A REGULATORY WRITING PRIMER FOR PREPARING AND SUBMITTING DOCUMENTS FOR THE UNITED STATED BIOMEDICAL INDUSTRY

by Joseph F. Tarsio, M.B.A., Ph.D.

July 17, 2013

I.Introduction

This Regulatory Primer is designed to benefit innovative thinkers who want to develop their understanding of the medical technology regulatory process in the United States. Readers may include those interested in learning about US regulations concerning Medical Devices, Pharmaceuticals, Biologics, and other biotechnology-related products. Whether you are a student, engineer or a doctor, or other professional interested in increasing your knowledge in this area, you will benefit greatly from this course.

This Regulatory Primer will be a self-study course targeted towards professional interested in starting a career in regulatory writing for the United States Pharmaceuticals, Medical Device, and Biotechnology Products Industry. Within the coursework, students will be provided the opportunity to take multiple-choice tests. At the end of this document the correct answers to the questions for each test will be supplied so that students may gauge their understanding of this subject matter. If they finish a test with a score of less than 75% of the correct answers, it is recommended that the subject matter pertaining to that test be reviewed again by the student. A correct score of 75% or above is considered acceptable mastering of the subject matter.

II.How are Medical Products Classified: Distinction Amongst Pharmaceutical Drugs, Biologics, Medical Devices, or Combination Products- Distinctions

a) Medical technology involves the application of various methods and systems to derive new medical products such as pharmaceutical drugs which can be chemically synthesized;naturally-derived compounds such as proteins, glycoproteins or lipids (collectively called “biologics”); or medical devices; to diagnose, prevent, or treat human disease.

b) Drugs are developed to prevent the occurrence of disease or to treat a prevailing disease in humans. Drugs may be comprised of “small molecule” compounds synthesized or purified from a natural source. An example of a small molecule drugis benzylpenicillin, commonly known as penicillin G, a β-lactam antibiotics discovered by Sir Alexander Fleming in 1928, which is produced and purification from the Penicilliummold. In 1942,U.S.-made penicillin G produced by Merck & Company was used for the first time in human patients to treatstreptococcal septicemia. Since then many different chemically modified derivatives of penicillin G have been produced and approved for use in the United States by the Food and Drug and Drug Administration (FDA). Another example of a small molecule drug is sildenafil, a compound that was synthesized by a group of pharmaceutical chemists working at Pfizer and the active component in Viagra which was patented in 1996 and approved for use in males for erectile dysfunction by the FDA on March 27, 1998.

c) Drugs that don’t exists in plentiful supply from a natural source may also be developed from "new" biotechnology techniques that enable scientists to modify the genetic material in cells, tissue or whole organisms at the cellular or molecular level. These latter compounds are called “biopharmaceuticals,” “biologic compounds,” or just “biologics.” For example bacteria and mammalian cells may be used to produce a protein that can be administered as a drug targeted to correct medical disorders in human patients. An example would be the insertion of the human insulin gene into a bacteria and the production of human insulin through fermentation. The human insulin produced would next be purified to a high degree and formulated into a drug that can be repeatedly administered to human patients. This corrects disorders in glucose production in human diabetics who have insufficient levels of insulin or a defect in the ability of their own body’s insulin to properly regulate glucose metabolism. This would be the use of a genetically engineered molecular drug to treat a chronic disorder in human patients. Another example would be the acute administration of a “clot-buster” drug comprised of genetically engineered and manufactured tissue plasminogen activator (TPA) to decrease a severe blockage in the blood vessels that supply the human heart with nourishment. The latter would be a biologic produced to treat a life-treating acute disorder.

d) Besides pharmaceutical and biopharmaceutical drugs to treat or prevent disease, medical devices need to enter a regulatory process in order to be approved for use in the United States.

Medical devices range from simple tongue depressors and bedpans to complex programmable pacemakers with micro-chip technology and laser surgical devices. In addition, medical devices include in vitro diagnostic products, such as general purpose laboratory equipment, reagents, and test kits, which may include monoclonal antibody technology. Certain electronic radiation emitting products with medical application and claims meet the definition of medical device. Examples include diagnostic ultrasound products, x-ray machines and medical lasers.

One description ( a medical device provided by a medical device development company is:

“Any instrument, apparatus, appliance, material, or other article, whether used alone or in combination, including the software necessary for its proper application intended by the manufacturer to be used for human beings for the purpose of:

  • diagnosis, prevention, monitoring, treatment, or alleviation of
    disease;
  • diagnosis, monitoring, treatment, alleviation of, or
    compensation for an injury or handicap;
  • investigation, replacement, or modification of the anatomy or
    of a physiological process;
  • control of conception; and which does not achieve its principal
    intended action in or on the human body by pharmacological,
    immunological, or metabolic means, but which may be
    assisted in its function by such means.”

According to the FDA, if a product is labeled, promoted or used in a manner that meets the following definition in section 201(h) of the Federal Food Drug & Cosmetic (FD&C) Act, it will be regulated by the FDA as a medical device and is subject to premarketing and postmarketing regulatory controls. A medical device is:

"an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:

  • recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them,
  • intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or
  • intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of it's primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes."

This definition provides a clear distinction between a medical device and other FDA regulated products such as drugs. If the primary intended use of the product is achieved through chemical action or by being metabolized by the body, the product is usually a drug.

See

e) When the intended use of a product is achieved by combining any of two or more of the above diagnostic or treatment typesit is classified as a combination device.

As defined in 21 CFR § 3.2(e), the term combination product includes:

“(1) A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity;

(2) Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products;

(3) A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose; or

(4) Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.” See:

Combination products (i.e., drug-device, drug-biologic, and device-biologic products) are increasingly incorporating cutting edge, novel technologies that hold great promise for advancing patient care. For example, innovative drug delivery devices have the potential to make treatments safer or more effective, or more convenient or acceptable to patients. Drug-eluting cardiovascular stents have the potential to reduce the need for surgery by preventing the restenosis that sometimes occurs following stent implantation. Drugs and biologics can be used in combination to potentially enhance the safety and/or effectiveness of either product used alone. Biologics are being incorporated into novel orthopedic implants to help facilitate the regeneration of bone required to permanently stabilize the implants.

Stakeholders report that FDA can expect to receive significantly more combination products for review as technological advances continue to merge therapeutic products and blur the historical lines of separation between the various medical product regulated by the FDA. Therefore combinations products are regulated by more than one regulatory division of the FDA ( This most likely will be combined regulation by FDA's new Office of Combination Products (OCP) and by one of three product centers -- the Center for Drug Evaluation and Research, the Center for Biologics Evaluation and Research, or the Center for Devices and Radiological Health – the latter division assigned to the combination product by the OCP (see Section III below).

Examples of recently approved FDA combination products include 1) the incorporation of Neupro (the drug-rotigotine) into a transdermal skin patch to treat symptoms of early Parkinson's disease (a device containing a drug), 2) dental bone grafting material with a growth factor (a device plus a biologic), and 3)a system that integrates a glucose meter and an insulin pump with a dose calculator into one device as a fully automated glucose monitoring and insulin delivery system to be used by human diabetic (contains multiple devices, software, and a drug). See:

III.FDA’s Regulatory Divisions

The FDA`s Center for Devices and Radiological Health (CDRH) is responsible for regulating firms who manufacture, repackage, relabel, and/or import medical devices sold in the United States. In addition, CDRH regulates radiation-emitting electronic products (medical and non-medical) such as lasers, x-ray systems, ultrasound equipment, microwave ovens and color televisions (

Manufacturer assistanceregarding medical devices can be obtained from the Division of Small Manufacturers, International and Consumer Assistance (DSMICA) or by writing to

FDA/CDRH/OCER/DSMICA (HFZ-220)
1350 Piccard Drive
Rockville, MD20850-4307U.S.A.

See:

If your product is not a medical device but regulated by another Center in the FDA, each component of the FDA has an office to assist with questions about the products they regulate. In cases where it is not clear whether a product is a medical device there are procedures in place to use the DSMICA Staff Directory to assist you in making a determination. See

Human pharmaceutical drugs are regulated by FDA's Center for Drug Evaluation and Research (CDER).

Biological products which include blood and blood products, and blood banking equipment were originally solely regulated by FDA's Center for Biologics Evaluation and Research (CBER). However, on October 1, 2003, FDA transferred certain product oversight responsibilities from the Center for Biologics Evaluation and Research (CBER) to the Center for Drug Evaluation and Research (CDER) ( See also

FDA's Center for Veterinary Medicine (CVM) regulates products used with animals.

Therefore, the FDA is organized into various components which each have separate responsibilities. Each component of FDA has an office to provide technical assistance to manufacturers. This includes assistance to manufacturers of human drugs, animal drugs and devices, biological products, food products and cosmetics. Besides the CDHR listed above, the following offices can also be contacted for technical assistance for products regulated by the FDA (see :

Human Drug Products:

Center for Drug Evaluation and Research (CDER)
Office of Training and Communication
Division of Drug Information (HFD-240)
5600 Fishers Lane, Room 12B-05
Rockville, MD 20857 U.S.A.
Telephone Number: 301-827-4573
Fax Number: 301-827-4577
CDER Home Page:
Email Address:

Biological Products:

Center for Biologics Evaluation and Research (CBER)
Office of Communication, Training and
Manufacturers Assistance (HFM-43)
1401 Rockville Pike, Room 200N
Rockville, MD 20852-1448 U.S.A.
Telephone Number: 301-827-2000 or 800-835-4709
Fax Number: 301-827-3843
Fax-On-Demand:888-223-7329 or 301-827-3844
CBER Home Page:
Email Address:
Manufacturers Assistance and Technical Training Team: MATT@.cber.fda.gov
Consumer & Health Professional Assistance:.

Animal Drugs and Devices:

Center for Veterinary Medicine (CVM)
Communications Staff
7519 Standish Place, HFV-12
Rockville, Maryland 20855
Telephone Number: 301-827-3800
Fax Number: 301-827-4065
CVM Home Page:
Email Address:

Food Products and Cosmetics:

Center for Food Safety and Applied Nutrition (CFSAN)
Outreach and Information Center
5100 Paint Branch Parkway, HFS-555
College Park, MD 20740-3835
Telephone Number: 1-888-SAFEFOOD (1-888-723-3366)
Telephone Number: 301-436-2600
Fax Number: 301-436-2618
CFSAN Home Page:
Email Address:

Combination Products:

The medical products industry expects the FDA to receive significantly more combination products for review as technological advances continue to merge therapeutic products and blur the historical lines of separation between FDA's medical product Centers.

Since combination products involve components that would normally be regulated under different types of regulatory authorities, and frequently by different FDA Centers, they also raise challenging regulatory, policy, and review management issues.

To address these concerns, FDA's Office of Combination Products (OCP) was established on Dec. 24, 2002, as required by the Medical Device User Fee and Modernization Act of 2002 (MDUFMA). The law gives the Office broad responsibilities covering the regulatory life cycle of drug-device, drug-biologic, and device-biologic combination products. However, the primary regulatory responsibilities for, and oversight of, specific combination products will remain in one of three product centers -- the Center for Drug Evaluation and Research, the Center for Biologics Evaluation and Research, or the Center for Devices and Radiological Health -- to which they are assigned.

OCP duties include:

  • assigning an FDACenter to have primary jurisdiction for review of a combination product
  • ensuring timely and effective premarket review of combination products by overseeing reviews involving more than one agency center
  • ensuring consistency and appropriateness of postmarket regulation of combination products
  • resolving disputes regarding the timeliness of premarket review of combination products
  • updating agreements, guidance documents or practices specific to the assignment of combination products
  • submitting annual reports to Congress on the Office's activities and impact.

The Office also has assumed the functions of the Combination Products Program begun in 2002 within the FDA Office of the Ombudsman. Among these functions:

  • working with FDA Centers to develop guidance or regulations to clarify the agency regulation of combination products
  • serving as a focal point for combination products issues for internal and external stakeholders.

See:

IV. Details Regarding Regulatory Planning, Documents Preparation, and FDA Submissions to Gain Market Approval of Drugs in the US

A. The Drug Regulatory Process

A description of the Drug Development Process is given in Figure 1. It is a general description of a successful scheme from the identification of a drug candidate and the movement of a pharmaceutical compound through the drug development pipeline that includes preclinical and clinical development, FDA approval, and post-approval monitoring. The development program for each specific drug candidate will vary somewhat from thisgenerally described process. In addition, there can be no assurance that a drug candidates will successfully complete the entire process, since the drug process for any specific candidate may end prematurely before US market approval is gained.

The Drug Development Process is comprised of the following:

1. Preclinical Testing

Laboratory tests and animal studies are conducted. These studies show biological activity of the compound in relation to animal models of the targeted human disease or condition. Along with these results, the compound is evaluated for toxicology.

2. Investigational New Drug Application (IND)

An Investigational New Drug Application (IND) is filed with the U.S. Food and Drug Administration (FDA) after completion of preclinical testing. This allows testing of the drug in humans to begin.

  1. Phase I Clinical Trials

Small numbers of healthy volunteers are tested with the drug to determine its duration in the bloodstream and the drug’s initial safety profile. This study also provides information about how the drug is absorbed, distributed, metabolized, and excreted in humans.

  1. Phase II Clinical Trials

Approximately 100-500 volunteer patients with the disease or condition are tested with the drug to assess its effectiveness.

  1. Phase III Clinical Trials

A large number of patients (usually at least 1,000-5,000 subjects) in clinics and hospitals are tested and monitored closely by physicians to confirm efficacy and to identify any adverse effects.

  1. New Drug Application (NDA)
  1. If the drug is determined to be safe and effective, an New Drug Application (NDA)

is filed with the FDA at completion of the clinical trials.

  1. Drug Approval

Once the FDA approves the NDA, physicians may prescribe the drug to patients.

  1. Phase IV

If adverse effects are reported by patients taking the drug, the FDA may require Phase IV trials to evaluate long-term effects of the drug.

Figure 1. The Drug Development Process

Discovery Research