UNIT VII


Regulatory submissions for new products

 Regulated Product Submission (RPS) is a Health Level Seven (HL7) standard designed to facilitate the processing and review of regulated product information. RPS is being developed in response to performance goals that the U.S. Food and Drug Administration (FDA) is to achieve by 2012, as outlined in the Prescription Drug User Fee Act (PDUFA) In addition to the U.S., regulatory agencies from Europe, Canada, and Japan are at varying levels of interest and participation. Currently, the second release of RPS is in development.


Authorities such as the FDA receive numerous submissions that address a variety of regulatory issues. The information contained in these submissions is divided into large numbers of files, both paper and electronic. Often, files in one submission are related to files in earlier submissions. Because the information is divided into numerous files sent over time, it can be difficult to efficiently process and review the information.

While the general data layouts of all regulated products are the same, different product types have different lists of topics that must be addressed within the submission. Therefore, the goal of RPS is to create an HL7 XML message standard for submitting information to regulatory authorities. Each message includes the contents of a regulatory submission plus information such as metadata, which is necessary to process submissions.The Refined Message Information Model (R-MIM) shows the structure of a message as a color-coded diagram. R-MIM diagrams are designed to capture all required information for the efficient processing and review of regulatory submissions and to explain what each message consists of. This makes RPS general enough to handle all regulated products while containing enough information to allow regulators to support structured review.

The project to develop a regulated product submission standard was initiated on June 22, 2005.Release 1 was spearheaded by Jason Rock of GlobalSubmit, with the aim of creating one standardized submission format to support all of the FDA's electronic product submissions. The Health Level 7 message was created by leveraging existing human pharmaceutical experience, such as The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).RPS Release 1 provides the capability to cross-reference previously submitted material owned by the sponsor as well as append, replace and delete parts of the document lifecycle.Release 2, led by Peggy Leizear of the Office of Planning at the FDA, grants the ability to exchange contact information, classify submission content and handle multi-region submissions.The second release of RPS also handles two-way communication—The regulatory authority (e.g. FDA) will use RPS to send correspondence (e.g. request for additional information, meeting minutes, application approval) to the submitter.

RPS structure

As the industry moves away from paper submissions, global companies producing regulated products will benefit from having a published electronic submission standard. The label of “regulated product” applies not only to pharmaceuticals, but also extends to include food additives, medical devices and radiologics, human therapeutics, biologics and veterinary products.
The submitted information is structured as a collection of documents, organized by report sections. Multiple documents can be assigned to a single report section. The actual table of required and optional report sections varies from product to product and is defined by regulatory authorities. Since the same information can be submitted to support multiple applications, it is imperative that RPS allow for the reuse of data between applications.

RPS and eCTD

RPS is in many ways comparable to the electronic Common Technical Document.Ideally, the FDA would like to implement RPS as the next iteration of eCTD. The idea behind RPS and ICH’s eCTD is the same—the use of a standardized format for regulatory submissions, including PDF documents and SAS datasets. Although document contents are the same for eCTD and RPS, the internal XML structures are very different.RPS will offer two obvious advantages over eCTD. First, RPS will establish two-way communication between the submitter and all FDA-regulated product centers within the agency.Second, RPS will manage the life cycle of submissions by allowing cross-referencing of previously submitted information.This means that for electronic Investigational New Drug (IND) applications, New Drug Applications (NDA), and Biologic License Applications (BLAs), information need only be submitted once and previously submitted electronic documents can be applied to marketing applications.With RPS, archived electronic IND, NDA, and BLA submissions will be retrievable through standardized automated links.eCTD lacks this cross-referencing capability.

Regulatory Submissions in Electronic Format for Biologic Products

There are extensive requirements in the Code of Federal Regulations (CFR) regarding the information that needs to be submitted in order to seek approval to begin clinical testing of a biologic product and to market a biologic product. FDA has started the transition to a more automated electronic review process for these submissions.

Key Resources

Electronic Submissions Gateway Information on how to submit documents to FDA electronically.
-
Information on Electronic Submission of Regulatory Documents to CBER

Food and Drug Administration Electronic Submissions Gateway (Federal Register Notice) - 8/9/2006 ---August 9, 2006

FDA Announces the Use of New Electronic Drug Labels to Help Better Inform the Public and Improve Patient Safety----November 2, 2005

Individual Case Safety Reports (ICSR) - Specifications

SOPP 8110: Submission of Paper Regulatory Applications to CBER Effective Date: June 3, 2010

SOPP 8116: Using Electronic Signatures for Investigational and Marketing Regulatory Document Concurrence/Signoff Effective Date: April 23, 2012

SOPP 8117: Issuing Submission Numbers in Advance of the Receipt of the Electronic Submission Effective Date: September 24, 2007

Submission of Data in CDISC Format to CBER Effective Date: May 15, 2010 Updated: January 3, 2010

Guidances & Rules

Postmarketing Safety Reports for Human Drug and Biological Products; Electronic Submission Requirements, Proposed Rule (Federal Register 8/21/2009

Medical Device Reporting: Electronic Submission Requirements, Proposed Rule (Federal Register) 8/21/2009

Providing Regulatory Submissions in Electronic Format – Drug Establishment Registration and Drug Listing  ---Drug Establishment Registration and Drug Listing, May 2009

Indexing Structured Product Labeling ---June 12, 2008

Providing Regulatory Submissions in Electronic Format – Postmarketing Individual Case Safety Reports ---June 11, 2008

Providing Regulatory Submissions in Electronic Format -Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications ---June 11, 2008

Providing Regulatory Submissions to the Center for Biologics Evaluation and Research (CBER) in Electronic Format - Biologics Marketing Applications----November 1999

(Ref: www.fda.gov/BiologicsBloodVaccines/.../ucm163685.htm)


 What data is needed ?

Current Federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines. Because a sponsor will probably want to ship the investigational drug to clinical investigators in many states, it must seek an exemption from that legal requirement. The IND is the means through which the sponsor technically obtains this exemption from the FDA.
During a new drug's early preclinical development, the sponsor's primary goal is to determine if the product is reasonably safe for initial use in humans, and if the compound exhibits pharmacological activity that justifies commercial development. When a product is identified as a viable candidate for further development, the sponsor then focuses on collecting the data and information necessary to establish that the product will not expose humans to unreasonable risks when used in limited, early-stage clinical studies.
FDA's role in the development of a new drug begins when the drug's sponsor (usually the manufacturer or potential marketer) having screened the new molecule for pharmacological activity and acute toxicity potential in animals, wants to test its diagnostic or therapeutic potential in humans.  At that point, the molecule changes in legal status under the Federal Food, Drug, and Cosmetic Act and becomes a new drug subject to specific requirements of the drug regulatory system.
There are three IND types:
An Investigator IND is submitted by a physician who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed.  A physician might submit a research IND to propose studying an unapproved drug, or an approved product for a new indication or in a new patient population.
Emergency Use IND  allows the FDA to authorize use of an experimental drug in an emergency situation that does not allow time for submission of an IND in accordance with  21CFR , Sec. 312.23 or Sec. 312.34.  It is also used for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist.
Treatment IND is submitted for experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.
There are two IND categories:
Commercial
Research (non-commercial)

The IND application must contain information in three broad areas:
Animal Pharmacology and Toxicology Studies - Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans.  Also included are any previous experience with the drug in humans (often foreign use).
Manufacturing Information -  Information pertaining to the composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product.  This information is assessed to ensure that the company can adequately produce and supply consistent batches of the drug.
Clinical Protocols and Investigator Information - Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose subjects to unnecessary risks.  Also, information on the qualifications of clinical investigators--professionals (generally physicians) who oversee the administration of the experimental compound--to assess whether they are qualified to fulfill their clinical trial duties.  Finally, commitments to obtain informed consent from the research subjects, to obtain review of the study by an institutional review board (IRB), and to adhere to the investigational new drug regulations.

Once the IND is submitted, the sponsor must wait 30 calendar days before initiating any clinical trials.  During this time, FDA  has an opportunity to review the IND for safety to assure that research subjects will not be subjected to unreasonable risk.
 (ref: http://www.fda.gov/drugs/)


Requirements for gaining approval  US perspective  

 The value of the global pharmaceutical  market is expected to grow 5-7 percent in  2011, to USD 880 billion according to IMS  Health. The pharmaceutical industry is one  of the highly regulated industries, to protect  the health and well being of the masses. The  structures of drug regulation that exist today  i.e. drug laws, drug regulatory agencies, drug evaluation boards, quality control
laboratories, drug information centers, etc., have evolved over time in response both to the increasingly sophisticated pharmaceutical sector, and to the apparent needs of society. In some countries, the passing of comprehensive drug laws was a result of crisis-led change, when public demand led to the adoption of more restrictive legislations to provide stronger safeguards for the public. While drug laws provide the basis for drug regulation, regulatory tools such  as standards and guidelines equip drug  regulatory authorities with the practical  means of implementing those laws. Though  the world pharmaceutical regulations are in  continuous process of harmonization, they  can be divided into four major categories  based on the region, development strategy,
regulations and marketing interest.
1.         North America (US, Canada)
2.         Europe (Europe Union, Eastern
Europe)
3.         Rest of the World (Asia Pacific minus
Japan, ANZ, GCC, LATAM, CEE,
CIS)
3.         Japan
(LATAM: Latin America; CEE – Central East Europe; CIS – Commonwealth  Independent States; ANZ – Australia, New  Zealand; ROW – Rest of World)
Based on the economy and regulatory  control of the countries, these are grouped  into Regulated markets (US, EU, Japan,  ANZ) or Emerging Markets (ROW excluding  ANZ). They not only differ by their region,  but also in various other aspects like: how  they regulate the pharmaceuticals, the different guidelines for registering the drugs,  requirements to maintain the registrations,  registration fee, patent regulations and so
on.

 North America

Both USA and Canada are the major markets in the pharma industry. The US enjoys the largest player tag in terms of value in the pharma sector. It is valued approximately at USD 300 bn in 2009. The US has evolved from no regulation in the 18th century to one of the highly admired,
favorite regulatory authority in the world. The Food and Drug Administration (FDA) within the U.S. Department of Health and Human Services, regulates the drug approval system in United States with the help of six product centers including Center for Drug Evaluation and Research (CDER) and Center for Biologicals Evaluation and Research (CBER).

The drug registration procedure in US is majorly categorized into three parts, New Drug Applications (NDA), Abbreviated New Drug Applications (ANDA) and the mix of both which is widely called as 505 (b)(2) Applications. Fig. 1 illustrates the different kinds of routes available to get the registration of pharmaceuticals in US under the Section 505 of the ‘Federal Food Drug
and Cosmetic Act’. Till 1980s, mostly innovators dominated the US pharma market. The introduction of “Drug Price Competition and Patent Term Restoration Act of 1984” i.e. Hatch-
Waxman Act can be termed as birth of generic industry in US which helped generic
companies to flourish in US.

New Drug Application  (NDA):
This route is mainly used to get the  approval for New Chemical Entities (NCE)  which contains full reports of investigations  of safety and effectiveness (Pre-clinical,  Phase I to Phase IV study reports). NDA is  preceded by the Investigational New Drug  Application (IND).



505(b)(2) Application:

This application is same as full  NDA, except that this NDA is based on  “investigations … relied on by the applicant  for approval of the application …and for  which the applicant has not obtained a  right of reference or use. The applicant  majorly relies on published literature, FDA’s
Federal Register. This route is often used  for changes to an approved drug (Change in
dosage form, strength, indication etc.)

505(j) or ANDA or Generic Drug  Application:

This section is used for obtaining  marketing authorization of exact or close  copies of already approved drugs. The  application is submitted under any of the  below subsections of 505(j) of Federal Act




In Canada, the manufacturer may seek authorization to sell the product in Canada by filing a New Drug Submission with Health Products and Food Branch (HPFB). A New Drug Submission (NDS), typically contains scientific information about the product’s safety, efficacy and quality. It includes the results of both the pre-clinical and clinical studies. An Abbreviated NDS (ANDS) is used for a generic product. The generic product must be shown to be as safe and efficacious as the reference product usually established with bioequivalence studies. A Supplemental NDS (SNDS) must be filed by the manufacturer if certain changes are made to already-authorized products.
Such changes might include the dosage form or strength of the drug product, the formulation, method of manufacture, labeling or recommended route of administration. An SNDS must also be submitted to HPFB if the manufacturer wants to expand the indications (claims or conditions of use) for the drug product.

(Ref: http://www.ipapharma.org/pt/sep2011/15-20.pdf)


Regulating control over marketing and sales of medical products

General Controls for Medical Devices

Introduction

General Controls are the basic provisions (authorities) of the May 28, 1976 Medical Device Amendments (hereafter referred to as the Amendments) to the Food, Drug and Cosmetic Act, that provide the FDA with the means of regulating devices to ensure their safety and effectiveness. The General Controls in the Amendments apply to all medical devices. They include provisions that relate to adulteration; misbranding; device registration and listing; premarket notification; banned devices; notification, including repair, replacement, or refund; records and reports; restricted devices; and good manufacturing practices.

 Application of The Provisions of General Controls

Devices are classified according to the degree of difficulty in assuring their safety and effectiveness. Class I, which is synonymous with General Controls, is the least stringent of the three device classes provided in the Amendments. Before placing a device in Class I, the FDA must first determine that there is sufficient information available to support such a classification decision. Second, the FDA must decide that the General Controls are sufficient to provide reasonable assurance of the device's safety and effectiveness. Class I devices are not subject to the restrictions of Class II - Special Controls or Class III - Premarket Approval. In addition, Class I devices are not intended for use in supporting or sustaining life or to be of substantial importance in preventing impairment to human health, and they may not present a potential unreasonable risk of illness or injury

Unless otherwise exempted, the General Controls provisions of the Amendments are applicable to all devices regardless of their classification status.

KEY POINTS

General Controls are the basic authorities of the Medical Device Amendments that provide the FDA with the means of regulating devices to ensure their safety and effectiveness.
General Controls apply to all three classes of medical devices; however, they are the only level of controls that apply to Class I devices.
Class I devices are not intended to be:
For use in supporting or sustaining life;
Of importance in preventing impairment to human life; and may not
Present a potential unreasonable risk of illness or injury
General Controls include the provisions of the Act pertaining to:
Adulteration;
Misbranding;
Device registration and listing;
Premarket notification;
Banned devices;
Notification and repair, replacement, and refund;
Records and reports;
Restricted devices; and
Good Manufacturing Practices.

Adulteration

Medical devices are subject to the adulteration provisions of the FD&C Act under Section 501. The first two provisions of Section 501 define adulteration for most cases. A device is held to be adulterated if it includes any filthy, putrid, or decomposed substance, or if it is prepared, packed, or held under unsanitary conditions. The FD&C Act further states that a device is held to be adulterated if:

Its container is composed, in whole or part, of any poisonous or deleterious substance;
It contains, for the purposes of coloring only, an unsafe color additive; and
Its strength differs from, or its purity or quality falls below, that which it claims to represent.
When the Medical Device Amendments were added to the FD&C Act, certain conforming laws, applying specifically to medical devices, were added to Section 501. These provisions relate directly to other portions of the Amendments, granting the FDA authority to control performance standards; compliance with premarket approval applications and product development protocol requirements; banning; good manufacturing practices; and investigational device exemptions. These sections state that a device will also be considered adulterated if:

It is subject to a performance standard and does not comply with all the requirements of the standard;
It is a Class III device and fails to conform to the requirements for an approved premarket approval application or a notice of completion of a product development protocol;
It is a banned device;
It is in violation of good manufacturing practice requirements; or
It fails to comply with an Investigational Device Exemption (IDE).

 Misbranding

The misbranding provisions of the FD&C Act in Section 502 cover various aspects of drug and device labeling requirements. Many of the provisions apply to drugs and devices both; however, there are also specific misbranding provisions that apply to only drugs or only devices. The misbranding provisions that apply to both drugs and devices are listed in the following:

Drugs and Device Misbranding Provisions

A drug or device is deemed to be misbranded if:

Its labeling is false and misleading.
Its packaging does not bear a label containing:
the name of the place of business of the manufacturer, packer, or distributor, and
an accurate statement of the quantity of contents in terms of weight, measure, or numerical count.
Reasonable variations and exemptions for small packages may be permitted.
Any word, statement, or other required information is not prominently placed on the labeling or not clearly stated so as to be read and understood by the ordinary individual under customary conditions of purchase and use.
It is for use by man and contains any quantity of a narcotic or habit forming substance, unless its label bears the name and quantity or proportion of the substance or derivative and the statement "Warning - may be habit forming."
Its label does not bear adequate directions for use. The label must include warnings against use in certain pathological conditions or by children where its use may be dangerous to health, or against unsafe dosage or methods or duration of administration or application. Adequate directions and warnings must be present when it is necessary to protect the health of the user. Exemptions to this provision may be obtained. The phrase "adequate directions for use" pertains to over-the-counter drugs and device.
It is dangerous to health when used in the dosage or manner, or with the frequency or duration prescribed, recommended, or suggested in the labeling.
It does not comply with the color additive provisions listed under Section 706 of the FD&C Act.

Device Misbranding Provisions Added by the Amendments

The Amendments added new authority relating to the misbranding of medical devices. These new provisions state that a device is misbranded if:

The device's established name (if it has one) or its name in an official compendium, or any common or usual name, is not prominently printed in type at least half as large as that used for any proprietary name or designation. Exemptions from this provision may be granted.
A restricted device offered for sale in any State uses false or misleading advertising, or is sold, distributed, or used in violation of restricted device regulations under Section 820(e) of the FD&C Act.
A restricted device manufacturer, packer, or distributor fails to include in all advertisements or other descriptive materials:
a true statement of the device's established name, prominently printed, and
a brief statement of the intended uses of the devices and relevant warnings, precautions, side effects, and contradictions.
The device commercially distributed without FDA concurrence on a Section 510(k) submission.
The device is subject to a performance standard and it does not bear the labeling prescribed in that standard.
There is a failure or refusal to comply with any requirement prescribed under section 518 (Notification and Other Remedies); to furnish any material or information required by or under Section 518; or to furnish any material or information requested by or under Section 519 (Records and Reports on Devices).

 False or Misleading Labeling

The FD&C Act states that a drug or device is misbranded "if its labeling is false or misleading in any particular." "Labeling" includes the label and any other written, printed, or graphic material that accompanies a device and any of its wrappers or containers. Operating and servicing instructions are also regarded as part of the labeling. The labeling must bear adequate directions for use and any warnings needed to ensure the safe and effectiveness use of the device

Medical Device Labeling Information

 Establishment Registration Requirements

The Amendments require in Section 510 that manufacturers and other specified processors of devices register their establishments with the FDA and provide to the FDA a list of all devices manufactured in any establishment which they operate. Repackers, relabelers, and importers are also required to register with the FDA.

 Device Listing Requirements

Section 510 also states that medical device manufacturers must submit to the FDA a list of all devices they produce or process. This listing is maintained by the FDA.


Premarket Notification Requirements

Section 510(k) of the FD&C Act requires a manufacturer who intends to market a medical device to submit a premarket notification [510(k)] to the Agency at least 90 days before introducing the device onto the market. Premarket approval status is automatic for all devices found to be not substantially equivalent to preamendments devices. Based on the information provided in the notification, the Agency must determine whether the new device is substantially equivalent to a device already marketed or if it is not an equivalent device. A non equivalent device must have an approved premarket approval (PMA) application or be reclassified into Class I or Class II before being marketed. The final determination of whether a device is substantially equivalent or non equivalent resides with the FDA.

Premarket Notification [510(k)] - How to market a 510(k) Medical Device

 Banned Devices

Section 516 of the FD&C Act authorizes the Agency to ban devices that present substantial deception or unreasonable and substantial risk of illness or injury. The procedures for banning a device are described below. If the Agency determines, on the basis of all available data and information and after consulting with the appropriate classification panel, that a device intended for human use presents such deception or risk of illness or injury, which cannot be corrected by a change in the labeling, then the Agency may publish a proposed regulation to ban the device in the Federal Register. If the deception or risk can be corrected by a change in the labeling, the Agency must notify the responsible person of the deception or risk, the change in labeling needed to correct it, and the time period within which the change should be made. If the labeling is not changed in the specified time and manner, then the Agency may publish the proposed regulation. After affording all interested persons an opportunity for an informal hearing on the proposal, the Agency will affirm, modify, or revoke the proposed regulation. If the proposal is affirmed or modified, the Agency will publish a final regulation banning the device. In this case, the device can no longer be legally marketed on and after the date of publication of the final regulation, except under an approved investigational device exemption. If the proposed regulation is revoked, the Agency will publish a notice to this effect in the Federal Register.

 Notification and Other Remedies

Section 518 of the Act deals with notification and other remedies for protecting the public from faulty or fraudulent devices.

Purpose Of Section 518

The main purpose of Section 518 is protection of the public health. Section 518 offers FDA a way of assuring that hazardous products in the hands of consumers and other users are repaired, replaced, or refunded. In addition to the public health purpose of Section 518, this section also gives consumers a procedure for economic redress when they have been sold defective medical devices that present unreasonable risks.

Notification [518(a)]
Under this Section of the FD&C Act, FDA may require manufacturers or other appropriate individuals to notify all health professionals who prescribe or use the device and any other person (including manufacturers, importers, distributors, retailers, and device users) of the health risks resulting from the use of the violative device, so that these risks may be reduced or eliminated.

Threshold Requirements

FDA can order notification if:

A device presents an unreasonable risk of substantial harm to public health;
Notification is necessary to eliminate the risk; and
No more practicable means are available under the FD&C Act to eliminate the risk.

Procedures

The procedures for a notification order are simple. They involve only prior consultation with the persons who are to provide the notification.

Repair, Replacement, or Refund Provisions [518(b)]

Section 518(b) authorizes the FDA, after offering an opportunity for an informal hearing, to order manufacturers, importers, or distributors to repair, replace, or refund the purchase price of devices that present unreasonable health risks.

Basic Criteria

The FDA can order repair, replacement or refund (3-R) if, after opportunity for an informal hearing , it determines that:

The device represents an unreasonable risk of substantial harm to the public health;
The device was not designed and manufactured in accordance with the then prevailing state of the art;
The risk is not due to negligent installation, maintenance, repair, or use of the device by persons other than a manufacturer, importer, distributor, or retailer; and
Notification alone is insufficient, and repair, replacement, or refund is necessary.

Procedures

The procedures for repair, replacement, or refund are complex and could result in multiple orders, regulatory hearings, and much delay if FDA and the manufacturer, or other responsible person, are unable to agree on a plan for addressing a risk. The Agency must consider available alternatives. Both notification orders and repair, replacement, or refund orders are discretionary. Before ordering notification, FDA must determine that no more practical means are available under the FD&C Act to eliminate the risk. Although there is no requirement that such a determination be made before FDA orders repair, replacement, or refund, FDA must determine that notification alone is insufficient before ordering repair, replacement or refund.

FDA's alternatives to Section 518 are the following approaches:

Legal actions (seizures, injunctions, prosecutions);
Regulations (e.g., banning or imposing restrictions on sale, distribution or use); and
Recalls (under FDA's recall regulations).

Records and Reports On Devices

Section 519 of the Act authorizes the FDA to promulgate regulations requiring manufacturers, importers, and distributors of devices to maintain records and reports to assure that devices are not adulterated or misbranded.
Records and reports regulations promulgated under Section 519:

May not impose requirements that are unduly burdensome to the manufacturer, importer, or distributor;
Must state the reason and purpose for procedures requesting reports or information;
Must state the reason and purpose for submission of reports or information;
May not require that the identity of any patient be disclosed; and
May not require a manufacturer, importer, or distributor to maintain or submit reports or information not in his/her possession.
Records and reports requirements do no apply to:

Practitioners who prescribe or administer devices solely in the course of their professional practice;
Manufacturers or importers of devices used solely in research or teaching; and
Other persons exempt by regulation.

Restricted Devices

Under the provision of Section 520(e) of the Amendments, the FDA is authorized to restrict the sale, distribution, or use of a device if there cannot otherwise be reasonable assurance of its safety and effectiveness. A restricted device can only be sold on oral or written authorization by a licensed practitioner or under conditions specified by regulation. Devices such as cardiac pacemakers and heart valves, for example, require a practitioner's authorization. Hearing aids are restricted by a regulation which limits their sale to persons who have obtained a medical evaluation of their hearing loss by a physician within six months prior to the sale of the hearing aid. The labeling of hearing aids must provide information on their use and maintenance.

 Quality System Regulation, Good Manufacturing Practices

Section 520(f) of the Amendments authorizes the FDA to promulgate regulations requiring the methods used in, and the facilities and controls used for, the manufacturing, packing, storage, and installation of a device to conform to current good manufacturing practices (GMPs).

(Ref:http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/GeneralandSpecialControls/ucm055910.htm)

Regulations Codes of practice Promotional materials

The research-based pharmaceutical industry is the primary source of information about its own products and recognizes its responsibility for ensuring product information is accurate and does not mislead. Advertising and promotion are essential for informing healthcare professionals about new medicines and new uses for existing medicines. Self-regulation, via the IFPMA Code of Practice, supplemented by member association and company codes, sets standards for the ethical promotion of medicines.

Self-Regulation of Pharmaceutical Promotion

The international research-based pharmaceutical industry is committed to the improvement of the health of mankind through the research, development, production, marketing and safety surveillance of new medicines of reliable quality, in accordance with internationally defined standards of good practice.
As part of its commitment to health, the industry has an obligation and responsibility to provide accurate information about its products to healthcare providers in order to appropriately use prescription medicines.
Promotional activities (i.e. interactions and marketing practices) must be consistent with high ethical standards and information should be designed to help healthcare providers to provide the best care to patients. Information provided must be objective, truthful and in good taste. It must also conform to all relevant laws and regulations. Claims for therapeutic indications and conditions of use must be based on valid scientific evidence and must include clear statements with respect to side effects, contra-indications and precautions.
The same high standards of ethical behavior should apply to the promotion of pharmaceutical products in all countries, regardless of the level of development of their economic and health care systems.
These principles are embodied in the IFPMA Code Practice, first adopted as the foundation of a global approach self-regulation by the pharmaceutical industry in 1981 and updated frequently since then. Building on the experience of the 2006 Code and discussions with key stakeholders, the scope of the 2012 revision of the IFPMA Code has expanded beyond marketing practices to cover interactions with healthcare professionals, medical institutions and patient organizations. The IFPMA continues to support self-regulation as the most appropriate mechanism for ensuring ethical marketing and promotion of medicines by pharmaceutical companies it represents.

The International Federation of Pharmaceutical Manufacturers and Associations (IFPMA)

member companies engage in medical and biopharmaceutical research in order to benefit
patients and support high-quality patient care. Pharmaceutical companies, represented by
IFPMA, promote, sell and distribute their products in an ethical manner and in accordance
with all the rules and regulations for medicines and healthcare.
The following Guiding Principles set out basic standards to inform the 2012 IFPMA Code of
Practice which applies to the conduct of IFPMA Member Companies and their agents. This
helps ensure that their interactions with stakeholders are appropriate.
1 The healthcare and well-being of patients are the first priority for pharmaceutical
companies.
2 Pharmaceutical companies will conform to high standards of quality, safety and efficacy
as determined by regulatory authorities.
3 Pharmaceutical companies’ interactions with stakeholders must at all times be ethical,
appropriate and professional. Nothing should be offered or provided by a company in a
manner or on conditions that would have an inappropriate influence.
4 Pharmaceutical companies are responsible for providing accurate, balanced, and
scientifically valid data on products.
5 Promotion must be ethical, accurate, balanced and must not be misleading.
Information in promotional materials must support proper assessment of the risks and
benefits of the product and its appropriate use.
6 Pharmaceutical companies will respect the privacy and personal information of
patients.
7 All clinical trials and scientific research sponsored or supported by companies will be
conducted with the intent to develop knowledge that will benefit patients and advance
science and medicine. Pharmaceutical companies are committed to the transparency of
industry sponsored clinical trials in patients.
8 Pharmaceutical companies should adhere to both the spirit and the letter of applicable
industry codes. To achieve this, pharmaceutical companies will ensure that all
relevant personnel are appropriately trained.
(ref: http://www.ifpma.org/fileadmin/content/Publication/IFPMA_Code_of_Practice_2012.pdf)