Guidance for Developing Products for Weight Management

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Guidance for Industry Development of Products for Weight Management, 1996: Original FDA draft guidance with recommendations for designing clinical trials for weigh-management products.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

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

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

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 drugs/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)

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:

1. 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
2. They receive negative test results on all 3 tests

   AND
3. 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.