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Guidance for Industry DRAFT GUIDANCE This guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register. For questions regarding this draft document contact (CDER) Lewis Schrager 301-827-7711 or Debra B. Birnkrant 301-827-2330, (CBER) Stephen Ripley 301-827-6210, or (CDRH) Steve Gutman 301-594-3084.
U.S. Department of Health and Human Services Clinical Antimicrobial Guidance for Industry Vaccinia Virus — Developing Drugs to Mitigate Complications from Smallpox Vaccination
Additional copies are available
from: http://www.fda.gov/cder/guidance/index.htm or
Office of Communication, Training
and http://www.fda.gov/cber/guidelines.htm Phone: the Voice Information System at 800-835-4709 or 301-827-1800 or
Office of Health and Industry
Programs http://www.fda.gov/cdrh/ggpmain.html DSMA Email: dsma@cdrh.fda.gov DSMA Fax Number: 301.443.8818 Manufacturers Assistance Phone Number: 800.638.2041 or 301.443.6597 Internt'l Staff Phone: 301.827.3993
U.S. Department of Health and Human Services March 2004 Clinical Antimicrobial TABLE OF CONTENTS
I. INTRODUCTION II. BACKGROUND III. REGULATORY APPROACH REGARDING DRUG DEVELOPMENT
IV. ANIMAL MODELS VI. SUMMARY
Guidance for Industry[1] This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.
I. INTRODUCTIONThis guidance provides recommendations on the development of drugs to be used to treat complications that may occur from smallpox vaccination with vaccinia virus. It is intended to help commercial and research sponsors plan and design appropriate nonclinical and clinical studies during the development of these drugs. This guidance does not make recommendations about the development of drugs to treat smallpox. That issue will be addressed separately in a future guidance document. This guidance also does not address the development of biological therapies, such as vaccinia immune globulin (VIG). The development of drugs to mitigate vaccinia virus complications raises unique and challenging issues. Many of the previous studies done on the topic were performed prior to the 1970s, before the United States abandoned routine vaccinia vaccination for smallpox. A concern that smallpox may be used as a bioterrorism agent has led to a limited reintroduction of smallpox vaccination, with the potential for widespread vaccination should an attack with smallpox occur. Therefore, it is critical that we develop drugs to treat the complications associated with the vaccine. Currently, there are no FDA-approved drugs indicated for treatment of vaccinia vaccine complications. We would like to strongly encourage the submission of pre-investigational new drug applications (pre-INDs) to promote discussions between sponsors and FDA addressing the sequence and content of nonclinical and clinical study proposals. To facilitate drug development, the sponsor may find it advantageous to collaborate with governmental agencies and academic centers. These collaborations may provide resources such as drug screening, improved access to target populations for clinical trials, and funding. Drug development also may be facilitated by investigating drugs that already have undergone substantial development and have a mature safety database. This guidance first summarizes appropriate nonclinical studies recommended during early drug development. The section on chemistry, manufacturing and controls (CMC) refers the sponsor to relevant guidances for CMC information. A nonclinical toxicology section outlines required and recommended in vitro and animal safety studies used to support the safety of clinical investigations. A microbiology section details both nonclincal and clinical issues important during drug development, such as identifying drug mechanism of action, antiviral activity, cytotoxicity, drug activity in combination with other drugs, and drug resistance. A clinical pharmacology section discusses analyses the sponsor should perform to elucidate an understanding of drug pharmacokinetics and pharmacodynamics, including data that should be obtained from special populations. Next, the guidance focuses on the acquisition of in vivo data through the use of animal models. Because the rate of serious vaccinia complications in the vaccinated population is low, the amount of efficacy data adequate for drug approval may not be obtainable through clinical trials. Therefore, animal models may provide a source of supportive efficacy data, or possibly contribute directly to drug approval under 21 CFR part 314, subpart I (the Animal Efficacy Rule). The guidance discusses the requirements of the Animal Efficacy Rule. The guidance concludes with sections addressing the acquisition of human efficacy and safety data. Issues surrounding the design of clinical trials are discussed. In addition, sections detailing data collection requirements and recommendations, along with consideration of long-term patient follow-up and special population data collection, are presented. A sample case report form is provided as an example of a data collection format. FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required. II. BACKGROUNDNaturally occurring smallpox was declared eradicated in 1980 following a global campaign initiated by the World Health Organization (WHO) that incorporated use of case identification, containment, and vaccination. The United States abandoned the routine use of smallpox vaccination in the civilian population in the early 1970s (Breman and Henderson 2002) due to concerns that the risks of developing an adverse event secondary to vaccinia inoculation outweighed the risk of developing smallpox. Although clinical smallpox has been eradicated, there are concerns that variola virus, the etiological agent of smallpox, could be used as a weapon of bioterrorism. Therefore, proposals for smallpox vaccination have been discussed and public health advisory groups have issued recommendations for administration of vaccine to selected groups (CDC 2003a). According to advisory panel evaluations and recommendations (CDC 2003a; 2001), vaccinia virus vaccine administered prior to exposure to variola virus produces substantial immunity against smallpox that usually lasts for at least several years. In addition, if performed within a few days after initial variola exposure, it may prevent disease or decrease the symptoms of smallpox. The currently licensed smallpox vaccine uses live vaccinia virus. According to the Dryvax package insert, the vaccine is contraindicated for routine non-emergency use for persons who are immunosuppressed, persons with eczema or a past history of eczema, persons with other acute, chronic, or exfoliative skin conditions, and pregnant women due to the potential development of complications secondary to the vaccine itself. Household contacts of such persons should not be vaccinated. Also, the Contraindications section of the package insert (non-emergency use) was updated to include persons with cardiac disease or certain risk factors for cardiac disease. (Please see the package insert for a complete listing of contraindications.) Important complications associated with the smallpox vaccine include, but are not limited to:
Vaccinia virus exposure may occur via vaccination, accidental person-to-person spread from a vaccinated individual to a close contact, or exposure from use of the virus as a recombinant vector for another investigational vaccine. For data on smallpox vaccine adverse event rates from 10 state-wide surveys see Table 1 (Lane et al., 1970). Available rates of vaccinia vaccination adverse events come mainly from studies done prior to 1970 (Lane et al. 1970; Lane et al. 1969). Current complication rates from vaccination may be difficult to predict accurately. Rates for certain complications could be anticipated to be higher now due to the larger number of at-risk individuals in today’s population. Table 1. Adverse event rates associated with vaccinia vaccination (cases/million vaccinations)
Adapted from: Lane MJ, Ruben FL, Neff JM, et al., 1970, "Complications of Smallpox Vaccination, 1968: Results of Ten Statewide Surveys," Journal of Infectious Diseases, 122:303-309. For example, there are an estimated 8.5 million persons with cancer, 850,000 persons with HIV/AIDS and 184,000 solid-organ transplant recipients in the United States (Kempner et al. 2002). In addition, many persons today who would receive a primary vaccination are at an older age compared to the majority who received vaccinations during the previous smallpox vaccination program era. This change in age distribution could increase the occurrence or detection of certain adverse events while possibly decreasing others. Alternatively, rigorous screening for persons with contraindications to the vaccine in a pre-event vaccination campaign could result in fewer adverse events. In addition, new smallpox vaccines are being developed that may cause complications that differ in scope and number from the previous profile. Currently, VIG, which is not FDA approved, is recommended by the Centers for Disease Control and Prevention (CDC) under an investigational protocol for specific vaccinia complications. Treatment is recommended for (1) eczema vaccinatum, (2) progressive vaccinia, (3) generalized vaccinia that is severe or occurs in a patient with an underlying illness that may increase risk of severity, and (4) in limited cases of severe lesions secondary to inadvertent autoinoculation. VIG is not recommended for benign self-limited complications or complications that are not believed to be associated with viral replication (CDC 2003d). To date, there are no drugs with FDA approval to treat vaccinia complications. However, the availability of therapies used to treat these complications may change, and investigators should address questions regarding this issue to FDA on a real-time basis. III. REGULATORY APPROACH REGARDING DRUG DEVELOPMENTIn each topic area below, the amount and timing of the information recommended relative to other steps in the development sequence may vary. We encourage initial discussions with FDA to address priorities and timelines for each proposed development plan. Pre-IND submissions are encouraged at an early stage of development to facilitate such discussions, to address questions about the development sequence, and to provide an opportunity for feedback on nonclinical and clinical study proposals. Sponsors should contact the appropriate review division for advice on the procedure for a pre-IND submission.[3] For other, more general information on development of approaches to medical countermeasures, the Division of Counter-Terrorism may be a useful resource. This guidance focuses on drugs designed to treat the complications associated with vaccinia virus replication. If candidate drugs are proposed that are not considered to have an antiviral mechanism of action, it is important that sponsors provide an adequate rationale and that they address other specific aspects of their proposed actions. For example, any product directed principally at treating bacterial superinfections of vaccination sites may be more appropriate for principal evaluation as an antibacterial therapy for complicated bacterial skin infections, and any product directed principally at characteristics of wound healing may call for consideration of wound-specific issues. If such cases occur, other guidances may prove useful.[4] However, we expect sponsors of such drug candidates to provide data from evaluation of the effect of the drug on viral replication and from assessment of drug-drug interactions with antiviral drugs targeted for vaccinia complications. Sponsors will want to ensure that all studies and procedures incorporate adequate precautions to avoid transmission of pathogenic virus or generation of novel biologic hazards, including containment measures and vaccination of study staff, as appropriate. A. Interactions Among Industry, Academic, and Government SponsorsSponsors are encouraged to explore areas of interaction and collaboration to increase the efficiency of drug development and resource use. For example, contacting the National Institute of Allergy and Infectious Diseases, National Institutes of Health, may be useful early in the course of development to identify sources of grants and contracts, and to learn about collaborative programs where aspects of drug development may be under way. For products in the development stage for which clinical trials are appropriate, discussions with public health programs through the CDC or state and local public health agencies may facilitate identification of target populations and setting priorities for resource use. In some circumstances, collaborations between sponsors of drugs and developers of new vaccine candidates may be beneficial. Opportunities, such as funding programs or collaborative efforts, may change substantially over time. Therefore, we recommend that the sponsor identify contacts for collaboration at the relevant stage of product development. B. Drugs with Previous or Concurrent Studies for Other IndicationsIf the drug under evaluation has not been previously approved but has already undergone substantial development and is currently under study for other indications (or for which such studies are planned) or has had approval sought for a nonvaccinia indication, it may be possible to expedite the development process. In this situation, some safety data will already exist, and the applicant may not need to collect as much additional data to complete the safety database. Furthermore, results of studies for other similar indications may provide ancillary supporting data for the evaluation of efficacy for vaccinia-related indications. It is the responsibility of the sponsor to document the adequacy of the available safety data to support the safety of the clinical protocol under consideration. If the sponsor does not own the supporting safety data and if those data are not in the public domain, it is the sponsor’s responsibility to get letters of authorization allowing FDA to refer to those studies during its evaluation of the proposed clinical trial. If the drug under evaluation has already been approved for other indications, the sponsor can either obtain a right of reference to the safety data or rely on the Agency’s previous finding of safety of that drug and provide any additional supportive data, as appropriate, to support the proposed investigational use (e.g., due to different dose or patient population as compared with the approved use). If the sponsor relies on the Agency’s previous finding of safety, however, any future submission of an NDA would be subject to the provisions of 21 CFR 314.54. Early discussion with the Agency may help to identify planning strategies that could lead to the most efficient design of overlapping development plans. For those drugs that are new chemical entities, please refer to section D of this section (Nonclinical Toxicology) for information regarding the recommended safety studies. C. Chemistry, Manufacturing, and ControlsWe recommend that the sponsor submit chemistry, manufacturing, and controls (CMC) information as described in the guidances Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs and INDs for Phase 2 and 3 Studies Chemistry, Manufacturing, and Controls Information. Depending on the situation, we recommend that sponsors consult other relevant guidances. D. Nonclinical ToxicologyA sponsor must supply information about the pharmacological and toxicological studies of a drug performed in vitro or in animal studies adequate to support the safety of proposed clinical investigations (21 CFR 312.23(a)(8)). The kind, duration, and scope of animal and other studies that should be submitted varies with the duration and nature of the proposed clinical investigations. Guidance documents are available from FDA that make recommendations about ways such requirements can be met; they are referenced in the following sections. The information submitted must include the identification and qualifications of the individuals who evaluated the results of these studies and concluded that it is reasonably safe to begin the proposed clinical investigations (§ 312.23(a)(8)). In addition, the sponsor must include a statement detailing where the investigations were conducted and where the records are available for inspection (§ 312.23(a)(8)). As drug development proceeds, the sponsor will be expected to submit nonclinical and clinical safety informational amendments. The sponsor must submit an integrated summary of the toxicological effects of the drug in vitro and in animals (§ 312.23(a)(8)(ii)(a)). Depending on the nature of the drug and the phase of the investigation, the summary should include the results of acute, subacute, and chronic toxicity tests, safety pharmacology tests, tests of the drug's effects on reproduction and the developing fetus, tests of the drug’s genetic toxicity, any special toxicity test related to the drug's particular mode of administration or conditions of use (e.g., inhalation, dermal, or ocular toxicology), and any in vitro studies intended to evaluate drug toxicity. We also expect that animal studies describing the pharmacological effects and mechanisms of action of the drug and information on the absorption, distribution, metabolism, and excretion of the drug will be submitted. For each toxicology study that is intended to support the safety of the proposed clinical investigation, a full tabulation of data suitable for detailed review must be submitted (§ 312.23(a)(8)(ii)(b)). The sponsor must submit a summary of previous human experience with the investigational drug (§ 312.23(a)(9)). A sponsor is required to submit detailed safety data as well as information relevant to the rationale of drug development for any investigational drug marketed in the United States or abroad (§ 312.23(a)(9)(i)). A list of countries in which the drug has been marketed or withdrawn from marketing for reasons related to its safety or efficacy must also be provided (§ 312.23(a)(9)(iii). Additionally, if the drug has been studied in controlled clinical trials, relevant data regarding the drug’s effectiveness for the proposed investigational trial should be submitted (§ 312.23(a)(9)(i)). Published material relevant to the safety or effectiveness of the drug or clinical investigation must be provided while less relevant published material should be provided as a bibliography. Regulatory and pharmaceutical industry representatives from the United States, Europe and Japan (The International Conference on Harmonisation of Technical Requirements of Registration for Pharmaceuticals for Human Use (ICH)) have written guidance documents for many of the nonclinical requirements for safety studies. These guidance documents recommend international standards for, and promote harmonization of, the nonclinical safety studies needed to support human clinical trials of a given scope and duration. 1. Timing of Nonclinical Studies to Support the Conduct of Human Clinical TrialsUsually, once a drug has been shown in nonclinical studies to be sufficiently safe for clinical trials to begin, trials are conducted to demonstrate the drug’s safety and efficacy in humans. Phase 1 trials evaluate the safety and pharmacokinetic profile of the drug. These trials start with relatively low drug exposure in a small number of subjects, often using healthy volunteers. The pharmacokinetic data, together with activity data in vitro, should ideally demonstrate that a high inhibitory quotient (IQ, see relevant section in III.E.2.d), can be expected at doses that are safe for the administration of drug. Efficacy evaluations are carried out in trials of longer duration. Therefore phase 1 trials are usually followed by clinical trials in which drug exposure increases by dose, duration, and/or size of the exposed patient population. In trials of drugs
designed to treat vaccinia complications, we expect that studies
to assess the safety of the drug in humans will be conducted first
in healthy volunteers. Sufficient nonclinical studies should be
carried out to support the safety of administration of the drug
for at least 2 weeks, or until pharmacokinetic measurements have
demonstrated that the drug has reached steady state in the normal
volunteers. In general, toxicology studies of 2 week duration in
a rodent and a nonrodent species will support submission of
protocols for review for phase 1 clinical trials of up to 2 weeks.
Upon the completion of such studies, a 1 month (or longer) study,
again in healthy volunteers, might be considered. However, to
support the dosing of humans in clinical trials for a period
longer than 2 weeks, nonclinical toxicology studies of a longer
duration should be performed.[5]
The clinical spectrum of serious vaccinia complications suggests
that some cases may require treatment for longer than 2 weeks, and
therefore we recommend that initial toxicology and safety studies
take this possibility into account. 2. Acute and Subacute Toxicity StudiesAcute toxicity studies are often the first studies carried out on a drug intended for humans and use a single dose or multiple-doses administered for no longer than a 24-hour period. Subacute studies are multiple-dose studies carried out for no longer than 6 months. Most commonly, an acute study with drug administration by the proposed clinical route of administration as well as a parenteral route (usually intravenous) is performed in a rodent and a nonrodent species to set the doses for longer term nonclinical studies and to evaluate the immediate toxicity profile of the drug. If the proposed clinical route of administration is to be intravenous, intravenous evaluations alone will usually suffice. We recommend that observational evaluations, as well as clinical chemistry and histopathologic evaluations, be performed at the end of 2 weeks. 3. Safety Pharmacology StudiesSafety pharmacology studies evaluate the interaction of the drug with organ systems such as the central nervous system, cardiovascular system and respiratory system. In some cases, the sponsor can incorporate some safety pharmacology evaluations in animals into the design of toxicology, kinetic, and clinical studies, while in other cases these endpoints are best evaluated in specific safety pharmacology studies. Although the adverse effects of a substance may be detectable at exposures that fall within the therapeutic range in appropriately designed safety pharmacology studies, such effects may not be evident from observations and measurements used to detect toxicity in conventional animal toxicity studies.[6] 4. Genetic ToxicityPrior to the administration of a new drug into humans, we recommend that the sponsor perform a comprehensive assessment of its genotoxic potential. Since no single test is capable of detecting all relevant genotoxic agents, the usual approach has been to carry out a battery of in vitro and in vivo tests for genetic toxicity. A standard test battery of studies has been selected under ICH to evaluate a new drug for its ability to cause genetic toxicity. In general, two of the in vitro tests should be completed prior to the initial submission of an IND, and the remainder of the battery should be completed prior to phase 2 studies.[7] If genetic toxicity is detected, one is confronted with an ethical dilemma. Generally, a genetically toxic drug is not administered to a healthy volunteer for greater than one dose. It is considered unethical to subject a healthy volunteer, who does not stand to benefit from drug administration, to a drug that might cause cancer. It is possible that some drugs with efficacy against vaccinia could also be genetic toxins. We recommend that the sponsor confer with the review division regarding such an issue as soon as possible. 5. Reproductive ToxicityReproductive toxicity studies assess the effect a drug may have on mammalian reproduction from premating (adult male and female reproductive function) to sexual maturity of the offspring. ICH guidances address the design of reproductive toxicity studies and offer a number of choices for carrying out reproductive toxicity studies.[8] The reproductive toxicity studies vary from indication to indication, but they are all expected to be submitted before phase 3 trials. In trials of vaccinia complications, women entering the trials while pregnant and toxicity to male and female fertility are concerns. We expect that a study of fertility from conception to implantation and at least one organogenesis study would be completed prior to the early studies in healthy volunteers, and the full complement of studies would be completed prior to the administration of the drug in patients. The informed consent should outline the hazards associated with drug administration. 6. Carcinogenicity StudiesIn general, carcinogenicity studies would not be expected for drugs used to treat vaccinia complications since the administration of the drug would not, in most cases, exceed 6 months. However, decisions regarding the performance of carcinogenicity studies would need to be made on a case-by-case basis and would depend on the mutagenic potential and/or possible structure-activity relationship of the test drug with other known carcinogens.[9] E. MicrobiologyThis section discusses issues that are important to consider during the microbiologic evaluation of candidate drugs. Some components may change as more investigations take place in this field (for example, increased opportunities to study cross-resistance or interactions with other anti-vaccinia drugs). The sponsor will be expected to make available for review adequate information on sample collection and assays performed and on validation approaches for these assays. Use of a specific procedure, method, or test system in an investigational protocol for a nonclinical laboratory study does not constitute FDA endorsement of that procedure, method, or test system, or FDA approval for clinical laboratory use. This guidance addresses these points further in the following descriptions, and sponsors are strongly encouraged to bring questions for discussion with the review division early in the drug development process. 1. Nonclinical Virology ReportsNonclinical virology reports are an important component in the review process of a candidate anti-vaccinia drug. They contribute to the evaluation of a candidate drug’s safety concerns and activity prior to its use in humans. We request that submitted reports identify the mechanism of action, establish specific antiviral activity of the compound in a model system, and provide data on the development of viral resistance (or reduced susceptibility of the virus) to the candidate drug. We would expect that these studies be well advanced or completed prior to the introduction of the candidate drug into humans. 2. Components of Nonclinical
Virology Reports
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* Monitor CD4
count and HIV viral load if patient is HIV positive.
SAMPLE CASE REPORT FORM
This sample case report may not be all-inclusive. Investigators are encouraged to contact FDA at an early stage of plan development for data collection to discuss plan details and subsequently to discuss development of a case report form specifically designed to address the concerns of their drug, the vaccinia complication(s) to be studied, and the circumstances of the study.
Page 8 Patient ID Number: __________________
Viral Culture to Screen for Resistance (if applicable):
Site of Culture: ___________________
Date:____________________________
Result (e.g., viral load if applicable): __________________________
Genotype Performed: Yes____ (attach results) No______
Assessment for evidence of bacterial superinfection (physical exam, cultures if applicable)
Other Tests/ X-rays (Include Date)_________________________________________________
______________________________________________________________________________
Pregnancy test: Pos._____ Neg. _______ (Place here if not part of inclusion/exclusion criteria; risk/benefit assessment of study enrollment should be documented)
SAMPLE CASE REPORT FORM
This sample case report may not be all-inclusive. Investigators are encouraged to contact FDA at an early stage of plan development for data collection to discuss plan details and subsequently to discuss development of a case report form specifically designed to address the concerns of their drug, the vaccinia complication(s) to be studied, and the circumstances of the study.
Page 9 Patient ID Number: __________________
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AE Event Description |
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Severity 1 – mild 2- moderate 3- severe |
Continuous (C) Vs. Intermittent (I) |
Relationship to the study drug 0 – unknown 1- NR 2- Probably NR 3- Possibly R 4- Probably R |
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Abbreviations: AE, adverse event; NR, not related; R, related (serious events should be reported in accordance with expedited procedures even if relationship to treatment is considered unlikely)
SAMPLE CASE REPORT FORM
This sample case report may not be all-inclusive. Investigators are encouraged to contact FDA at an early stage of plan development for data collection to discuss plan details and subsequently to discuss development of a case report form specifically designed to address the concerns of their drug, the vaccinia complication(s) to be studied, and the circumstances of the study.
Page 10 Patient ID Number: __________________
Post-Treatment Follow-Up (Make additional copies of this page for each assessment scheduled per protocol and any additional assessments needed)
Include Current Medications/Treatments
Physical Examination
Laboratory Tests
Complications and Subsequent Courses of Action
(Refer to previous case report form for sample of layout design)
References
Breman JG, Henderson DA, 2002, “Diagnosis and Management of Smallpox,” New England Journal of Medicine, 346:1300-1308.
Centers for Disease Control and Prevention (CDC), 2003a, “Recommendations for Using Smallpox Vaccine in a Pre-Event Vaccination Program,” Morbidity and Mortality Weekly Report, 52(RRO7):1-16.
CDC, 2003b, “Update: Cardiac-Related Events During the Civilian Smallpox Vacciniation Program — United States, 2003,” Morbidity and Mortality Weekly Report,52(21):492-496.
CDC, 2003c, “Notice to Readers: Supplemental Recommendations on Adverse Events Following Smallpox Vaccine in the Pre-Event Vaccination Program: Recommendations of the Advisory Committee on Immunization Practices,” Morbidity and Mortality Weekly Report, 52(13):282-284.
CDC, 2003d, “Smallpox Vaccination and Adverse Reactions: Guidance for Clinicians,” Morbidity and Mortality Weekly Report, 52(RR04):1-28.
CDC, 2001, “Vaccinia (Smallpox) Vaccine Recommendations of the Advisory Committee on Immunization Practices (ACIP),” Morbidity and Mortality Weekly Report, 50(RR10): 1-25.
Chou TC, Talalay P, 1984, “Quantitative Analysis of Dose-Effect Relationships: The combined Effects of Multiple Drugs or Enzyme Inhibitors”, Advances in Enzyme Regulation, 22:27-55.
Dryvax® (Smallpox Vaccine, Dried, Calf Lymph Type) package insert (Wyeth Laboratories, Inc.), Rev 6/26/2003.
Karjalainen J, Heikkila J, Nieminen MS, et al., 1983, “Etiology of Mild Accute Infectious Myocarditis. Relation to Clinical Features,” Acta Medica Scandinavica, 213(1):65-73.
Kempner AR, Davis MM, Freed GL, 2002, “Expected Adverse Events in a Mass Smallpox Vaccination Campaign,” Effective Clinical Practice, 5:84-90.
Kern E, Hartline C, Harden E, et al., 2002, “Enhanced Inhibition of Orthopoxvirus Replication In Vitro by Alkoxyalkyl Esters of Cidofovir and Cyclic Cidofovir,” Antimicrobial Agents and Chemotherapy, 46: 991-995.
Lane MJ, Ruben FL, Neff JM, et al., 1970, “Complications of Smallpox Vaccination, 1968: Results of Ten Statewide Surveys,” Journal of Infectious Diseases, 122:303-309.
Lane MJ, Ruben FL, Neff JM, et al., 1969, “Complications of Smallpox Vaccination, 1968, National Surveillance in the United States,” New England Journal of Medicine, 281:1201-1208.
Smee D, Sidwell R, Kefauver D, et al., 2002, “Characterization of Wild-Type and Cidofovir-Resistant Strains of Camelpox, Cowpox, Monkeypox and Vaccinia Viruses,” Antimicrobial Agents and Chemotherapy, 46:1329-1335.
[1] This guidance has been prepared by the Division of Counter-Terrorism and the Division of Antiviral Drug Products in the Center for Drug Evaluation and Research (CDER) in cooperation with the Division of Dermatologic and Dental Drug Products and the Division of Anti-Inflammatory, Analgesic, and Ophthalmologic Drug Products, CDER; the Center for Biologics Evaluation and Research (CBER); and the Center for Devices and Radiological Health (CDRH) at the Food and Drug Administration.
[2] Myo/pericarditis was reported rarely following smallpox vaccination (Karjalainen et al., 1983). In the current civilian and military smallpox vaccine programs, myo/pericarditis has been reported recently in vaccinees (CDC 2003b). Therefore, current recommendations state that persons with known underlying heart disease or who have three or more known major cardiac risk factors should also be excluded from smallpox vaccination pending further assessment of causality (CDC 2003c).
[3] For example, contact the Division of Antiviral Drug Products for systemic therapies, the Division of Anti-Inflammatory, Analgesic and Ophthalmologic Drug Products for ophthalmic products, or the Division of Dermatologic and Dental Drug Products for topical products that have no systemic formulation.
[4] Draft guidances on Uncomplicated and Complicated Skin and Skin Structure Infections – Developing Antimicrobial Drugs for Treatment and Chronic Cutaneous Ulcer and Burn Wounds – Developing Products for Treatment were issued in July 1998 and June 2000, respectively. If and when finalized, they will represent the Agency’s thinking on these topics.
[5] See ICH guidance on M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals
[6] See ICH guidance on S7A Safety Pharmacology Studies for Human Pharmaceuticals.
[7] See ICH guidances S2B Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals and S2A Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals.
[8] See ICH guidances S5A Detection of Toxicity to Reproduction for Medicinal Products and S5B Detection of Toxicity to Reproduction for Medicinal Products: Addendum on Toxicity to Male Fertility.
[9] See ICH guidances S1A The Need for Long-Term Rodent Carcinogenicity Studies of Pharmaceuticals and S1B Testing for Carcinogenicity of Pharmaceuticals.
[10] For example, Kern et al., 2002, or Smee et al., 2002.
[11] See FDA guidance Exposure–Response Relationships — Study Design, Data Analysis, and Regulatory Applications .
[12] A draft guidance on General Considerations for Pediatric Pharmacokinetic Studies for Drugs and Biologics issued in November 1998. Once finalized, it will represent the Agency’s perspective on this issue.
[13] See FDA guidance on Pharmacokinetics in Patients with Impaired Renal Function and Pharmacokinetics in Patients with Impaired Hepatic Function
[14] See FDA guidance Drug Metabolism/Drug Interaction Studies.
[15] See FDA guidance In Vivo Metabolism/Drug Interaction Studies.
[16] See FDA guidance Population Pharmacokinetics.
[17] Federal Register 67(105): 37995-37996, May 31, 2002.
[18] See FDA guidance Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products.
[19] For example, draft guidances on Uncomplicated and Complicated Skin and Skin Structure Infections – Developing Antimicrobial Drugs for Treatment and Chronic Cutaneous Ulcer and Burn Wounds – Developing Products for Treatment were issued in July 1998 and June 2000, respectively. If and when finalized, they will represent the Agency’s thinking on these topics.
[20] See the Federal Register 67(105): 37995-37996, May 31, 2002.
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Date created: 12/27/2005
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