The Development of Therapeutics for the Treatment and Prevention of CMV Disease in the Transplant Population: A Regulatory Perspective

Abstract

Cytomegalovirus (CMV) remains an important pathogen in the transplant population. As such, the US Food and Drug Administration has published a guidance to encourage and inform the development of therapeutics for the treatment and prevention of CMV disease in this population. This review summarizes important phase 3 trial design considerations for industry and provides rationale for some of the recommendations included in the guidance.

Among immunocompromised patients, including recipients of a solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT), primary cytomegalovirus (CMV) infection, CMV reinfection, and CMV reactivation are associated with significant morbidity and mortality. CMV can directly invade tissues (ie, tissue-invasive disease) leading to clinical disease such as pneumonitis, retinitis, colitis, and hepatitis. CMV is also thought to be indirectly associated with numerous effects in transplant recipients, including but not limited to, atherosclerosis, allograft rejection, and opportunistic infections [1–4]. One recent retrospective study found that among HSCT recipients CMV viremia was associated with increased overall mortality [5]. Therefore, the availability and utilization of safe and effective therapies for the treatment and prevention of CMV infection and disease can markedly improve clinical outcomes in transplant recipients.

Table 1 summarizes the currently approved CMV antiviral drugs and corresponding indications. As shown, there are currently no drugs approved for the treatment of CMV disease (other than CMV retinitis) in transplant recipients. Further, there is an unmet medical need for drugs to treat CMV infection that is resistant or refractory to available CMV antiviral drugs.

Table 1.

FDA-Approved CMV Antiviral Drugs

Drug	Approved Indication(s)
Ganciclovir sodium (injection)a [6]	Treatment of CMV retinitis in immunocompromised patients including patients with AIDS
	Prevention of CMV disease in transplant recipients
Valganciclovir hydrochloride (tablets and oral solution) [7]	Treatment of CMV retinitis in patients with AIDS
	Prevention of CMV disease in SOT recipients
Letermovir (tablets and injection) [8]	Prophylaxis of CMV infection and disease in HSCT recipients
Foscarnet sodium (injection) [9]	Treatment of CMV retinitis in patients with AIDS
Cidofovir (injection) [10]	Treatment of CMV retinitis in patients with AIDS

Abbreviations: AIDS, acquired immunodeficiency syndrome; CMV, cytomegalovirus; FDA, Food and Drug Administration; HIV, human immunodeficiency virus; HSCT, hematopoietic stem cell transplant; SOT, solid organ transplant.

^aThere is also an oral formulation of ganciclovir that is currently not available in the United States. Oral ganciclovir was approved for the maintenance treatment of CMV retinitis in immunocompromised patients and for the prevention of CMV disease in patients with advanced HIV infection and SOT recipients.

In 2018, the US Food and Drug Administration (FDA) published a draft guidance, entitled “Cytomegalovirus in Transplantation: Developing Drugs to Treat or Prevent Disease” [11]. The purpose of this guidance is to assist sponsors in the clinical development of drugs for the treatment or prevention of CMV disease in patients who have undergone SOT or HSCT. The guidance covers early drug development (including nonclinical considerations) through late stages of drug development. Recommendations from this draft guidance, with a focus on phase 3 trial design considerations, were presented at a 2018 National Institutes of Health workshop entitled CMV Infection: Advancing Strategies for Prevention and Treatment. This article summarizes the components of the guidance that were presented and provides rationale for some of these recommendations. For additional information, please see the published draft guidance [11].

PHASE 3 TRIAL DESIGN

A product may be developed for transplant recipients for 1 or more of the following CMV indications: prophylaxis (ie, drug administered to at-risk patients with no evidence of CMV DNAemia or CMV disease), preemptive therapy (PET) (ie, drug administered for the treatment of patients with CMV replication in the blood to prevent the development of CMV disease), or treatment of CMV disease. Further, a product may be evaluated in an SOT population, HSCT population, or both. Sponsors are encouraged to stratify subjects by important baseline risk factors for CMV infection/disease, such as the CMV serostatus of donor and recipient, the type of transplant (ie, HSCT or SOT) or by organ type (kidney, liver, heart, etc.) in studies enrolling SOT recipients. The choice of trial design depends on the intended indication and population. Table 2 summarizes key phase 3 trial design considerations as described in further detail in the draft CMV guidance.

Table 2.

Trial Design Elements for Phase 3 Trials in HSCT or SOT Recipients^a

Indication	Potential Trial Designs	Study Population	Potential Study Endpoints
Prophylaxis	Noninferiority trial against active control Superiority trial against active control Add-on superiority trial against active control	HSCT: CMV R+	HSCT: Composite endpoint defined as the occurrence of either: tissue-invasive CMV disease, OR the initiation of PET based on clinically significant CMV DNAemia
		SOT: CMV D+/R−	SOT: CMV diseaseb
Preemptive therapy (treatment of asymptomatic CMV viremia)	Superiority trial against SOC Add-on superiority trial against SOC Noninferiority trial against SOC	Any donor/recipient CMV serostatus	Absence of CMV diseaseb OR a composite endpoint of CMV DNA < LLOQ and absence of CMV diseaseb
Treatment of CMV disease	Superiority trial against SOC Add-on superiority trial against SOC	Any donor/recipient CMV serostatus	Resolution or improvement in clinical signs and symptoms of CMV diseaseb AND CMV DNA < LLOQ

Abbreviations: CMV, cytomegalovirus; CMV D+/R−, CMV seropositive donor and CMV seronegative recipient; HSCT, hematopoietic stem cell transplant; LLOQ, lower limit of quantification; PET, preemptive therapy; CMV R+, CMV seropositive recipient; SOT, solid organ transplant.

aRecommendations in this table apply to both HSCT and SOT populations unless otherwise specified.

^bFor trials conducted in SOT recipients, CMV disease encompasses both CMV syndrome and tissue-invasive CMV disease (whereas for HSCT recipients, CMV disease refers exclusively to tissue-invasive CMV disease).

In 2017, members of the CMV Drug Development Forum, including academicians, pharmaceutical industry representatives, and regulators, published definitions for CMV infection and disease [12]. We encourage the use of these definitions in clinical trials to allow for consistent, meaningful comparisons of study populations and clinical outcomes. However, despite the existence of these definitions, some ambiguity may remain. It is therefore recommended that cases of CMV disease reported in a clinical trial be adjudicated by an independent committee.

In general, superiority trials are preferred over noninferiority trials. However, a noninferiority trial design could be considered when there is an FDA-approved drug available to serve as an active comparator, as is the case for CMV prophylaxis. However, noninferiority trials are presently not recommended for clinical trials of drugs intended to treat CMV infection or disease (as there are no drugs approved for this indication with the exception of CMV retinitis), unless the treatment effect of the standard of care (SOC) (ganciclovir or valganciclovir) over placebo is determined to support an appropriate noninferiority margin. In noninferiority design trials, the proposed noninferiority margin should be justified and discussed with the FDA. See the guidance for industry “Non-Inferiority Clinical Trials to Establish Effectiveness” for additional information on determining noninferiority margins [13].

In addition to the indications described above, a sponsor may choose to develop a drug for the treatment of resistant and/or refractory CMV infection. As noted by several presenters at the National Institutes of Health workshop, this remains an area of an unmet medical need. Sponsors are encouraged to discuss their proposed definitions of resistant and refractory CMV infection for use in trials with the FDA. Trials aimed at demonstrating efficacy in the treatment of resistant and/or refractory CMV infection should be superiority trials as there are currently no drugs approved for the treatment of resistant/refractory CMV infection. In the event that a trial includes both patients with resistant infection and patients with refractory infection, statistical significance should be established in the overall population and efficacy in each subgroup (ie, resistant and refractory) should be consistent with the overall treatment effect. Trials could compare the study drug to the SOC or compare the study drug added on to the SOC to the SOC alone. Subjects with CMV DNAemia, with or without CMV disease, could be eligible for participation in a trial for resistant/refractory CMV infection.

EFFICACY ENDPOINTS

As shown in Table 2, the choice of primary efficacy endpoint depends on the intended population and indication. Similarly, the optimal timing of the primary endpoint assessment will vary. In general, in prophylaxis trials the endpoint should be assessed at 6 to 12 months posttransplant (depending on the duration of prophylaxis), and in PET and treatment trials the endpoint should be assessed at a prespecified timepoint after treatment initiation. Assessment of the endpoint postprophylaxis is strongly preferred to assessment at the end of prophylaxis in order to establish that the benefit is durable and that there is not a high rate of infection or reactivation in the period immediately following prophylaxis.

The FDA now considers CMV DNAemia as a validated surrogate endpoint for use as part of a composite endpoint that includes a clinical component to support traditional approval. The use of CMV DNAemia as a surrogate endpoint is well supported in the scientific literature. CMV DNAemia has been shown to predict CMV disease in both SOT and HSCT recipients [5, 14]. The absence of CMV DNAemia also generally predicts an absence of CMV disease [15], although the occurrence of CMV disease (particularly gastrointestinal disease) in the absence of detectable CMV DNAemia is well described [16]. In the VICTOR trial of oral valganciclovir versus intravenous ganciclovir for the treatment of CMV disease in SOT recipients, clearance of DNAemia was associated with clinical resolution of disease [17]. Lastly, the presence of CMV DNAemia in HSCT recipients has been associated with increased overall mortality [5] and the prevention of CMV DNAemia has been associated with decreased overall mortality [18, 19]. This association between CMV DNAemia and mortality is observed irrespective of the presence or absence of CMV disease.

Sponsors developing a product for CMV prophylaxis in HSCT recipients are encouraged to use a composite primary endpoint defined as the occurrence of either tissue-invasive CMV disease or the initiation of anti-CMV PET based on the presence of clinically significant CMV DNAemia. The FDA recognizes that in such a study the endpoint will likely be driven by the initiation of PET rather than the occurrence of tissue-invasive CMV disease given the low rate of CMV disease in the setting of appropriate monitoring and PET.

VIROLOGY CONSIDERATIONS

Polymerase chain reaction (PCR) has largely become the standard method for monitoring CMV DNA levels in the blood in clinical practice and PCR is recommended for use in clinical trials as well. Monitoring of CMV DNA levels during clinical trials should be conducted using an FDA-approved/cleared assay. A World Health Organization international standard for CMV quantification is available [20]. However, interassay and interlaboratory variability remain problematic [21]. It is therefore recommended that CMV DNA quantification be conducted at a central laboratory, in addition to the local laboratory, to minimize interlaboratory variability.

In a prophylaxis trial of a CMV antiviral, testing for CMV resistance should be conducted any time there is detectable CMV DNA or a confirmed diagnosis of CMV disease. In a treatment trial, resistance testing is recommended when subjects experience virologic breakthrough, decline to plateau viral load decay phase, virologic rebound (ie, an increase in viral DNA without prior clearance of viremia), or virologic relapse (ie, an increase in viral DNA following clearance of viremia). Given the complexity of CMV resistance analyses, we encourage sponsors to discuss their resistance analysis plans with the FDA early and often.

CHALLENGES

Conducting clinical trials for CMV infection and disease in the transplant population has many challenges. First, this patient population has a high frequency of comorbidities. These comorbidities confound observed adverse effects making the identification of drug-related toxicities challenging. Similarly, these patients’ complex medical histories often require numerous concomitant medications and drug-drug interactions can be problematic. The transplant population is a very heterogeneous population. Because of this variability, there is increasing interest in utilizing individualized cell-mediated CMV immunity assays to guide therapy. However, use of these testing modalities in clinical trials is currently considered exploratory. Lastly, patients are not the only source of variability in CMV clinical trials. Variability in CMV DNA quantification between assays and between compartments, as well as a lack of well-defined CMV DNA thresholds for the initiation of PET, can make the interpretation of study results difficult and can limit the generalizability of the results to the broader transplant population.

Given the numerous trial design considerations and the complexities of conducting clinical trials in the transplant population, sponsors are strongly encouraged to discuss their development plans with the FDA. The pre-IND program is an excellent source of feedback and guidance from the FDA early in drug development and information on the pre-IND program is available on the FDA website [22].

CONCLUSION

The recommendations conveyed in this publication and in the draft guidance document represent the FDA’s current thinking on the development of therapeutics to treat or prevent CMV disease among transplant recipients. Sponsors are encouraged to discuss considerations unique to their product with the FDA to promote effective and efficient drug development.

Notes

Acknowledgments. The authors acknowledge all members of the Cytomegalovirus in Transplantation: Developing Drugs to Treat or Prevent Disease guidance working group. Further, we thank Jeffrey Murray, MD, MPH, Debra Birnkrant, MD, and John Farley, MD, MPH, for comments and suggestions on the article.

Supplement sponsorship. This supplement was sponsored by NIAID and NICHD.

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Presented in part: National Institutes of Health workshop Cytomegalovirus Infection: Advancing Strategies for Prevention and Treatment, 4 September 2018, Rockville, MD.