Pharmaceutical, biotechnology and medical device companies that market blockbuster products can earn over $1 billion dollars per year once their products are approved for sale by the United States Food and Drug Administration (FDA). Approval by the FDA can result in rapid approval to market products on a global level. Companies can invest $1 billion dollars or more over the course of the discovery, research, and development phases of their product candidates. Patent protection can be extended minimally by certain strategies of the developing company. Once patents expire generic products can enter the market at a fraction of the development cost and reimbursement rates of original products.
These factors mean that speeding time to market results in both competitive and financial benefits to the company that reaches the market first. These factors also mean that any shortcomings in the development strategy or the regulatory strategy can result in negative consequences to the company's "revenue picture" as well as enable competitors to establish a beachhead in the minds of the prescribing physician, the consumer and medical care reimbursers.
The current global regulatory environment is very challenging due to the rapidly aging patient population, the pressure regulators who are responding to concerning safety issues and the redesign of health care to extend coverage to a larger patient population at significant cost savings.
All companies planning to market applications to health authorities for permission to market their products and derive revenue from their use must demonstrate that their products are safe, that they work for the intended indication (disease), and that they can be reliably and repeatedly manufactured to meet international standards of quality.
Pharmaceutical and biotechnology are fortunate, in that a consortium of regulatory authorities and trade organizations have developed standards for documents and data that must be collected to support a company's claims of the quality, safety, and efficacy of their products.
The International Conference on Harmonisation (ICH) has been working since the late 1980s to develop standards that enable companies to conduct studies once and submit the results globally. In addition, ICH has developed a standard for submissions to health authorities that enable these submissions to be delivered in a standardized electronic format for review by regulators. This standard - the electronic Common Technical Document (eCTD) -- means that the majority of the content of a submission can be compiled once and submitted electronically to multiple health authorities where regulators can perform their reviews in a fully-electronic environment. What had once been a semi-trailer truckload of paper that took up to a year to compile into three-ring binders can now be 100 percent electronically managed.
The ICH initially covered the requirements of US, European Union and Japan. The applicability of the ICH submission standards has grown exponentially with the expansion of the European Union to 28 member states, and the endorsement of the eCTD format by Canada, the World Health Authority (WHO), Switzerland, Australia, and the Association of Southeast Asian Nations (ASEAN).
The eCTD is a common organizational structure for the content of submissions for drug and biologic products intended for human use (see Figure 1). It is divided into five modules in the following organizational structure:
To take advantage of the eCTD format, and to help with speeding time to market, companies should take the following actions, prior to the initiation of development activities on their drug and biologic product candidates:
All regulatory authorities that accept eCTD format for review have reported issues with receipt of submissions that contained noncompliant content. To be compliant, eCTD submissions must pass programmatic validation routines that are run by each regulatory authority on all eCTD submissions they receive for review. A summary of the high-level requirements include:
Companies that fail to follow these requirements will, at minimum, delay the start of the review. All regulatory authorities have published their validation criteria along with severity ratings. High severity errors mean the agency cannot process, archive or review the submission. In this case, the pharmaceutical or biotechnology company is notified of the errors and told to correct them as the review cannot start. This delay creates a huge impact in terms of time-to-market and—depending on the nature of remediation needed to recover from the validation failures—can be very time consuming and expensive to correct.
Companies that have egregious failures within the content of their submissions (e.g, not following agency and ICH guidances about what types of studies to conduct and what evidence to accumulate during discovery, research, and development, or inadequate content or organization) can receive a "refuse-to-file" (RTF) notice from the health authority. RTFs can take years to recover from as they indicate inadequate design of the quality, safety, and/or efficacy of the entire program.
Companies should institute the following best practices to avoid critical validation errors that prevent review from starting; that prevent refusals to file that halt the review from continuing and that prevent other regulatory delays:
The medical device industry is in the early stages of a process similar to the ICH. The medical device industry organization, Advanced Medical Technology Association (www.advamed.org), is working with industry to develop content standards for the PreMarketing Authorization (PMA) submission. The FDA PDUFA IV information technology plan calls for the establishment of a common all-electronic review environment across all centers of FDA – including the Center for Devices and Radiological Health. The RPS development underway within FDA has been designed to provide the electronic submission infrastructure and bi-directional messaging required for device submissions.
Finally, the Global Harmonization Task Force (GHTF) is developing applicable standards for device submissions and quality management practices as appropriate for the medical device industry.
Although not as far along as the pharmaceutical and biologics industries, medical device companies can institute best practices today to assure that the documents and data they are collecting today will be in compliant formats for electronic submission for marketing authorization by regulators worldwide.
Regulators worldwide are instituting the complete infrastructure to support electronic receipt, electronic review, and electronic bi-directional communication with the sponsoring companies. The aim of the regulators is to meet the legislative timelines that have been imposed to complete reviews in return for industry paying large user fees to support the review process. By moving to the eCTD electronic submission format, the regulators are both meeting their timelines and bringing the cost of performing such reviews under control. Industry will take advantage of this infrastructure and global standards to reduce the cost of collecting, compiling, and shipping submissions to regulators, speeding time to market for approved products, avoiding costly delays from handling paper, and averting the cost of noncompliance from submitting electronic submissions that do not pass validation or that are incomplete from a review standpoint.
All companies today work in an electronic environment using desktop/laptop computers, on computer networks, using standard office productivity tools. By setting expectations and providing detailed specifications along with adequate tools and training in the form of word processing templates optimized for eCTD granularity and for conversion to PDF file format with appropriate navigation aids, sponsors can speed time to market.
Antoinette Azevedo is general manager of Sage Submissions, LLC, which develops templates conforming to eCTD granularity which contain embedded aids to assure navigability of PDF files after conversion, and are integrated with the MasterControl Documents module.
She is also president, CEO, and founder of e-SubmissionsSolutions.com, a consultancy that provides services to assist pharmaceutical and biotechnology companies in making the transition from paper to electronic submission formats. Services include vendor selection, system implementation, validation, system administration and staff augmentation services for electronic document management systems (EDMS) and submission publishing systems. She can be reached at (619) 220-7081 or AAzevedo@e-SubmissionsSolutions.com.
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