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European Biopharmaceutical Review

The Survey Says

Regulatory uncertainty has been identified as a significant challenge for commercialisation in the field of regenerative medicine. A recent series of informal interviews reveals the views of industry stakeholders and how they anticipate the effects of this in future drug development.

Many stakeholders remain steadfast in their commitments to bring stem cell therapies to the marketplace by engaging industry, trade associations and the regulators (for example, FDA) in an effort to pave a more certain regulatory pathway. This article presents the findings from an informal survey by the California Institute for Regenerative Medicine (CIRM) conducted to ascertain the industry’s ‘wish list’ with respect to the FDA regulatory environment. It describes the CIRM’s funding programmes which bridge over the ‘valley of death’ (for example, the early stages of research where investor funding is very scare), with the hope of ushering in a new era of medicine comprised of cell-based therapies and drugs derived from stem cell assays.

Recipe for Improving Regulatory Certainty for Stem Cell Therapies

Stem cell researchers agree that the US and European regulatory pathway for these therapies is quite uncertain (1). In a difficult economic environment, this is particularly problematic because of the lack of investment in this field. The uncertainty arises not from a lack of understanding of what needs to be established for authorisation (for example, safety and efficacy) but rather of how to accomplish regulatory approval using currently existing paradigms.

Cell therapies present an added layer of regulatory complexity as compared to small molecules and proteins. The complexities arise from the fact that cells are influenced by their environment, can change in vivo and may even migrate from their site of delivery. Tracking cell migration in vivo requires the labelling of cells which introduces a new set of regulatory concerns such as whether such labelling will alter the cells’ behaviour or biology (2). Moreover, suitable animal models do not exist for certain therapeutic applications. A report from a European Medicine Agency workshop held in May 2010 summarises a number of the regulatory issues that need to be addressed (3). The regulatory challenges presented by stem cell therapies were also considered at a workshop held in March 2011 by the US National Institutes of Health and the US Food and Drug Administration (see Table 2 for a list of regulatory challenges presented by stem cell therapies, page 50) (4).

The question then is what can be done to advance these potentially gamechanging therapies when technological limitations hinder the ability to apply more conventional approaches to establishing safety and efficacy? CIRM queried 17 executives at companies developing both autologous and allogeneic therapies using a variety of cell types to shed light on these issues (see Table 1). CIRM was able to obtain candid responses based on a commitment to maintain confidentiality of the respondent.

General Observations

One of the more salient trends that emerged in our discussions was the relative ease in which companies working with mesenchymal stem cells (MSCs) were able to enter into the clinic as compared to therapies based on pluripotent and multipotent cell types. Perhaps this is not surprising because of the relatively long regulatory history for bone marrow transplants and the fact that it has been generally accepted that MSCs are transient (non-integrating) when transplanted into patients, making their risk profile considerably more favourable as compared to therapies based on long-term integrating and renewing pluripotent cells.

A few interviewees also commented that the FDA may be placing too much emphasis on animal studies, which is standard practice for small molecule drug discovery but may be less helpful in the cell therapy context. Most recently, the Alliance for Regenerative Medicine (having a broad membership of private and public funders such as CIRM and the New York Stem Cell Foundation, as well as industry and disease foundations) expressed a similar position in response to FDA’s request for public comments on existing regulations and increasing their effectiveness. Its submission to FDA’s docket included the following statement: “ARM urges the FDA to work collaboratively with the regenerative medicine community to develop flexible approaches for efficacy testing that are less reliant on animal models for IND approvals” (5).

The Industry’s Wish List

With respect to administrative changes that could be made to foster more regulatory certainty, four general desires emerged from the interviews. Three of these focused on methods or approaches to add more predictability to the review process. A fourth focused on the FDA’s approach to balancing risk and benefit. Predictability is particularly important to smaller companies in this field as they often have only 12 to 18 months of funding available at any one time.

Implementing some of these changes could be difficult because of staffing limitations at the FDA, which many believe is underfunded. Two executives recognised this and they volunteered, without prompting, that they would be willing to pay FDA for increased costs that it would incur if it adopted their suggestions. The particulars around a potential payment scheme were not discussed.

More Opportunities for Consultation and Increased Communication

One of the four desires which emerged was the wish for increased consultation at the FDA. Some companies desired a more consultative approach with FDA while others stated that they were very pleased with the level of engagement and input they received from FDA. For those seeking a more consultative relationship, they specifically desired an opportunity for more dialogue with the ability to obtain a commitment on at least some of the most basic aspects of their preclinical plans. They felt that such an agreement or understanding would be helpful during their own fundraising efforts. Two executives stated that they had to build contingencies in their preclinical plans, which made their programmes appear expensive to potential investors. Yet, on the other hand, one company explained that regardless of what their projected costs were, their investors would assume preclinical work would exceed estimates because of both regulatory and scientific uncertainties.

More Publication

The second desire to emerge related to increased frequency of publication and dissemination of information helpful to the field. In recognition that the field is learning how best to navigate the regulatory approval pathway, FDA’s issuance of documents akin to earlier FDAissued Points to Consider would be useful. As noted independently by four of the industry executives, in many instances the FDA is entering into unchartered territory. As the FDA obtains knowledge that has general application, these executives believed it would be helpful if this information could be shared with industry in a more timely manner.

In terms of publication, researchers have an important role as well. Increased publication of translational research, including publication of data from clinical trials that do not meet their endpoints, would help advance the field significantly.

Locking-in Preclinical and Clinical Plans

Three executives mentioned that they believed that the process was very reviewer dependent. They believed that the loss of key regulatory review staff has at times created difficulties for their companies. More consistency across reviewers was desired, as was the need to find mechanisms to ensure a change of staff does not result in revisiting prior decisions of the regulator. It was also suggested that the review be staffed by a team approach and that a docket contain write-ups of prior decisions, with the supporting background information presented and that these be given compelling if not precedential and controlling authority.

Reconsidering the Approach to Risk Evaluation

Finally, without prompting, three executives opined that the risk/ benefit balance paradigm needed to be re-examined. On a few occasions executives argued for the inclusion of patients or patient advocates, within the process of evaluating risk, especially for entry of novel therapies into the clinic. One executive suggested that the impact of a delayed IND on patients should be part of the calculation of risk and benefit. It was noted that while there is a need to be cautious, being over conservative may discourage investment and adversely affect patient’s ability to access new technology. Some specific suggestions included considering the merits of shorter animal studies, reduced sampling on lots and the ability to validate release criteria concurrently with an ongoing clinical trial. The cost/ benefit of long-term animal studies needs closer consideration according to CIRM’s interviews.

Government and Private Foundation Funding

Even with a more certain regulatory pathway, a reliable source of funding of early stages of research and translation is critical, and significant barriers to commercialisation of stem cell therapies will continue to exist without it. Yet the amount of venture funding for all of drug discovery has dramatically decreased as a result of the recession. As reported by Burrill & Company, “Venture capital under management in the US fell 11.9 per cent in 2009 from the previous year and more than 35 per cent from its reported peak in 2006, according to the National Venture Capital Association” (6).

In light of these difficult economic times, the importance of funding from government agencies and private foundations has increased significantly. New York, Maryland, and Connecticut have all passed legislation authorising significant annual funding for this work. However, in recent years the annual appropriations have all been reduced from the original promised sums. Fortunately for researchers in California this later source of uncertainty has been eliminated. In 2004 the taxpayers of California voted in favour of a bond funding scheme that provided authorisation for $3 billion of bonds to be sold over a minimum of 10 years to fund stem cell research. By structuring the initiative as one based on bond financing rather that funding through California’s general fund, the architect of the initiative and former Chairman of CIRM’s board, Robert Klein, was able to ensure that the agency’s funding would not fall prey to changing political winds and shorter-term economic conditions (7).

As a result, CIRM has been able to make funding commitments totalling $1.3 billion as of 30 June 2011. In doing so it seeded both the physical infrastructure for this field (contributing to the building of 12 new state of the art stem cell facilities), but also the intellectual infrastructure with programmes including grants for training faculty in the field of stem cell research. This is a model which CIRM hopes other governments will adopt as it is important that researchers around the globe have access to funding which is critical to the commercialisation of this technology. Moreover, in order to advance the field of stem cell research it is important that governments around the world provide not only the funding but also the opportunities that will allow researchers to collaborate as members on international project teams.

Conclusion

Increased regulatory certainty in the area of stem cell therapies will help advance this field. While advancements in regulatory science could help in this regard, industry leaders have offered various suggestions as to how regulatory review practices can as well. These include increased access to FDA reviewers, increased publication by the FDA, mechanisms that increase consistency across reviewers and minimise re-opening of prior advice, and in certain circumstances re-examination of the risk/benefit paradigm. Yet, even with a more certain regulatory roadmap, the field of stem cell research requires a reliable source of funding. Maintaining government funding and fostering collaboration across state and country boundaries is critical to delivering stem cell therapies to patients.

References

  1. Plagnol AC, Rowley E, Martin P and Livesey F, Industry perceptions of barriers to commercialization of regenerative medicine products in the UK, Regen Med 4(4): pp549-559, 2009
  2. Jeffrey M Perkel, In vivo Stem Cell Imaging-Regulatory Challenges and Advances, StemBook, Harvard Stem Cell Institute, www.stembook.org/ node/708, 21 June 2011
  3. 22 June 2010 EMA/319294/ 2010, Human Medicines Development and Evaluation Summary report on the EMA workshop on stem cell based therapies, London, 10 May 2010
  4. NIH-FDA Workshop, Pluripotent Stem Cells in Translation: Early Decisions March 2011, videocast, http://videocast.nih.gov/summary. asp?Live=10081
  5. Alliance for Regenerative Medicine submission to Docket No FDA- 2011-N-0259 in response to FDA’s proposal published in the Federal Register on 27 April 2011
  6. Burrill & Company, Biotech 2011 – Life Sciences – 25 Years, Looking Back to See Ahead, The Burill & Company 25th Annual Report on the Life Sciences Industry: p339
  7. Klein RN and Trounson A, A New Political-Financial Paradigm for Medical Research: The California Model, The Delivery of Regenerative Medicines and Their Impact on Healthcare, C Prescott and J Polak, eds, Boca Raton: Taylor & Francis, 2010

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Alan Trounson is President of the California Institute for Regenerative Medicine (CIRM) in San Francisco, California. Prior to joining CIRM in January 2008, Trounson was Professor of Stem Cell Sciences and Director of the Monash Immunology and Stem Cell Laboratories at Monash University, where he retains the title of Emeritus Professor. He founded the National Biotechnology Centre of Excellence and has held various positions at Monash University. A Fellow of the Royal College of Obstetricians and Gynaecologists and an Honorary Fellow of the Australian and New Zealand College of Obstetricians and Gynaecologists, Trounson was awarded an honorary doctorate by the faculty of medicine at the University of Brussels. Email: atrounson@cirm.ca.gov

Elona Baum is the General Counsel and Vice President of Business Development of the California Institute for Regenerative Medicine and a member of CIRM’s executive team. From 1996 to 2009, Elona held the positions of Associate General Counsel, and later Director of Regulatory Policy and Strategy at Genentech, Inc. Prior to Genentech, she practiced law at private firms where she had an environmental litigation and real estate transactions practice. Elona received her BA in Economics from the University of California and her JD from the University of San Francisco School of Law. She served as an extern for Justice John A Arguelles, California Supreme Court. Email: ebaum@cirm.ca.gov

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