Background

Cytomegalovirus (CMV), a common herpes virus that remains latent under normal circumstances, can be reactivated and shed when the immune system is compromised. People who are immune-incompetent or immunocompromised, such as transplant patients, HIV/AIDS patients, and newborn babies, are at risk for severe and life-threatening infections involving fever, pancytopaenia, and inflammatory changes in multiple organs.

Currently available drugs for the prevention and treatment of CMV disease in transplant patients, such as intravenous ganciclovir, oral valganciclovir, foscarnet, and cidofovir, are constrained by dose-limiting toxicity and drug resistance. New drugs in development with improved toxicity profiles include brincidofovir (CMX001) and letermovir [1, 2]. In the absence of a standardized and validated surrogate marker for CMV disease, developers face challenges including consensus on the appropriate clinical trial design in the setting of hematopoietic-cell transplantation or solid organ transplantation [3].

A safe and protective vaccine for CMV is one of the high priorities in the US Institute of Medicine vaccine prioritization reports [4, 5]. After four decades of failure, two recent studies of therapeutic vaccination show promise: gB/MF59 and TransVax (VCL-CB01) [6, 7]. In addition, monoclonal antibodies, such as RG7667 and TCN-202 are in development. Consensus on study design and endpoint definition for therapeutic vaccines, monoclonal antibodies, and small molecules is needed.

Read more about The Forum for Collaborative Research's history, achievements, operating procedures and working process.

Publication: 

Definitions of CMV infection and disease in transplant patients for use in clinical trials.  Available for advance access online at http://cid.oxfordjournals.org/content/early/2016/09/27/cid.ciw668.abstract

Aims

Our aim is to advance the regulatory sciences for the treatment of TAVI and its associated morbidities by providing an independent and neutral venue for ongoing multi-stakeholder dialogue.  As our collective knowledge and experience with the treatment and prevention of TAVI diseases in different settings advance, our work will facilitate the making of science-based decisions regarding efficacy and safety in real-time.

Once new drug candidates and therapeutic strategies are identified, their rapid and safe development is in the best interest of all stakeholders, most of all, the patients [10]. Careful deliberation on issues of common interest and concern by an independent body whose neutrality and objectivity is ensured through representation and active engagement of scientific experts from all stakeholder groups, including academia, industry, patient community, and regulatory agencies, in a non-competitive and safe environment, breaks down inefficiencies by increasing clarity and standardization and decreasing uncertainty, thereby allowing the whole field to benefit from valuable lessons learned.

Action Plan

The Forum for Collaborative Research will convene a project group to address regulatory hurdles and advance drug development for the treatment of TAVI.

The Forum, established in 1997 following a series of Keystone Dialogue meetings convened at the request of Vice President Al Gore, has successfully addressed specific hurdles in drug development for HIV and HCV [8, 9]. The Forum hallmark is inclusion of all stakeholder groups, including patients and advocacy organizations, academia, federal agencies, industry, professional societies and other relevant entities. The Forum works closely with the US Food and Drug Administration and the European Medicines Agency, providing a trans-Atlantic regulatory scope and breadth to the deliberations. 

The availability of a dedicated space for neutral discussions allowing continuity of dialogue over a period of time is a key component for success, facilitating a learning process that engages all stakeholders.

The project will be led by a Steering Committee and managed by Forum staff. We envision two annual in-person meetings, with topic-specific working group conference calls and email/web-based communication in the intervening time. Project members will be recruited from academia, community, federal agencies, professional societies, and industry. The project is open to all pharmaceutical, biotech and diagnostic companies involved in relevant clinical research, with industry members asked to contribute to the project's financial needs. The project agenda is set by the steering committee, and will include discussion of topics such as the:

CMV: 1) standardization of CMV QNAT reporting units (c/mL vs IU) and terminology; 2) establishment of CMV thresholds for preemptive therapy management; and 3) the role of antigenemia testing and the emerging role of immunologic assessments.

Adenovirus infection: the role of virologic surrogates in clinical trials, and clinical trial designs in pediatric and adult populations.

BK Virus: developing a gold standard definition of BKV disease and investigating how well BKV DNA predicts clinical outcomes in kidney transplant patients.

Membership 

The TAVI Forum membership is by invitation only. Project members are recruited from academia, community, federal agencies, professional societies, and industry. Membership is open to scientific experts from pharmaceutical, biotech, and diagnostic industry organizations committed to and actively engaged in research and development in TAVI.

Participation from industry is conditional on an annual sponsorship contribution.  Industry members will be acknowledged as TAVI Forum sponsors. Sponsorship includes participation in-person meetings, working groups, webinars, remote attendance, and project updates. Non-sponsoring industry will have access to information published on the TAVI Forum’s website. Annual contributions from non-industry organizations are encouraged. Members from pharmaceutical, biotech, device, and diagnostic industry organizations must be scientific or regulatory experts actively engaged in research and development in the field of TAVI. Industry members join as an organization. Commercial, marketing, and investment experts are not permitted to attend closed TAVI Forum members meetings, but will be allowed to participate in any public meetings the Forum sponsors.

The Forum does not cover any honoraria or provides items of value (gifts) to any speakers or attendees. Membership cannot be combined/divided for participation in different disease specific projects at the Forum.

References

1. Marty FM, Winston DJ, Rowley SD, Vance E, Papanicolaou GA, Mullane KM, et al. CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation. The New England journal of medicine. 2013;369(13):1227-36.

2. Stoelben S, Arns W, Renders L, Hummel J, Muhlfeld A, Stangl M, et al. Preemptive treatment of Cytomegalovirus infection in kidney transplant recipients with letermovir: results of a Phase 2a study. Transplant international : official journal of the European Society for Organ Transplantation. 2014;27(1):77-86.

3. Marty FM, Boeckh M. Maribavir and human cytomegalovirus-what happened in the clinical trials and why might the drug have failed? Current opinion in virology. 2011;1(6):555-62.

4. Rieder F, Steininger C. Cytomegalovirus vaccine phase Ii clinical trial results. Clinical Microbiology and Infection. 2013;20 (suppl5):95-102.

5. Krause PR, Bialek SR, Boppana SB, Griffiths PD, Laughlin CA, Ljungman P, et al. Priorities for CMV vaccine development. Vaccine. 2014;32(4-10).

6. Griffiths PD, Stanton A, McCarrell E, Smith C, Osman M, Harber M, et al. Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial. Lancet. 2011;377(9773):1256-63.

7. Kharfan-Dabaja MA, Boeckh M, Wilck MB, Langston AA, Chu AH, Wloch MK, et al. A novel therapeutic cytomegalovirus DNA vaccine in allogeneic haemopoietic stem-cell transplantation: a randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet infectious diseases. 2012;12(4):290-9.

8. Miller V. The forum for collaborative HIV research: a model for an integrated and inclusive approach to clinical research and drug development. Clin Pharmacol Ther. 2009;86(3):332-5.

9. Hutchison C, Kwong AD, Ray S, Struble K, Swan T, V M. Accelerating drug development through collaboration: The hepatitis C drug development advisory groups. Clin Pharmacol Ther. 2014;In press.

10. Baird LG, Banken R, Eichler HG, Kristensen FD, Lee DK, Lim JC, et al. Accelerated Access to Innovative Medicines for Patients in Need. Clin Pharmacol Ther. 2014.