Regulatory Affairs is Integral in Efficient Drug Development
Participation of Regulatory Affairs professionals is integral to the timely and successful development of all therapeutic products. As Senior Regulatory Advisor at PROMETRIKA, I am proud to be part of the PROMETRIKA team, which has been providing pivotal support for therapeutics development to their clients for more than 20 years. With our new offering of global Regulatory Affairs Consulting, we are strategically poised to provide fully integrated services from early development to marketing application approval to post-approval support.
Personally, I always loved science but was never sure what discipline would become my career trajectory. After graduating from college with a degree in biochemistry, and while I loved science and reading the results of scientific experiments, I concluded that laboratory work at the bench was not specifically where my interests lay.
My first job in industry was in the biochemistry laboratory at what was, at the time, the healthcare division of Revlon. The cosmetic giant had decided to enter into the healthcare field with the purchase of what was then USV Laboratories and Armour Pharmaceutical Company. They opened a research and development organization in Westchester County in New York with the goal of advancing new medicines in the cardiovascular and allergy/asthma therapeutic areas. My job was to develop and run assays to discover targets to treat allergies and asthma.
One of the great advantages of working for an integrated company at the start of my career was the possibility of advancement from within. Many departments were willing to hire employees from other areas of the company to fill entry level positions. After three and a half years of working in the laboratory, I applied for my first job in Regulatory Affairs and was offered the position.
I soon realized that Regulatory Affairs was an area I truly enjoyed. Reflecting back on my career, which spans over 40 years as a regulatory affairs professional working in large, mid-size, and small start-up companies, and as a consultant, I believe that one of the reasons that I continue to find Regulatory Affairs exciting and rewarding is that I’ve had the opportunity to interact with, and incorporate data from, other disciplines within the organization. One needs to meld this information and present it to regulatory agencies in a format that meets their regulations and guidelines. To do this well, an in-depth knowledge of the therapeutic product and the therapeutic area in which the product is being developed, the different disciplines involved in research (manufacturing and testing, preclinical development, clinical development, and drug safety), the regulatory requirements, and a bit of psychology, are all necessary. While meeting regulatory requirements is mandatory, a regulatory advisor also needs to manage the objectives of the company and consider the best and most efficient way to develop the therapeutic. Additionally, one must never forget that good science is an integral component of the successful development of a therapeutic.
Step 1 The IND
My first assignment in my initial regulatory position was to prepare an Investigation New Drug (IND) application for one of the molecules that we had identified in the laboratory as a potential therapeutic for allergic rhinitis. This IND was for a first-in-human, normal volunteer study and my task was to work with many of my former laboratory colleagues to obtain the information necessary to prepare and complete the filing. The information on how the molecule was manufactured and tested came from an area that was new to me at the time. Reports on how the drug substance and drug product were manufactured, tested, and shown to be stable were prepared by the responsible departments and provided for inclusion in the IND. I worked with my former colleagues to obtain information on the laboratory testing of the therapeutic, and with medical writers for the preparation of the required reports and summaries, and the Investigator Brochure. The protocol for the clinical study and the required information on the investigator who would be involved in testing our product came from Clinical Operations. In Regulatory Affairs, my role was to review the information and request modifications/updates as necessary, assemble the information in the appropriate format, and complete the IND filing. At that time, all of the many volumes of information were provided in paper; three copies of each in color-coded binders. Today these filings are all electronic, in the eCTD format.
At the time I started my career, many development programs were focused on individual countries or regions of the world. Today, product development is nearly simultaneous around the globe; the majority of clinical programs are multi-national. This requires a knowledge of the regulatory requirements in other regions and the need for strategic decisions as to when have discussions with the different regulatory agencies on development plans, and when to start studies in different regions.
Pre-IND Interactions
The role of Regulatory Affairs in drug development does not start with the IND submission. Many times, it is important to have discussions with regulatory agencies prior to the onset of the clinical program. In the US, this may include a pre-IND meeting. In determining whether a pre-IND meeting is a useful step in the early clinical development of a therapeutic, the first question I always ask is if the issues to be discussed with the regulatory agency are ones for which the answers will be necessary or useful in designing the first clinical study. If the answer to this question is yes, then a pre-IND meeting is in order. If the answer is that the main regulatory issues relate to items later in development, a meeting after the IND is in effect and the agency review team has been assigned may be more advantageous.
Main topics for pre-IND discussions can be the design of IND-enabling toxicology studies, and/or the design of the first study to be conducted under the IND. If the first study to be conducted under the IND is an efficacy study to support marketing approval, or the therapeutic is to be used in an orphan population or fulfills an unmet need, these types of early discussions actually can save the sponsor time and money by elucidating the regulatory agency’s thoughts and expectations for study design and analyses.
Planning the timing of the pre-IND interaction, at the same time making sure that this does not delay the clinical development timeline, is part of regulatory strategy and requires buy-in from all clinical team members. The pre-IND package needs to include summaries of the information on the therapeutic, a good draft of the clinical protocol, including details of the clinical assessments, and a description of the proposed data analysis. In the US, there is a requirement to provide promotional information to FDA. Questions need to be focused on the important issues and the company position clearly outlined. Input and participant are sought from all of the required disciplines: Clinical Operations, Data Management, Biostatistics & Programming, and Medical Writing.
Input from the pre-IND discussions with the regulatory agency are incorporated into the documents included in the IND submission. Module 1 should contain a summary of the pre-IND discussions together with those items incorporated into the program. For suggestions not incorporated, an explanation of why it was decided to take a different direction and not completely follow the agency feedback should be included.
Regulatory Support During Clinical Program Execution
The role of Regulatory Affairs does not end with a successful IND submission and the notification from regulators that the clinical study may proceed. Unlike filings in other countries, where each clinical study requires a new Clinical Trial Application (CTA), a US IND is for a particular therapeutic product and indication. Regulatory Affairs follows the IND and therapeutic through the development cycle as it proceeds from Phase 1 to 2 to 3 and, hopefully, to a marketing application and approval. During this time, the IND is updated with new information as product development proceeds.
With the planning of the IND submission, one also needs to plan for submissions in other countries if the study will be multi-national. In parallel with IND preparations, these CTA submissions need to be planned in advance and the information needed for a successful CTA submission outlined and compiled so that studies may start on schedule.
Chemistry, Manufacturing and Controls (CMC) information is updated as the manufacture of the drug substance and drug product is optimized and scaled up, methods are refined and validated, and longterm stability data are generated. As the therapeutic reaches Phase 3 development and primary efficacy studies are implemented, the CMC section of the IND will have been updated to include a level of detail nearly equivalent to what will be in the subsequent marketing application.
This is also true for the non-clinical sections where the results of additional mechanistic and interaction studies are included in IND amendments. Long-term toxicology studies, often conducted in parallel with early clinical studies to support longer duration of dosing, are completed and submitted to the IND to support the clinical program.
Protocols for new clinical studies, as well as supporting investigator documentation, are submitted prior to starting each study. As clinical studies are completed, the data are reviewed by Data Management, analyzed by Biostatistics & Programming, and reported by Medical Writing.
Drug Safety is also a critical stakeholder in the clinical development of a therapeutic, as they are responsible for receiving, analyzing and preparing safety reports on serious adverse events reported in the clinical program. Clinical Operations, Data Management, Biostatistics and Programming, Drug Safety and Medical Writing all contribute to the regularly scheduled safety reviews and IND Annual Reports or Development Safety Update Reports when a product is being studied internationally.
Regulatory Oversight and Guidance to Development Teams
In addition to keeping the IND current and making sure that supporting data is submitted to the IND prior to its use in clinical trials, another role for the regulatory professional is providing guidance to the study team on the appropriate times for regulatory interactions. Regulatory interactions should be planned for the major countries in which marketing applications are planned. FDA recommends EOP2 meetings and Pre-NDA meetings. When applicable, an EOP1 Meeting or joint EMA/FDA scientific advice request may be appropriate. It is the role of the regulatory lead to recommend and discuss the most appropriate interactions and work with the study team in the preparation and planning of these interactions. A significant stakeholder for these activities is Medical Writing, which will take the lead in the preparation of the Briefing Package. Other departments such as Biostatistics and Programming are instrumental in the preparation of the Statistical Analysis Plan (SAP) for individual studies, as well as any proposed integrated analyses for the marketing application summaries. Clinical Operations and Data Management are essential to overseeing the clinical study and reviewing and preparing the data for analysis. Drug Safety also plays a central role in the safety assessment process. Successful regulatory interactions require that all stakeholders work together to prepare a concise and comprehensive briefing document with targeted questions for agency consideration and a well thought-out sponsor position.
After receiving feedback from FDA, EMA and other stakeholders, decisions need to be made as to the best way to incorporate the advice as well as what to do when conflicting advice is received from different regulatory agencies.
Special Protocol Assessments (SPA)
For trials intended to form the primary basis of an efficacy claim, the completion of a Special Protocol Assessment (SPA) with FDA should be considered. SPAs may be requested for animal carcinogenicity protocols, drug substance and drug product stability protocols, and animal efficacy protocols initiated under the animal rule. The most common use of an SPA is for primary efficacy studies to support approval. The completion of an SPA (from the initial FDA meeting request to final FDA action on the SPA request) can take 3-6 months depending on the number of interactions. Studies cannot be initiated until the SPA process is complete. Sponsors should strongly consider the value of having FDA agreement on the proposed study endpoints and methods of analysis. After the agency response to an SPA is obtained and the requests or changes agreed upon, subsequent protocol design changes also require a request for an SPA modification. While sponsors may be reluctant to initiate the SPA because of the potential for a longer study initiation process, one should always consider the advantage of having agency agreement for the study design and analysis. The added control over changes can be a benefit, as it limits one’s ability to make changes during the study, which may have the unwanted consequence of jeopardizing data integrity and usability.
The SPA process requires planning and input from all of the relevant disciplines including Clinical Operations, Data Management, Biostatistics & Programming, Medical Writing, and Drug Safety. Planning may begin up to 6 months before initiating an SPA request. For the SPA process and submission to flow smoothly, the first step is to have a well-designed protocol and an analysis plan that is based on the results of previously conducted studies. For the SPA submission, one needs the final protocol, SAP, draft case report forms for the major efficacy variables, and a description of the important safety variables to be collected. All of these documents should be part of a Briefing Package prepared by Medical Writing and including a short description of the product and the proposed indication, the study design, primary efficacy and safety endpoints, and questions from the Sponsor. While FDA may comment on items that are not in the list of questions, their focus will be on the questions. One of the essential roles of the regulatory professional is to assist the team in identifying the critical items to include in the questions and to formulate the company rationale for how they will be addressed in the study. The second step of the SPA process is a meeting with the relevant FDA division, which could also be the EOP1 or EOP2 meeting, where the study design is discussed in detail with FDA. If one has a productive meeting, wherein agreement on the major design issues are reached, the SPA process should run smoothly.
Interactions With Regulatory Agencies and Marketing Applications
Having had successful interactions with regulatory agencies and positive results of the clinical studies, it will be time to plan for the marketing application. Over my career, I have had the opportunity to follow a number of therapeutic products from IND filing to NDA/BLA filing. This is a very interesting and gratifying process. The planning process for the marketing application should not start with the availability of the results of the study; the initial planning should begin at the time the pivotal study(ies) starts. Since reports of all studies are needed for the filing, a major task is to identify all of the studies to be included in the filing and the planning and completion of the final reports for these studies.
The regions where the filing(s) will take place and the major regulatory stakeholders need to be identified. One also starts to prepare for pre-submission (Pre-NDA/MAA) meetings with the health authority(ies) in the major region, which can include EMA and/or FDA. The agreement on the analyses and data presentations can be done by the sponsor team prior to the availability of the top line data. Again, this is a multi-disciplinary activity, with Biostatistics preparing the integrated analyses plans and Medical Writing taking the lead in preparing the briefing documents.
As you may anticipate, the marketing application process requires all departments to prepare, review, and finalize the documents, and properly format them for final publishing and submission to regulatory agencies. While a marketing application in eCTD format is accepted by all regulatory agencies, different regions will have specific requirements regarding the content of Module 1 and, potentially, other sections.
During the review process, Regulatory Affairs is the main contact among the different disciplines. They are responsible for interacting with the regulatory authorities, obtaining the required information, and completing the submission. If one should have an expedited filing, this requires that the responsible departments be on continual standby so that requests can be addressed within 24 to 48 hours of submission.
Regulatory Affairs in the Post-Approval Setting
Once agency approval of a marketing authorization is obtained, one is still not finished. There are required post-marketing safety reports and periodic reports on the marketed product. Production of these reports is coordinated by Regulatory Affairs. The Drug Safety and Medical Writing departments gather and consolidate the data, respectively, and Regulatory Affairs submits the documents.
Regulatory Affairs remains engaged with a substance throughout its life-cycle. There may be new indications for the marketed product and/or additional information developed from long-term toxicology studies. The processes described above may be repeated multiple times during a product’s market experience. All drug development professionals, with the guidance of Regulatory Affairs work together to support all phases of a new product.
