Guidance for Industry: Diabetes Mellitus--Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes

Name of Guidance:

Guidance for Industry: Diabetes Mellitus—Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes

Status of Guidance:

Final

Date of Guidance:

December 2008

Name of Organizations Releasing the Guidance:

U.S. Department of Health and Human Services (HHS)

U.S. Food and Drug Administration (FDA)

Centers for Drug Evaluation and Research (CDER):

Target Audience:

Sponsors of clinical trials for drugs and therapeutic biologics to treat type 2 diabetes mellitus

Guidance Laws and Regulations Referenced Guidance:

Draft guidance: Diabetes Mellitus Drugs and Therapeutic Biologics for Treatment and Prevention, March 2008: Guidance providing recommendations for sponsors for the design and conduct of phase 2 and 3 clinical trials for evaluating new drugs and biologics to treat type 2 diabetes mellitus

Definitions:

BLA:  Biologic Licensing Application. An application submitted to FDA for approval of interstate marketing of a new device.

Blinded: Here, a blinded assessment means the person or persons doing the assessment have no information about the subject or treatment.

Cardiovascular endpoint: an event that can be used as a measure of cardiovascular risk, eg, myocardiatl infarction (heart attack), stroke, or hospitalization for cardiovascular procedures

NDA: New Drug Application. An application submitted to FDA for approval of interstate marketing of a new drug.

Sponsor: A company or an institution that finances a clinical trial.

Background:    

Diabetes mellitus is a chronic disease of epidemic proportions causing a significant worldwide financial burden. Because of its importance in the world, many therapies are being used and developed. The disease is caused by defective insulin secretion by the pancreas, resistance to insulin, or both. This leads to abnormal levels of sugar in the blood (high or low blood glucose). Type 1 and 2 diabetes are heritable; type 1 is more severe and insulin treatment is indicated, whereas type 2 can be controlled without insulin. Patients with type 2 diabetes represent an approprieate group in which new treatments for diabetes can be tested, and in whom long-term cardiovascular risk can be assessed. Cardiovascular events that may be used as endpoints for risk assessment include death, myocardial infarction, stroke, or hospitalization for cardiovascular procedures.

Summary:

The present guidance is a final guidance issued after a draft guidance of March 2008 which gave recommendations for developing drugs and biologics for treatment of diabetes mellitus. At a meeting in July 2008, the Endocrinologic and Metabolic Drugs Advisory Committee of the FDA decided that assessment of cardiovascular risk should be addressed in a final guidance to be implemented immediately. This final guidance was issued in December 2008. Another final guidance will be issued separately addressing currently marketed drugs and biologics.

Rationale:

Because diabetes mellitus is associated with abnormal lipid metabolism, cardiovascular risk is elevated in these patients. The FDA recommends that new drugs and biologics in development should be assessed to avoid excessive cardiovascular risk in patients with diabetes mellitus.

Resulting Recommendations:

1) For studies in the planning stage:

·        Sponsors of phase 2 and 3 clinical trials should appoint an independent committee to define and assess cardiovascular endpoints in a blinded manner.

·        Sponsors should design phase 2 and 3 clinical studies so that meta-analyses can be performed at completion of the study, taking into account several study design characteristics. Patients at higher risk of cardiovascular events should be included in the studies (eg, patients who are elderly, with advanced disease, or with renal impairment). Longer studies may be required to assess long-term cardiovascular risk (ie, 2 years compared to the usual 3 to 6 months).

2) For completed studies before submission to FDA for an NDA or BLA:

·        Meta-analyses should be performed comparing treated patients with control groups to demonstrate absence of excessive cardiovascular risk. If the analysis is inconclusive, 1 or more large clinical trials for safety may be required to satisfy statistical requirements.

·        Sponsors should show results of meta-analyses using graphical and tabular displays of data that can be verified.

Impact:

Drugs being developed for treatment of type 2 diabetes mellitus will be evaluated for cardiovascular safety before being submitted to FDA for NDAs and BLAs. Clinical trials will be longer (to evaluate long-term safety) and more costly. Patients with the disease will be protected from excessive cardiovascular risk caused by new drugs or biologi

Brief Summary: uideline for the Format and Content of the Human Pharmacokinetics and Bioavailability Section of an Application

Name of Guidance

Guideline for the Format and Content of the Human Pharmacokinetics and Bioavailability Section of an Application

Status of Guidance

Final Guidance

Date of Guidance

February 1997

Released by

Center for Drugs and Biologics, Federal Drug Administration, Department of Health and Human Services

Link to Guidance

Target audience

Developers of drugs/biologics

Laws and Regulations

This guidance refers to the following regulations and amendments:

· CFR 21 Part 320 - Bioavailability and Bioequivalence Requirements - defines biopharmaceutic vocabulary and lays out the appropriate steps for establishing the bioavailability of drugs

· Waxman-Hatch Act (aka Drug Price Competition and Patent Term Restoration Act of 1984) - this Act established the Abbreviated New Drug Application (ANDA) process for generics, providing a faster review track for applications to market generic versions of brand-name drugs without running costly and duplicative clinical trials; instead this Act requires that generic drugs demonstrate bioequivalence to the already approved dosage form

· Federal Food, Drug and Cosmetic Act – the series of laws empowering the FDA to oversee the safety of drugs, food, and cosmetics in the United States

· 21 CFR 10.90 (Food and Drug Administration regulations, recommendations, and agreements) – description of the types of documents issued by the FDA in the form of regulations, recommendations, and agreements

Definitions

Abbreviated New Drug Application (ANDA): application used for a generic drug seeking approval from the US FDA for sale and marketing

Analysis of variance – a statistical test(s) that examines the role of selected factors in the variance of response for a particular variable

AUC - area under the curve; pharmacology term describing the concentration of a drug in the blood over time; used to estimate the bioavailability and total clearance of drugs

Bioavailability: the amount of drug that actually reaches the target area in the body after it has been administered

Bioequivalence: state in which two different formulations of the same drug in the same dose amount have comparable bioavailability, with the same amount of each drug reaching the same target tissue and having similar effects

Biopharmaceutics: area of pharmaceutical science focusing on what happens to a drug once it enters the body and travels to the target area, including metabolism, elimination

C_max- maximum or peak plasma concentration (after administration and before a second dose is administered); state in which the rate of drug absorption equals the rate of elimination

Confidence interval – the measure of confidence that a result will fall within a limited range of numbers; the smaller the confidence interval, the more likely the result is not due to chance

Kel - elimination rate constant that represents the amount of drug eliminated from the body per unit of time.

Pharmacokinetic linearity – state in which the dose concentration is proportional to that dose and the rate of elimination of the drug is proportional to the concentration; dose-independent

New drug application (NDA): application a drug company gives to the US FDA when seeking approval to sell and market a new drug for which there is no already approved equivalent

Pharmacokinetics: The area of pharmacology focusing the effect of body processes on drugs, including absorption, distribution, metabolism, and elimination

Sensitivity – used to assess the results of diagnostic and screening tests, “sensitivity” indicates the proportion of diseased persons in a screened population, measuring the probability of correctly diagnosing a condition

Specificity – used to assess the results of diagnostic and screening tests, “specificity” indicates the proportion of nondiseased persons, measuring the probability of correctly identifying a nondiseased person

T_max – the amount of time it takes a drug to reach maximum plasma concentration (C_max) following administration

Vd - volume of distribution; in pharmacology, the ratio of the total amount of drug in the body to the concentration of the drug in the blood

Background

The New Drug Application (NDA) and abbreviated new drug application (ANDA) for the United States Federal Drug Administration (FDA) include a Human Pharmacokinetics (PK) and Bioavailability section. Here a drug company will detail what tests and procedures they conducted to demonstrate what a drug does once it enters the body, and how certain processes in the body affect the drug and, ultimately, determine the effect of the drug.

Specifically, this section of the application must describe the bioavailability of the drug, particularly how much of a drug reaches the target area for a given dosage form. If the drug being tested is a generic form of an already approved drug, this section must demonstrate the generic’s bioequivalence to the already approved drug. The PK tests must show that the same amount of the generic drug in a given dosage form reaches the target tissue as the currently approved drug.

Summary

This guideline suggests how to prepare the section of the NDA and ANDA that deal with the pharmacokinetics and bioavailability of the drug seeking approval for sale and marketing.

Rationale

Drug developers conduct various tests on a drug at different stages of drug development. Deciding what tests are necessary and useful can be difficult. Knowing exactly what data the FDA will be looking for in an NDA or ANDA would help drug companies choose appropriate tests to conduct. An FDA guidance that delineates the types of tests that will reveal these data and outlines a format to follow when writing up the NDA or ANDA will help streamline the drug review and approval process, avoiding unnecessary, wasteful steps.

Resulting Recommendations

The guideline recommends including data collected from the following studies. Drug developers should choose those studies that are appropriate for their particular drug.

· Pilot/background studies – use small patient pool; assess absorption, distribution, metabolism, and elimination of study drug to help in design of preliminary clinical trials and kinetic studies; suggest using radioisotope techniques

· Bioavailability/bioequivalence studies – determine how quickly and how much of the active ingredient of a drug is absorbed by the body and reaches the target area of the body

· PK studies – demonstrate how long the drug is active in the body and what are the resulting concentrations of related metabolites; studies showing how quickly drug is absorbed into blood and then eliminated are of especial importance, particularly regarding changes in kinetic parameters with dose (ie, dose-dependent kinetics) within the recommended clinical dosing range, and influences of demographics, disease states, other drugs, drug binding, and the effect of drug on special populations (eg, patients with impaired hepatic or renal function).

· Other in vivo studies - test bioavailability in animals or humans using pharmacological or clinical endpoints

· In vitro studies – dissolution studies used to determine how quickly the active ingredient of a drug releases from the dosage form and, thereby, portray dosage form and ensure consistent performance of drug

The guideline also recommends that applicants follow a particular format in presenting the data for the NDA and ANDA. The suggested format includes the following sections, templates for which are provided as attachments to the NDA and ANDA.

· Summary of studies – summary of all in vivo biopharmaceutic studies presented in table format, with most important studies listed up front

· Summary of data and overall conclusions – provided in table format, including data on PK parameters (ie, peak concentration [C_max], area under the curve (AUC), time to reach peak concentration (T_max), elimination constant (Kel), distribution volume (Vd), plasma and renal clearance, and urinary excretion.

· Drug formulation – all formulations of drug used during drug development should be described and related studies identified, as well as any changes in manufacturing or formulation

· Analytical methods – description of methods used in in vivo biopharmaceutic study

· Dissolution – information regarding dissolution of each strength and dosage form of formulation seeking approval, including comparison dissolution study of drug lot used in in vivo biopharmaceutic study; includes dissolution performance and summary of dissolution method and suggested specification

· Individual study reports format - should include objective, dosage form(s) investigated, name of principal investigator, premises where clinical trials and assays of collected sample took place, all individual data needed for conclusions (eg, info on patient demographics, medication taken during trial, adverse reactions, etc), analysis of data, and conclusion. Analytical method(s) should also be described, including information on sensitivity, linearity, specificity, and reproducibility of method. Appropriate statistical methods should be used in the data analysis, including such tests as Analysis of Variance (ANCOVA), calculations of power analysis and PK parameters, confidence intervals, and ratio analysis. Report should end with a paragraph summing up the main conclusions of the study.

Impact

This guidance will help guide drug developers when they plan what tests to conduct on during preclinical and clinical drug development in order to ensure that the data they collect are the actual data the FDA is interested in seeing in the NDA and ANDA. It will also help streamline the application process and save time for both the drug developer and FDA employees who review the applications.

Early Clinical Trials with Live Biotherapeutic Products: Chemistry, Manufacturing, and Control Information

Name of Guidance
Early Clinical Trials with Live Biotherapeutic Products: Chemistry, Manufacturing, and Control Information

Status of Guidance
Draft

When was the Guidance released?
September 2010

Which organization released the Guidance?
Center for Biologics Evaluation and Research (CBER)

Target Audience
Drug sponsors submitting Investigational New Drug Applications (INDs) for early clinical trials with live biotherapeutic products (LBPs)

Laws and Regulations Referenced
21 CFR 312.2 (a) & (b): Investigational New Drug Applications (INDs) are required for drugs undergoing approval for marketing except those that are already approved for sale and are not seeking new indications or any significant changes to labeling or dosing or route of administration or advertising of the product.

21 CFR 312.23: Covers required IND content and format.

21 CFR 312.23(a)(1): Sponsors must submit a cover sheet with their IND application.

21 CFR 312.23(a)(7) and 312.23(a)(7)(ii): Covers chemistry, manufacturing, and control (CMC) information. The amount of CMC information to be submitted varies according to the scope of the clinical trial.

21 CFR 312.23(a)(7)(iv): INDs must include (a) a description of a drug substance including physical, chemical, and biological characteristics, the name and address of its manufacturer, methods of preparation, and information on stability; (b) A list of all components of the drug products (including reasonable alternatives for inactive compounds) used in the manufacture of the product; (c) a brief description of composition, manufacture, and control of placebos used in the trial; (d) a copy of all labels and labeling to be provided to trial investigators; and (e) a claim for categorical exclusion from the need for environmental analysis or environmental impact statement.

21 CFR 312.23(a)(8): Sponsors must provide adequate pharmacology and toxicology information about an investigational drug. This includes animal and in vitro studies.

21 CFR 312.3(b): Provides definitions of terms relevant to IND submissions.

21 CFR 312.140(a)(3): INDs for biological products regulated by CBER should be submitted to: Document Control Center (HFM-99), CBER/FDA, 1401 Rockville Pike, Suite 200N, Rockville, Maryland 20852-1448.

21 CFR section 600.3(h)(1): A “virus” is defined as a product containing living cause of an infectious disease.

21 CFR 610.13(a)(1): Each lot of dried biologic drug product must be tested for residual moisture and must not exceed established limits.

21 USC 321(g)(1): A “drug” is defined as a substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of a disease in humans or other animals. Claims made about the ability of an substance to act as a drug must be truthful and not misleading.

42 USC 262: Covers regulation of biological products.

42 U.S.C. 262(i): A biological product is defined as a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.



42 U.S.C. 262(j) and Section 505 of the Federal Food, Drug, and Cosmetic Act: Interstate commerce of any new drug requires approval from FDA.

501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 351(a)(2)(B)): The manufacture, processing, packing, and holding of a drug must conform to current good manufacturing practices. Otherwise, the drug is considered to be adulterated.


Definitions

• Clinical trials: Studies of new drugs or treatments in humans. Also known as Phase 2, 3, and 4 trials. Conducted after non-clinical trials. Requires IND approval from FDA.
• Live biotherapeutic product (LBP): A virus, therapeutic serum, toxin, antitoxin, blood, blood component or derivative, allergenic product, protein, or analogous product that contains live microorganisms (such as bacteria or years) and is use to prevent, treat, or cure a disease or condition in humans. This does not include vaccines.
• Investigational New Drug Application (IND): An application submitted by a sponsor to FDA seeking approval to test a new drug or treatment in humans. Includes data from non-clinical trials.
• In vitro: Translated literally as “within glass.” In drug development this refers to laboratory tests conducted in test tubes or culture dishes, or otherwise outside any living organism.
• Non-clinical trials: Studies of new drugs or treatments either in vitro or in animals to determine basic safety information. Often referred to as “Phase 1” studies, they are conducted before trials in humans (Phase 2, 3, and 4 clinical trials) can begin.
• Sponsor: An individual or organization (often a pharmaceutical company) that takes responsibility for and initiates clinical trials. The sponsor submits applications to FDA including INDs.

Background
Live biotherapeutic products (LBPs) vary widely in where they are sourced, how they have been modified for medical use, what they are used for, how they act in the body, how doses are measured, and how they are administered to patients. As such, clinical trials meant to evaluate whether LBPs can prevent, treat, or cure diseases in humans involve collecting a wide range of types data. This means the content of Investigational New Drug Applications (INDs) for LBPs are also diverse.

This is a challenge to sponsors of new LBPs because there is no model application they can reference while preparing an IND. Inexperience with LBP filings or in interacting with the Center for Biologics Evaluation and Research (CBER) and US Food and Drug Administration (FDA) compounds the problem.

This Guidance helps sponsors correctly prepare and submit the Chemistry, Manufacturing, and Control (CMC) section of the IND. The advice in the Guidance is meant to reduce the risk of having an application denied due to avoidable mistakes in its preparation.


Summary
Before a new drug can be tested in humans FDA must approve an IND from the drug’s sponsor. Sponsors submit the IND when they feel they have enough positive data from non-clinical trials (ie, in vitro and animal testing) to justify clinical trials in humans.

The IND is a complex document with many parts. And the data collected during non-clinical trials of new LBPs is widely varied. To help sponsors navigate the IND preparation and submission process, CBER uses the Guidance to give advice on what should be included in the CMC section.

First and foremost, communication with CBER is critical. Pre-IND meetings can help sponsors understand what data to include in their applications and how to present it. These meetings can also help everyone involved anticipate each milestone in the process. Second, applicants are urged to avoid delays by mailing the completed IND in triplicate to the correct address at CBER. Electronic submissions are also possible and are addressed in a separate guidance.

In terms of CMC information, sponsors should start by reading the guidance on Current Good Manufacturing Process (CGMP). Detailed information on the LBP is required including the source and strain, the name and address for the manufacturer, a complete list of active and inactive ingredients, a description of the conditions where the LBP is manufactured, and a plan for preventing contamination from other substances or microbes.

Finally, the Guidance summarizes advice on presenting non-clinical and clinical data.


Rationale
Sponsors who fail to follow requirements for submitting CMC information in INDs risk having their application denied by FDA. These unnecessary errors are costly to sponsors and can delay the availability of new drugs. This Guidance is needed to give advice to sponsors who have never worked with CBER, are new to applications involving LBPs, or who simply want to increase their chances of a successful submission.


Resulting Recommendations

Administrative and Regulatory Procedures

• Establish formal communication with FDA before preparing and submitting an IND, especially if this is the first interaction with CBER.
• Submit the original, completed IND (FDA Form 1571) plus any IND amendments in triplicate with a cover letter to: Document Control Center (HFM-99), CBER/FDA, 1401 Rockville Pike, Suite 200N, Rockville, Maryland 20852-1448. For information on submitting the IND electronically, refer to “Guidance for Industry: Providing Regulatory Submissions to CBER in Electronic Format-Investigational New Drug Applications (INDs)”.
• If the IND sponsor is not also the manufacturer of the biologic drug of product, FDA may ask the manufacturer to submit a Drug Master File (DMF).

Chemistry, Manufacturing, and Control (CMC) Information

• Current good manufacturing practices for investigational drugs vary by clinical trial phase. Refer to “Guidance for Industry: CGMP for Phase 1 Investigational Drugs”.
• Include a description of the live biotherapeutic product (LBP) with its biological name and strain designations, original source, and documentation of any modifications made.
• Characterize the LBP (species and strain at a minimum) and include a description of acceptable limits and analytic methods used to assure its identity, strength, quality, and purity. Report actual laboratory data and quantitative information in a table rather than a written summary.
• Provide the name and address of the manufacturer of the drug plus a comprehensive list of other products that are manufactured or manipulated on the same premises. If there is any possibility of contamination from the sharing of equipment, proximity of production, or extraneous microorganisms, indicate how the equipment will be cleaned between the manufacture of different products. A floor diagram is recommended.
• Provide a list of all materials used to produce the drug, a flow chart of the manufacturing process, a detailed description of the cell banking procedures, descriptions of how cells are grown and harvested, descriptions of how the drug is purified, and a description of how the drug is sampled and tested during production.
• Include preliminary specifications and tests for the drug, including assays for identity, purity, microbial contamination, potency, stability, etc.
• Describe all necessary ingredients, both active and inactive, used in the manufacture of the drug. Include the names and addresses of the manufacturers.

Non-Clinical Information

• Submit adequate data from pharmacological and toxicological studies in laboratory animals or in vitro to justify evaluation of the LBP in human trials.
• Consult with CBER to determine how much non-clinical data is considered necessary and adequate.

Clinical Information

• If submitting third party data from clinical trials involving the same LBP, be sure to obtain all relevant study reports, records, data listings, and documentation of statistical analyses so conclusions can be verified. Be sure to account for final disposition of all trial participants because missing data due to a large number of dropouts, withdrawals, or protocol violations weaken the analysis and conclusions.
• Define diseases and criteria for milestones (worsening, relapse, improvement) of the disease that are relevant to the population being studied. Refer to the International Conference on Harmonisation (ICH) guidance documents for Efficacy, Joint Safety/Efficacy, Quality, and Safety for information on clinical studies in different populations.

Impact
The Guidance helps make the requirements of CBER and FDA more transparent to sponsors of LBPs. Sponsors are therefore less likely to have INDs denied due to avoidable mistakes in the preparation of the application. As a result, costs associated with preparing and submitting INDs are decreased and new drugs that are shown to be suitable for the treatment, cure, and prevention of diseases can be made available faster and more efficiently.

Adaptive Design Clinical Trials for Drugs and Biologics

Name of Guidance
Adaptive Design Clinical Trials for Drugs and Biologics

Status of Guidance
Draft

When was the Guidance released?
February 2010

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

Target Audience
Drug company sponsors who design and/or run clinical trials, and FDA staff who review clinical trial data

Laws and Regulations Referenced
21 CFR 314.126: Drug sponsors must conduct adequate and well-controlled studies to demonstrate the safety and efficacy of new drugs before they can be approved for marketing. This includes having a clear objective for the study, comparing the new drug to a valid control drug or treatment, choosing appropriate participants, assigning participants to a treatment or control group in an unbiased way (usually by random assignment), minimizing bias wherever possible, and using valid methods to observe and analyze response to treatment.

Definitions

• Adaptive design clinical study: A clinical trial that is structured with prospectively planned changes that usually go into effect after an interim analysis of data.
• Bias: A tendency to design a study in a way that favors a particular outcome, or a tendency to interpret data in a way that overstates the effect of a drug. May lead to Type I errors.
• Blinded analysis: A study of data collected during a clinical trial where the personnel doing the analysis does not know which participants received which drug or treatment. Important for avoiding bias in the study results.
• Endpoint: An event or outcome that marks an important change in a disease or condition due to treatment. For example, an endpoint in a clinical trial could be improvement or worsening of symptoms, or a blood test showing the drug has had some effect on the body. Most clinical trials have both primary and secondary endpoints.
• Interim analysis: A study of data collected during a clinical trial before the trial is complete.
• Primary endpoint: The outcome believed to be most useful and reliable in determining whether a drug is effective against a disease.
• Prospective: Planned in advance. In the Guidance this refers specifically to planning modifications in one or more aspects of a clinical trial design before the data is unblinded to personnel making the modifications.
• Protocol: The “recipe” for running a clinical trial. Includes descriptions of who is eligible/ineligible to participate in the trial, how participants must be assigned to receive drugs being tested, dose and delivery method of the drug, how participants should be monitored, how long participants should take part in the trial, etc.
• Secondary endpoint: An outcome believed to demonstrate the effect of a drug, but may not be as definitive as the primary endpoint.
• Type I error: A statistical term for believing a drug has an effect on a disease or condition when it actually does not.
• Type II error: A statistical term for believing a drug has no effect on a disease or condition when it actually does.
• Unblinded analysis: A study of data collected during a clinical trial in which the personnel doing the analysis knows which participants received which drugs or treatments. Considered to be an unreliable method of analysis because it introduces bias and increases the risk of committing Type I errors.

Background
Sponsors who run clinical trials must determine the design of each trial (including goals, protocols, and methods for collecting and analyzing data) before testing begins. By defining the design up front and adhering to it closely through the conclusion of the trial, the sponsor is more likely to get valid and meaningful results.

However, there can be benefits to adapting the design while a clinical trial is still in progress. For example, if an interim analysis shows convincing evidence that a drug is effective the sponsor may be able to reduce the duration of the trial and make the drug available to the public faster. Or the sponsor may be able to get more useful data on the effect of the drug by adjusting the dosages given to participants. In order to make trials more efficient or informative, sponsors should use an adaptive design that provides flexibility without detrimental effects on the results.

This Guidance outlines approaches to adaptive design clinical trials that can help preserve the integrity of trial data.



Summary
Clinical trials (also known as clinical studies) are necessary to determine if new drugs are safe and effective enough for public use. In addition to FDA regulations for adequate and well-controlled studies drug sponsors aim to follow principles for good statistical and clinical practices. Everything is planned carefully in advance. Once a trial starts, it is critical that the protocol and planned methods for gathering and analyzing data remain unchanged. Any revisions that are made along the way can introduce bias and compromise the outcome of the trial.

However, there are times when a clinical trial will benefit from having some flexibility in its design. For example, if a sponsor realizes 8 months into a 2-year trial that a drug is not effective, it would make sense to stop the trial early. Or if a sponsor is trying to establish that a drug is effective across several races but the participant pool for the trial is disproportionately composed of people from one race, it would make sense to change their recruiting or eligibility criteria so the participants are more racially diverse. Even if a sponsor has the best intentions when making changes, if not done carefully the trial results can be called into question. In cases like these sponsors need guidance on how to introduce flexibility without compromising quality. Trials that are planned to be flexible are known as “adaptive design clinical studies.”

The Guidance starts by describing general concerns associated with using adaptive design clinical trials. Specifically it addresses the increased risk of committing Type I statistical errors, added difficulty in interpreting positive study results, limitations introduced by adaptive design, and the need for more planning and coordination with FDA.

The Guidance then addresses both familiar and less familiar methods for adapting trial designs. The familiar methods are well established and therefore thought to be less risky. The less familiar methods, however, should be used with caution; the number of trials in which these forms of adaptation have been used is too low for CDER and CBER to determine whether the benefits outweigh the risks. Irrespective of which method a sponsor chooses, all changes must be planned prospectively to be considered valid.

Finally, the Guidance outlines statistical considerations for adaptive design clinical studies.


Rationale
Straying from a rigid, conventional clinical trial design can introduce bias, increase the risk of making errors (particularly Type 1), and cast doubt on the validity of the results. Adaptive designs allow sponsors to make preplanned revisions. Ultimately this can make clinical trials more efficient, successful, and informative. However, some methods of adaptation are more familiar than others. The Guidance is needed to help sponsors understand the different ways they can incorporate flexibility in their clinical trial designs.


Resulting Recommendations
These recommendations are meant for trials in which preplanned revisions occur before data is unblinded to the persons planning or making the revisions. Unplanned revisions made after unblinding to these persons raise concerns about study integrity and should be avoided.

Familiar approaches to adaptive design (well-established, relatively low-risk)

• Modify eligibility criteria to attract participants more quickly or round out the existing participant population with desired baseline characteristics
• Increase sample size to achieve desired study power
• Conduct an unblinded analysis if participants are experiencing negative dose-related issues (such as a serious side effect due to high doses) so they can discontinue treatment
• Discontinue a study if interim data shows the drug has little or no benefit
• Make limited changes to the statistical analytical plan (SAP) if study data makes the planned SAP invalid, but only if blinding has been meticulously maintained

Less familiar approaches to adaptive design (not well-studied, risk level is unclear)

• Discontinue treatment with dosages that are shown to be ineffective or unsafe after an unblinded interim analysis
• Adjust the method by which participants are assigned to receive treatment so that while the assignments are still random, more people are assigned to the treatment that has the best response data collected to date
• Increase the size of the participant pool if an unblinded interim analysis shows the effect of treatment is smaller than expected but still clinically relevant
• If baseline characteristics (eg, genetic or physiologic differences) are thought to cause different responses to the drug, either change the eligibility criteria so only participants with the preferred characteristic are enrolled or limit final analysis to include data from these participants only
• Change the order of the primary and secondary endpoints if they were not well understood when the trial was planned and the data collected in the trial warrants the change

Changes that are not considered adaptive design (should be avoided)

• Revisions that were not planned prospectively
• Revisions based on information from an external source

Impact
The Guidance will help drug sponsors run clinical trials more efficiently and effectively, increasing their chances of having a successful application to market a new drug or biologic product. Specifically, sponsors will be able to design trials that can be modified at preplanned stages with less risk of compromising the integrity of the data and any conclusions drawn from the data.

Guidance for Industry and FDA Staff: Spinal Systems 510(k)s

Guidance for Industry and FDA Staff: Spinal Systems 510(k)s

Status of Guidance:
Final

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

Date of Guidance:
September 2000

Target Audience:
Makers of spinal devices and reviewers at the U.S. Food and Drug Administration (FDA).

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 801.109: Defines the term “prescription device”
21 CFR 807.87: Outlines the requirements of a Premarket Notification
21 CFR 812: Outlines the requirements of an Investigational Device Exemption
21 CFR 888.3050: Classifies spinal interlaminal fixation orthoses as Class II medical devices under the FDA’s classification system
21 CFR 888.3060: Classifies spinal intervertebral body fixation orthoses as Class II medical devices under the FDA’s classification system
21 CFR 888.3070: Classifies pedicle screw spinal systems as either Class II or Class III medical devices under the FDA’s classification system, depending on nature of clinical use
63 FR 40025: Reclassifies certain pedicle screw spinal systems as Class II medical devices under the FDA’s classification system

Definitions:
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.

Spinal system: A complete spinal implant including all parts (Source: Preparation and Review of Investigational Device Exemption Applications for Total Artificial Discs)

Component: An individual part of a spinal system (Source: Preparation and Review of Investigational Device Exemption Applications for Total Artificial Discs)

Background:
The FDA issued this guidance to help the makers of spinal devices create complete 510(k) applications that include the information the FDA needs to decide whether to approve the devices.

Summary:
A device maker may submit a 510(k) application to request FDA approval of a spinal device. The device may be (1) new but similar to one the FDA has already approved, (2) an approved device that has been modified with new parts, or (3) an approved device that is intended to treat a condition that wasn’t listed in the original approval. This guidance applies to spinal systems that are made of metal plates and rods, and various types of screws that are inserted into the pedicle bones of the spine (pedicle screw systems). The guidance does not apply to systems that use screws inserted into the facet bones (facet screw systems).

The guidance provides simple tables showing various types of spinal systems, the conditions they are used to treat, and their classification under the FDA’s risk category system. It recommends that device makers state at the beginning of their 510(k) application where their device falls on these tables. It also recommends including a table listing all components of the device and the details of each component (size, material, where it attaches to the spine, etc.)

An important part of any 510(k) application is the description of conditions the product is intended to treat. This guidance recommends that applicants include detailed descriptions and avoid general terms like “instability.” The guidance provides examples of how these statements should be worded.

In order to show how a device performs when the spine is in motion, the FDA recommends the device maker conduct mechanical testing and submit the results with the 510(k) application. The guidance provides tables showing which types of testing are recommended for the various types of spinal systems. The two main types of mechanical testing are static testing, in which the device must be able to withstand certain weights, and fatigue testing, in which the device must continue to perform well after many repetitions of certain motions. The guidance gives detailed recommendations on how many samples should be used and how the tests should be designed. It also outlines a recommended structure for the test report.

The guidance further recommends wear testing be conducted on any device that may shed particles of material into the body. It recommends animal studies for new uses and new materials, or following unfavorable mechanical testing results.

While all drugs must be tested in humans before gaining FDA approval, most medical devices can avoid this type of costly testing. If the device maker can show that their new product is similar to an existing, approved product, clinical testing is usually not required. Moreover, a traditional 510(k) application may not even be necessary if the device is a minor modification of an already approved product. In such cases, the device maker may submit a Special 510(k), which is simpler to produce.

In addition to the testing results and detailed device description, the 510(k) application should also include the proposed package labeling and the full package insert for FDA review. The guidance specifically recommends certain warning labels for devices that are surgically challenging to implant, or in cases where the approved uses are very specific and using the implant otherwise would pose serious risk. Finally, the application should also include a manual that provides instructions to the spinal surgeon on how to implant the device, and how to remove it if necessary.

Rationale:
Many different types of spinal systems exist to treat a wide variety of conditions. The FDA needs different testing results and information depending on the design and intended use of the spinal system. This guidance helps clarify what information the device maker should submit based on the type of product they wish to market.

Resulting Recommendations:

· A spinal system may be approved under a 510(k) application without human testing if it is similar to a system that was already approved.

· The 510(k) application should explain whether the device is new, a modification of an existing device, or an existing device proposed to treat a new condition.

· The type of device should be defined according to the condition it is intended to treat.

· The list of conditions the device is intended to treat should be specific (eg, spinal stenosis) and should avoid vague terms (eg, instability).

· The 510(k) application should include a table listing all components of the spinal system.

· Mechanical testing (both static and fatigue) should be performed depending on the device type, and according to the recommendations outlined in the guidance.

· Wear testing should be conducted in any spinal system that may shed particles of material into the body.

· Animal studies should be conducted if the device is being used to treat new conditions, if it is a substantially new design, if it consists of a new material, or if results of mechanical testing are unfavorable.

· Animal studies should include a control group of animals for comparison.

· All mechanical testing should replicate a “worst case scenario,” ie, the situation in which the device is most likely to fail.

· Package labels, package inserts, and surgical manuals should be included in the 510(k) application.

Impact:
This guidance clarifies what type of testing and information should be included in a 510(k) application depending on the type of spinal device being submitted. It helps device makers submit a complete application to the FDA, which in turn should allow more efficient review and a quicker decision, potentially bringing the latest advances in spinal device technology to patients without delay.