A view to the future

New product development requires the close collaboration of virtually all functions inside a company. The existence of an effective cross-functional team, with clearly defined objectives, is thus critical to the successful development of any new medical product. Over the recent past, new industry trends evolved. Future industry leaders will be those who embrace these trends fully, as these early adopters will have a critical competitive edge.

With this in mind, it is important to assess how industry trends in several critical areas are evolving, thus defining future industry leaders in terms of clinical development. Indeed, the early adoption of sound processes that build on these trends will provide this critical competitive edge.

In order to succeed, cross-functional teams must have very clearly defined objectives, shared by all team members. In the context of developing a new medical product or a new indication, the primary goals can be summarised as follows:
1.  Regulatory clearance / approval
2.  Market adoption
3.  Reimbursement
These steps apply of course to the initial indications, but also to each subsequent indication in the context of life cycle management.

A good Clinical Development Plan requires contributions from all potentially interested parties, such as potential users, payers and beneficiaries of the new product or new indication. All these entities will assess the relevance of the new product in terms of risk to benefit ratio and cost effectiveness, each with a potentially different point of view. Users in particular are critical to the rapid adoption of any new medical device. Their position vis-à-vis the new product (or indication) is crucial, especially at the time of launch, and is normally based on published clinical experience. Opinions and anecdotal experience usually do not convince anyone but the most maverick adopters.

This reflects the reality that imposes basic requirements on the industry, whether or not these requirements are actually embraced. This reality dictates that teams must integrate all parties in a transparent, collaborative process that builds on sound science, and it affects a number of areas relevant to the development of products aimed at addressing medical needs, from interactions with the scientific community to working with regulatory agencies. Eventually, all parties share the same goal of making good products available. The extent to which this reality is identified and embraced will define the leaders of tomorrow.

Trend: Transparency
Over the years, regulatory agencies, sponsors, practicing physicians, key opinion leaders, professional associations, patients, and payers have increasingly insisted that all pertinent information be shared. The recent requirement that virtually all trials be fully disclosed on ClinicalTrials.gov and related web sites illustrates that, despite the initial resistance, the industry as a whole has had little choice but to agree to disclose all study information.

One can of course resist such requirements further by complying minimally, i.e., providing the least information possible. Doing so however seems a battle not worth fighting. Embracing the trend fully will help business in the long run. Let’s take two opposite scenarios, one, the “good scenario”, the other, the “bad” one.

First, the good scenario: the results of a recently concluded trial demonstrate beyond any doubt that a product is safe and effective. Clinical study registries could conceivably allow for the immediate dissemination of these results, enabling the quick, low-cost sharing of this new knowledge across the world. It seems obvious that such a rapid, virtually free, and succinct way of disseminating critical information should bolster adoption by physicians and users upon launch.

Now, the bad scenario: a recently terminated trial, related to an already marketed product, suggests potential safety concerns that were not known at the time of approval. This is obvious bad news. Yet the rapid dissemination of the results may actually protect the manufacturer from law suits because such information will thus become available to the medical community, whose insights and interest should help the manufacturer greatly in assessing the issue and mitigating the consequences.

Achieving transparency should not require much additional work. Indeed, properly built systems can allow, today, for results to be shared on an ongoing yet controlled manner with the relevant parties. The public disclosure of protocols and results is only one limited example. What about regulatory reviews?

Trend: Integration
Data standards (such as CDISC) and the evolution of electronic filing, i.e., the eCTD, open new perspectives in regards to regulatory review of submissions.

Current requirements, regardless of standard, basically dictate that the conclusion of all studies (whether preclinical or clinical) be filed, that the related data and statistical analysis programmes be made available, and that full assurances be made that the data is complete and accurate.

Current systems do not allow for the complete integration and seamless distribution of such information. Yet, albeit with some work, systems can be built that could in fact reduce regulatory submissions to simply providing the assigned personnel at regulatory agencies with a user name and password, along with appropriate privileges. Such privileges would include access to the documents defined in the eCTD, organized as specified, as well as drill-down capabilities to allow reviewing the data, possibly  to the record level and electronically catalogued supporting documents.

Interim reports (e.g., safety updates and annual progress reports) and key pre-approval submissions (e.g., pre-IND, pre-IDE, End of Phase 2) could be managed in a similar way, thus creating an efficient, collaborative environment.

Such collaboration will result in easier regulatory reviews, better workflows both for manufacturers and regulators, and ultimately, the faster market release of better characterized, safer products.

Trend: Collaboration   
For many years, the FDA and other regulatory agencies have openly offered to collaborate much more closely with the industry. This makes good sense, assuming that all parties genuinely share the same goal: to make safe and effective products available, save lives and restore or protect human health.

Still, many companies have not taken full advantage of this offering. Close collaboration with regulators means that issues and expectations are identified early on and can be managed proactively, ideally with meaningful consensus. Open, transparent communication between manufacturers and regulators is critical to success here. Such collaborations, usually successful, allow for more focused development plans, tighter time lines, and faster, easier reviews. Indeed, from the onset of the development programme, all collaborative parties would share in the same objectives and address issues in a consensual manner.

Pushing the concept further, one could imagine the complete integration of the regulatory review process within shared information systems, allowing for near continuous dialogue around data results, and issues.

Trend: Convergence
However, given the current situation, this idea seems very utopian. Not only do regulators around the world have varying general requirements, but regulations and standards vary across products types, sometimes widely, generating more inconsistencies and misinterpretations.

For example, and irregardless of geographical borders, until very recently there were no GCP guidelines for medical devices. Manufacturers were left to figure out how to comply, and the accepted reference for device studies was the GCP Guidelines, which had actually been designed for drug studies. This is changing under the auspices of the ICH.

It seems straightforward that the requirements particular to medical devices can be integrated into GCP, and that generally, GCP applies to any study involving human subjects. The current issuance and ongoing adoption of device-specific guidelines is good news in that it demonstrates that such consensus is possible. It may not be such good news, however, if the end result is further divergence between the standards that apply to drugs and devices. If this were the case, this divergence would result in creating higher walls between the two industries, despite current trends to the contrary. Convergence, however, would help take existing barriers down, aligning the expectation for scientific quality and sound, rationale product development across pharmaceuticals and medical devices.

The critical accomplishments of the ICH cannot be overvalued. Here again, this effort demonstrates that cross-border collaboration is possible, and definitely improves the quality of submissions, while saving time and effort. Yet, while ICH is a well-established force today, emerging countries add yet more additional standards to an already confusing array, instead of joining previously-established collaborations. Cross-cultural issues and regional peculiarities must be accounted for and are important. Still, why do we need significant differences in the body of an eCTD for submission in the US, Europe, Japan, or ASEAN countries? Differences in filing standards, however slight, do create and add confusion with little real purpose: indeed, if the substance is sound, format and structure should not affect the safety and efficacy of any product.

Convergence in standards would allow for submissions to be prepared consistently across the world, thus allowing for the rapid distribution of new treatments globally. Of course, one may consider this effort to be aimed at serving the cause of Big Business. However, cynics should consider that delaying the availability of new, useful treatments without meaningful reason results in human suffering. Divergent standards cause delays and do betray the actual purpose of all involved, including manufacturers and regulators: to make treatments that help patients available.

Likewise, although accepting data from diverse sources has become increasingly possible, it is still surprising that developing products on a global scale remains a daunting challenge. There are a number of reasons for difficulties that go beyond the absence of truly global regulatory standards.

On the manufacturers’ side, few companies have in-house expertise to design globally symbiotic development programmes. As a result, these companies avoid falling out of their “comfort zone” by dealing with one region at a time. Besides the delay in obtaining approval across different regions, this approach has immediate impact on the underlying design of clinical trials. Indeed, although it is possible to design programmes that are consistent, say, with both European and US requirements, the opportunity of running a single trial for both EMEA and FDA submissions is lost if it is not exploited at the very beginning of the design process. The end result of this “prudent” approach is the very high risk of having to repeat or supplement an already-completed study when preparing a submission for the next competent agency. Delays resulting from such a sequential approach would add up quickly and be reasonably expected to exceed two years. Of course, if the additional expertise and resources needed for a global approach are engaged from the beginning, companies will realize that going faster, better and cheaper may actually be possible. Resources are available to all companies, as long as fully integrating outsourcing into internal work processes is an option.

Trend: Scientific and Medical Relevance
The success of any product, drug or device depends dominantly upon the scientific and medical relevance of the data supporting it. The paramount importance of leading scientific endeavors and top quality studies is made evident by the success of products such as statins, angiotensin converting enzyme inhibitors or bi-ventricular pace makers. Despite the fact that virtually all leading products attain such status from solid clinical research, proportionally few companies actually endorse or promote research and help knowledge progress. However, as more transparency evolves, as collaboration among and between key players increases, and as the technical tools that facilitate such approaches become available, it will make clear business sense for all companies to join the few trailblazers who support genuine scientific endeavors while marketing their products.

“Genuine” and transparency” are critical words here. Scientific research is based on facts and data or does not exist. Even though business priorities dictate the areas where sponsored research is relevant and the scope of the related investment, the staff assigned to these programmes should remain independent of business imperatives and marketing strategies.

Conclusion
We have observed a few key trends emerge in clinical development: increased transparency, integration, collaboration, and convergence of key processes, while enhancing focus on medical relevance and quality research. These trends will continue to propagate, building on this recent evolution. Companies will find success by focusing on the proactive planning of valid, quality research, which requires transparency and collaboration, to the benefit of all.

Paul-André de Lame, M.D. is President and CEO of Anabase International Corp. He has more than 20 years of industry experience and a broad knowledge of product development, clinical research, and related regulatory issues. He has made a critical contribution to a number of new product launches while organizing multiple research projects at the domestic and international levels.