Regulatory Law Blog

Does FDA’s expanded access program serve the best interests of terminally ill patients?

2011-08-29T10:10:00.000-07:00

Background
In 2007 FDA once again broadened its policy for expanded access to new drugs when it amended the Food and Drug Administration Modernization Act (FDAMA) to include criteria for approved drugs with risk evaluation and mitigation strategies (REMS).(Fed Reg 2009;74(155)) This marks the 3rd major revision in 3 decades to regulations that grant seriously ill patients increasingly open access to investigational drugs.

Access to investigational drugs via treatment Investigational New Drug (IND) applications was first formalized in 1987 following intense pressure from AIDS activists. Supporters applaud each move towards easier access to unapproved drugs, but the regulation, in essence, reverses elements of the Food, Drug, and Cosmetic Act (FD&C) which were put in place to protect all patients from unsafe medications and charlatanism. This nullifies the attempts to protect the best interests of patients, including those who are terminally ill.

In the context of this paper I define “best interests” as: meeting one’s fundamental rights to self-preservation, ensuring one’s safety, ensuring no person or persons has fewer or more rights than others, and ensuring benefits are equitably distributed. This definition corresponds to the criteria listed in the “Rule” below.

ISSUE:
Does FDA’s expanded access program serve the best interests of terminally ill patients?

RULE:
FDA’s expanded access program serves the best interests of terminally ill patients if all of the following are true:

Expanded access meets a fundamental right of access to investigational drugs
The benefits of using an investigational drug outweigh the risks and the patient is not exposed to unreasonable and significant additional risk of illness or injury, even if the patient is already terminally ill.
Terminally ill patients do not need the same protection against unsafe or ineffective drugs as patients with less serious or non-life-threatening illness.
All terminally ill patients have equal access to the drugs in question.
Expanded access does not interfere with development of new drugs and thereby negatively affect future access to other patients.

ANALYSIS:

CRITERIUM 1: Expanded access meets a fundamental right to access investigational drugs

The current laws do not support fundamental right to access investigational drugs. According to the FD&C Act, “no person shall introduce or deliver for introduction into interstate commerce any new drug” unless it has been approved for marketing by FDA. Approval requires that the new drug has been proven both safe and effective in humans based on at least 3 phases of “adequate and well-controlled” clinical studies. [See 21 CFR 312.21 Phases of an investigation and 21 USC 355 Section (d)] Drug sponsors are permitted to submit treatment INDs to provide Phase 3 or, less commonly, Phase 2 drugs to patients with “a serious or immediately life-threatening disease condition in patients for whom no comparable or satisfactory alternative drug or other therapy is available.” [See 21 CFR 312.34] However, FDA reserves the right to deny access if there is “insufficient evidence of safety and effectiveness to support such use” or there is an “unreasonably and significant additional risk of illness or injury,” even if the patient’s illness is immediately life-threatening. [See 21 CFR 312.34] Furthermore, no one can compel the drug sponsor to provide investigational drugs to patients not enrolled in clinical studies, or make such a request on their behalf; participation in a treatment IND is voluntary. So the current laws do not support the existence of a fundamental right.

This argument is supported by the 2007 ruling in a recent case: Abigail Alliance for Better Access to Developmental Drugs v. von Eschenbach. The Abigail Alliance was formed by Frank Burroughs after his daughter, Abigail, died of head and neck cancer in 2001. She had been denied access to then-investigational treatments cetuximab (Erbitux) and gefitinib (Iressa), both of which went on to win FDA approval after her death. Convinced the denial of access (and possibly Abigail’s premature death) was caused by unnecessary regulation and bureaucracy, the Abigail Alliance sued FDA (Andrew von Eschenbach was Commissioner at the time) in an attempt to change the existing regulations and permit terminally ill patients to access new drugs as soon as they have completed Phase 1 trials.

In its argument the Abigail Alliance claimed “the concepts of self-defense, necessity, and interference with rescue are broad enough to demonstrate the existence of the fundamental right they seek—a right for ‘persons in mortal peril’ to ‘try to save their own lives, even if the chosen means would otherwise be illegal or involve enormous risks.’” In support of its argument, the Alliance cited Washington v Glucksberg saying FDA’s regulations violated the Constitutional concept of Due Process and the right to self-protection. But the US Court of Appeals for the District of Columbia dismissed the argument by saying, “The Alliance’s effort to focus on efficacy regulation ignores one simple fact: it is unlawful for the Alliance to procure experimental drugs not only because they have not been proven effective, but because they have not been proven safe.” The Court disagreed with the Abigail Alliance’s interpretation of Washington v Glucksberg stating, “A tradition of protection does not alone establish a fundamental right."

In addition, the US Court of Appeals for the District of Columbia asserted, “There is no fundamental right ‘deeply rooted in this nation's history and tradition’ of access to experimental drugs for the terminally ill.” The Abigail Alliance took its appeal to the US Supreme Court, but they were denied certiorari in 2008 and the District Court decision stood.

I feel it is also important to add here that a fundamental right should not, and could not, apply to only to a segment of the population (terminally ill people). If the right is truly fundamental, all persons should have the same access to investigational drugs even if their illness is mild and non-life-threatening. Current laws and the Constitution include no such fundamental right, and so this first criterium is not met.

CRITERIUM 2: The benefits of taking investigational drugs outweigh the risks

The FD&C Act was enacted in 1938 after 100 Americans died as a result of taking an unregulated formulation of elixir sulfanilamide. The drug had been given successfully in tablet form to treat streptococcal infections, but when it was dissolved in diethylene glycol to create a liquid form the results were lethal. FD&C therefore required sponsors to demonstrate the safety of their drugs before being able to sell them. The subsequent 1962 Kefauver-Harris Amendments to FD&C required sponsors to demonstrate that new drugs were also effective by completing 3 phases of clinical trials and gaining approval on a New Drug Application (NDA). The Amendments were meant to protect patients against charlatans who made false promises to cure ill people, including patients with terminal diseases.

Phase 1 clinical trials are conducted in a handful of healthy volunteers to “determine the metabolism and pharmacologic actions of the drug in humans, the side effects associated with increasing doses.” Phase 2 clinical trials are conducted in no more than a few hundred patients with the disease under study to “determine the common short-term side effects and risks associated with the drug.” It isn’t until Phase 3 that trials are conducted in a wider population (several hundred to several thousand patients with the disease under study) that the sponsor is able to “gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labeling.” [See 21 CFR 312.21]

The expanded access program violates the protection afforded by FD&C by exposing patients to drugs that do not have proven safety or efficacy profiles. Medical and physiological responses of healthy Phase 1 volunteers are not representative of the effects of a drug in sick patients who may suffer from concomitant illnesses, have compromised abilities to metabolize drugs or manage side effects, and may be taking other medications. Even Phase 2 and 3 trials may not be representative of the larger population afflicted with a given disease because the number of trial participants is small compared to the total population, and the controlled conditions of clinical trials differ from the “real world” experience of patients.

Furthermore, only 11% of drugs that enter clinical trials are ever approved for marketing. For cancer drugs the approval rate is 6%. (Okie 2006, Society for Clinical Trials Board of Directors 2006) Researchers have been surprised in the past when drugs that appeared to be effective and safe in Phase 1 or 2 trials turned out to be ineffective, dangerous or both once the drug was used to treat a larger population in Phase 3. [Society for Clinical Trials Board of Directors 2006, Cortez 2011, Ray 2011] Of course, some drugs are recalled or have additional warnings added to their labels after they are approved for marketing. [eg, Vioxx, Meridia, Avastin, Avandia, Darvon & Darvocet, Depo-Provera, Plavix] This demonstrates the limitations of even Phase 3 trials in establishing safety and efficacy in the broader population.

Investigational drugs have, by definition, an incomplete safety and efficacy profile. So the expanded access program cannot predict whether the benefits of taking investigational drugs outweigh the risks. Therefore this second criterium is not met.

CRITERIUM 3: Seriously or terminally ill patients do not need the same protections as people with less serious disease

There is no legal precedent indicating seriously ill people, even those with terminal disease, have less need for protection than people with less serious diseases. In United States v Rutherford cancer patients argued that they had a right to Laetrile, an investigational drug that was said to be useful in treating cancer. Laetrile was never shown to be effective and was never approved by FDA, but in their arguments the plaintiffs claimed that denying them access was an infringement on their Constitutional privacy rights to benefit their personal health. They also claimed that the safety and efficacy standards outlined in FD&C are not reasonable applicable to terminally ill cancer patients.

A District Court sided with the plaintiffs and a Court of Appeals approved the District Court’s decision, but on certiorari the US Supreme Court reversed the decision. In the unanimous opinion Justice Thurgood Marshall wrote: “Nothing in the history of the 1938 Food, Drug, and Cosmetic Act, which first established procedures for review of drug safety, or of the 1962 Amendments, which added the current safety and effectiveness standards in § 201(p)(1) suggests that Congress intended protection only for persons suffering from curable diseases. To the contrary, in deliberations preceding the 1938 Act, Congress expressed concern that individuals with fatal illnesses, such as cancer, should be shielded from fraudulent cures...For the terminally ill, as for anyone else, a drug is unsafe if its potential for inflicting death or physical injury is not offset by the possibility of therapeutic benefit.”

I would also add that terminally ill people are more at risk for being manipulated because they are making decisions under duress. They are more likely to believe a treatment will be helpful because it provides them with hope, whereas if their illnesses were not life-threatening they may be more wary and skeptical of the same investigational drugs.

Just as the Declaration of Helsinki protects vulnerable populations (prisoners, children, pregnant women) those who are desperately ill need protection, even if they don’t always perceive regulations to be protective. The expanded access program fails to protect terminally ill people in the same way as people with non-life-threatening diseases, because it allows them to be exposed to unknown risks that are otherwise considered unacceptable for the rest of the population.

The program also falsely raises the hopes of the terminally ill simply because by granting early access FDA implies the drugs are acceptable for use. Due to these failures of protection, the third criterium is not met.

CRITERIUM 4: All terminally ill patients have equal access to the drugs in question

Expanded access was meant to make treatments available to terminally ill patients who do not qualify for clinical trials and who have no alternative approved treatments. However, this access is not equal.

First, to apply for the drug an individual patient (as opposed to a population represented by a drug sponsor) needs a physician who is dedicated and willing to complete the treatment IND. Not all treating physicians are willing or able to commit their time to this work and some physicians may be uneducated on the process or even the availability of a treatment IND. So a patient may be denied access based on their choice of physician (if they had a choice).

Second, sponsors are permitted to charge for investigational drugs so long as they are only recouping their costs to manufacture the drug. Insurance companies generally do not cover investigational drugs so the cost, which can be considerable, may fall to the patient. This favors patients with more financial resources. (Sponsors can choose to waive costs, but they are not required to do so.)

Third, even if drug sponsors are willing to take on treatment INDs their eligibility criteria can exclude some patients. Drug sponsors want to get the best results possible and so they are prone to recruiting patients who are most likely to respond well. This bias will always prevent some portion of the population from equal access to investigational drugs.

Fourth, investigational drugs are typically manufactured in small quantities. Even if the sponsor is willing to provide the treatment free of charge, there simply may not be enough medication available for all patients who apply for it through the expanded access program. And the sponsor cannot be compelled to make enough of the drug to meet all possible demand.

Fifth, patients can be disadvantaged by their geographical location. If a condition of treatment is proximity to a location where the drug can be administered, patients who are unable to travel (for financial, health, or any other reasons) are excluded.

For these reasons the fourth criterium is not met.

CRITERIUM 5: Expanded access does not interfere with development of new drugs (and therefore decrease access to the wider population of patients)

Drug sponsors have legitimate reasons not to want to participate in expanded access. For example, expanded access can decrease enrollment in clinical trials. Patients who are terminally ill generally do not want to risk being randomized to placebo or existing treatment arm if they think the investigational drug offers more hope. So they opt out of the clinical trial and apply instead for expanded access. Each time FDA loosens restrictions around investigational drugs the demand for access outside of clinical trials grows. This makes it more difficult for sponsors to recruit participants for controlled studies.

Additionally, unfavorable side effects, injuries, or deaths resulting from the use of investigational drugs outside of clinical trials results must be reported to FDA and can put post-approval marketing efforts at risk. Sponsors are understandably skittish about potential negative impacts on revenue.

Finally, expanded access exposes drug sponsors to potential lawsuits. In several recent cases patients have also sued sponsors for not making investigational drugs available to them indefinitely. [See Abney v Amgen and Suthers v Amgen] This legal and financial exposure is a deterrent to sponsors.

The potential for negative impact on clinical trials and safety data threatens profitability and can drive sponsors to curb research and development (R&D) investments in new drugs that are targets for expanded access (eg, serious but relatively uncommon diseases). This interferes with the development of new treatments and can unfairly prevent future patients from access to life-saving drugs.

For these reasons, the fifth criterium is not met.

CONCLUSION:
While terminally ill patients can sometimes benefit from getting investigational treatments, the expanded access program does not serve the best interests of terminally ill patients.

Guidance for Industry: Enforcement Policy OTC Sunscreen Drug Products Marketed Without an Approved Application

2011-08-08T16:28:00.000-07:00

Name of Guidance:

Guidance for Industry: Enforcement Policy OTC Sunscreen Drug Products Marketed Without an Approved Application

Status of Guidance:

Draft guidance, final expected to be issued in 2011

Date of Guidance:

June 2011

Names of Organizations Releasing the Guidance:

United States Department of Health and Human Services (HHS)
United States Food and Drug Administration (FDA)
Center for Drug Evaluation and Research (CDER)

Target Audience:

Manufacturers of over-the-counter (OTC) sunscreen drug products without an approved application.

Guidance Laws and Regulations Referenced in the Guidance:

21CFR 201.327, §201. §327(c)(3), §201.327(g), §201.327(l): FDA guidances pertaining to SPF labeling and testing requirements for OTC sunscreens.
21 CFR 352.10, 21CFR 352.20
21CFR 330.1: Guidance addressing GRASE drugs, ie, drugs generally recognized as safe and effective.
21CFR 310.545(a)(29)(ii): Guidance regarding active ingredients found in OTC drugs, including sunscreens.

Definitions:

Drug monograph: A description of a drug or class of drug that specifies their ingredients, directions for use, conditions of use, and contraindications.

GRASE: Acronym for Generally Recognized as Safe and Effective.

OTC: Over-the-counter. Here, OTC sunscreens are those sold directly to customers without a prescription.

SPF: Sun protection factor. A rating; for sunscreens from 2 to 50 plus, that indicates the extent of protection provided by a sunscreen.

UVA and UVB: Ultra-violet rays A and B, which are responsible for tanning, but also for sunburn, skin damage, or sometimes skin cancer.

Background:

Some over-the-counter (OTC) sunscreens appear on the market without FDA application approval. Since there is no final description, or drug monograph, of this class of drug, the FDA has been unable to finalize guidances pertaining to these products. Concern over safety and effectiveness led the FDA to issue numerous publications to guide manufacturers by expressing its viewpoint. This draft guidance is the most recent publication on the topic and the final guidance, pending the drug monograph and other studies, should also be available in 2011. The main concerns regarding OTC sunscreens are testing and labeling requirements and proposed enforcement policy.

Summary:

Numerous Federal Register notices have be published by the FDA on the topic of OTC sunscreens. Key dates follow:

1978: Publication of notice of intent to address safety issues (SPF and GRASE).

1993: Safety issues addressed. A minimum SPF value of 2, as well as views on safe dosage forms are proposed.

1996-2000: Several active ingredients added to list of those eligible for inclusion in drug monograph.

2007: Safety and effectiveness discussed. Products containing insect repellent examined.

2011; Labeling and testing requirements modified (21CFR 201.327) for marketed sunscreens without application approval. SPF label upper limit of 50 plus required. Dosage forms eligible for inclusion in drug definition proposed.

Because a drug monograph has not yet been finalized for .OTC sunscreens, the FDA intends to use enforcement discretion until the monograph is finalized. Additional safety and efficacy data is being collected and will be incorporated in the final guidance expected to be issued in 2011. Other issues to be addressed in the final guidance include active ingredients, special warnings on sprays, and combination sunscreen and insect repellent.

Rationale:

Manufacturers are currently marketing sunscreens without approved applications since there are no final requirements for testing and labeling of these products at this time. In addition, a final drug monograph of sunscreens is not yet completed. This guidance expresses the FDA’s expected finalized recommendations and intended enforcement approach. Manufaturers of OTC sunscreens should follow these recommendations while the final guidance is pending.

Resulting Recommendations:

The following recommendations express the FDA’s intended enforcement policy pending finalization:

· OTC sunscreens may be marketed without application approval if they are not potentially dangerous to use.

General safety issues concern:

o Safety of active ingredients (21 CFR 352.10 and 352.20)

o Appropriate claims in labeling (21CFR 201.327(c)(3) and (g) and 310.545(a)(29)(ii)

o Adverse event reporting (21CFR 330.1) and adulteration.

o Labeling and testing requirements (CFR 201.327)

· In vitro broad spectrum testing must be done to test for protection across different UVA wavelengths (21CFR 201.327(i)).

· OTC sunscreens claiming to have an SPF of over 50 should be marked 50+ or 50 plus,

· Dosage forms differ in eligibility for inclusion in future drug definitions. Sprays.

should be labeled with special warnings to prevent inhalation, in compliance with 21CFR 201.327(e)(l)(ii).

Impact:

This draft guidance serves to inform manufacturers of OTC sunscreens without approved applications of the FDA’s intended enforcement approach in regards to testing and labeling of these products. This will facilitate adherence to the final FDA guidance, expected to be issued in 2011.

Brief Summary: E15 Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding Categories

2011-08-07T08:46:00.001-07:00

Name of Guidance

E15 Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding Categories

Status of Guidance

Final Guidance

Date of Guidance

April 2008

Released by

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

Link to Guidance

Target audience

Developers of drug s/biologics

Laws and Regulations

This guidance does not refer to any laws or regulations.

Definitions

Biomarker: Any substance used to detect and identify a type of cell, organelle, sub-component, biological state, or biological process

Deoxyribonucleic acid (DNA): genetic material that comprises an organism

Genome: the ordering of an organism’s full DNA sequence (or genetic code)

Genomics: the branch of genetics that focuses on organisms in terms of their genomes (or DNA sequences)

International Conference on Harmonisation (ICH): With the full name of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, the ICH is a global organization with the mission of creating a single procedural platform for regulatory and pharmaceutical entities worldwide, specifically in Europe, Japan and the US, to follow to “harmonize” the steps involved in drug development and registration.

Pharmacodynamics (PD): the study of the biochemical and physiological effects of drugs, and the mechanisms of their actions, including the relationship of their actions and effects with their chemical structure

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

Ribonucleic acid (RNA): a nucleic acid composed of repeating nucleotide units of ribose sugar, phosphate group, and nitrogenous base that is involved in protein synthesis. RNA is different from DNA in that it includes the sugar ribose and the base uracil while DNA includes the sugar deoxyribose and the base thymine.

Single nucleotide polymorphisms (SNPs): a deviation in a sequence of DNA that involves the switch of a single nucleotide base for its alternate, as in replacing the cytosine base with the thymine base. These variations occur at an increasing rate in the population.

Background

The International Conference on Harmonisation (ICH) formed to promote the use of the same procedures and documents in the development and registration of drugs by regulatory and pharmaceutical entities worldwide. Formerly, each region of the world followed its own procedures. Part of the problem with having different procedures around the world is the accompanying discrepancy on the meanings of vocabulary used in these processes. In an effort to clarify and consolidate the vocabulary and to streamline communication, the ICH advocated for the adoption of specific vocabulary to be used with agreed-upon definitions.

Another area in drug development that needed consolidation and clarification is the labeling of biological samples that are used for research in the fields of pharmacogenomics and pharmacogenetics. Different countries use different systems for identifying and tracking these samples and the data collected on these samples. Accordingly, the ICH called for a single system for coding for these samples and data that would simplify research and the development of new drugs.

Summary

This guidance is endorsed by the ICH and provides agreed-upon definitions for commonly used words in the fields of pharmacogenetics and pharmacogenomics, and in genomic data and sample coding.

Rationale

Lack of consistency of definitions for commonly used terms in drug development around the world creates great confusion, creates work, and wastes money. Creating a system in which all parties involved in drug development and registration around the world can communicate clearly would address and end this confusion and waste, and ensure proper interpretation and communication while making drug discovery more efficient.

Resulting Recommendations

This guidance provides the following definitions to clarify meanings of terms and to ensure consistent understanding.

· Genomic biomarker: a measurable DNA and/or RNA characteristic that is an indicator of normal biologic processes, development of disease, and/or response to therapy (eg, the expression, function, or regulation of a gene)

· Pharmacogenomics (PGx): the study of variations in the characteristics of DNA and RNA as related to drug response in terms of drug discovery, drug development, and clinical practice

· Pharmacogenetics (PGt): a subset of pharmacogenomics, focusing on the study of variations in DNA sequence as related to drug response drug discovery, drug development, and clinical practice

· Drug: refers to investigational (medicinal) product, medicinal product, medicine, and pharmaceutical product (including vaccines and other biological products)

· Drug response: the processes of drug absorption and disposition (meaning pharmacokinetics), and drug effects (meaning pharmacodynamics, drug efficacy, and adverse effects of drugs).

Samples, and the data generated by them, can be labeled with one or two codes during research. This guidance recommends using a system including the following 4 specific categories for coding biological samples (and the generated genomic data).

· Identified: the samples and/or data are identified with personal information to allow tracing back to the subject from whom the sample/data was derived. Samples/data with this code can be withdrawn or returned, permitting clinical monitoring, subject follow-up, and future addition of new data from the identified subject. Clinical trials in drug development typically do not use identified samples/data.

· Coded: these samples/data do not include any personal information and are tagged with one (single-coded) or two (double-coded) codes. Single- and double-coded samples/data can be traced back to the subject, so sample withdrawal and return of results are possible. It also enables clinical monitoring, subject follow-up, and future addition of new data from the identified subject. Single-coding is the most commonly used method in clinical research today. Double-coding allows an extra layer of security on samples/data.

· Anonymized: these data/samples are single- or double-coded and increase the level of confidentiality and privacy because they do not include personal information on the subject from whom the sample came. The samples/data are not traceable back to the subject so it is not possible to withdraw the sample, return the results, conduct clinical monitoring or subject follow-up, or add new data from the subject at a future date.

· Anonymous: these samples/data are completely anonymous, with no personal information included, voiding any possibility to trace data back to the subject. The samples/data are not traceable back to the subject so it is not possible to withdraw the sample, return the results, conduct clinical monitoring or subject follow-up, or add new data from the subject at a future date.

Impact

Using an agreed-upon set of vocabulary and coding categories for biological samples (and their genomic data) will improve communication and streamline drug research worldwide.

Guidance Document for the Preparation of IDEs for Spinal Systems

2011-08-01T05:40:00.000-07:00

Status of Guidance:
Final

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

Date of Guidance:
January 2000

Target Audience:
Makers of spinal devices who wish to apply to the U.S. Food and Drug Administration (FDA) for an Investigational Device Exemption (IDE)

Laws and Regulations Referenced:
21 CFR 25: Describes the FDA’s considerations relating to environmental impact
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 58: Describes good laboratory practices studies that are not conducted on humans
21 CFR 801: Describes the labeling requirements for medical devices
21 CFR 812: Outlines the requirements of an IDE application
21 CFR 860: Explains how device classification is determined based on safety and effectiveness data

Definitions:
Investigational Device Exemption (IDE): The FDA grants device makers the ability to test their new devices in humans by approving an IDE.

Spinal system: A complete spinal implant including all parts.

Component: An individual part of a spinal system.

Background:
The latest spinal devices are often designed in totally different ways than older devices. They may use new materials and pose greater risks along with potentially new benefits to patients. Before a new device can be tested in humans, the device maker must apply to the FDA for an IDE. The IDE includes all details of how the clinical studies will be conducted and how the results will be interpreted. This guidance outlines the FDA’s areas of concern specific to IDEs for spinal devices.

Summary:
Before testing a new spinal device in humans, the device maker must show that the new product appears to be reasonably safe. They may do this in various ways including:

(1) Citing scientific articles describing clinical trials conducted in other countries or on similar devices or components,

(2) Providing the results of animal testing to show that the material will likely be safe in the human spine, will stabilize the spine as intended, and will promote or prevent fusion, depending on the intended use,

(3) Providing the results of mechanical testing showing the device withstands certain weights (static testing) and repetitive motions (fatigue testing).

After establishing preliminary safety, the device maker describes the details of the human studies they plan to conduct. The applicant states the goals of the study and proposes a study design. The preferred design is a randomized control trial, in which one group of patients (control group) is given a standard treatment and a similar group (experimental group) is given the new treatment and the outcomes compared.

The IDE application should outline the factors that will determine whether a patient is eligible for the study. Patients may be included if they are within a specific age range, have a certain condition affecting a specific area of the spine, and are deemed likely to adhere to the follow-up schedule. Patients may be excluded if they have other diseases that could affect results, if they have had previous surgeries, are pregnant, or are deemed unlikely to follow up.

The number of patients to be included in the study should ensure that results are statistically meaningful. Patients should be followed for at least 2 years. The FDA recommends that patients be evaluated at the start of the study (before surgery), and 2 weeks, 3 months, 6 months, 1 year, and 2 years following surgery.

There are many ways to determine the success of a new spinal implant. The FDA notes that the outcomes should be both statistically and clinically meaningful. This means that there should be a measurable (objective) improvement in range of motion and/or anatomical measurements of the spine, as well as a patient-reported (subjective) improvement in pain and functionality.

Safety of the implant should be evaluated by documenting any repeat surgeries or adverse events during the follow-up period, and testing for any neurological problems that did not exist prior to surgery.

The IDE application must also describe how statistical methods will be used to analyze the study results. This explanation should include how the sample size was determined, and how trends in the data will be detected.

Finally, the IDE must include proposed labeling for the device. The package label, the information contained inside the package, and the manual describing the surgical technique for implanting the device must all clearly state that the product is an investigational device.

Rationale:
Spinal systems are complex medical devices that can pose serious risks that are unique to their design and their uses in the spine. The FDA must evaluate the safety and effectiveness of these devices in humans before approving them for widespread use. Device makers must create a lengthy and complex IDE application that addresses the FDA’s concerns specific to these devices. This guidance outlines those areas of concern to help device makers produce a complete IDE application.

Resulting Recommendations:

· Device makers should consult the FDA early in the development of proposed human testing of their devices.

· Devices should be shown likely to be safe in the human spine through evidence in the scientific literature, animal testing, and mechanical testing.

· The proposed clinical study should have a clear hypothesis and objective.

· The proposed clinical study should include enough patients to make it statistically relevant.

· Study participants should be randomly assigned to either a control group or the testing group.

· Patient inclusion and exclusion criteria should be defined in the IDE application.

· Patients should be followed up for at least 2 years.

· Effectiveness of the device should be determined by both objective measurements and reports of patient satisfaction, including improvements in pain and function.

· Safety should be evaluated by analyzing adverse events, reoperations, and neurological problems.

· Planned statistical analyses should be described in the IDE application.

· The IDE application should include proposed package labeling, informational insert, and surgeon instructions, all of which should identify the device as investigational.

Impact:
By explaining the FDA’s main areas of concern relating to the safety and efficacy of spinal devices, this guidance should shorten the time to ultimate device approval by helping device makers submit a successful IDE application on their first attempt.

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

2011-07-26T17:17:00.000-07:00

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

2011-07-22T22:28:00.000-07:00

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 drug s/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

2011-07-21T15:11:00.000-07:00

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

2011-07-20T10:02:00.000-07:00

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

2011-07-18T10:14:00.001-07:00

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.

Guidance for Developing Products for Weight Management

2011-06-28T10:26:00.000-07:00

Guidance for Industry Pertaining to the Development of Products for Weight Management

Name of Guidance:

Guidance for Industry Development of Products for Weight Management

Status of Guidance:

Draft, revision 1

Date of Guidance:

February 2007

Name of Organizations Releasing the Guidance:

United States Department of Health and Human Services
United States Food and Drug Administration (FDA)
Center for Drug Evaluation and Research (CDER)

Target Audience:

Persons involved in drug development, clinical research investigators, clinical trial sponsors

Guidance Laws and Regulations Referenced:

Guidance for Industry Development of Products for Weight Management, 1996: Original FDA draft guidance with recommendations for designing clinical trials for weigh-management products.
Guidance Drug Interaction Studies —Study Design, Data Analysis, and Implications for Dosing and Labeling: FDA guidance addressing drug-drug interaction studies.
ICH E8 General Considerations for Clinical Trials: International Conference on Harmonisation (ICH) guideline providing general recommendation for the design of clinical trials.
ICH E9 Statistical Principles for Clinical Trials: ICH guideline (topic E9), providing general recommendations for the use of statistical analysis in clinical trials.
ICH E11 Clinical Investigation of Medicinal Products in the Pediatric Population: ICH guideline providing recommendations for designing clinical trials for children.
ICH M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceutitics: ICH guidance providing recommendations for conducting nonclinical safety studies on products before testing in humans.

Definitions:

BMI: A measure of atty tissue calculated using weight (kg) and height (m):
BMI=weight (kg)/height (m)². A BMI>30 indicates obesity.
A comorbidity: A pathological or disease process coexisting with, but unrelated to another.
Obese: A BMI>30 indicates obesity (see definition of BMI above).
Weight-management products: Products that are used to reduce body mass, primarily by reducing body fat.
Pharmacokinetics: The branch of pharmacology concerned wit.h the way drugs are taken into, move through, and are eliminated from, the body.
A stand-alone indication: In this context, a weight-related comorbidity that could be treated with a weight-management product, but the mechanism of action is unrelated to weight loss.

Background:

Obesity is a chronic health risk caused by excessive body fat and is assessed by BMI (BMI<30 indicate obesity). It is associated with risk of death and comorbidities, including type 2 diabetes, hypertension, and cardiovascular disease. A change in lifestyle is the recommended treatment for this condition, but when it fails, weight-management products can be used. Since these products present a potential health risk, benefits and risks should be taken into account. When conducting clinical trials, only subjects presenting a substantial amount of risk should be included in the study to avoid unnecessary harmful effects. The appropriate adult and pediatric patient population to be included in clinical trials is discussed and defined in this guidance. Other issues related to clinical trial design are: assessment of safety and efficacy, stand-alone use for prevention and treatment of weight-related comorbidities, use in patient with medication-induced weight gain, and statistical and labeling considerations.

Summary:

This guidance gives investigators and sponsors FDA’s recommendations for developing weight-management products and designing appropriate clinical trials. This revision adds recommendations not given in the previous draft (Draft guidance September 1996), including: clinical assessment in adult and pediatric patients, safety assessment, combination products, stand-alone indications, use of weight-management products in patients with medication-induced weight gain, and statistical and labeling considerations. Lifestyle changes are always recommended as the treatment of choice, and weight-management products should only be considered after a sufficient course of personal effort. If this fails, persons to be included in clinical trials should be carefully selected by use of inclusion criteria which identify those who have sufficient risk due to their condition (BMI>30 [obese] or BMI>27 with at least one weight-related comorbidity). Clinical and safety assessment recommendations are provided for adults and pediatric patients. Products to be used in combination or in patients with medication-induced weight gain should be tested using pre-clinical pharmacokinetics and evaluated for drug-drug interactiuon. Use of these products for stand-alone indications should be proven to have a mechanism of action independent of weight loss. Advice is given for statistical considerations (sample size, methods of analysis, graphics, and missing data issues) and labeling considerations (inclusion of secondary endpoints).

Rationale:

This revision of the September 1996 guidance provides additional recommendations for clinical trial design not addressed in the original draft.

Resulting Recommendations not included in previous draft (September 1996):

· Adult volunteers should not be included in a study of weight-management products unless:

o They have a BMI>25 and have at least one other weight-related comorbidity

· Long-term studies on pediatric patients should only be conducted after pharmacokinetic and studies on different doses have been done (in accordance with ICH M3, ICH E11).

· Studies on pediatric patients should first be done on obese patients with one or more weight-related comorbidities.

· Weight-management products used in combination should be studied in preclinical and phamacokinetics studies. Efficacy and safety of combination drugs should be compared to the individual product components in phase 2 trials.

· Weight-management products for patients with medication-induced weight gain

· Stand-alone indications for the prevention or treatment of weight-related comorbidities (such as type 2 diabetes) can only be considered if there is proof that the drug works in a way unrelated to weight loss.

· Weight-management products for patients with medication-induced weight gain and combination drugs should only be studied in a trial after doing drug-drug interaction and pre-clinical toxicology studies (see Guidance on FDA Drug Interaction Studies —Study Design, Data Analysis, and Implications for Dosing and Labeling).

Impact:

The development of weight-management products will be better designed, increasing the benefits compared to risks for patients involved in clinical trials.

Public Availability of Advisory Committee Member's Financial Interest Information and Waivers

2011-06-28T06:55:00.000-07:00

Name of Guidance: Public Availability of Advisory Committee Member's Financial Interest Information and Waivers

Status of Guidance: Draft guidance

Date of Guidance: Draft dated October 2007

Name of Organizations Releasing the Guidance:

United States Department of Health and Human Services, Food and Drug Administration (FDA)

Target Audience: This guidance is intended for the general public and for government employees planning to participate as FDA advisory committee members under the Federal Advisory Committee Act (FACA).

Guidance, Laws and Regulations Referenced:

5 Code of Federal Regulations (CFR) 2634.903 (a) and (b)(3) – Executive Branch financial disclosure, general requirements, filing dates, and extensions.

5 CFR 2635.502 – Impartiality in performing official duties, personal and business relationships.

5 CFR 2640.103(a)(1) – Interpretation, exemptions, and waiver guidance concerning 18 U.S.C. 208’s general provisions.

21 CFR 14.5 - Public hearing before a public advisory committee. It addresses the purpose of proceedings before an advisory committee.

21 CFR 20 – This regulation refers to what should be disclosed as public information

41 CFR 102-3.105 and 102-3.130 – These are federal management regulations regarding advisory committee management.

5 United States Code (U.S.C.) Appendix 2 part 9 (b) – This is part of the Federal Advisory Committee Act directed to government organizations and employees. This section refers to the establishment and purpose of advisory committees, publication in the Federal Register, charter: filing, contents, and copy.

18 U.S.C. 208 (a), (b)(1), and (b)(3) – Refers to acts affecting a personal financial interest, bribery, graft, and conflicts of interest.

18 U.S.C. 712 (c) – This is a copy of the FDA advisory committee waiver.

21 U.S.C. 355 (n)(4) – This code refers to new drugs’ scientific advisory panels.

21 U.S.C. 393 – This code describes FDA’s general administration procedures.

Definitions:

Federal Advisory Committee Act (FACA) – Act created to maintain the public informed of the different government committees available, their function, membership, activities and cost.

Background:

The FDA uses advisory committees to obtain expert advice on different scientific, technical and policy matters under its supervision. In order to obtain objective recommendations, the FDA screens all advisory committee participants, their immediate family members, and business partners, for any possible conflicts of interests and for any possible behaviors that may seem unacceptable. This guidance refers to the financial information that needs to be disclosed by advisory board participants and the different waivers that can be granted by the FDA.

Summary:

The FDA has implemented agency-wide procedures for all government employees participating in advisory board committees as experts. All participants are required to disclose any possible conflict of interest. These disclosures are not made public unless the FDA decides to grant a waiver to the participant. All such waivers will be signed by the committee member and posted on the FDA’s website before the advisory meeting takes place. A roster of all committee members will also be available for public review before each committee meeting.

A copy of the “Advisory Committee Member Acknowledgement of Financial Interest” template is attached to this guidance as well as a copy of the “Waiver to Allow Participation in the Advisory Committee”.

Rationale:

The FDA has the responsibility of regulating medicines, medical devices, and food within the United States. The agency does not want to show a hint of possible impropriety and must take these extra steps to assure the public’s confidence on its dealings.

Resulting Recommendations:

Expand the ‘conflict of interest acknowledgements’ to any non-government employees participating in advisory board meetings.

Impact:

The implementation of this guidance will increase the transparency that needs to exist between the FDA and the general public.

Clinical Trial Considerations: Vertebral Augmentation Devices to treat Spinal Insufficiency Fractures

2011-06-27T12:39:00.000-07:00

Clinical Trial Considerations: Vertebral Augmentation Devices to Treat Spinal Insufficiency Fractures

Status of Guidance:
Final

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

Date of Guidance:
October 2004

Target Audience:
Medical device manufacturers and clinical trial investigators testing materials to be injected into the spine to stabilize broken vertebrae.

Laws and Regulations Referenced:
21 CFR 812.3(d): Defines “implant” as a device that remains in the body for more than 30 days.
21 CFR 812.25(e): Defines “monitoring procedures” as they relate to the testing of medical devices.
21 CFR 820.30(g): Defines “design validation” process for ensuring that a medical device meets patient needs.
21 CFR 888.3027: Classifies polymethylmethacrylate (PMMA) bone cement as a Class II medical device under the FDA’s classification system.
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.

Definitions:
Vertebral augmentation device: Material, such as bone cement, injected into the spine to provide stability after a fracture.

Spinal insufficiency fracture: A break in a vertebra (bone of the spine), which may be caused by minor injury, osteoporosis, or other conditions.

Osteoporosis: Weakening of the bones, which occurs with aging.

Vertebroplasty: A surgical procedure in which material (such as bone cement) is injected into a broken vertebra to stabilize it.

Kyphoplasty: A surgical procedure in which material (such as bone cement) is injected into a broken vertebra to stabilize it, after an instrument is used to return the bones to their original shape.

Background:
A spine that is weakened by osteoporosis, minor injury, or other medical condition, may develop small fractures or breaks. When these breaks cannot be treated by physical therapy, medication, or a brace, they may require surgery. Surgery involves injecting bone cement or similar material into the broken vertebra to help stabilize it and relieve pain. The materials used for this are referred to as “devices” because they stay in the body over the long term. The FDA categorizes them as Class II medical devices under their classification system, meaning they pose moderate risk to the patient, and may require testing in humans before they are approved for use. This guidance outlines areas that a device manufacturer or researcher designing testing should consider when studying the safety and efficacy of these materials.

Summary:
When applying for approval of a new type of vertebral augmentation device for the treatment of spinal insufficiency fractures, the FDA may require testing in humans. This typically happens when the material is substantially different than any currently approved materials. New types of plastic are continually being developed, some of which may be absorbed by the body over time after the spinal fracture has healed. These newer materials must be tested for safety and effectiveness in humans before the FDA can approve them.

Spinal insufficiency fractures are usually treated first with physical therapy, bracing, or medication, or a combination of these. If these treatments do not relieve the patient’s pain after 8 weeks, surgery may be recommended. Two types of surgery are used. The first, vertebroplasty, involves injecting bone cement or similar material into the broken vertebra. The second, kyphoplasty, first manipulates the bones with instruments to return them to their original shape before injecting the bone cement.

When designing a study of these devices, the FDA recommends the use of a control group to compare with the group of patients treated with the new device. A control group may be treated with an FDA-approved device, or may receive physical therapy, medication and bracing, or a sham procedure. The use of a sham procedure, in which the patient undergoes surgery without knowing it is a placebo or simply an injection of pain medication, raises ethical issues and is appropriate in very few cases. Patients who undergo a sham procedure or any other control treatment are typically offered the actual treatment at a later date.

The guidance recommends certain criteria for including or excluding patients from the study. These involve the severity of the spinal fracture, how many vertebrae are involved, the severity of pain and limitation of movement, patient age and other medical conditions, the health of the tissue surrounding the fracture, the curvature of the spine, allergies, pregnancy, heart problems, and neurological conditions.

The FDA recommends following up with patients over the course of 2 years after treatment to determine how well the device works over the long term. The success of the device is determined primarily by reduction in pain and increase in functional abilities.

The safety of the device should be measured by the rate of infection following the procedure, the need for additional surgeries, and any unwanted side effects. X-rays should show that the injected material has not moved out of place. Other safety concerns include additional fractures above or below the original and arthritis in the spine.

Certain risks are known to exist in patients requiring vertebral augmentation. They include heart attack, low blood pressure, breathing problems, infections, blood in the urine, uncontrolled bleeding, pain, numbness, bone fracture, pneumonia, rib fracture, leg pain, and stroke. The device maker should consider these risks when developing a risk analysis.

All studies of vertebral augmentation devices should be monitored by qualified experts to make sure the studies are conducted according to plan and that records are kept accurately.

Rationale:
Vertebral augmentation devices pose specific known risks and their testing should be designed with these risks in mind. As newer materials are developed to treat spinal insufficiency fractures, it is important for device makers and investigators to perform ethically and scientifically sound studies of safety and efficacy in humans.

Resulting Recommendations:

· If a material is substantially different from those previously approved by the FDA to treat spinal insufficiency fractures, it may require testing in humans.

· Testing of spinal augmentation devices should include a control group for comparison. The control group may receive physical therapy, medication, bracing, or a sham treatment.

· Patients should be evaluated for inclusion or exclusion based on factors such as fracture location, age, other medical conditions, number of fractures, pain, functional limitation, spinal instability, spinal curvature, pregnancy, heart or lung problems, infection, and allergies.

· Patients should receive 8 weeks or more of conservative treatment prior to evaluation for surgery.

· Patients should be followed up for at least 2 years.

· Determination of device effectiveness should be based on reduction in pain and restoration of function.

· Determination of device safety should be based on rates of infection and reoperation, neurological problems, additional spinal fractures, arthritis in the spine, and other serious side effects.

· A thorough risk analysis should be made, which considers, among other factors, cardiac problems, breathing complications, urinary problems, bleeding disorders, infections, neurological problems, pneumonia, rib fractures, leg pain, and stroke.

Impact:
This guidance helps the developers of spinal augmentation devices to design studies that thoroughly test the safety and efficacy of new materials, while minimizing the risks to patients. By following the recommendations in this guidance, a device maker is more likely to gain FDA approval by addressing all safety and efficacy concerns, which may result in the earliest possible access to the latest treatments for patients in the US.

Brief Summary: Available Therapy

2011-06-27T10:23:00.000-07:00

Name of Guidance

Available Therapy

Status of Guidance

Final Guidance

Date of Guidance

July 2004

Released by

Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER)

Link to the Guidance

Target audience

Developers of drug s/biologics

Laws and Regulations

This guidance refers to various sections of the 21 Code of Federal Regulations (CFR). These sections deal with investigational new drug applications, accelerated approval of new drugs and biologics for serious or life-threatening illnesses, and humanitarian use devices.

The specific sections mentioned are:

312.34(b)

Subpart E part 312

312.84

314.500

601.40
Subpart H

Definitions

Accelerated approval regulations: procedures that permit quicker approval of investigational new drugs to treat serious or life-threatening diseases and provide “meaningful therapeutic benefit to patients” in a more effective manner than that already provided by existing therapies. These trials typically use surrogate endpoints.

Fast-track drug development programs: Federal Drug Administration (FDA) programs that purposely work to speed up the review process of investigational new drugs and biologics that are not yet approved to treat life-threatening or serious conditions in a more effective manner than that already provided by existing therapies.

IND: investigational new drug application; application for a waiver from the FDA to allow the movement of an investigational drug (not yet approved for marketing by the FDA) across state lines.

Restricted distribution: controlled availability of a drug/biologic/medical device, with the authority to prescribe and dispense limited to preordained prescribers and pharmacists registered with the FDA’s special restricted distribution program. Patients agree to abide by special rules for use of the restricted entity.

Subpart E regulations: regulations contained in 21 CFR part 312 that call for the quick development, review, and marketing of therapies that show ability to address life-threatening or serious medical conditions currently without appropriate treatment.

Surrogate End Point: an endpoint used as a substitute for a primary endpoint in a clinical study because designing a study with the actual primary endpoint is not practical or safe. Surrogate endpoints are measurable and quantifiable, and represent a clinically meaningful outcome, eg, survival or improvement of symptoms

Background

No official definition has been provided previously for “available therapy” when used in documents issued by agencies of the FDA such as the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation (CBER). “Available therapy” is often used interchangeably with “existing therapy” or “existing treatments” in documents issued by these agencies.

“Available therapy” and related terms are used in many FDA programs created to speed up the review process of promising new drugs. This term can be found in the following FDA documents but without any clarification as to its specific meaning:

Treatment investigational new drug applications (INDs) (including treatment protocols)
Subpart E Regulations
Accelerated approval regulations
Fast track drug development programs
Priority review policies

Without an official definition for “available therapy,” uncertainty has resulted over whether “available therapy” includes FDA-approved products and/or off-label use of FDA-approved products, or non–FDA regulated therapies.

Summary

This guidance clarifies what “available therapy” (and the related words “existing therapy” and “existing treatment”) refers to when included in documents created by agencies of the FDA such as the CDER and CBER. Specifically, this guidance defines available therapy/existing treatments/existing therapy as “therapy that is specified in the approved labeling of regulated products, with only rare exceptions.” “Approved labeling” in this definition refers to therapies approved under normal or accelerated approval schedules. Additionally, in certain and rare situations, “available therapy” may refer to a therapy not yet approved by the FDA but for which ample evidence exists in the published literature. This definition will be used for regulations and policy statements that do not include a specific definition for available therapy.

Rationale

Many documents issued by agencies of the FDA use the terms “available therapy,” “existing therapy,” and “existing treatment” without clarifying what these terms specifically mean. Without clarification, these terms could be interpreted to mean FDA-approved products only, FDA-approved products as well as products not approved by the FDA, and/or off-label use of FDA-approved products. Off-label use of an FDA-approved product refers to using a product for a use other than it has been approved for by the FDA.

Resulting Recommendations

· “Available therapy” (and related words existing treatment and existing therapy) should be interpreted to mean “therapy that is specified in the approved labeling of regulated products, with only rare exceptions.”

· In certain and rare situations, “available therapy” may refer to a therapy not yet approved by the FDA but for which ample evidence exists in the published literature.

· More than one therapy seeking approval for the same indication can apply for accelerated approval.

· When in reference to a therapy involved in accelerated approval regulations, the term “existing treatment” can have different meanings depending on the context of the approval. If the term is used in the context of an approval based on results from a clinical trial using a surrogate, or substitute, endpoint, then “existing treatment” will mean a treatment that has been proven efficacious “under conventional approval standards.” In contrast, if the term is used in the context of a previous approval based on “restricted distribution,” then “existing treatment” will mean a therapy already approved for the same indication without restricted distribution.

Impact

By clarifying what “available therapy” and related terms mean, the FDA will avoid potential confusion that may arise over possibly different and/or conflicting interpretations of the terms “available therapy,” “existing therapy,” and “existing treatment.” In this way, the FDA will ensure that the readers of FDA guidances will understand that in most cases the terms refer to FDA-approved products and to their use as defined by approved labeling.

Requalification Method for Reentry of Blood Donors Deferred Because of Reactive Test Results for Antibody to Hepatitis B Core Antigen (Anti-HBc)

2011-06-25T09:15:00.000-07:00

Name of Guidance
Requalification Method for Reentry of Blood Donors Deferred Because of Reactive Test Results for Antibody to Hepatitis B Core Antigen (Anti-HBc)

Status of Guidance
Final

When was the Guidance released?
May 2010

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

Target Audience
Organizations (such as hospitals and blood banks) that collect either whole blood or blood components to be used for medical use such as transfusions.

Laws and Regulations Referenced
21 CFR 610.40(a): Any organization that collects human blood or blood components for medical use (such as transfusions) must first test a sample of each potential donor’s blood for Human Immunodeficiency Virus (HIV) types 1 and 2, Hepatitis B virus, Hepatitis C virus, and Human T-lymphotropic virus types I and II.

21 CFR 610.40(h)(1) and (2): Human blood or blood components that have tested positive for 1 or more of the diseases listed in 21 CFR 610.40(a) may not be shipped or used EXCEPT if the blood is for use by the original donor, or if the shipper gets written permission from FDA and labels the package with the appropriate warnings required by FDA. Also, donated blood that tests positive for anti-HBc (but none of the other diseases listed in 21 CFR 610.40(a)) may be used to extract proteins from the plasma portion of whole blood without FDA approval.

21 CFR 610.41(a) and (b): Organizations that collect human blood or blood components must refuse any blood donations (now and in the future) from donors whose blood tests positive for the diseases listed in 21 CFR 610.40(a) and syphilis EXCEPT if the donor is requalified by an FDA-approved method or if the donor tests positive for anti-HBc or anti-HTLV (types I and II) on only one occasion but never again upon retesting.

Definitions

Anti-HBc: An antibody for Hepatitis B virus commonly used to screen would-be blood donors for Hepatitis B.
Antibody: A protein produced by the body’s immune system in response to the presence of a harmful substance (known as an antigen) such as a virus or bacterium.
Antigen: A foreign substance such as a virus or bacterium that is identified by the body’s immune system as harmful.
Blood bank: An organization that collects, tests, and stores human blood for medical use.
Blood transfusion: A procedure in which blood is given intravenously.
Deoxyribonucleic acid (DNA): Genetic material found in human cells, bacteria, viruses, and other living organisms.
False positive: A lab test result that indicates the tested person has a certain disease when in fact they do not.
Hepatitis B: A liver disease that can cause cirrhosis, liver failure, or liver cancer.
Hepatitis B Antigen (HBsAg): An antigen that indicates the presence of Hepatitis B virus. A positive test for HBsAg indicates active Hepatitis B infection.
Hepatitis B virus nucleic acid test (HBV NAT): A blood test that detects the presence of nucleic acids specific to Hepatitis B virus. A positive test indicates active Hepatitis B infection.
Hepatitis B virus (HBV): The virus that causes Hepatitis B.
Negative test result: A lab test result that indicates the tested person does not have the disease for which they were screened.
Nucleic acid: A small piece of genetic material. DNA contains 4 nucleic acids: adenosine, cytosine, guanine, and thymine.
Plasma: A components of whole blood. The clear, yellow liquid in which red blood cells, white blood cells, and platelets are suspended.
Positive test result: A lab test result that indicates the tested person has the disease for which they were screened.
Whole blood: Blood that contains all the components of blood: red blood cells, white blood cells, platelets, and plasma.

Background
Hepatitis B is a liver disease that can be transmitted from person to person in blood and other bodily fluids. To prevent transmission during blood transfusions, blood banks, hospitals, and other organizations that collect whole blood and/or components of blood pre-screen donors to determine if they have Hepatitis B. Anyone who tests positive is not permitted to donate blood.

However, the most commonly available screening test (which detects the presence of an antibody of Hepatitis B, known as anti-HBc, in a sample of the potential donor’s blood) is not 100% accurate and occasionally donors will test positive for Hepatitis B during screening when in fact they do not have the disease. These “false positives” prevent blood banks and hospitals from receiving badly-needed blood donations. Researchers who conducted a study funded by the National Heart, Blood and Lung Institute estimated that at least 200,000 potential donors who have received multiple false positive anti-HBc tests but otherwise met all criteria for being blood donors could be eligible to give blood again.

Summary
In spite of precautions, the transmission of disease-causing viruses like Human Immunodeficiency Virus (HIV) and Hepatitis B and C viruses from transfusions of donated blood can occur. Transmission is relatively rare but researchers estimate that approximately 1 in 205,000 to 1 in 269,000 units of donated blood carries Hepatitis B Virus (HBV). As a result, blood banks and other organizations that collect blood screen would-be donors for the presence of an antibody to HBV known as anti-HBc. Would-be donors who test positive are deferred but may donate in the future if they receive a negative test result on their second anti-HBc test. Would-be donors who test positive for anti-HBc more than once are blocked from donating blood indefinitely.

However, the anti-HBc test is not fool-proof and a substantial number of blood donors (approximately 20,000 per year) are turned away due to a positive test result when they do not have Hepatitis B.

In 2004, FDA and the Blood Products Advisory Committee (BPAC) held a meeting to discuss how would-be donors who had tested positive for anti-HBc more than once could be eligible again to donate blood. This Guidance is an outcome of that meeting and the identification of a highly sensitive test that can confirm whether an anti-HBc positive would-be donor actually has Hepatitis B. The new test, called Hepatitis B Virus Nucleic Acid Test (HBV NAT), detects pieces of DNA from the Hepatitis B virus. These pieces of DNA are present in blood only when the person is infected with the virus. A third test, which looks for the Hepatitis B antigen (HBsAg) which is present during active Hepatitis B infection, was added to the protocol to help protect the nation’s blood supply.

The resulting recommendation allows anti-HBc positive donors to give blood if they receive negative tests for HBsAg, anti-HBc, and HBV DNA by NAT at least 8 weeks (56 days) after the last positive anti-HBc test.

Rationale
Existing laws (21 CFR 601.40 and 21 CFR 61.41) require organizations that collect blood and blood components for medical use to test donor blood for Hepatitis B and refuse to collect or use blood from would-be donors who have tested positive for anti-HBc (an antibody of Hepatitis B virus) unless there is an FDA-approved method for requalifying donors. Before this Guidance was published, there was no such method and blood banks and hospitals had no choice but to reject donations from people with more than 1 positive anti-HBc test regardless of whether they actually had Hepatitis B. This Guidance describes the first such FDA-approved method and will help to expand the blood donor pool.

Resulting Recommendations
Would-be donors who have previously tested positive for anti-HBc on more than one occasion may regain eligibility for donating blood if:

At least 8 weeks (56 days) after the last positive anti-HBc test they are retested using FDA-licensed tests for HBsAg, anti-HBc, and HBV DNA by NAT.  
AND
They receive negative test results on all 3 tests 
AND
They meet all other eligibility criteria for blood donors

Would-be donors have previously tested positive for anti-HBc on more than one occasion and who receive a positive result for any of the 3 FDA-licensed tests (HBsAg, anti-HBc, and HBV DNA by NAT) upon retesting after 8 weeks are barred from giving blood indefinitely.

Impact
Donated blood is a critical source of blood and blood products used to save the lives of millions of Americans who need transfusions due to sickle cell disease, cancer, traumatic accidents, surgery, and other medical conditions. Organizations such as the American Red Cross frequently report shortages in the supply to donated blood. This problem is compounded by the enormous baby boomer population which will require increasing amounts of donated blood as they age even as they become ineligible to donate blood and replenish the supply. Allowing would-be donors who have been rejected due to multiple positive anti-HBc tests to donate blood if they meet the criteria described in the Guidance expands the pool of donors and the amount of donated blood available while still keeping the blood supply safe.

Guidance for Industry Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Product Applications and Related Submissions using

2011-06-17T11:49:00.000-07:00

Name of Guidance: Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Product Applications and Related Submissions using the eCTD Specifications

Status of Guidance: Final

Date of Guidance: October 2005

Name of Organizations Releasing the Guidance:

United States Department of Health and Human Services, Food and Drug Administration (FDA)
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)

Target Audience: This guidance was designed for applicants preparing electronic regulatory submissions to the FDA using the CTD.

Guidance, Laws and Regulations Referenced:

Code of Federal Regulations (CFR), chapter 21 – Regulation that outlines the content of regulatory submission documents. Subsections referenced include:

11.2(b)(2) – Gives guidance on what type of documents are acceptable in electronic format.
314.81(b)(3)(i) – Advertising and promotional labeling.
314.101 – Regulations for abbreviated new drug applications.
314.50(b) – Indexing of applications for FDA approval to market new drugs.
314.80(c)(2)(ii)(a) – Narrative summary of alert report.
314.550 – Promotional materials
600.80(c)(2)(ii)(a) and (c) – Periodic adverse experience report requirements and history of actions taken.
601.12(f)(4) – Advertising and promotional labeling, post marketing.
601.2 – Regulations for biologics licenses and procedures for filing the application.
601.45 – Biological products promotional materials.

Guidance that describe formatting for specific subsections of the CTD:

M2 eCTD: Electronic Common Technical Document Specification
M4: Organization of the CTD
M4Q: The CTD – Quality – Focuses on all quality sections of the CTD.
M4S: The CTD – Safety – Focuses on all safety sections of the CTD.
M4E: The CTD – Efficacy – Focuses on all efficacy sections of the CTD.

International Conference of Harmonisation (ICH) E3 guidance – General guidance on all sections of the Clinical Study Report.

Definitions:

Common Technical Document (CTD) – Also referred to as electronic CTD (eCTD). It is the standard format for submitting regulatory documents to Drug Regulatory Agencies in Europe, Japan, and the United States.
International Conference on Harmonisation – Organization that addresses technical requirements for regulatory documents submitted in Europe, Japan, or the United States.
eCTD backbone files – Indexing of files present in an electronic submission.
Submission – Collection of documents containing information which may include forms, reports, and datasets.

Background:

This guidance is intended to improve communication between the FDA and sponsors submitting electronic documents for regulatory review. It implements ICH recommendations by encouraging the use of eCTD backbone files. Additionally, because of the agency’s limited accessibility to newer technology, a list of acceptable file formats are provided.

Summary:

This guidance applies to marketing applications, investigational applications, and related electronic submission documents. It gives specific direction on the use of the CTD, and lets the reader know where to find content guidance for each subsection of the CTD.

During an electronic submission, each document is provided as a separate file and arranged into one of the 5 CTD modules. Each document in turn becomes part the electronic indexing which facilitates review by the agency. Since each file has a specific given location, referencing to previously submitted material is simple.

The following are some of the issues specifically addressed by this guidance:

Scanned documents – Text files are preferred because of their smaller size and because they are searchable.
Naming of files and folders – The file names should be short and descriptive.
Bookmarks and hyperlinks – They facilitate review and are essential.
Organization of the main submission folder – For organizational purposes, subfolders should be included.
Module 1 folder – Should include: a comprehensive table of contents, labeling documents, promotional materials, marketing annual reports, and informational amendments. A cover letter is optional.
Module 2 and Module 3 folders – Each containing a table of contents and a PDF copy of all documents required by their appropriate guidance.
Module 4 folder – Should include: a comprehensive table of contents, and complete non‑clinical study reports.
Module 5 folder – Should include a comprehensive table of contents, a tabular list of all clinical study reports, complete copies of all clinical study reports, and periodic safety reports.
Utility folder – This folder should contain information on the technology used to create the electronic submission.

Failure to comply with this guidance can result in the FDA refusing to accept the application.

Rationale:

This guidance was created to generate consistency across all regulatory submissions to the FDA and to simplify the review process.

Resulting Recommendations:

The agency will eventually need to update its list of acceptable file formats.

Impact:

Moving to electronic submissions has had the following accomplishments:

Decreased the amount of paperwork created by the sponsored.
Decreased the amount of time needed for review by the agency.
Decrease the turn around time of decisions by the agency.

Guidance for Industry M4: Organization of the Common Technical Document

2011-06-15T18:24:00.000-07:00

Name of Guidance: Guidance for Industry. M4: Organization of the Common Technical Document (CTD)

Status of Guidance: Final

Date of Guidance: August 2001

Name of Organizations Releasing the Guidance:

International Conference on Harmonisation (ICH)
United States Department of Health and Human Services, Food and Drug Administration (FDA)
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)

Target Audience: This guidance is targeted to applicants preparing the CTD for the registration of pharmaceutical products with the corresponding regulatory agency.

Laws and Regulations Referenced: None

Guidance Referenced:

General Considerations for Submitting Marketing Applications According to the ICH/CTD Format – This guidance describes the organization of new drug applications, abbreviated new drug applications and biological license applications for submission to the FDA.
Guidance that describe formatting for specific subsections of the CTD:

Uniform Requirements for Manuscripts Submitted to Biomedical Journals – Guidance sited to address references.

Definitions:

Common Technical Document (CTD) – Also referred to as electronic CTD (eCTD). It is the standard format for submitting regulatory documents to Drug Regulatory Agencies in Europe, Japan, and the United States.
GAIYO – Part of Japanese dossier. Summarizes all technical information of the drug under review.

Background:

The CTD was created through the International Conference on Harmonisation in an effort to simplify regulatory submission efforts among three main regulatory regions, Japan, Europe, and the United States. The same documents can be submitted to Japan, Europe and the United States for regulatory evaluation. This guidance addresses general formatting and presentation of data collected.

Summary:

The CTD is organized by sections or ‘Modules’. This guidance gives specific information on the order and numbering for all documents to be included in each Module:

· Module 1 is region specific and contains administrative information specific to each regulatory agency receiving the documents (GAIYO for Japan) including an application form, and the proposed label for the region.

· Module 2 gives a general description of the drug being evaluated and it contains summaries and overviews of the studies included in the regulatory submission.

· Module 3 contains all the quality information relevant to the regulatory submission.

· Module 4 contains nonclinical study reports.

· Module 5 contains clinical study reports.

Rationale:

The CTD was created to reduce or eliminate the requirement for industries to adapt their documents for each of the ICH regions,[1] and to expedite the review processes.

Resulting Recommendations:

Harmonization of technical requirements across 3 regulatory agencies.
Reduction of animal and human testing without compromising the safety or efficacy of the new test product.

Impact:

Reduction of testing and reporting in the development of new medicines[2] - Creation of a common approach to drug approval among the 3 main regulatory agencies (the CTD) has enabled the industry to reduce the number of trials performed to accommodate each regulatory agency’s requirements, and by this the reporting of findings has been reduced.
Cost savings for industry² – The harmonization of drug regulatory documents has made an impact in cost reduction. Fewer personnel hours are needed, the utility bills are lower, and the expenses in computer software and hardware have also been decreased.
Improvement in communication between regulatory agencies and industry² –With the development of the CTD, regulatory agencies have been able to create review templates and expedite review practices.

[1] International Conference on Harmonisation website. M4: The common Technical Document. http://www.ich.org/products/ctd.html. Accessed 09 June 2011.

[2] International Conference on Harmonisation website. The value and benefits of ICH to drug regulatory authorities. http://www.ich.org/fileadmin/Public_Web_Site/News_room/C_Publications/ICH_20_anniversary_Value_Benefits_of_ICH_for_Regulators.pdf. Accessed 10 June 2011.

Acceptance of Foreign Clinical Trial Data

2011-06-07T10:10:00.000-07:00

Guideline Title:

Acceptance of Foreign Clinical Trial Data

Status:

Finalized

Date of Guidance:

June 1998

Organizations Releasing Guidance:

Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), and Center for Devices and Radiological Health (CDRH)

Link to the Guidance:

http://www.fda.gov/RegulatoryInformation/Guidances/ucm126426.htm

Target Audience:

Clinical investigators and Internal Review Boards (IRBs)

Small and large biomedical/pharmaceutical companies doing research and development and/or manufacturing of drugs, biologics, or medical devices outside of the United States (U.S.)

Laws and Regulations Referenced:

21 CFR part 312 IND

21 CFR 312.120(c)(1), Foreign clinical studies not conducted under an IND
21 CFR part 812, IDE
21 CFR 814.15(a) and (b), Research conducted outside the United States

Definitions:
BLA: a request for permission to introduce, or deliver for introduction, a biologic product into interstate commerce.
Declaration of Helsinki: An international agreement pertaining to ethics in research on humans.
Evidence-based science: Definition debatable. Here, results are based on hypothesis testing, with quantifiable outcomes and peer review
Foreign clinical data: results gathered from studies outside the United States
Guidance: Formal advice or regulation (not a law). Here, given by a competent authority (FDA).
Good Clinical Practices (GCP) ICH E6: A guidance for the pharmaceutical industry published by FDA and agreed upon by the U.S., Japan, and Europe during the International Conference on Harmonisation (ICH E6).
Human subject: A person participating in a study or clinical trial
IDE: Investigation device exemption. Allows shipment of experimental devices without the need to be tested as normally required/
IND: Investigational new drug application. Request submitted to FDA for permission to investigate a new drug in humans.
Investigator: An individual who actually conducts a clinical investigation, i.e., under whose immediate direction the test article is administered or dispensed to, or used involving, a subject, or, in the event of an investigation conducted by a team of individuals, is the responsible leader of that team.
Informed consent: A document with the information FDA and IRBs consider necessary to present to potential subjects of a clinicat trial. Subjects must understand the contents and willingly sign the consent form before being included in the study.
IRB: Institutional Review Board. Members of this board address ethical questions of a proposed study and give approval (or deny it) for the initiation of a study.
NDA: New drug application. Request for approval of a new drug to be released on the interstate market after conducting clinical trials.
PMA: Premarketing approval. Approval needed before releasing a medical device on the market.

Background:

In the current economic climate, foreign drug development and manufacturing activity has been increasing rapidly. American pharmaceutical companies, in an effort to save money, have turned to offshoring (moving manufacturing to foreign countries). In addition, foreign countries conducting their own clinical trials are applying for INDs, NDAs, IDEs, PMAs and BLAs using their own data. This guidance, providing a standardized methodology for obtaining FDA acceptance of foreign clinical trial data, was implemented by FDA in order to address the questions of scientific validity, good conduct of clinical trials, protection of human subjects, and application to the population in the United States.

Summary:

This guidance states the criteria for acceptance of foreign clinical trial data to be used to support PMA, IND, NDA, IDE and BLA applications. Under 21CFR 312 IND, these approvals are subject to FDA informed consent and IRB requirements. To be accepted, the clinical trial must provide protection to human subjects (in accordance with the Declaration of Helsinki or local standards, whichever ensures the most protection). The trial must have been conducted in accordance with Good Clinical Practices (ICH E6), ensuring a level of validity agreed upon by the countries involved (the U.S.A., Japan, and Europe). The investigators must be recognized as competent, and results must be based on valid evidence-based science. These data are subject to FDA audits. Finally, the data must be applicable to the population and medical practices in the U.S. If all these criteria are met, the foreign data may be submitted for acceptance as support for FDA marketing applications.

Resulting Recommendations:

For FDA approval:

· Trial must be in accordance with the Declaration of Helsinki or local standards, whichever ensures the most protection to human subjects

· Trial must be in accordance with Good Clinical Practices (GCP), ICH E6

· Clinical investigators must have recognized competence

· Results must be evidence based and valid

· Results of trial must be applicable to the population and medical practices in the United States

(Kumar, 2009)

Rationale:

As foreign activity in drug development and manufacturing has been increasing (more than 50% of INDs come from sites in foreign countries, more than 40% of investigators are non U.S. citizens, Kumar, 2009) and marketing applications in the U.S. have, in turn, been more numerous, a standard methodology with clear criteria was needed to help investigators and review boards ensure good conduct of foreign clinical trials and to streamline the drug development process which was hindered due to differing practices and study populations. By following this guidance, foreign clinical trial data can be evaluated more easily by competent authorities. New drugs, biologics, and medical devices can obtain approval in less time and at a substantially lower cost for small and large companies worldwide.

Impact:

Providing an FDA-approved methodology for acceptance of foreign clinical trial data has a substantial worldwide financial impact on small manufacturers (savings of thousands of dollars) and large companies (savings of millions of dollars). This is especially advantageous for large global pharmaceutical companies who develop and manufacture drugs. (Biomedical Marketing Newsletter, 2001) Investigators can now refer to the guidance when designing their studies. IRB members also have a reference on which they can base their decisions. Ultimately, the general public benefits from this streamlining of the drug-approval process, as medicines become more readily available.

Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics

2011-06-06T14:29:00.000-07:00

Name of Guidance
Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics

Status of Guidance
Final

When was the Guidance released?
May 2007

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/ucm071590.pdf

Target Audience
Sponsors submitting clinical trial data in support of a new drug application (NDA) or biologics license application (BLA), or supplemental application for cancer treatments.

Laws and Regulations Referenced

21 CFR part 314, subpart H: Accelerated Approval of New Drugs for Serious of Life-Threatening Illnesses - New drug products intended to treat serious or life-threatening illnesses may be considered for fast-track approval if there is sufficient data showing that the drug is safe and treatment will be more effective than existing treatments. Postmarketing safety reporting requirements still apply and the sponsor may not distribute promotional materials about the drug until at least 120 days after the FDA approves the treatment.

21 CFR part 601, subpart E: Accelerated Approval of Biological Products for Serious or Life-Threatening Illnesses - New biologic products intended to treat serious or life-threatening illnesses may be considered for fast-track approval if there is sufficient data showing that the drug is safe and treatment will be more effective than existing treatments. As with the corresponding regulation for drugs (21 CFR part 314, subpart H), postmarketing safety reporting requirements still apply and the sponsor may not distribute promotional materials about the biologic product until at least 120 days after the FDA approves the treatment.

21 CFR 314.126: Adequate and well-controlled studies - Sponsors of new pharmaceutical or biologic drug products must conduct adequate, well-controlled clinical studies to demonstrate safety and efficacy. This includes valid comparison to a control product, minimization of bias in how participants are assigned to treatment and control groups, use of appropriate analytic and statistical methods to assess data from clinical trials, and other requirements.

Definitions

Biological marker (biomarker): A physical characteristic that can be measured objectively to indicate the progression of a disease or normal biological process, or the response to a therapeutic intervention. Examples include elevated blood glucose concentration (used to diagnose diabetes mellitus), blood cholesterol concentrations (used to determine risk of heart disease), and tumor size (used to assess efficacy of treatment in certain cancers).
Clinical endpoint: A measure of what a patient experiences directly as a result of a treatment including how the patient feels (eg, reduction in pain or other symptoms), functions (eg, regaining mobility or normal organ function), or survives (eg, outliving expected lifespan). In clinical trials, clinical endpoints are the most reliable indicators of whether the new treatment is effective and safe. For serious or life-threatening diseases such as cancer, the clinical endpoints usually include survival (how long the patient lives) or progression-free survival (how long the patient lives without the disease getting worse).
Complete response: Regression of a tumor to the point where there is no clinical evidence of the tumor. However, does not imply that the patient is “cured.”
Disease-free survival: The time from the patient enters the clinical trial until recurrence of the tumor or death from any cause.
Objective rate response: The proportion of patients whose tumors are reduced by a predetermined amount for a minimum time period.
Overall survival: The time from the patient enters the clinical trial until death from any cause.
Progression-free survival: The time from the patient enters the clinical trial until there is objective evidence that the tumor has progressed or death.
Surrogate endpoint: A biomarker that is used as a substitute for a clinical endpoint in a clinical trial. Surrogate endpoints predict clinical benefit based on existing scientific evidence but are not as reliable as clinical endpoints and may not always predict clinical benefit accurately. Surrogate endpoints are used when a sponsor is seeking accelerated marketing approval for a drug or biologic product.
Time to progression: The time from the patient enters the clinical trial until there is objective evidence that the tumor has progressed.
Time to treatment failure: The time from the patient enters the clinical trial to discontinuation of treatment for any reason (eg, disease progression, toxicity from the treatment, death).

Background
Clinical and surrogate endpoints are used to demonstrate the safety and efficacy of drugs and biologic products. Clinical endpoints are considered to be the most reliable, but surrogate endpoints were permitted so long as their usefulness in predicting clinical outcomes was well established.

In 1992, FDA started permitting the use of less established surrogate endpoints in clinical trials for drugs and biologic products meant to treat serious or life-threatening diseases (21 CFR part 314, subpart H and 21 CFR part 601, subpart E). These additional surrogates had to be reasonably likely to predict clinical benefit. The goal was to shorten drug development time and accelerate the marketing approval process. (Patients reach surrogate endpoints (eg, tumor shrinkage) much faster than clinical endpoints (eg, symptom improvement or survival), so clinical trials can be completed in less time.)

Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (“the Guidance”) is the first in a series of guidances that will help pharmaceutical and biotechnology sponsors choose meaningful endpoints for clinical trials for new cancer treatments. Subsequent guidances focus on endpoints for specific cancers.

Summary
The Guidance provides an overview of commonly used clinical and surrogate endpoints along with the advantages and disadvantages of each. Also discussed is the appropriateness of different study designs for each type of endpoint.

Of the clinical endpoints listed in the Guidance, FDA considers overall survival to be the most reliable for cancer treatment because it is precise and easy to document and measure. Symptom endpoints reported by patients are somewhat less reliable because data is frequently incomplete and blinding can be difficult, but they are appropriate.

The surrogate endpoints listed in the Guidance can all be used for accelerated or regular approval, but are less statistically valid and are often not direct measures of benefit. Disease-free survival, for example, is not statistically validated and may even be defined differently among studies. Objective response rate and complete response are not considered direct measures of benefit and progression-free survival is subject to assessment bias.

Biomarkers taken from blood or body fluids have not been validated as surrogate endpoints and are rarely used as primary endpoints in cancer drug trials.

The Guidance is nonbinding and sponsors are urged, but not required, to follow the recommendations provided.

Rationale
The Guidance and subsequent publications in the series were put together based on input from oncologists, hematologists, statisticians, patient advocates, and industry representatives through public workshops and discussions before the FDA’s Oncologic Drugs Advisory Committee (ODAC).

Resulting Recommendations

The following are considered to be clinical endpoints:

Overall survival - this is the most reliable cancer endpoint
Symptom endpoints (patient-reported outcomes)

The following are considered to be surrogate endpoints:

Disease-free survival
Objective response rate
Complete response
Progression-free survival
Time to progression

The following are not recommended for use as endpoints:

Time-to-treatment failure
Biomarkers assayed from blood or body fluids

It is recommended that sponsors consult with FDA to select appropriate endpoints for cancer drugs and biologics before submitting clinical trial protocols.

Impact
The Guidance will improve the quality of clinical trials for cancer treatments and facilitate accelerated marketing approval for promising drugs and biologics. Patients suffering from serious and life-threatening cancers will benefit from getting access to treatments more quickly. Sponsors will save time and money by understanding the advantages and disadvantages of using various endpoints before initiating clinical trials. However, the Guidance is general and cancer-specific guidances should be consulted because each type of cancer is so different.

Brief summary: General Considerations for Pediatric Pharmacokinetic Studies for Drugs and Biological Products

2011-06-06T13:41:00.000-07:00

Name of Guidance

General Considerations for Pediatric Pharmacokinetic Studies for Drugs and Biological Products

Status of Guidance

Draft Guidance

Date of Guidance

November 1998

Released by

U.S. Department of Health and Human Services, Food and Drug Administration

Center for Drug Evaluation and Research (CDER)/Center for Biologics Evaluation and Research (CBER)

Link to the Guidance

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072114.pdf

Target audience

Developers of drug s/biologics

Laws and Regulations

· 59 FR 64240: aka the 1994 rule; FDA ruling asking manufacturers to include more information about the use of a drug in the pediatric population in the product labeling

· 62 FR 43899: the 1997 FDA ruling mandating that new drugs and biologics include labeling on how to safely use medicines indicated for adults in the pediatric population

· FDA Modernization Act of 1997 revised the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act to enhance the regulation of food, drugs, devices, and biological products

· 21 U.S.C.: part of the FDA Modernization Act of 1997 that provide incentives such as market exclusivity to drug developers who conduct pediatric studies on drugs already approved in adults

· Department of Health and Human Services (DHHS), Policy for Protection of Human Research Subjects 45 CFR 46: regulations to protect human research subjects in clinical trials

· 21 CFR 50: Informed consent regulation

· 21 CFR 56: Institutional review board regulation

· Declaration of Helsinki: a series of recommendations and guidelines to direct the conduct of biomedical research involving human subjects, based on the principles of the Nuremberg Code

· 21 CFR 312.120: regulation regarding when the results of foreign clinical studies not conducted under an investigational new drug (IND) application can be accepted as support for an IND or an application for marketing approval

Definitions

Absorption: the movement a drug into the bloodstream from the skin, lungs, stomach, intestinal tract, or muscle

ADME: absorption (A), distribution (D), metabolism (M), and elimination (E) of a drug within the body; pharmacokinetic measures

AUC: area under the curve; PK parameter indicating the quantity of a therapeutic agent present in the circulation in a time period, often 24 hrs

Clearance: The rate at which a substance is removed from the blood

Cmax: maximum concentration; PK parameter indicating the maximum plasma concentration of the drug

Distribution: the spread of a drug to body tissues after it enters the blood

Elimination: The act of removing something, such as a drug, from the body

Half-life: the amount of time it takes for the concentration of a specified chemical or drug to decrease to half its original concentration in the specified fluid or blood

Linear PK: constancy of PK parameters of a drug throughout a wide range of dosages, allowing for concentrations at the site of measurement to always be directly related to dose, both for single and multiple doses

Metabolism: process by which a set of chemical reactions modify a molecule into another for storage, or for immediate use in another reaction or as a byproduct

PD: pharmacodynamics; the study of the biochemical and physiological effects of drugs and the mechanisms of their actions, including the relationship of their actions and effects with their chemical structure

Pediatric: individuals aged <16 years

PK: pharmacokinetic(s); the science and study of the factors that determine the amount of chemical agents at their sites of biological effect at various times after the application of an agent or drug to biological systems; includes the study of the effect of ADME on a drug

Protein binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds

Volume of distribution: A hypothetical volume of body fluid that would be required to dissolve the total amount of drug needed to achieve the same concentration as that found in the blood

Background

Many drugs on the market are indicated for use in adults (individuals aged ≥16 years). Many of these same drugs also may be useful in the pediatric population (individuals aged <16 years old), with some possibly already being used off-label in this young population. However, without official trials that investigate the safety, efficacy, and appropriate dosing of drugs in the pediatric population, it is impossible to know how to appropriately use these drugs in the pediatric population—and if it is wise to do so at all.

In an effort to encourage drug manufacturers to investigate the effect of drugs and biologics in the pediatric population, the FDA has passed several rules and regulations such as 59 FR 64240, which asked manufacturers to include more information about the use of a drug in the pediatric population in the product labeling; 62 FR 43899, which mandated that new drugs and biologics include labeling on how to safely use these medicines in the pediatric population; and the FDA Modernization Act of 1997, which gave incentives to motivate sponsors to run pediatric trials (21 U.S.C. 355a).

Summary

This guidance is meant to help drug manufacturers perform pharmacokinetic studies in the pediatric population. It advises that pediatric PK studies be conducted in all age groups within the pediatric population to verify appropriate dosing and what dose adjustments should be made to the dosage regimen to ensure that pediatric patients will achieve a comparable systemic exposure to adults that is as safe and effective. This information should then be included in the product labeling of this drug or biologic. This guidance should only be considered for conditions with a similar disease course in adult and pediatric populations, as well as a similar association between dose/response.

Rationale

The safety and efficacy of a drug is based on the achievement of a defined amount of systemic exposure of a drug within a therapeutic window. This systematic exposure is measured by the area under the curve (AUC) and concentration at the maximum (Cmax) from which the clearance, half-life, and volume of distribution of a drug is determined. PK studies show what the body does to a drug in terms of how it is absorbed, distributed, metabolized, and eliminated—all of which affect the AUC and Cmax of the drug. Drugs typically vary in PK measures between persons and within the same person. The many changes occurring in pediatric patients as they develop into adults can affect the way the body absorbs, distributes, metabolizes, and eliminates a drug.

The appropriate AUC and Cmax values that mean safe and efficacious use in children are generally different than those in adults. Therefore it is necessary to test the PK of a drug in different age groups, including a full range of ages within the pediatric population. This will help assess the systemic exposure of a drug in various age groups and determine appropriate dosing.

Resulting Recommendations

1. Pediatric PK studies should assess the absorption, distribution, metabolism, elimination, and protein binding of a drug as these processes are affected by the changes occurring in the rapidly growing and developing bodies of pediatric patients.

2. In vitro plasma protein studies should be conducted.

3. PD studies should be conducted in the pediatric population to determine how blood concentration, efficacy, and toxicity of a drug relate to help better understand dose and/or concentration/response differences between pediatric and adult populations.

4. Pediatric PK studies should include the influence of body size (eg, height, weight, surface area) and age on a drug. Additional covariates should include, if relevant, gestational age, birth weight, lab tests on organs involved in drug elimination, and concomitant and recent drug therapy.

5. In the pediatric population, single-dose studies should be conducted for drugs with linear PK in adults and steady-state studies for drugs with nonlinear PK.

6. The population approach is preferred over the standard approach to PK studies in the pediatric population.

7. Samples such as blood should be collected with utmost safety, minimizing frequency and quantity.

8. Data derived from PK studies should be included in the labeling of the drug specific to use of the drug in the pediatric population. If available, data should be included in the following sections of the prescribing information (labeling): CLINICAL PHARMACOLOGY (eg, variations in absorption, distribution, metabolism, and/or elimination between adult and pediatric populations); PRECAUTIONS: Pediatric Use (eg, information on safety and what the drug does in the pediatric body according to age); and DOSAGE AND ADMINISTRATION (eg, dosing modifications for the pediatric population according to age and body weight).

9. The safety and rights of pediatric participants in any studies should be upheld in any trials involving these patients according to ethical standards.

10. Pediatric PK studies should be conducted in all age groups within the pediatric population to verify what dose adjustments should be made to the dosage regimen to ensure that pediatric patients achieve a comparable systemic exposure that is as safe and effective as in adults.

Impact

Studies in pediatric populations of drugs indicated for adults will allow drug developers to determine if their drugs can be safely and efficaciously used in pediatric patients. These studies will help determine what doses are safe and effective in the pediatric population, too. Conducting pediatric studies will help decrease the unsubstantiated off-label use of adult drugs in pediatric patients.

Guidance for Industry. Consumer-Directed Broadcast Advertisement

2011-06-01T18:17:00.000-07:00

Name of Guidance: Guidance for Industry. Consumer-Directed Broadcast Advertisements

Status of Guidance: Final

Date of Guidance: August 1999

Name of Organization: United States Food and Drug Administration (FDA)

Target Audience: This guidance is intended for sponsors who advertise prescription products directly to the public using any electronic communication system.

Laws and Regulations Referenced:

21 United States Code (USC) 352 (n) - Requirements for prescription drug advertisements.
21 Code of Federal Regulations (CFR) 202.1 (e)(1) – Differences between print prescription drug advertising and broadcast prescription drug advertising.

Definitions:

Adequate provision – An alternative way for a drug company to provide the drug’s prescribing information.
Broadcast advertisement - Advertisements that are transmitted through electronic media such as television, radio, or telephone
Major statement – During commercials, it is the spoken description of the drugs’ most important risks.

Background:

Broadcast advertisements must give a summary of all risks associated with a drug’s permitted uses (adequate provision), and must highlight the drug’s major risks (major statement). This guidance describes how to fulfill the adequate provision requirement.

Summary:

To fulfill the adequate provision requirement, the drug’s sponsor must use a convenient and unintimidating approach for the consumer to obtain more information on the drug. This approach may include:

A. Including a toll-free telephone number in the advertisement which will give consumers more information on the product by having the information read or mailed to them.

B. Let the consumer know where complete printed information can be found, such as an internet address, a magazine article or magazine advertisement.

C. Remind the consumer that more information may be obtained from a physician, pharmacist, or veterinarian (if drug refers to an animal product).

Additionally, if the drug information is broadcasted in a foreign language, all printed informational materials need to be translated to the language of the broadcast advertisement.

Rationale:

The FDA requests this unintimidating approach as a way for consumers to obtain drug related information in a private manner. Furthermore, the agency requests that all printed informational material be translated to the language of the broadcast advertisement because there are many television channels and radio stations that broadcast information in a foreign language particularly in large metropolitan areas.

Resulting Recommendations:

Simple way of providing prescription drug information to consumers
Making prescription drug information available in foreign languages

Impact:

Additional expenses are incurred by the sponsors of prescription drugs in order to comply with this guidance.
The consumer is better informed and able to make an educated decision on whether to take a particular prescription drug or not.

Class II Special Controls Guidance Document: Intervertebral Body Fusion Device

2011-05-26T09:57:00.000-07:00

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

2011-05-24T09:32:00.000-07:00

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.

Publié par Valquirit à l'adresse 12:01 0 commentaires

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

2011-05-23T11:54:00.000-07:00

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

2011-05-23T11:53:00.001-07:00

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

2011-05-23T08:45:00.000-07:00

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.