REGULATORY AFFAIRS & CLINICAL OPERATIONS: KEY DOCUMENT TYPES BY MILESTONE
The pressure to compress clinical development time continues to mount, and companies continue to look for new ways to shorten the time to market.
CLINICAL DEVELOPMENT PLAN
Involving medical writers as early as possible in your clinical development program yields the best results.
REGULATORY GAP ANALYSES
Ideally, a regulatory gap analysis is conducted early in the preclinical development and drug formulation process. Teams use all available information, including prior human experience and a SWOT analysis of the product's strengths, weaknesses, opportunities, and threats, to assess the current development status of a potential new product and identify gaps to more effectively present data and, ideally, improve the speed of regulatory approval.
As the basis for developing a regulatory strategy, the predicate or precedence search
is an extensive search of the scientific literature:
Support the proposed mechanism of action
Build sound scientific rationale for the proposed product's efficacy and adverse event potential
Provide invaluable information on overall strategy, preclinical and clinical information, study designs, demographics, and endpoints and postmarketing issues
TARGET PATIENT PROFILE
"Using a Target Product Profile (TPP) helps you have a clear goal and organizational structure for your IND application by specifying the proposed drug product label. White it may sound premature, doing this allows you to align your strategy and goals first and then work backwards, providing you with a clearer path from the beginning. This way, each component of your submission becomes a rung on your IND ladder; every single section will be built upon the last with overlapping support."
Identify the Minimal Threshold for Regulatory Review
"The final goal is not to identify all that is needed per the guidance, but to identify the minimum threshold for regulatory review. With today's resource constraints and tight timelines, it is important not only to do all the required studies but also to avoid unnecessary studies, both nonclinical and clinical."
MILESTONE 1: EARLY-PHASE REGULATORY WRITING SERVICES
Ensuring that early-stage documents, which serve as core resources for disease state information, messaging, scientific rationale, and others, are well written improves the quality of all subsequent documents and speeds up the time needed to write and review later documents.
IND AND IMPD DOSSIERS AND IND ANNUAL REPORTS
Investigational New Drug (IND) applications (in the US) and Investigational Medicinal Product Dossiers (IMPDs) (in Europe)
INDs include nonclinical data; chemistry, manufacturing, and controls (CMC) information; clinical protocols and investigator information; and informed consent documents
PROTOCOLS, AMENDMENTS, AND INFORMED CONSENT FORMS
Protocol Concept Sheets
Protocols
Site- and Country-Specific Protocol Amendments
Summary of Changes Documents
Informed Consent Forms
TransCelerate CPT Word Template and Implementation Toolkit
BRIEFING BOOKS AND REGULATORY RESPONSES
Briefing book preparation for major developmental milestones, including pre-IND/CTA, end of Phase 2, and EMA/National Scientific Advice meetings
Consider the Long-Game When Writing Clinical Study Protocols
"Too many protocols are poorly written--wrought with inconsistencies in endpoint descriptions, timing of assessments, approaches to gathering data--and lacking consistency across the program."
"The first step in any clinical study is the protocol; if that first step is organized, well-placed, and developed with the downstream activities in m ind, the rest of the journey will go that much more smoothly."
Medical writers can bring a variety of strengths to the clinical study protocol preparation process, including "clarity, consistency, adherence to process, coordination of reviews, balance of objectives speed and completeness, and creation of the building blocks for downstream documentation)."
Streamline the IND Process: Difficult-to-Read Submissions More Likely to Be Rejected or Put On Hold
Streamline the IND preparation process by ensuring that
- The document follows FDA guidance
- Data are organized
- Eliminate irrelevant information
- "Check that your key messages support the importance of your submission"
- The document is thoroughly edited for grammar, clarity, and consistency; abbreviations are correctly defined
- Ensure consistent writing style if multiple groups contributed
- "Provide explanations and supporting data for results, and ensure that your results match your protocol; "
- Uses tables and figures where possible in place of text
MILESTONE 2: INITIATING THE PHASE 1 TRIAL
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PHASE 1 CLINICAL TRIALS
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PREPARING FOR END-OF-PHASE 2 (EOP2) MEETING (TYPE B)
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PHASE 2 PROTOCOLS AND REPORTS
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SPECIAL PROTOCOL ASSESSMENTS
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MILESTONE 3: CONDUCTING THE PIVOTAL PHASE 3 TRIALS
XXX
CLINICAL STUDY REPORTS (CSRs)
Synopsis, Phase 1-4 CSRs, Full, Abbreviated, Interim, and Synoptic CSRs
CORE Reference
PLAIN-LANGUAGE SUMMARY OF CLINICAL TRIAL RESULTS
The Clinical Trial Transparency initiative by the European Medicines Agency requires that a summary of the results of every clinical trial be prepared for the lay audience within 1 year of the end of the trial in the European Union.
RESPONDING TO REVIEWER QUESTIONS
The need for medical writing services does not stop once the "button has been pushed" and the eCTD has been submitted to the regulatory authorities. In fact, this is one of the most challenging parts of the approval process.
After initial review, the regulatory authority will respond to the Sponsor with questions that typically address perceived weaknesses in the Sponsor's clinical development program.
MILESTONE 4: SUBMISSION OF THE NEW DRUG APPLICATION
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THE PRE-NDA MEETING (TYPE B)
Uncover any major unresolved problems
Determine the adequacy of the Sponsor's dossier for the submission of an NDA
Review the status of ongoing studies to assess pediatric safety and effectiveness
Acquaint FDA reviewers with the general and technical information that will be submitted in the marketing application
NEW DRUG APPLICATIONS (NDA)
Module 2.5 Clinical Summary
Module 2.7.1
Module 2.7.2 Clinical Pharmacology
Module 2.7.3 Efficacy
Module 2.7.4 Safety
Module 2.7.5
MID- AND LATE-CYCLE MEETINGS AND REGULATORY AGENCY INFORMATION REQUESTS
A rapid-response team, including medical writers with "legacy knowledge" of the dossier, should be on standby to assist with regulatory agency information requests for more data, alternative analyses, or further interpretation of
included analyses.
PREPARATION FOR FDA ADVISORY COMMITTEE MEETING (US) OR ORAL EXPLANATION MEETING (EUROPE)
Medical writers can also support the larger team by assisting with the preparation of briefing documents and presentation slide decks in advance of regulatory authority meetings.
Key Role of Medical Writers in CTD Preparation
"Preparation of a CTD is often regarded as the epitome of regulatory medical writing due to its complexity and the experience needed. The challenges involved are numerous, and for medical writers vary according to dossier size, team experience, data complexity, and available time."
"As early as possible in the project, medical writers must ensure that the project team agrees on key messages and how these can be effectively communicated."
"Medical writers often need to remind the project team that their audience for the clinical summaries and the clinical overview is primarily made up of regulatory reviewers charged with assessing suitability of the medicinal product approval."
ABBREVIATED NEW DRUG APPLICATIONS (ANDAs)FOR GENERIC DRUGS
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ABBREVIATED NEW DRUG APPLICATION (ANDA)
In 2018, the FDA's Office of Generic Drugs approved approximately XXX abbreviated new drug applications, or ANDAs. Given the extremely competitive generic market, time to market--especially first to market--is extremely important.
Unlike New Drug Applications, ANDAs generally do not require preclinical or clinical data to establish safety and effectiveness. Instead, for ANDAs the Sponsor must establish that its generic drug product performs in the same manner as the innovator (non-generic) drug.
SOLUTIONS
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90% of Abbreviated New Drug Applications Are Rejected the First Time
The two most common reasons for ANDA rejection are refusal to receive (RTR) or lack of equivalence.
CLINICAL EVALUATION REPORT (CER) AND POST-MARKETING CLINICAL FOLLOW-UP (PMCF)
- CER contains the following:
- Evidence-based assessment of efficacy and safety
- Benefit-risk analysis
- State-of-the-art review of the clinical setting in which the device is to be used
- Review of current knowledge of the targeted medical condition
- Information on relevant guidelines or international standards, current treatments, and clinical needs that would be met (or are being met) by the medical device under review
PEDIATRIC STUDY PLANS (PSPs) AND PAEDIATRIC INVESTIGATION PLAN (PIP)
Initial PSP (iPSP): study objectives and design, age groups, relevant endpoints, statistical approach; requests forwaiver
Amended PSPs (aPSPs)
POSTMARKETING RESEARCH
The goals of postmarketing research is to look for rare safety events, provide evidence of safety in clinical practice; compare effectiveness with other treatments; evaluate the use of approved doses and patient population in the clinical setting; evaluate the role of the treatment on quality of life and other patient-focused outcomes; and evaluate treatment costs.
TYPES OF POST-MARKETING STUDIES
- Clinical trials
- Post-Authorization Safety Study (PASS)
- PMR registries (REMS/RMP)
- Epidemiological studies (disease specific)
- Prospective observational studies (comparative effectiveness research [CER]; product-specific studies)
- Cross-sectional studies
- Observational, retrospective studies
- Case-control studies
- Database evaluations
- Market research