Focus on the USA The lexicon of US regulatory affairs

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1 2 Regulatory Rapporteur Focus on the USA The lexicon of US regulatory affairs Alison Bowers, North Carolina, USA The special language of regulatory affairs can be difficult to translate when working across cultures, countries and scientific disciplines. Here is a handy reference guide to some US terms that are often confused with one another. Comparative observations with the EU or other regions are presented in italics. Abbreviations used are expanded at the end of this article. 21 USC 21 CFR The United States Code is the codification by subject matter of the general and permanent Laws of the United States. It is divided by broad subjects into 50 titles and published by the Office of the Law Revision Counsel of the US House of Representatives. Title 21 relates to Food and Drugs and Chapter 9 addresses the Federal Food, Drug, and Cosmetic Act. The official version of the Code is held on GPO Access. The US Code does not include Regulations issued by executive branch agencies (eg, FDA), decisions of the Federal courts, treaties, or laws enacted by State or local governments 1. US Law is translated (promulgated) into interpretive Federal Regulations written in plain English by federal regulatory agencies, eg, FDA. These Regulations are initially published in the Federal Register and are subsequently codified in the Code of Federal Regulations (CFR). Title 21 of the Code of Federal Regulations addresses Food and Drug Law 2, 3. US Regulatory Affairs professionals use the CFR like Volumes 1 and 2 of the Rules Governing Medicinal Products in the European Union 4. The nearest EU analogies are those Regulations and Directives issued by the Commission Screening IND Screening INDs are appropriate for initial human testing of up to five closely-related compounds different salts or esters of active moieties that appear to have similar pharmacodynamic properties. Screening IND studies are single or repeat-dose clinical trials (less than three days of dosing) designed to compare the properties of these compounds and thus screen for further development. When the trial is completed, the screening IND should be withdrawn 5. Exploratory IND This is intended to address a clinical trial that occurs very early in Phase I, involves very limited human exposure, and has no therapeutic intent (eg, microdose studies). Exploratory IND studies are conducted prior to traditional dose escalation, safety, and tolerance studies. The duration of dosing in an exploratory IND study is expected to be limited (eg, seven days) 6. This new guidance was stimulated in part by the March 2004 Critical Path Report 7. T O P R A T H E O R G A N I S A T I O N F O R P R O F E S S I O N A L S I N R E G U L A T O R Y A F F A I R S

2 October Issue Fast Track This is a US programme where the applicant may propose to FDA during the IND phase that the product appears to address an unmet medical need with respect to a serious or life-threatening disease. FDA has defined an unmet medical need as a medical need that is not addressed adequately by an existing therapy 8. Fast Track status allows the applicant more opportunities for dialogue with FDA during development and the potential to submit portions of the NDA in advance but does not guarantee an Accelerated Review for the NDA 9. Priority Review On receipt of an NDA, BLA, snda or sbla, FDA makes a determination about whether the application warrants a Priority Review or a Standard Review. The applicant may make a case for a Priority Review but FDA makes the determination 10. Products regulated by CDER (eg, drugs, monoclonal antibodies, therapeutic proteins, immunomodulators, growth factors) are eligible for Priority Review if they provide a significant improvement compared to marketed products in the treatment, diagnosis, or prevention of a disease. For products regulated by CBER (eg, blood products, vaccines, cellular products, antitoxins) there is an extra hurdle applications are eligible for Priority Review if they provide a significant improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of a serious or life-threatening disease 11. The performance goals for CDER and CBER for fiscal years 2003 through 2007 under the reauthorisation of the Prescription Drug User Fee Act are to review and act on 90% of Priority NDA, snda, BLA and sbla submissions within six months of receipt 12. Thus Priority Review only applies during review and the decision is not made until the Marketing Application has been filed. There are some parallels between Priority Review and the rapid review schedules adopted for life-saving products reviewed under the Centralised Procedure. TOPRA the global organisation for Regulatory Affairs professionals TOPRA is inclusive TOPRA is the leader in training for regulatory affairs TOPRA is a reliable and current information source TOPRA is much more! See our website for details: Focus on the USA continued

3 4 Regulatory Rapporteur PREA The Paediatric Research Equity Act (PREA) amended the Federal Food, Drug, and Cosmetic Act to require research into paediatric uses for drugs and biological products. It came into effect on December 3, 2003 and was retroactive to April 1, Any NDA, snda, BLA or sbla associated with a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration should include data to assess the safety and effectiveness of the product for the claimed indications in all relevant paediatric subpopulations 13. There are several ways to address the requirements of PREA if clinical trials in children are not available when the NDA/sNDA/ BLA/sBLA is otherwise ready to submit. If the course of the disease and the effects of the drug are similar in adults and paediatric patients, extrapolation of safety and efficacy data generated in adults may be possible. In this event, a paediatric pharmacokinetics study will probably be needed to create the bridge between adult and paediatric data. It may also be necessary to develop an ageappropriate formulation. Another approach is to include a request for Deferral in the Marketing Application. This would be appropriate if: Paediatric studies should be delayed until additional safety or effectiveness data have been collected in adults Paediatric studies are still ongoing Development of a paediatric formulation is proving problematic. Applicants may request a Full or Partial Waiver if: Paediatric studies are impossible or highly impracticable (eg, very small number of patients) Evidence strongly suggests that the product would be ineffective or unsafe in all paediatric age groups The product does not represent a meaningful therapeutic benefit over existing therapies for paediatric patients BPCA The Best Pharmaceuticals for Children Act (BPCA) became law on January 4, This legislation reauthorises and amends the Paediatric Exclusivity programme introduced through the Food and Drug Administration Modernization Act (FDAMA) of The incentives described by BPCA can only be earned through cooperation between FDA and the applicant to initiate, conduct, complete and report clinical study(ies) in paediatric patients that provide meaningful benefit and would not otherwise be done. The applicant submits a Proposed Paediatric Study Request for FDA evaluation 18. If FDA agrees that the proposal has merit it issues a Written Request which typically details the protocol design, sample size and endpoints. As of July 31, 2005, FDA had issued 303 such requests 19. If the applicant conducts the clinical study(ies) in accordance with the Written Request and submits the final study report(s), whether or not the data generated support changes to the existing prescribing information, they receive an intellectual property incentive. This takes the form of an additional six months of protection from approval of a generic copy of any product containing the same active ingredient. As for all applications, FDA has to make a summary of the clinical review publicly available 20. PREA and BPCA are not mutually exclusive a product previously studied and approved in the majority of the paediatric population under PREA could still be eligible for exclusivity if a suitable BPCA study proposal was developed. A proposal for paediatric study incentives is under review in EU - the Commission released a proposal for a Regulation on Medicinal Products for Paediatric Use on September 29, The proposal has now been presented to the Council of (Health) Ministers and the European Parliament and may become law in late In the meantime the UK MHRA is formally requesting completed paediatric study data from companies whose products appear on the FDA paediatric exclusivity granted list and who have not already submitted these data to EU Agencies for review 22. The product is not likely to be used in a substantial number of paediatric patients Efforts to develop a paediatric formulation necessary for a particular age group have failed 14. PREA is compatible with ICH E9 15. T O P R A T H E O R G A N I S A T I O N F O R P R O F E S S I O N A L S I N R E G U L A T O R Y A F F A I R S

4 October Issue Marketing Exclusivity For the first approval of a product containing a new chemical entity, the applicant receives five years of exclusivity from the date of NDA approval. This means that an ANDA (generic copy) cannot be submitted for that product for five years unless the company submitting the ANDA seeks to challenge the original applicant s patent. When a clinical study conducted by the applicant under the US IND is used as the basis of an NDA or snda, the applicant receives three years of exclusivity from the date of NDA/sNDA approval. This means that an ANDA cannot be approved for the same thing for three years unless the company submitting the ANDA seeks to challenge the original applicant s patent 23. In some cases this might protect a formulation (eg, NDA for a new product containing an approved active ingredient), in others it might only extend to a portion of the labelling (eg, snda for a new patient population). Paediatric Exclusivity This was introduced through Section 111 of FDAMA in If the applicant conducted clinical study(ies) in paediatrics to match the details of a Written Request and submitted the final study report(s), with or without any changes to the prescribing information, they received an intellectual property incentive. This constituted an additional six months of protection from approval of a generic copy of any product containing the same active ingredient. This approach was much more effective than previous legislative efforts to get data relating to paediatric use added to the prescribing information of existing products 24. Paediatric Exclusivity under FDAMA ended ( sunset ) on January 1, 2002 but was so effective that BPCA (see above) was enacted on January 4, This is under discussion as part of the EU Future Medicines Legislation but marketing exclusivity is analogous to the six to ten year essentially similar provisions of Article 10.1(a)(iii) of Directive 2001/83/EC. Marketing Exclusivity See above. Exclusivity does not impact the patent life of the compound but it does affect the time to generic competition. Patent Term Restoration This was provided through the Drug Price Competition and Patent Term Restoration Act of 1984 (Waxman-Hatch Amendments 25 ) and seeks to restore a portion of the patent life lost during the time it takes to bring a drug to market. The extension to the patent life may be a maximum of five years, it cannot exceed 14 years from the NDA approval date, and it is calculated using the IND effective date and the NDA review time. The nearest EU equivalent is the Supplementary Protection Certificate 26. Focus on the USA continued

5 6 Regulatory Rapporteur CTR (Clinical Trial Registries) Section 113 of FDAMA required registration of all clinical studies for serious or life-threatening diseases on This listing of clinical trials has been used to increase patient and physician awareness of these studies 17, 27. The International Committee of Medical Journal Editors (ICJME) established a requirement, effective from July 1, 2005, that all clinical trials be entered in a public registry before patients are enrolled as a pre-requisite for future publication in their scientific journals 28. CTR (Clinical Trial Registers) The site is a central, widely accessible, web-based repository for clinical study results in a reader-friendly, standardised format. The repository was set up under the auspices of PhRMAs Principles on Conduct of Clinical Trials and Comunication of Clinical Trial Results to express the commitment of PhRMA member companies to communicate the results of clinical studies, both positive and negative 30. This remains a rapidly evolving area with significant potential to change the global regulatory environment. ClinicalTrials.gov is only one of the clinical trial registries recognised by ICMJE. It was developed by the National Library of Medicine and is maintained by the National Institutes of Health (part of the US Department of Health and Human Services). Other registers exist for disease-specific organisations and several companies. The nearest UK equivalents are and the EU EuroPharm database now under development. Proposals for additional clinical trial registries and registers and ways to link existing systems are under consideration in EU, Canada, Australia and New Zealand. IFPMA is planning to launch an Internet search portal to establish links between the various registries 29. PI Package Inserts (PIs) for all marketed prescription products are published in the Physician s Desk Reference 31. The PI is the primary prescribing information document submitted to and approved by FDA. A change to the format, to provide a summary at the beginning and to alter the order of presentation to improve the use of this document by a prescribing physician is planned (eg, Indications are currently presented after the chemical structure and a potentially lengthy description of clinical pharmacology study results). In addition, a change control system for managing PI text in electronic format (SPL or Structured Product Labelling) will be launched shortly. The US prescribing information typically presents significantly more detail than the European SmPC, including the design and results of clinical studies and lists of spontaneous adverse events. As in the EU, text in the prescribing information determines what may be used in marketing materials; sales representatives use the PI extensively during visits to doctors, and lawyers use the PI extensively during litigation. The Physician s Desk Reference is analogous to the ABPI Data Sheet Compendium. SPL is somewhat analogous to PIM 32. PI Patient s Instructions for Use are included within the text of the US PI but are not always dispensed with the product if the product is not presented in Unit of Dose packaging. The dispensing pharmacist sometimes provides the patient with a Patient Instruction sheet, accessed from a variety of sources but not necessarily using text provided by the manufacturer or reviewed by FDA. For products where Dosing Instructions are particularly important (eg, asthma inhalers), a separate leaflet may be provided with the pack. For products with known risk management issues, a Medication Guide is required (eg, Accutane). Patient Instruction Leaflets written by the manufacturer and approved by regulatory agencies are mandated in EU and readability testing is becoming increasingly important 33. T O P R A T H E O R G A N I S A T I O N F O R P R O F E S S I O N A L S I N R E G U L A T O R Y A F F A I R S

6 October Issue ISS M2.7.4 Summary of Clinical Safety The intent for a US NDA to contain an Integrated Summary of Safety (ISS) is described in 21 CFR (d)(5)(vi)(a). A comprehensive description of the ISS was provided in the July 1988 guidance on Format and Content of the Clinical and Statistical Section of Applications 34. Both the format and content of this NDA component have effectively been superseded by ICH M4E: The CTD Efficacy 35. Despite the term Integrated Summary, FDA wants to see an integrated analysis of all relevant data, not a summary. If the requirements of 21 CFR can be met for a particular application by what is included in the CTD Module 2.5 Clinical Overview and Module Summary of Clinical Safety, there is no need for a separate ISS. In some cases, it will be necessary to supplement these modules with information, appendices or full details of additional meta-analyses in Module Most of the headings suggested for inclusion in a traditional NDA format ISS are included in the CTD Module Summary of Clinical Safety. For products with substantial data packages or complex safety issues, it may not be possible to describe all the data and conclusions from the integration of data within the page constraints of Module 2 in this case a separate meta-analysis report of the integrated safety data can be prepared and located in Module Thus FDA will accept an NDA where all the needs of an ISS are addressed within Module 2.7.4, but it is worth clarifying expectations at, for example, a pre-nda meeting. Regardless of the location of these data in the NDA, the FDA reviewer is obligated to conduct an Integrated Review of Safety 37, which has the following aims: 1) To identify and closely examine serious adverse events that suggest, or could suggest, important problems with a drug specifically, adverse reactions severe enough to prevent its use altogether, to limit its use, or require special risk management efforts 2) To identify and estimate the frequency of the common (usually non-serious) adverse events that are, or may be, causally related to the use of the drug 3) To evaluate the adequacy of the data available to support the safety analysis and to identify the limitations of those data, including an assessment of whether the extent of exposure at relevant doses is adequate 4) To identify unresolved safety concerns that will need attention prior to approval or post-marketing, including high-risk populations or potential interactions. The Clinical Overview (Module 2.5) and Summary of Clinical Safety (Module 2.7.4) play an equally important role during review of EU MAAs. It would be unusual for EU reviewers to reanalyse the raw datasets and perform their own searches for signals on the integrated data, as FDA typically does. Focus on the USA continued TOPRA Special Interest Groups TOPRAVETNET and TOPRACompMedNET networks have now been established for TOPRA members with interests in the Veterinary/Animal Health and Complementary (Alternative) Medicines fields, respectively, of regulatory work. A number of members present at the recent TOPRA : EMEA meeting on PIM/eCTD have expressed interest in the establishment of one for those interested in ectd. A network is also planned for TOPRA members based in North America. Further networks for those involved in the Medical Technologies (Devices) and in the Biotechnology areas are under consideration. If there is sufficient interest, a network could also be established for those with an interest in Cosmetics regulation. The objective of the networks is to enable members to network together, share experiences, seek/provide advice, and generally discuss topics/issues of common interest... If you are a TOPRA member and would be interested in participating in any of these networks, please your details and field of interest to the following address: spin@topr a.or g

7 8 Regulatory Rapporteur Safety Update While an NDA is under review the applicant has to update the pending application with new safety information that may reasonably affect the prescribing information (eg, from clinical studies that were still ongoing when the NDA was submitted or from spontaneous adverse events from countries where the product is already approved). These Safety Update Reports must include the same kinds of information and be submitted in the same format as the integrated summary of safety in the original application (see ISS and Module above) and provide case report forms for each patient who died or who did not complete a clinical study because of an adverse event 38. Applicants should consult with FDA about their needs but Safety Update Reports are typically required four months after the initial submission and following receipt of an approvable letter. PSUR Periodic Safety Update Reports (PSURs) present the worldwide safety experience of a medicinal product at defined times postapproval. The US regulations require quarterly reports during the first three years, then annual reports. Within CTD format, the PSUR is located in Module PSURs are intended to report new safety information that may reasonably affect the prescribing information, relate these data to patient exposure and summarise the Market Authorisation status in different countries. The time periods for submission of PSURs may not be perfectly synchronised around the world and new risk management discussions in EU may lead to further evolution in this area (ICH E2C) 39, 40. Intelligence Applied Comprehensive, reliable regulatory consulting and services. We have 20 years of experience in designing and delivering quality training to the pharmaceutical industry. Proven public and in-company courses in: Regulatory affairs Drug development Medical writing Contact us at: regulatory.euro@mdsps.com 270 Wharfedale Road Winnersh Triangle, Wokingham Berkshire RG41 5TP United Kingdom Europe: +44-(0) E A R L Y S T A G E D E V E L O P M E N T. L A T E S T A G E D E V E L O P M E N T. Abbreviations: ANDA = Abbreviated New Drug Application BLA = Biologics License Application CBER = Center for Biologics Evaluation and Research CDER = Center for Drug Evaluation and Research FDA = Food and Drug Administration FDAMA = Food and Drug Administration Modernization Act of 1997 ICJME = International Committee of Medical Journal Editors ICH = International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use IFPMA = International Federation of Pharmaceutical Manufacturers and Associations IND = Investigational New Drug Application MAA = Marketing Authorisation Application MHRA = Medicines and Healthcare Products Regulatory Agency NDA = New Drug Application PhRMA = Pharmaceutical Research and Manufacturers of America PIM = Product Information Management sbla = Supplemental Biologics Licence Application snda = Supplemental New Drug Application T O P R A T H E O R G A N I S A T I O N F O R P R O F E S S I O N A L S I N R E G U L A T O R Y A F F A I R S

8 October Issue References 1. United States Code: About 2. Code of Federal Regulations (April 2005) 3. Bowers A. Cracking the Code of US Federal Regulations. Regulatory Rapporteur. (March 2005); 2(3): The Rules Governing Medicinal Products in the European Union 5. Centre for Drug Evaluation and Research Manual of Policies and Procedures MAPP : INDs: Screening INDs (May 2001) 6. FDA Guidance for Industry, Investigators, and Reviewers: Exploratory IND Studies (April 2005) 7. Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products (March 2004) 8. FDA Guidance for Industry: Available Therapy (July 2004) 9. FDA Guidance for Industry: Fast Track Drug Development Programs - Designation, Development, and Application Review (July 2004) FDA Guidance for Industry: Standards for the Prompt Review of Efficacy Supplements, Including Priority Efficacy Supplements (May 1998) Centre for Drug Evaluation and Research Manual of Policies and Procedures MAPP : Priority Review Policy. (April 1996) PDUFA-related documents Paediatric Research Equity Act of th CONGRESS 1st Session S CFR : Paediatric Use information FDA Guidance for Industry ICH E11: Clinical Investigation of Medicinal Products in the Pediatric Population (December 2000) Paediatric Drug Development Food and Drug Administration Modernization Act (FDAMA) of PL (November 21, 1997) FDA Guidance for Industry: Qualifying for Paediatric Exclusivity Under Section 505A of the Federal Food, Drug, and Cosmetic Act (Revised, September 1999) Paediatric Exclusivity Statistics as of July 31, CDER Manual of Policies and Procedures MAPP : Public Dissemination of a Summary of the Medical and Clinical Pharmacology Reviews of Paediatric Studies EMEA: Medicines for Children - The European Paediatric Initiative: Legislative process for a paediatric initiative in Europe Committee on Safety of Medicines Summary Minutes: Paediatric Medicines Working Group (June 2004) htm#csm CF : New Drug Product Exclusivity The Paediatric Exclusivity Provision January 2001 Status Report to Congress 01.pdf 25. Drug Price Competition and Patent Term Restoration Act of 1984 (Waxman-Hatch) (summary) m2=m& TOM:/bss/d098query.html 26. Council Regulation No (EEC) 1768/92, of 18 June 1992, Concerning the Creation of a Supplementary Protection Certificate for Medicinal Products _1768_EN.pdf 27. ClinicalTrials.gov ClinicalTrials.gov Protocol Registration System Patients and Physicians to Gain Easy Access to Clinical Trials Information via New IFPMA Search Portal PhRMA s Position on Clinical Trials and Communication of Clinical Trial Results Physician s Desk Reference Buxton, T and Marr, A. PIM a New Method for the Submission of Product Information in the Centralised Procedure. Regulatory Rapporteur (April 2005);2(4): Guideline on the Readability of the Label and Package Leaflet of Medicinal Product for Human Use FDA Guideline for the Format and Content of the Clinical and Statistical Sections of an Application. (July 1988) FDA Guidance for Industry ICH M4E: The CTD - Efficacy (August 2001) FDA Guidance for Industry ICH M4: The CTD - Efficacy Questions and Answers (December 2004) FDA Reviewer Guidance: Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review (February 2005) CFR (c)(2): Periodic adverse drug experience reports FDA Guidance for Industry: ICH E2C Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs (November 1996) Addendum To ICH E2C: Clinical Safety Data Management: Periodic Safety Update Reports For Marketed Drugs (February 2003) All Internet links accessed and confirmed as current on September 1, 2005 Focus on the USA continued