedicine, please contact:

Dr. Klaus-Michael Weltring
Gesellschaft für Bioanalytik Münster e. V.
Tel. +49 (0)251 38450333
weltring@bioanalytik-muenster.de

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