The guidance a regulatory document answers to
A regulatory document answers to guidance of several kinds that bind it to different degrees: regulations that are law, guidances that are strongly recommended but not mandatory, and international guidelines grouped by the kind of question they address. Each pre-approval document has its own set of guidelines and regulations, and knowing when to keep to the letter of a guideline and when to depart from it is part of the regulatory writer's skill.
What a regulatory document has to satisfy
Regulatory documents are usually taken to be documents submitted in some form to the health authorities. These documents should adhere to the relevant guidance and be fit for purpose, meaning that they transmit the necessary information accurately, transparently and clearly to the target audience. The target audience is usually the reviewers at the health agencies, but readers might also be investigators or members of ethics committees.
Regulations, guidances and guidelines
An editor of regulatory documents must be familiar with regulations, guidances and guidelines. In the United States, the editor reads the section of the Code of Federal Regulations that applies to the assigned document, in order to guide the authors on what content they might include. Compliance with the Code of Federal Regulations is mandated by US law. For a document slated for a non-US submission, the editor should at the very least ask the author whether the project's regulatory affairs personnel are aware of any special needs unique to the submission region. In addition to regulations, most countries issue guidance documents on various subjects, which could be specific to a document type, an indication or even a process. In the United States these are called guidances, and those that apply are must-read. Compliance with FDA guidances is not required by law, but it is strongly recommended. International guidelines, produced by the International Conference on Harmonisation (ICH), are also must-read. Following ICH guidelines is also not mandatory, and there can be many reasons to deviate from them, as they are not all-inclusive.
Regulatory documents in pharmaceutical medicine and drug development normally have to consider guidelines on several levels: ICH guidelines, the guidelines of regulatory authorities in countries that are not part of the ICH, company-specific internal guidelines, and project-specific guidelines.
The ICH guideline families
Before 1990, regulatory authorities in different countries had country-specific guidelines, so getting regulatory approval for new medicines in several countries was complicated. The ICH was established in 1990 in an attempt to harmonize the regulatory guidelines of major regulatory authorities, and it brought together the regulatory authorities of Europe, Japan and the USA with key representatives of the pharmaceutical industry to discuss the technical and scientific aspects of drug registration. The ICH guidelines initially comprised three sections, on the quality, efficacy and safety of new medicinal products, and a multidisciplinary section, including the guideline for compiling the Common Technical Document, was added later.
The quality series addresses chemistry, manufacturing and controls issues, the safety series addresses nonclinical issues, and the efficacy series addresses clinical issues. The multidisciplinary guidelines are integrated guidelines that address two or more of the other categories and do not fit exclusively into any one of them. For medical and scientific writers working in drug development, the multidisciplinary category is perhaps the most important.
When the four families were numbered Q1–Q10, S1–S9, E1–E16 and M1–M8, they covered these topics:
| Family | Topics |
|---|---|
| Quality | Stability, analytical validation, impurities, pharmacopoeias, quality of biotechnical products, specifications, good manufacturing practice, pharmaceutical development, quality risk management, and pharmaceutical quality system |
| Safety | Carcinogenicity studies, genotoxicity, toxicokinetics and pharmacokinetics, duration of chronic toxicity testing, reproductive toxicity, preclinical safety evaluation of biotechnological products, safety pharmacology, immunotoxicity, and nonclinical evaluation of anticancer pharmaceuticals |
| Efficacy | Clinical safety, clinical study reports, dose-response studies, ethnic factors, good clinical practice, clinical trials, principles for clinical evaluation by therapeutic category, regulatory compliance, clinical evaluation of QTc prolongation, and pharmacogenomics |
| Multidisciplinary | MedDRA terminology, electronic transmission of individual case safety reports, nonclinical safety studies for human clinical trials and marketing authorization, the Common Technical Document, data elements and standards for drug dictionaries, gene therapy, genotoxic impurities, and the electronic Common Technical Document |
At a meeting on ICH E6(R3), regulators advised that ICH E8, which covers study design and the protocol, should be considered ICH E0: the baseline for everything and an umbrella document that covers every efficacy guideline.
The guidance for each pre-approval document
The most common pre-approval regulatory documents for drugs, with the guidelines and regulations associated with each in 2014, are these:
| Document | Abbreviation | Guidance named in 2014 |
|---|---|---|
| Case report form | CRF | Good clinical data management practices, version 3, September 2003, Society for Clinical Data Management |
| Clinical development plan | CDP | None named |
| Clinical overview | CO | ICH M4E |
| Clinical study protocol | CSP | ICH E6; ICH E8; ICH E9 |
| Clinical study protocol amendment | CSP amendment | ICH E6; ICH E8 |
| Clinical study report, full or abbreviated | CSR | ICH E3; ICH E9; FDA guidance for industry on submission of abbreviated reports and synopses in support of marketing applications |
| Clinical trial application, EU | CTA | EudraLex Volume 10 clinical trials guidelines; detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use, August 2003 |
| Common technical document | CTD | ICH M2; ICH M4; ICH M8 |
| Data management plan | DMP | Good clinical data management practices, version 3, September 2003, Society for Clinical Data Management |
| Developmental periodic safety update report | DSUR | ICH E2F; see also the periodic benefit-risk assessment report |
| Electronic case report form | eCRF | As for the case report form; 21 CFR Part 11 |
| Electronic common technical document | eCTD | ICH M2; ICH M4; ICH M8 |
| Informed consent form | ICF | ICH E6; HIPAA |
| Integrated summary of effectiveness, US | ISE | FDA guidance for industry on the integrated summary of effectiveness, and on the location of integrated summaries within the common technical document |
| Integrated summary of safety, US | ISS | FDA guidance for industry on the location of integrated summaries within the common technical document |
| Investigational medicinal product dossier, full or abbreviated, EU | IMPD | Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use, March 2010 |
| Investigational new drug annual report, US | INDR | FDA information on IND application reporting |
| Investigational new drug application, US | INDA | FDA information on IND applications |
| Investigator's brochure | IB | ICH E6 |
| Investigator's brochure update | IB update | ICH E6 |
| Document | Abbreviation | Guidance named in 2014 |
|---|---|---|
| Marketing authorisation application, EU | MAA | EMA guidance on applying for EU marketing authorisation for medicinal products for human use; EudraLex Volume 2, notice to applicants and regulatory guidelines for medicinal products for human use |
| New drug application, full or abbreviated, US | NDA, ANDA | FDA information on NDAs and ANDAs |
| Orphan drug application | ODA | Common EMA and FDA application for orphan medicinal product designation; EMA regulatory and procedural guidance |
| Paediatric study plan, US | PSP | ICH E11; FDA guidance for industry on the content of and process for submitting initial and amended paediatric study plans |
| Paediatric investigation plan, EU | PIP | ICH E11; EMA information on the standard plan, waivers and modifications |
| Patient or subject narratives | — | ICH E2 series; ICH E3 |
| Periodic benefit-risk assessment report | PBRER | ICH E2C(R2) |
| Risk assessment plan | RAP | EMA information on the plan for marketing authorisation holders |
| Safety management plan | SMP | ICH E2 series |
| Statistical analysis plan | SAP | ICH E9; ICH E3 |
| Summary of clinical pharmacology | SCP | ICH M4E |
| Summary of clinical efficacy | SCE | ICH M4E |
| Summary of clinical safety | SCS | ICH M4E |
Finding guidance and keeping up with its changes
A writer starting to compose a regulatory document is strongly advised to consult regulatory websites. A regulatory writer can start by reading parts of Title 21 of the Code of Federal Regulations and becoming familiar with searching the Federal Register, where proposed changes to federal rules are posted.
Online resources on US regulations and regulatory guidance include the Code of Federal Regulations, starting with Title 21, parts 50, 54, 56, 58, 312 and 314; the Federal Register; the Food and Drug Administration; its Center for Biologics Evaluation and Research, Center for Devices and Radiological Health and Center for Drug Evaluation and Research; its pages on the development and approval process for biologics and for drugs; and its FDA Basics and FDA Basics for Industry pages.
A writer should also study any ICH guidelines applicable to the document they are assigned. Protocols, informed consents and investigator's brochures are discussed in ICH E6, and clinical trial reports are covered in ICH E3.
It can be difficult to keep up with the changes in regulation and guidance, but the major components of regulatory documents do not often change drastically. Guidance changes and clarifications are issued as questions-and-answers documents that address contradictory or ambiguous aspects of the guidance. So while the core skills needed for regulatory writing remain fairly constant, the details may change, and the regulatory environment evolves. A writer who is the first to point out a new regulation or guideline governing a document being written can impress the team.
Departing from a guideline's letter
The ICH guidelines are invaluable for medical and scientific writers preparing the documents required during drug development, and observing them greatly enhances the chances of a positive outcome. In most instances it is advisable to follow regulatory guidelines precisely to have the best chance of a successful outcome. Guidelines are there to guide, however, and occasionally situations might occur where they are inadequate. In unusual circumstances, a writer should be prepared to be innovative in deviating from guidelines, while clearly justifying every change and adjustment made. Intentional deviations from guidelines should be well motivated and preferably discussed with the regulatory authorities. An editor should be prepared to give concrete reasons for any deviation from the ICH guidelines if asked, as the ICH guidelines are considered primary sources for international content.
Regulatory writers have instant and complete access to almost all the guidelines governing their documents, yet there is rather little information in the public domain on how those guidelines should be applied and interpreted in practice. Unthinking and rather slavish application of guidelines has its pitfalls. One regulatory writer thinks that many companies want to be as compliant as possible with the perceived letter of the guidelines while perhaps losing sight of their intent. A necessary skill of a regulatory writer is knowing when to treat guidance as set in stone and when it is appropriate to deviate from the letter of the guidance to ensure clarity and readability.