Class II Special Controls Guidance Document: Intervertebral Body Fusion Device

Name of Guidance:
Class II Special Controls Guidance Document: Intervertebral Body Fusion Device

Status of Guidance:
Final

Name of Organization:
US Food and Drug Administration
Center for Devices and Radiological Health

Date of Guidance:
June 2007

Target Audience:
Sponsors submitting 510(k) applications for intervertebral body fusion devices

Laws and Regulations Referenced:
21 CFR 50 Describes how human subjects are to be protected in clinical trials
21 CFR 56 Describes the role of institutional review boards
21 CFR 801 Describes the labeling requirements for medical devices
21 CFR 807 Describes establishment registration and device listing for manufacturers and importers of medical devices
21 CFR 812 Outlines the requirements of an Investigational Device Exemption
21 CFR 820 Describes quality control for medical device manufacturing
21 CFR 888 Defines various orthopedic medical devices
Federal Food, Drug, and Cosmetic Act, Section 514 Describes performance standards for medical devices

Definitions:
Intervertebral body fusion device – A piece of medical equipment that is implanted in the spine to help two adjacent vertebrae fuse together into a single unit.

Class II (special controls) – The FDA classification for medical devices that pose moderate risk to a patient (as opposed to Class I General Controls, which pose minimal risk, and Class III Premarket Approval, which pose greatest risk).

510(k) submission – The application under Section 510(k) of the Federal Food, Drug, and Cosmetic Act, which provides a streamlined way to request FDA approval for a device that is substantially similar to another device the FDA has already approved.

Background:
Certain disorders of the spine may be treated by surgery that permanently fuses two or more vertebrae together. A device is implanted in the spine to help the vertebrae become one fixed unit. This device is called an intervertebral body fusion device. The US Food and Drug Administration (FDA) groups medical devices into three categories depending on how much risk they pose to patients. Class I devices involve the least risk, Class II devices involve moderate risk, and Class III devices involve the most risk. Intervertebral body fusion devices fall under Class II and require “special controls,” meaning their safety and effectiveness must be demonstrated in ways that are specific to their design and intended use. This guidance provides device makers with suggestions on how to demonstrate the safety and effectiveness of their proposed intervertebral body fusion devices.

Summary:
When seeking permission from the FDA to market a new intervertebral body fusion device, the device maker must submit a 510(k) application. This application describes the device in detail, compares it to similar devices that are already in use, and provides the results of safety testing. The goal of the application is to demonstrate that the device is “substantially equivalent” to a device the FDA has already approved. If the FDA agrees that the device is equivalent, the device maker does not have to test it in humans before marketing.

Intervertebral body fusion devices contain material that encourages bone growth. This speeds the process of fusion. This guidance applies only to devices that contain bone graft material, not to those that contain therapeutic biologics (for example, bone morphogenic protein). Those that contain biologics fall under Class III and require human testing before marketing.

The FDA recommends that device makers submit the following information to demonstrate “substantial equivalence” of their intervertebral body fusion devices:

Device description. This detailed description should include specifications, engineering drawings, and photographs of the device attached to a spine model. It should identify all materials used in the device, typically certain metals and plastics. It should also describe any special surgical instruments that are used to implant the device.

Risk analysis. Certain risks that are common to all surgeries must be addressed. These include infection, pain, and tissue injury. Other risks that are specific to the fusion device must also be described, such as injury to the vertebrae, and the risk that fusion will not occur.

Device materials. Two of the biggest concerns about spinal implants are whether they leach foreign substances into the body, and whether tiny fragments may break off over time and cause a harmful response. Device makers must test for these issues and report on the results. They must also simulate the aging of the devices to see whether results change over time.

Mechanical performance. The human spine is capable of a wide range of movement in a variety of directions. Therefore, spine implants must be able to withstand mechanical forces without breaking, slipping out of place, or otherwise failing. The FDA recommends that a device be able to withstand 5 million repetitions of a mechanical test without failure.

Animal testing. If a fusion device is to be used to treat a new disorder, if its design is considered novel, or if it is shown to produce particles that are different than previous devices, the FDA may require safety testing in animals. Animal testing may also be required if the materials used in the device have not been previously tested in the spine or if mechanical testing raises safety concerns.

Human testing. Sometimes the FDA will require a new intervertebral body fusion device be tested in humans. This typically happens when the device uses a new technology, is designed to treat a new disorder, or when animal testing raises safety concerns. In such cases, the device makers must apply for Investigational Device Exemptions.

As part of the 510(k) application, the device maker should also indicate whether the device will be packaged in sterile form (preferred) or whether it must be sterilized before implantation. They should also provide proposed labeling describing when and how the device is used, in what areas of the spine it may be implanted, as well as warnings and precautions.

Rationale:
The FDA uses the 510(k) provision to reduce the time and cost required to market a medical device that is substantially similar to one that is already FDA-approved. The goal of this system is to bring better devices to market faster while ensuring patient safety. This guidance addresses safety concerns that are specific to intervertebral body fusion devices, outlining the areas that device makers should cover in their 510(k) applications.

Resulting Recommendations:

· A successful 510(k) application for an intervertebral body fusion device must show that the device is substantially equivalent to another such device already approved by the FDA.

· The application should provide detailed specifications of the design and materials used in the device.

· The applicant should analyze the risks involved in the use of the device and explain how they have minimized each risk.

· All materials used in the device should be tested to determine whether they pose a risk of leaching foreign substances into the body.

· Materials should also be tested to determine whether their performance differs after long-term implantation.

· The device should be tested mechanically to determine that it will withstand the loads present in the human spine without failure.

· Animal testing may be required to demonstrate safety of materials and mechanics of the device, particularly if it is to be used to treat new conditions, or its design or mechanics differ substantially from previous devices.

· Human testing may be required through the IDE process if substantial equivalence of the device is not established through mechanical and animal testing.

Impact:
This guidance helps the makers of intervertebral body fusion devices write successful applications that address the FDA’s specific concerns about their product. This should enable device makers to bring their products to market faster, giving patients in the US access to the latest versions of these devices in a timely manner.

Amendment to Draft Guidance Concerning Donor Deferral for Transfusion in France Since 1980

Guidance Title:

Amendment (Donor Deferral for Transfusion in France Since 1980) to “Guidance” for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products”

Status:

Draft guidance

Date of Guidance:

August 2006

Organizations Releasing Guidance:
United States Food and Drug Administration (FDA) and the United States Department of Health and Human Services (HHS)

Link to the Guidance:
http://www.fda.gov/BiologicsBloodBaccines/SafetyAvailability/BloodSafety/ucm095

Target Audience:
Blood collection center personnel and healthcare providers

Laws and Regulations Referenced:
21CFR 607.3 Definitions, November 27, 2002
21CFR 610.41 Donor deferral, August 24, 2007

Definitions:
“Blood and blood product means a drug which consists of human whole blood, plasma, or serum or any product derived from human whole blood, plasma, or serum, hereinafter referred to as ‘blood product’” (21CFR 607.3)

Creutzfeld-Jakob Disease (CJD)-A rare and fatal degenerative disease in humans which has no cure at the present time and is related to, but not the same as, Mad Cow Disease, know as Bovine Spongiform Encephalopathy (BSE), found in cows.

Variant Creutzfeld Jakob Disease (vCJD)-A different type of Creutzfeld-Jakob Disease (BSE)

Donor deferral-The refusal to accept blood products from a potential donor

A blood transfusion-Here, transfer of blood from one person to another

Background:
This amendment was published after new findings were presented at a meeting of the Transmissible Spongiform Encephalopathies Advisory Committee (TSEAC). Studies showed that contaminated meat originating from the United Kingdom (U.K.) during the peak epidemic period caused deaths due to contaminated human blood from transfusions in France (see draft guidance amendment). The incubation period of up to 38.5 years determined the starting date of 1980 as the date after which potential donors should be deferred if they received transfusions in France. Other European countries were not considered as a threat for infection. Non injectable blood products from these donors may be used and should be labelled as such.

Summary:
This draft guidance, when finalized, will act as a means for blood collecting centers to prevent the transmission of CJD/vCJD from blood donors to other persons.

Rationale:
CJD/vCJD is suspected to have infected beef imported to France from the U.K. starting from1980, resulting from an epidemic of BSD in cows. Since cases of BSD transmission have been reported in the U.K. from donors having had blood transfusions in France, FDA has decided to defer potential donors in the U.S. with this history.

Resulting Recommendations:
FDA recommends that blood collection centers defer potential blood donors who have received blood transfusions in France since 1980. However, non injectable products may be used and should be labelled as such.

Impact
This amendment will enable American blood collection centers to prevent patients from being infected with CJD/vCJD. Deaths have already occurred in the U.K. due to this fatal and incurable disease and FDA would like to keep it out of the U.S.

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Adverse Reactions Section of Labeling for Human Prescription Drug and Biological Products — Content and Format

Name of Guidance
Guidance for Industry: Adverse Reactions Section of Labeling for Human Prescription Drug and Biological Products — Content and Format

Status of Guidance
Final

When was the Guidance released?
January 2006

Which organization released the guidance?
Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER)

Link to the Guidance
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM075057.pdf

Target audience
Sponsors preparing product labels for new or existing drugs and biologics, CDER and CBER reviewers

Laws and Regulations Referenced
21 CFR 201.56(a)(2): Drug labeling must be informative and accurate, never promotional or misleading. Labeling must be updated when new data makes the existing label incorrect.

21 CFR 201.57(c)(7): The adverse reaction profile of a drug must be described based on the entire safety database. Adverse reactions are defined as undesirable effects associated with the use of a drug.

21 CFR 201.57(c)(7)(i): Descriptions of adverse reactions must include enough background information (eg, frequency of adverse reaction in a clinical trial, nature of exposure to the drug) for healthcare providers to adequately interpret the data.

21 CFR 201.57(c)(7)(ii): Adverse reactions must be categorized by body system, by severity, in order of decreasing frequency, or some combination of these, as appropriate.

21 CFR 201.57(c)(7)(iii): Comparisons of adverse reactions between drugs must be supported with adequate and well-controlled clinical studies.

21 CFR 314.126: Adequate and well-controlled clinical studies are required to determine the effect of a drug.

Definitions

• Adverse event: Any undesirable medical event occurring during treatment that may or may not be related to use of a drug or biologic product.
• Adverse reaction: An undesirable effect (eg, symptom, change in laboratory parameters, or change in other measures of critical body function) caused by the use of a drug or biologic product. Commonly known as a “side effect.”
• Biologics: Products derived from living materials (eg, human, animal, or microorganism) that are meant to treat, prevent, or cure diseases in humans.
  
• Center for Biologics Evaluation and Research (CBER): The division of the FDA responsible for reviewing and approving applications from sponsors who wish to market biologics.
• Center for Drug Evaluation and Research (CDER): The division of the FDA responsible for reviewing and approving applications from sponsors who wish to market drugs.
• Drugs: Products derived from chemical compounds that are meant to treat, prevent, or cure diseases in humans.
• Postmarketing phase: Period after FDA marketing approval when a drug or biologic is available on the market.
• Sponsor: Company (usually pharmaceutical or biotechnology) that wishes to market and sell a drug or biologic.

Background
Regulation on product labels for pharmaceutical drugs and biologics was last published in 1979. In the intervening years, product labels became increasingly cluttered with unnecessary information making it difficult for healthcare providers to make consistently well-informed decisions about patient treatments. A 1995 Food and Drug Administration (FDA) telephone survey revealed that only 5% of office-based physicians consulted drug product labels when they needed drug information.

In December 2000, FDA proposed overhauling the structure of drug product labels to make them easier to use. The FDA solicited extensive feedback from physicians via surveys and focus groups to determine what information is most clinically useful. The resulting Physicians Label Rule (PLR) was published in January 2006.

“Adverse Reactions Section of Labeling for Human Prescription Drug and Biological Products — Content and Format” (“the Guidance”) was published in January 2006 as supporting documentation for the PLR. The goal of this Guidance is to help sponsors of pharmaceutical drugs and biologics create clearer, more useful drug labels.


Summary
The Adverse Reaction section of a drug label is critical in helping physicians determine whether the treatment is appropriate for a patient. It outlines which adverse reactions are associated with the drug, how severe those reactions may be, and who is affected. Inconsistencies in what information is included in the Adverse Reaction section and how the section is organized make it difficult for physicians to extract clinically useful information. The Guidance helps pharmaceutical and biotechnology companies write clear, easy-to-use Adverse Reaction section of drug labels.

Within the Guidance are 4 major sections addressing best practices: Adverse Reactions Section—Content and Format, General Principles for Selecting and Characterizing Data in the Adverse Reaction Section, General Principles for Presenting Adverse Reactions Data in a Table or List, and Updating the Adverse Reactions Section.

FDA recommends highlighting information that is useful in making clinical treatment decisions and eliminating irrelevant details. For example, the most common adverse reactions should be listed first and any adverse events that aren’t clearly associated with administration of the drug or biologic should be eliminated from the label.

FDA also provides suggestions as to how to present adverse reaction data in a clinically useful way, and reminds sponsors of the need to review and update labeling regularly.

While this Guidance was published in support of the mandatory changes to drug product labels described in the Physician Labeling Rule (PLR) of 2006, the Guidance itself is nonbinding. Sponsors may view the contents as recommendations and use their own judgement when creating drug labels so long as they satisfy all legal requirements.


Rationale
This Guidance is the product of extensive physician surveys and focus groups. Having solicited feedback from active practitioners, FDA believes the Guidance reflects the needs of healthcare providers.

Resulting Recommendations
Here are the major recommendations from each section of the Guidance:

Adverse Reactions Section—Content and Format

• Cross-reference serious or important adverse reactions that are discussed in other sections of the product label
• Highlight the most commonly occurring adverse reactions
• Make note of any adverse reactions that resulted in a significant rate of discontinuation or other clinical intervention in clinical trials
• Provide sufficient information about clinical trials conditions for healthcare providers to interpret adverse reaction data accurately

General Principles for Selecting and Characterizing Data in the Adverse Reaction Section

• Include an adverse reaction only if there is sufficient certainty about a causal relationship between administration of the drug and the adverse reaction
• Acknowledge any and all rare but serious adverse reactions associated with drug therapy, even if there is only a single event
• Calculate adverse reaction rates based on all reported reactions of that type, not a subset
• Use specific language to avoid misinterpretation
• Comparisons of the drug’s safety profile to that of another drug must be backed up with data from a well-controlled clinical study

General Principles for Presenting Adverse Reactions Data in a Table or List

• Use specific and clinically meaningful terms when describing adverse reactions
• Rank adverse reactions in the most appropriate order: frequency, severity, body system, or some combination of these

Updating the Adverse Reactions Section

• Sponsors should review the Adverse Reactions section for accuracy at least once per year
• If postmarketing data renders the existing Adverse Reactions section inaccurate, false, or misleading, the label must be updated accordingly

Impact
This Guidance makes the Adverse Reaction section of pharmaceutical drug and biologic drug labels easier to read and more useful for healthcare providers. This should help healthcare providers better understand the risks associated with a given treatment and decrease unanticipated adverse reactions.

Preparation and Review of Investigational Device Exemption Applications (IDEs) for Total Artificial Discs

Name of Guidance:
Preparation and Review of Investigational Device Exemption Applications (IDEs) for Total Artificial Discs

Status of Guidance:
Final

Name of Organization:
Food and Drug Administration
Center for Devices and Radiological Health

Date of Guidance:
April 2008

Target Audience:
Sponsors submitting IDE applications for artificial disc devices and FDA staff reviewing these applications

Laws and Regulations Referenced:

21 CFR 812.20 Describes when and how a sponsor should file an
Investigational Device Exemption (IDE) application
21 CFR 812.25 Outlines what should be included in a device investigation plan
21 CFR 812.27 Describes what should be included in a report of previous
investigations when submitting an IDE application
21 CFR 812.43 Describes how study investigators and monitors should be selected
21 CFR 860.7 Explains how device classification is determined based on safety and
effectiveness data
21 CFR Part 50 Describes how human subjects must be protected during clinical trials
21 CFR 50.25 Outlines what is involved in obtaining informed consent from subjects
in clinical trials
21 CFR Part 58 Explains what constitutes good laboratory practice for nonclinical
studies

Definitions:

Total artificial disc – An implant that replaces a vertebral disc in the human spine

Spinal system – The complete spinal implant including all parts

Component – An individual part of a spinal implant

Construct – The entire spinal implant system
Device/system – Interchangeable terms referring to the artificial disc

Background:
The artificial disc was first approved in the United States in 2004 to treat certain disorders of the spine.¹ The US Food and Drug Administration (FDA) still considers the artificial disc to be a new technology.^2(p13) Before the FDA will consider approving a new artificial disc, or an existing disc for a new use, the device must be tested in animals and humans. Because artificial discs pose substantial and unique health risks to patients, the FDA must grant permission before human studies are conducted. This permission is called an Investigational Device Exemption (IDE). In this guidance, the FDA issues recommendations specific to applying for an IDE for a total artificial disc device.

Summary:
This guidance provides recommendations to those who wish to apply for permission to test artificial discs in humans. The guidance outlines each section of the IDE application, and explains what type of information should be included.

The IDE application should begin with a detailed description of the artificial disc, including photographs, drawings, and material specifications. Following this description, the authors should include all information already known about the device or similar devices. This section, entitled Report of Prior Investigations, should describe previous results from testing in animals and humans. Animal data should establish that the device poses a minimal risk of toxicity, and provides basic functionality and performance over time. A variety of animals are used to test spinal devices, and the investigators must provide a rational for their choice of animal model.

The IDE should address the issue of wear debris, which is a major area of safety concern. Normal wear may cause the device to break down on a microscopic level, releasing particles of foreign material into the body. Investigators must test the effects of such particulate matter in animals prior to testing the device in humans.

Artificial discs are designed to preserve the motion of the spine, as opposed to traditional spinal fusion, in which motion is eliminated. Mechanical testing of the artificial disc should establish its ability to preserve the 6 primary motions, which are lateral bending (to the left and right), flexion and extension (to the front and back), and axial rotation (twisting left and right). The testing parameters should be presented in detail, any device failures documented, and the results interpreted.

Mechanical testing should be conducted, with results measured after 10 million repetitions of a given motion. The maximum range of motion the device allows should be documented. Such testing is typically performed using cadaver specimens.

Mechanical testing should also verify that the device is not prone to migration (moving out of position), or stress relaxation (in which the more flexible components of the device stretch out and lose elasticity over time). Testing should further establish that the surrounding bones of the spine (vertebrae) grow into the areas in which they come in contact with the device, providing stability (osseointegration) over time. They must also show that any coatings applied to the device do not wear off or break down over time.

Finally, prior investigations should examine the shelf life of the device to determine whether the components degrade with age.

The next section of the IDE application outlines the investigator’s plan to conduct a human study. After outlining the purpose of the study, the application should describe the design of the study in detail. The FDA recommends various criteria for including and excluding potential study participants. Many of these criteria relate specifically to the condition of the patients’ spines. Patients may be excluded because they have complex and interconnected spinal disorders, which would make it difficult to assess the performance of the device to be tested.

The FDA also addresses the fact that very few studies have tested the use of artificial discs at more than one spinal level in the same patient. They recommend that, if multi-level disc replacement is studied, enough patients are included to provide useful data, and that results be analyzed separately for patients with a one- and multi-level treatment.

The guidance describes various spinal problems that should exclude a patient from participating in a study of artificial discs, but allows the investigators to include such subjects if they provide an acceptable rationale.

The FDA recommends that subjects be followed for at least 2 years after surgery. They also recommend asking patients to consent to long-term follow-up that may continue for 5-10 years.

The guidance describes in detail the ways in which the failure or success of the device may be determined. These include x-ray images of device positioning, bone ingrowth, and spinal motion, as well as evaluations of the health of the spinal levels above and below the implant. They also include patient surveys about pain and their ability to perform daily activities.

The guidance lists potential risks that test subjects may face, some related to surgery, and others related specifically to the artificial disc. It recommends the IDE applicant address how the study design minimizes these risks.

In the interest of providing information on the long-term use of artificial discs, the FDA also recommends that any devices that are eventually removed from patients be analyzed.

Finally, the IDE application should include proposed packaging and surgeon instructions for the artificial disc. These instructions should describe not just the implantation of the device, but also the removal of the device or revision of the surgery if required.

Rationale:
This guidance provides important detail that is useful in submitting an artificial disc IDE. Artificial discs pose numerous safety risks and their effectiveness remains controversial. Therefore, it is appropriate that the FDA describe its specific areas of concern about these relatively new devices, and guide applicants in addressing them through appropriate testing, analysis, and documentation.

Resulting Recommendations:

· The investigator’s choice of animal model should be justified by providing a description of its relevance to the expected human use of the artificial disc.

· Wear debris should be evaluated in a small animal model and after 10 million repetitions of a given motion in a cadaver specimen.

· Animals should be studied after 3 and 6 months of device implantation.

· The range of motion allowed by the artificial disc should be documented.

· Artificial discs should be evaluated for their tendency to migrate or slip out of position.

· The durability of any coatings applied to the artificial disc should be tested.

· The shelf life of the artificial disc should be evaluated.

· Clinical trials should involve multiple centers, control groups, and patient randomization to test the safety and effectiveness of artificial discs.

· If artificial discs are to be implanted at more than one level in a single patient, the study should include enough such cases to provide adequate data, and these data should be analyzed separately from single-level cases.

· Patients should be excluded from the study if they have less than 5 mm of disc height between vertebrae, if they have a spinal problem other than the one being studied, if they are taking medications affecting bone metabolism, if they have myelopathy (spinal cord disorder),³ if they have certain degenerative diseases or deformities of the spine, or if they have had certain prior spine surgeries.

· Patients should be followed for at least 2 years after surgery, and preferably for 5-10 years.

· Endpoints for studies should include back, leg, neck, and arm pain, ability of patients to perform daily activities, device stability, amount of spinal motion, bone growth into device, disc height, and overall satisfaction of the patient.

· Successful bone ingrowth should be defined as covering at least 75% of the implant contact surface.

· Studies should examine the relationship between range of motion and pain to determine whether the preservation of motion is associated with reduced pain.

· Levels of the spine above and below the implant should be assessed for their disc height and range of motion.

· Studies should be designed to minimize patient risks, including breakage or slippage of the artificial disc, fracture of bone adjacent to the implant, loss of spinal motion, undue wear of the device, degeneration of adjacent vertebrae and discs, infection, and neurological side effects.

· Devices that are surgically removed should be studied for wear.

· Device packaging should include surgical instructions not only for implanting the artificial disc, but also for removing it or revising the original surgery.

Impact:
Artificial discs have the potential to treat a variety of spinal disorders while preserving motion in the spine. New devices may provide significant improvements on original designs, and their safety and efficacy must be studied in humans before widespread use. Moreover, the long-term effects of artificial disc implantation must be examined. To these ends, this guidance provides useful advice to device manufacturers and investigators who wish to obtain FDA approval to test their artificial discs in humans.

1. Feder BJ. An Alternative to Spinal Fusion. New York Times. December 24, 2004. Accessed May 23, 2011.

2. U.S. Food and Drug Administration. Guidance for Industry and FDA Staff: Preparation and Review of Investigational Device Exemption Applications (IDEs) for Total Artificial Discs. April 11, 2008. Accessed May 19, 2011.

3. Myelopathy. The Free Dictionary. Accessed May 23, 2011.

Brief Summary: Drug Metabolism/Drug Interaction Studies in the Drug Development Process: Studies In Vitro

Name of Guidance

Brief Summary: Drug Metabolism/Drug Interaction Studies in the Drug Development Process: Studies In Vitro

Status of Guidance

Final Guidance

Date of Guidance

April 1997

Released by

Center for Drug Evaluation and Research/Center for Biologics Evaluation and Research

Link to the Guidance

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072104.pdf

Target audience

Developers of drugs or biologics

Laws and Regulations

No laws or regulations were referenced in this guidance.

Definitions

Genetic polymorphism: A genetic variation that results in different forms or types of individuals among the members of a single species.

Excretion: The removal of a waste product of metabolism.

Metabolite: Any product of metabolism.

Prodrug: A substance that becomes a pharmacologically active after being chemically converted through metabolic processes.

Background

Drugs entering the body are eventually removed from the body. This can happen in one of two ways. One way is through the outright elimination of the drug through the process of excretion. The other way is through metabolism in which the drug is modified into one or more active or inactive metabolites. In addition, a drug can also interact with other drugs or foods a patient may be taking concurrently, causing the drug’s effect to be decreased (inhibited) or increased (induced), or causing the other drug’s effect to be inhibited or induced.

Summary

This guidance advocates investigating whether a drug is excreted unchanged or metabolized (and by what metabolic pathways) as early as possible (eg, before phase 2 testing) to determine how the drug is affected once it is in the body, including potential drug-drug interactions. This guidance pertains to drug molecules with a molecular weight <10 kD.

Rationale

It is important for a drug developer to know how a drug is removed from the body (by excretion or metabolism) because the process can significantly determine the safety and efficacy of a drug and, thereby, determine how it should be used. When a drug is metabolized, it may go through one or more metabolic (enzymatic) pathways, producing a modified form of the drug, called a metabolite.

If a drug is metabolized, it is necessary to know which metabolic route/routes are involved because genetic variations (aka genetic polymorphisms) from one person to the next can influence the rate of metabolism and potentially cause large differences in the concentrations of the drug and its metabolite in the blood. These differences can mean the difference between a safe drug concentration within the designated therapeutic window, a low concentration in which the drug will not have a therapeutic effect, or a high concentration in which the drug level will be toxic. Knowledge of a drug’s route(s) of metabolism can help a drug developer determine proper doses and necessary dose adjustments to ensure safe and efficacious use of the drug. It is also necessary to know about the nature of the metabolites produced by the metabolic process.

Resulting Recommendations

The FDA recommends drug developers to consider the following approaches to in vitro studies of drug metabolism and drug interactions:

1). Investigate metabolic processes (including route[s] of metabolism) and drug-drug interactions as early as possible in the drug development process, ideally prior to phase 2 studies (eg, as early as pharmacokinetic/phase 1 studies). The data produced will enhance the design of subsequent studies regarding clinical dose/response, interaction, and special populations.

2. Allow more concomitant drug use during studies early in the development process.

3. Identify significant metabolites and prodrugs and their pharmacological properties.

4. Identify metabolic differences in patient groups based on genetic polymorphisms, or other demographic factors (eg, age, race, gender). Doing so will assist in determining proper dosing in different patient populations, and, ultimately, dose adjustments.

5. Use the information gained from early identification of metabolic routes of elimination and metabolites in in vitro studies to guide the design of preclinical studies in animals to compare drug and metabolite exposure in humans and animals. Also conduct these studies in animals early in the course of drug development, as the information obtained can be used to help plan and interpret later clinical studies.

6. Give precedence to results from in vivo studies over results from in vitro studies. However, if in vitro studies determine that certain metabolic pathways are not involved in the elimination of a drug, in vivo testing may be unnecessary.

7. Conduct in vitro studies of drug at concentrations that will be relevant in vivo to identify if other substances inhibit or induce the effect of the drug.

8. Label for class effects for various metabolic enzymes. Use the data gained in in vitro studies about metabolic pathways to draw generalizations about what substances the drug may interact with and include this in the product labeling. For example, knowing that the drug is metabolized by CYP450 enzymes, certain inhibition and/or induction interactions can be expected, and dose adjustments may be necessary. Fully disclose on the labeling if generalizations are being made from in vitro studies.

Impact

Compliance with this guidance should help drug/biologic developers plan efficient, cost-saving drug testing plans, allowing them to gain an understanding of metabolic pathways and potential drug interactions early on in a drug’s development (eg, in the in vitro stage). Gaining this knowledge early in a drug’s development will help eliminate unnecessary subsequent testing that would be costly and inefficient at a later stage (eg, clinical) of development.