UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM 10-K
☒ ANNUAL REPORT PURSUANT TO SECTION 13 OR
15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For fiscal year ended December 31, 2025
☐ TRANSITION REPORT PURSUANT TO SECTION
13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For the transition period from ______ to ______
Commission file number: 000-55347
Relmada Therapeutics, Inc.
(Exact name of registrant as specified in its
charter)
2222 Ponce de Leon Blvd., Floor 3
Coral Gables, FL33134
(Address of principal executive offices) (Zip
Code)
(786)629 1376
(Registrant’s telephone number, including
area code)
Securities registered pursuant to Section 12(b)
of the Act:
Title of each class Trading Symbol(s) Name of each exchange on which registered
Common Stock ($.001 par value) RLMD The NASDAQ Capital Market
Securities registered pursuant to section 12(g)
of the Act:
None
Indicate by check mark if the registrant is a
well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐ No ☒
Indicate by check mark if the registrant is not
required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes ☐ No ☒
Indicate by checkmark whether the registrant
(1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12
months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements
for the past 90 days. Yes ☒ No ☐
Indicate by check mark whether the registrant
has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§ 232.405
of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files). Yes ☒
No ☐
Indicate by check mark whether the registrant
is a large accelerated filer, an accelerated filer, a non-accelerated filer, smaller reporting company, or an emerging growth company.
See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,”
and “emerging growth company” in Rule 12b-2 of the Exchange Act.
Large accelerated filer ☐ Accelerated filer ☐
Non-accelerated filer ☒ Smaller reporting company ☒
Emerging growth company ☐
If an emerging growth company, indicate by check
mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting
standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Indicate by check mark whether the registrant
has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial
reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or
issued its audit report. ☐
If securities are registered pursuant to Section
12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction
of an error to previously issued financial statements. ☐
Indicate by check mark whether any of those error
corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrant’s
executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐
Indicate by check mark whether the registrant
is a shell company (as defined in Rule 12b-2 of the Act). Yes ☐ No ☒
As of June 30, 2025 (the last business day of
the registrant’s most recently completed second fiscal quarter), the aggregate market value of the registrant’s common stock
held by non-affiliates of the registrant was $18,893,422, based on the closing price on that date as reported on the NASDAQ.
As of March 16, 2026, there were 104,890,223 shares
of common stock, $0.001 par value per share, outstanding.
Documents Incorporated by Reference
Portions of the registrant’s definitive
proxy statement for its 2026 Annual Meeting of Stockholders (the “Proxy Statement”), to be filed within 120 days of the registrant’s
fiscal year ended December 31, 2025, are incorporated by reference in Part III of this Annual Report on Form 10-K. Except with respect
to information specifically incorporated by reference in this Annual Report on Form 10-K, the Proxy Statement is not deemed to be filed
as part of this Annual Report on Form 10-K.
TABLE OF CONTENTS
Item Number and Caption Page
Forward-Looking Statements ii
PART I 1
1. Business 1
1A. Risk Factors 14
1B. Unresolved Staff Comments 37
1C. Cybersecurity 37
2. Properties 38
3. Legal Proceedings 38
4. Mine Safety Disclosures 38
6. [Reserved] 40
7A. Quantitative and Qualitative Disclosures About Market Risk 44
8. Financial Statements and Supplementary Data 44
9A. Controls and Procedures 44
9B. Other Information 45
9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 45
PART III 46
10. Directors, Executive Officers, and Corporate Governance 46
11. Executive Compensation 46
13. Certain Relationships and Related Transactions, and Director Independence 46
14. Principal Accountant Fees and Services 46
15. Exhibits and Financial Statement Schedules 47
Signatures 54
i
CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS
This Annual Report on Form 10-K (this “Annual
Report”) contains forward looking statements that involve risks and uncertainties, principally in the sections entitled “Description
of Business,” “Risk Factors,” and “Management’s Discussion and Analysis of Financial Condition and Results
of Operations.” All statements other than statements of historical fact contained in this Report, including statements regarding
future events, our future financial performance, business strategy and plans and objectives of management for future operations, are
forward-looking statements. We have attempted to identify forward-looking statements by terminology including “anticipates,”
“believes,” “can,” “continue,” “could,” “estimates,” “expects,”
“intends,” “may,” “plans,” “potential,” “predicts,” “should,”
or “will” or the negative of these terms or other comparable terminology. Although we do not make forward-looking statements
unless we believe we have a reasonable basis for doing so, we cannot guarantee their accuracy. These statements are only predictions
and involve known and unknown risks, uncertainties and other factors, including the risks outlined under “Risk Factors” or
elsewhere in this Report, which may cause our or our industry’s actual results, levels of activity, performance or achievements
to differ materially from those expressed or implied by these forward-looking statements. Moreover, we operate in a very competitive
and rapidly changing environment. New risks emerge from time to time and it is not possible for us to predict all risk factors, nor can
we address the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause our actual
results to differ materially from those contained in any forward-looking statements. All forward-looking statements included in this
document are based on information available to us on the date hereof, and we assume no obligation to update any such forward-looking
statements.
You should not place undue reliance on any forward-looking
statement, each of which applies only as of the date of this Annual Report. Before you invest in our securities, you should be aware
that the occurrence of the events described in the section entitled “Risk Factors” and elsewhere in this Annual Report could
negatively affect our business, operating results, financial condition and stock price. Except as required by law, we undertake no obligation
to update or revise publicly any of the forward-looking statements after the date of this Annual Report on Form-10-K to conform our statements
to actual results or changed expectations.
ii
PART I
All brand names or trademarks appearing in
this report are the property of their respective holders. Unless the context requires otherwise, references in this report to “Relmada,”
the “Company,” “we,” “us,” and “our” refer to Relmada Therapeutics, Inc., a Nevada corporation.
ITEM 1. BUSINESS
Business Overview
Relmada Therapeutics, Inc. (Relmada, the Company, we or us) (a Nevada
corporation), is a publicly traded, clinical-stage biotechnology company. We substantially redesigned our development programs following
a comprehensive strategic review in late 2024 and early 2025. We concluded in our review that the most promising path to create shareholder
value was to lever our extensive drug development expertise and clinical operations capabilities by acquiring new development candidates,
while terminating further work on esmethadone (d-methadone, dextromethadone or REL-1017). Hence we accelerated ongoing efforts to augment
our development pipeline while diversifying its risk, which culminated in the licensing of NDV-01, a novel delivery formulation of a chemotherapy
regimen widely used to treat non muscle-invasive bladder cancer (NMIBC) that is currently in Phase 2, and the acquisition of sepranolone,
a Phase 2b-ready neurosteroid with potential applications in Prader-Willi syndrome (PWS), Tourette Syndrome (TS), essential tremor and
other diseases related to excessive GABAergic activity.
Following the 2024 REL-1017 setback and subsequent
post hoc analyses, the program was terminated effective July 7, 2025.
We also had been developing REL-P11, a modified-release
formulation of psilocybin, as an investigational agent for the treatment of metabolic disease. Effective May 12, 2025, this program was
terminated.
Currently, our lead product, NDV-01 is a novel, controlled-release
intravesical formulation of gemcitabine and docetaxel. NDV-01 is currently in a Phase 2 clinical trial in Isreal to assess its safety
and efficacy in patients with aggressive forms of NMIBC. We intend to develop NDV-01 for two separate indications: (1) the treatment of
high-risk, 2nd line Bacillus Calmette-Guérin (BCG)-unresponsive NMIBC and (2) the treatment of intermediate risk patients in the
adjuvant setting. We expect to initiate Phase 3 programs for each indication mid-2026.
Our second product, sepranolone is a novel neurosteroid epimer of allopregnanolone.
Sepranolone is being developed for the potential treatment of PWS, TS, essential tremor and other diseases related to excessive GABAergic
activity. We expect to initiate a Phase 2b study in PWS mid-2026.
Progress in Strategic Execution
On February 6, 2025, Relmada announced the acquisition from Asarina
Pharma AB (Asarina) of sepranolone, a Phase 2b ready neurosteroid being developed for the potential treatment of PWS, TS, essential tremor
and other diseases related to the excessive GABAergic activity.
On March 25, 2025, Relmada announced the in-license
agreement from Trigone Pharma Ltd. (Trigone) of NDV-01, a novel delivery formulation of a widely used chemotherapeutic regimen used to
treat NMIBC.
Key Upcoming Anticipated Milestones
We expect multiple key milestones over the next
12 months. These include:
● sepranolone - Initiation of a Phase 2 clinical trial in PWS – Mid-2026
1
Our Development Programs
NDV-01 Program
NDV-01, our lead program, was in-licensed on
March 24, 2025, NDV-01, is a novel intravesicular delivery technology designed for the long-acting, controlled release of gemcitabine
and docetaxel. This combination therapy has gained significant interest as an alternative to BCG for treating NMIBC, especially given
the global BCG shortage since 2019. Clinical studies have shown that gemcitabine and docetaxel achieve response rates and Recurrence-Free
Survival comparable to or better than BCG. However, conventional administration is cumbersome, requiring sequential drug delivery over
three to four hours, with limited tumor exposure time.
NDV-01 potentially addresses these limitations by enabling a single
administration in less than 5 minutes, delivering sustained, localized chemotherapy for up to 10 days. This extended exposure enhances
the therapeutic effect while improving patient convenience.
NDV-01 is formulated as a controlled-release intravesical
therapy containing gemcitabine and docetaxel. By maintaining continuous drug exposure within the bladder, NDV-01 may optimize local efficacy
while minimizing systemic absorption and associated side effects. Unlike conventional intravesical instillations, which result in fluctuating
drug levels, NDV-01 provides a continuous release of both agents over 10 days. This sustained delivery may improve cancer cell eradication
and reduce recurrence risk while lowering the frequency of administration.
NDV-01 is currently in a Phase 2 clinical trial evaluating its safety
and efficacy in patients with aggressive NMIBC. The Phase 2 study is a single-arm, single-center study evaluating the safety and efficacy
of NDV-01 in patients with High Grade-NMIBC. Patients are treated with NDV-01 in a biweekly induction phase, follow by monthly maintenance
for up to one year, with regular assessments via cystoscopy, cytology, and biopsy, as indicated. The primary efficacy endpoints are safety
and complete response rate (Complete Response Rate at 12 months), and secondary efficacy endpoints are duration of response (DOR) and
event free survival (EFS).
Twelve-Month Safety and Efficacy Data
We obtained twelve-month safety and efficacy data for our Phase 2 study
of NDV-01 in high-risk NMIBC. Among 48 enrolled patients who received at least one dose, no new safety signals were observed with respect
to the type, frequency or severity of adverse events. No patients experienced Grade ≥3 treatment-related adverse events, and no patients
discontinued treatment due to adverse events. Of the 48 patients, 30 (63%) experienced a treatment-related adverse event. Among treatment-related
adverse events, 54% were transient uncomfortable urination (dysuria), 8% were asymptomatic positive urine culture and 8% were hematuria.
2
Efficacy and Tolerability
Efficacy Evaluable Patients (Complete Response (CR)) (n/N) %
12 month KM analysis - 83 %
N= 48 patients in overall population; KM: Kaplan-Meier analysis; 10 patients awaiting 3 month response assessment
BCG-UR Subpopulation* CR (n/N) %
12 month KM analysis - 84 %
N= 20 patients dosed in BCG-UR subpopulation;
* BCG-UR defined by FDA definition; BCG-UR: Bacillus Calmette-Guérin (BCG)- Unresponsive; KM: Kaplan-Meier analysis; 3 patients
awaiting 3 month assessment
● No patient had progression to muscle-invasive disease
● No patient underwent radical cystectomy
The Company also previously announced the successful completion and
receipt of written feedback from a Type B pre-IND submissions with the U.S. Food and Drug Administration (FDA) regarding the planned Phase
3 program for NDV-01 in NMIBC patients. Relmada secured FDA alignment on certain key elements of the planned Phase 3 pivotal program for
NDV-01, expected to begin in mid-2026, and incorporating two studies for two separate indications:
Also, importantly, the FDA agreed with our proposal to rely on FDA’s
prior findings of safety for Gemzar and Taxotere and published literature for the non-clinical safety assessment of NDV-01 because this
is a proposed 505(b)(2) approval.
3
About the Planned High-Grade Registrational
Study
The planned pivotal Phase 3 study in 2nd-line, refractory, high-grade
BCG-unresponsive NMIBC with CIS will be an open-label, single-arm trial evaluating:
● Primary endpoint: CR rate at any time
● Key secondary endpoint: DOR
● Assessments: Cystoscopy, cytology, and biopsy per protocol
The design reflects FDA’s
written guidance on the study population, endpoint selection, and evaluation methodology and is consistent with prior FDA precedents for
single-arm registrational trials in NMIBC.
About the Planned
Intermediate-Risk Registrational Study
The planned pivotal Phase 3 study in intermediate-risk NMIBC in the
adjuvant setting will be an open label randomized-to-observation study:
● Primary endpoint: Disease Free Survival (DFS)
● Key secondary endpoint: DOR
● Assessments: Cystoscopy, cytology, and biopsy per protocol
The design reflects FDA’s written guidance on the study population,
endpoint selection, and evaluation methodology.
Sepranolone Program
The GABAergic system is the primary inhibitory
neurotransmitter pathway. It consists of two types of receptors, GABAA and GABAB. GABAA receptors are
a major target for neuropsychiatric drugs, including benzodiazepines, barbiturates and anesthetic agents. The GABAergic system regulates
a host of physiological and neurological functions and their related moods and behaviors. The principal positive physiologic modulators
of the GABAergic system are the neurotransmitter GABA (γ-aminobutyric acid) and the positive allosteric modulator Allopregnanolone.
GABA generally inhibits nervous system excitability and thereby produces a calming effect that reduces anxiety and compulsive behavior,
among other manifestations. While Allopregnanolone typically enhances GABA’s calming effects, in some individuals it paradoxically
exacerbates anxiety and compulsive behavior.
Sepranolone is a synthetic version of isoallopregnanolone,
a naturally occurring neurosteroid that counteracts the effects of allopregnanolone. Sepranolone is designed to normalize GABAA receptor
activity by targeting two specific receptor subtypes (alpha-2 and alpha-4) without directly interfering with GABA signaling, making it
a novel and selective treatment approach for diseases such as PWS and TS and other disorders that feature compulsive behavior.
Data from an open-label Phase 2a randomized study
demonstrated that sepranolone has the potential to improve TS symptoms versus standard of care alone, as measured by changes in the YGTSS
scoring system (the world-standard Yale Global Tic Severity Scale) compared to baseline. In the 12-week, dual-center, parallel-group study,
26 subjects were treated with sepranolone (10 mg, administered by subcutaneous injection twice weekly in addition to standard of care
(SOC) versus standard of care alone.
The Phase 2a results showed competitive tic reduction and improved
quality of life while displaying no CNS off-target effects. Sepranolone not only reduced tic severity in its primary clinical endpoint
as measured by YGTSS by 28% (p=0.051) – but also achieved positive results in four key secondary endpoints compared with standard
of care:
● 50% greater reduction in impairment (YGTSS)
Importantly, no off-target CNS effects or systemic side effects were
observed in this study. Further, sepranolone has been evaluated in multiple clinical neuro/hormonal studies involving over 335 participants.
Sepranolone was well tolerated with no serious treatment emergent adverse
events reported. The most common adverse events were of mild or moderate intensity related to injection sites, with pain, erythema and
pruritus being the most common.
Relmada expects to initiate a Phase 2 pilot study
of sepranolone in PWS in mid-2026.
4
Our Corporate History and Background
We are a clinical-stage, publicly traded biotechnology
company developing new chemical entities (NCE) and novel versions of drug products that potentially address areas of high unmet medical
need in the treatment of cancer, neurological disorders, and other diseases.
Currently, none of our product candidates has
been approved for sale in the United States or elsewhere. We have no commercial products, nor do we have a sales or marketing infrastructure.
In order to market and sell our products we must conduct clinical trials on patients and obtain regulatory approvals from appropriate
regulatory agencies, like the FDA in the United States, and similar organizations elsewhere in the world.
We have not generated revenues and do not anticipate generating revenues
for the foreseeable future. We had net loss of approximately $57,385,200 and $79,979,400 for the years ended December 31, 2025 and 2024,
respectively. As of December 31, 2025, we had an accumulated deficit of approximately $698,267,200.
Business Strategy
Our strategy is to leverage our considerable
industry experience, understanding of pharmaceutical markets and development expertise to identify, develop and commercialize product
candidates with significant market potential that can fulfill unmet medical needs. We have assembled a management team along with both
scientific advisors, and business advisors with significant industry and regulatory experience to lead and execute the development and
commercialization of our product candidates.
Intellectual Property Portfolio and Market Exclusivity
We have more than 40 issued patents and pending
patent applications related to sepranolone for multiple uses, including diseases and disorders exhibiting compulsive behaviors such as,
TS, obsessive-compulsive disorder, and gambling disorder, potentially providing coverage beyond 2038.
We have more than 10 issued patents and pending
patent applications related to NDV-01 for multiple uses, including formulations and methods for controlled release of therapeutics for
treatment of diseases such as bladder cancer, potentially providing coverage beyond 2038.
Esmethadone License Agreement
Following the 2024 REL-1017 setback and subsequent post hoc analyses,
this license agreement was terminated effective July 7, 2025.
Sepranolone Acquisition
On February 3, 2025, we entered into an Asset
Purchase Agreement with Asarina, a Swedish corporation, pursuant to which we purchased, subject to the terms and conditions set forth
therein, from Asarina all right, title, and interest in sepranolone. The total purchase price was €3,000,000. The Company paid Asarina
$2,756,000 on February 5, 2025, which includes a credit of $250,000 for a previous payment made by the Company to Asarina pursuant to
an exclusivity agreement in October 2024.
We only assumed liabilities arising after the effective date of the
Purchase Agreement. All other liabilities, including those arising before the effective date of the Purchase Agreement, taxes, employment-related
liabilities, and those related to the negotiation and consummation of the Purchase Agreement, remained with Asarina.
5
NDV-01 In-License Agreement
On March 24, 2025, the Company entered into an Exclusive License Agreement
with Trigone, a privately held Israeli company. The license agreement is for Trigone’s NDV-01 product, which is a novel, sustained-release,
intravesical gemcitabine/docetaxel, ready-for-use product candidate for the treatment of NMIBC. Under the terms of the agreement, the
Company made a $3,500,000 upfront payment on March 25, 2025, and issued 3,017,420 shares of common stock, which represented 10% of the
Company’s outstanding shares, for exclusive worldwide rights to NDV-01, excluding Israel, India and South Africa.
In addition, the Company will pay up to $200
million in development, regulatory and commercial milestones pending successful commercialization. The Company will also pay a royalty
of 3% on any net sales. As of December 31, 2025, a milestone had been achieved with a $2 million
payment. The milestone payment was accrued for as of December 31, 2025 and paid to Trigone in January 2026.
Inturrisi / Manfredi
On July 7, 2025, the Company delivered to Dr. Charles E. Inturrisi
and Dr. Paolo Manfredi formal notice of termination of the License Agreement entered into in January 2018, under which we had licensed
certain rights, including patents and patent applications, to esmethadone, in the context of other indications, thus ending the Company’s
esmethadone development program. As a result of the notice of termination, all material obligations under the license agreement with the
Licensor ceased as of October 5, 2025, which was 90 days after the date of the notice. There were no fees or costs associated with the
termination of the License Agreement.
Psilocybin License Agreement
On May 12, 2025, the Company delivered to Arbormentis LLC a formal
notice of termination of the License Agreement entered into in July 2021, under which the Company had licensed development and commercial
rights to a noval psilocybin and derivative, thus ending the Company’s psilocybin development program. As a result of the cancellation,
all obligations under the license agreement with Arbormentis ceased as of August 10, 2025, which was 90 days after the date of notice.
There were no fees or costs associated with the termination of the License Agreement.
Key Strengths
We believe that the key elements for our market success include:
● Compelling lead product opportunities in NDV-01 and sepranolone
● Multiple potential bladder cancer related indications for NDV-01
● Substantial and growing IP portfolio for both NDV-01 and sepranolone
● Experienced management team with considerable drug development expertise
6
Competition
The pharmaceutical and biotechnology industry
is characterized by intense competition, rapid product development and technological change. Competition is intense among manufacturers
of prescription pharmaceuticals and other product areas where we may develop and market products in the future. Most of our competitors
are large, well-established pharmaceutical or healthcare companies with considerably more financial, marketing, sales and technical resources
than are available to us. Additionally, many of our competitors have research and development capabilities that may allow such competitors
to develop new or improved products that may compete with our products. Our products could be rendered obsolete or made uneconomical
by the development of new products.
Regarding our competitive position in the industry,
we currently have no products approved for sale.
Government Regulation
Government authorities in the United States,
at the federal, state and local level, and in other countries and jurisdictions extensively regulate, among other things, the research,
development, testing, manufacture, quality control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution,
marketing, post-approval monitoring and reporting, and import and export of pharmaceutical products. The processes for obtaining regulatory
approvals in the United States and in foreign countries and jurisdictions, along with subsequent compliance with applicable statutes
and regulations and other regulatory authorities, require the expenditure of substantial time and financial resources.
FDA Approval Process
In the United States, pharmaceutical products
are subject to extensive regulation by the FDA. The Federal Food, Drug, and Cosmetic Act (FDCA) and other federal and state statutes and
regulations govern, among other things, the research, development, testing, manufacture, storage, recordkeeping, approval, labeling, promotion
and marketing, distribution, post-approval monitoring and reporting, sampling and import and export of pharmaceutical products. Failure
to comply with applicable U.S. requirements may subject a company to a variety of administrative or judicial sanctions, such as FDA refusal
to approve pending new drug applications (NDAs), warning or untitled letters, product recalls, product seizures, total or partial suspension
of production or distribution, injunctions, fines, civil penalties and criminal prosecution.
Pharmaceutical product development for a new product or certain changes
to an approved product in the U.S. typically involves non-clinical laboratory and animal tests, the submission to FDA of an investigational
new drug application (IND) which must become effective before clinical testing may commence, and adequate and well-controlled clinical
trials to establish the safety and effectiveness of the drug for each indication for which FDA approval is sought. Satisfaction of FDA
pre-market approval requirements typically takes many years and the actual time required may vary substantially based upon the type, complexity
and novelty of the product or disease.
Non-clinical tests include laboratory evaluation of product chemistry,
formulation and toxicity, as well as animal trials to assess the characteristics and potential safety and efficacy of the product. The
conduct of the non-clinical tests must comply with federal regulations and requirements, including good laboratory practices. The results
of non-clinical testing are submitted to FDA as part of an IND along with other information, including information about product chemistry,
manufacturing and controls, and a proposed clinical trial protocol. Long-term non-clinical tests, such as animal tests of reproductive
toxicity and carcinogenicity, may continue after the IND is submitted. A 30-day waiting period after the submission of each IND is required
prior to the commencement of clinical testing in humans. During this period, if FDA concludes that a deficiency exists in a clinical investigation
that may be grounds for the imposition of clinical hold, FDA will usually attempt to discuss and satisfactorily resolve the matter with
the IND applicant. If such resolution is not possible, FDA may issue a clinical hold order by telephone or other means of rapid communication
or in writing. No more than 30 days after imposition of the clinical hold, a written explanation of the basis for the hold will be issued
by FDA and sent to the applicant. The applicant must respond in writing to each deficiency before the clinical hold can be lifted. If
FDA has neither commented on nor questioned the IND within this 30-day period, the clinical trial proposed in the IND may begin. Clinical
trials involve the administration of the investigational new drug to healthy volunteers or patients under the supervision of a qualified
investigator. Clinical trials must be conducted: (i) in compliance with federal regulations; (ii) in compliance with good clinical practice,
or GCP, an international standard meant to protect the rights and health of patients and to define the roles of clinical trial sponsors,
administrators and monitors; as well as (iii) under protocols detailing the objectives of the trial, the parameters to be used in monitoring
safety and the effectiveness criteria to be evaluated. Each protocol involving testing on U.S. patients and subsequent protocol amendments
must be submitted to FDA as part of the IND.
7
FDA may not permit a clinical trial to begin,
or may order the temporary, or permanent, discontinuation of a clinical trial at any time, or impose other sanctions, if it believes
that the clinical trial either is not being conducted in accordance with FDA requirements or presents an unacceptable risk to the clinical
trial patients. The study protocol and informed consent information for patients in clinical trials must also be submitted to an institutional
review board (IRB) for approval. An IRB may also require the clinical trial at the site to be halted, either temporarily or permanently,
for failure to comply with the IRB’s requirements, or may impose other conditions.
Clinical trials to support NDAs for marketing approval are typically
conducted in three sequential phases, but the phases may overlap. In Phase 1, the initial introduction of the drug into healthy human
subjects or patients, the drug is tested to assess metabolism, pharmacokinetics, pharmacological actions, side effects associated with
increasing doses, and, if possible, early evidence of effectiveness. Phase 2 usually involves trials in a limited patient population to
determine the effectiveness of the drug for a particular indication, dosage tolerance and optimum dosage, and to identify common adverse
effects and safety risks. If a drug demonstrates evidence of effectiveness and an acceptable safety profile in Phase 2 evaluations, Phase
3 trials are undertaken to obtain the additional information about clinical efficacy and safety in a larger number of patients, typically
at geographically dispersed clinical trial sites, to permit FDA to evaluate the overall benefit-risk relationship of the drug and to provide
adequate information for the labeling of the drug. In many cases, particularly for prevalent diseases, the FDA requires two adequate and
well-controlled Phase 3 clinical trials, each convincing on its own, to demonstrate the efficacy of the drug. In many other conditions,
particularly for rare disease therapies, a single adequate and well-controlled Phase 3 trial may be sufficient when in conjunction with
confirmatory evidence. A single adequate and well-controlled Phase 3 trial may also be sufficient, through it is less common, where the
study is a large multicenter trial demonstrating internal consistency and a statistically very persuasive finding of a clinically meaningful
effect on mortality, irreversible morbidity or prevention of a disease with a potentially serious outcome and confirmation of the result
in a second trial would be practically or ethically impossible.
After completion of the required clinical testing, an NDA is prepared
and submitted to FDA. FDA approval of the NDA is required before marketing of the product may begin in the U.S. The NDA must include the
results of all non-clinical, clinical and other testing and a compilation of data relating to the product’s pharmacology, chemistry,
manufacture and controls. The cost of preparing and submitting an NDA is substantial. The submission of most NDAs is additionally subject
to a substantial application user fee, and the applicant under an approved NDA is also subject to an annual program fee for each prescription
product. These fees are typically increased annually. Sponsors of applications for drugs granted Orphan Drug Designation are exempt from
these user fees.
FDA has 60 days from its receipt of an NDA to determine whether the
application will be filed based on the agency’s threshold determination that it is sufficiently complete to permit substantive review.
Once the submission is filed, FDA begins an in-depth review. FDA has agreed to certain performance goals in the review of NDAs to encourage
timeliness. Applications for most standard review drug products are reviewed within twelve months from submission of NDAs for new molecular
entities (NMEs) and ten months from submission of NDAs for non-NMEs. Priority review can be applied to drugs that FDA determines offer
major advances in treatment or provide a treatment where no adequate therapy exists. The review process for both standard and priority
review may be extended by FDA for three additional months to consider information that the FDA considers to be a major amendment to the
NDA.
FDA may also refer applications for novel drug
products, or drug products that present difficult questions of safety or efficacy, to an outside advisory committee – typically
a panel that includes clinicians and other experts – for review, evaluation and a recommendation as to whether the application
should be approved. FDA is not bound by the recommendation of an advisory committee, but it generally follows such recommendations.
Before approving an NDA, FDA will typically inspect
one or more clinical sites to assure compliance with GCP. Additionally, FDA will inspect the facility or the facilities at which the
drug is manufactured. FDA will not approve the product unless compliance with current good manufacturing practices (cGMPs) is satisfactory
and the NDA contains data that provide substantial evidence that the drug is safe and effective in the indication studied.
After FDA evaluates the NDA and the manufacturing
facilities, it issues either an approval letter or a complete response letter. A complete response letter generally outlines the deficiencies
in the submission and may require substantial additional testing, or information, in order for FDA to reconsider the application. If,
or when, those deficiencies have been addressed to FDA’s satisfaction in a resubmission of the NDA, FDA will issue an approval
letter. FDA has committed to reviewing such resubmissions in two or six months depending on the type of information included. An approval
letter authorizes commercial marketing of the drug with specific prescribing information for specific indications. As a condition of
NDA approval, FDA may require a risk evaluation and mitigation strategy (REMS) to help ensure that the benefits of the drug outweigh
the potential risks. REMS can include medication guides, communication plans for healthcare professionals, and elements to assure safe
use (ETASU). ETASU can include, but are not limited to, special training or certification for prescribing or dispensing, dispensing only
under certain circumstances, special monitoring and the use of patient registries. The requirement for a REMS can materially affect the
potential market and profitability of the drug. Moreover, product approval may require substantial post-approval testing and surveillance
to monitor the drug’s safety or efficacy. Once granted, product approvals may be withdrawn if compliance with regulatory standards
is not maintained or problems are identified following initial marketing.
Changes to some of the conditions established
in an approved application, including changes in indications, labeling, or manufacturing processes or facilities, require submission
and FDA approval of a new NDA or NDA supplement before the change can be implemented. An NDA supplement for a new indication typically
requires clinical data similar to that in the original application, and FDA uses the same procedures and actions in reviewing NDA supplements
as it does in reviewing NDAs.
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Fast Track Designation
FDA is required to facilitate the development,
and expedite the review, of drugs that are intended for the treatment of a serious or life-threatening disease or condition for which
there is no effective treatment and which demonstrate the potential to address unmet medical needs for the condition. Under the Fast
Track program, the sponsor of a new drug candidate may request that FDA designate the drug candidate for a specific indication as a Fast
Track drug concurrent with, or after, the submission of the IND for the drug candidate. FDA must determine if the drug candidate qualifies
for Fast Track Designation within 60 days of receipt of the sponsor’s request.
If a submission is granted Fast Track Designation,
the sponsor may engage in more frequent interactions with FDA, and FDA may review sections of the NDA before the application is complete.
This rolling review is available if the applicant provides, and FDA approves, a schedule for the submission of the remaining information
and the applicant pays applicable user fees. However, FDA’s time period goal for reviewing an application does not begin until
the last section of the NDA is submitted. Additionally, Fast Track Designation may be withdrawn by FDA if FDA believes that the designation
is no longer supported by data emerging in the clinical trial process.
Orphan Drugs
Under the Orphan Drug Act, FDA may grant Orphan
Drug Designation to drugs intended to treat a rare disease or condition – generally a disease or condition that affects fewer than
200,000 individuals in the U.S. Orphan Drug designation must be requested before submitting an NDA. After FDA grants Orphan Drug Designation,
the generic identity of the drug and its potential orphan use are disclosed publicly by FDA. Orphan Drug Designation does not convey
any advantage in, or shorten the duration of, the regulatory review and approval process. The first NDA applicant to receive FDA approval
for a particular active ingredient to treat a particular disease with FDA Orphan Drug Designation is entitled to a seven-year exclusive
marketing period in the U.S. for the active ingredient in that product, for that indication. During the seven-year exclusivity period,
FDA may not approve any other applications to market the same drug for the same disease, except in limited circumstances, such as a showing
of clinical superiority to the product with orphan drug exclusivity. Orphan drug exclusivity does not prevent FDA from approving a different
drug for the same disease or condition, or the same drug for a different disease or condition. Among the other benefits of Orphan Drug
Designation are tax credits for certain research and an exemption from the application user fee.
Disclosure of Clinical Trial Information
Sponsors of clinical trials of FDA regulated
products, including drugs, are required to register and disclose certain clinical trial information. Information related to the product,
patient population, phase of investigation, study sites and investigators, and other aspects of the clinical trial is then made public
as part of the registration. Sponsors are also obligated to discuss the results of their clinical trials after completion. Disclosure
of the results of these trials can be delayed in certain circumstances for up to two years after the date of completion of the trial.
Competitors may use this publicly available information to gain knowledge regarding the progress of development programs.
Pediatric Information
Under the Pediatric Research Equity Act (PREA),
NDAs or supplements to NDAs must contain data to assess the safety and effectiveness of the drug for the claimed indications in all relevant
pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the drug is safe and effective.
FDA may grant full or partial waivers, or deferrals, for submission of data. With certain exceptions, PREA does not apply to any drug
for an indication for which orphan designation has been granted.
The Best Pharmaceuticals for Children Act (BPCA)
provides NDA holders a six-month extension of any exclusivity – patent or nonpatent – for a drug if certain conditions are
met. Conditions for exclusivity include FDA’s determination that information relating to the use of a new drug in the pediatric
population may produce health benefits in that population, FDA making a written request for pediatric studies, and the applicant agreeing
to perform, and reporting on, the requested studies within the statutory timeframe. Applications under the BPCA are treated as priority
applications, with all of the benefits that designation confers.
Post-Approval Requirements
Once an NDA is approved, a product will be subject
to certain post-approval requirements. For instance, FDA closely regulates the post-approval marketing and promotion of drugs, including
standards and regulations for direct-to-consumer advertising, off-label promotion, industry-sponsored scientific and educational activities
and promotional activities involving the internet. Drugs may be marketed only for the approved indications and in accordance with the
provisions of the approved labeling.
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Adverse event reporting and submission of periodic reports are required
following FDA approval of an NDA. FDA also may require post-marketing testing, known as Phase 4 testing, REMS and surveillance to monitor
the effects of an approved product, or FDA may place conditions on an approval that could restrict the distribution or use of the product.
In addition, quality control, drug manufacture, packaging and labeling procedures must continue to conform to cGMPs after approval. Drug
manufacturers and certain of their subcontractors are required to register their establishments with FDA and certain state agencies. Registration
with FDA subjects entities to periodic unannounced inspections by FDA, during which the Agency inspects manufacturing facilities to assess
compliance with cGMPs. Accordingly, manufacturers must continue to expend time, money and effort in the areas of production and quality-control
to maintain compliance with cGMPs. Regulatory authorities may withdraw product approvals or request product recalls if a company fails
to comply with regulatory standards, if it encounters problems following initial marketing, or if previously unrecognized problems are
subsequently discovered.
FDA strictly regulates marketing, labeling, advertising
and promotion of drugs that are placed on the market. Advertising and promotion of drugs must be in compliance with the Federal FDCA and
its implementing regulations and only for the approved indications and in a manner consistent with the approved labeling. FDA and other
agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly
promoted off-label uses may be subject to significant liability, including investigation by federal and state authorities.
Generic Competition
In seeking approval for a drug through an NDA, applicants are required
to list with the FDA each patent whose claims cover the applicant’s product. Upon approval of a drug, each of the patents listed
in the application for the drug is then published in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations,
commonly known as the Orange Book. Drugs listed in the Orange Book can, in turn, be cited by potential generic competitors in support
of approval of an abbreviated new drug application (ANDA). An ANDA provides for marketing of a drug product that has the same active ingredients
in the same strengths and dosage form as the listed drug and has been shown through bioequivalence testing to be therapeutically equivalent
to the listed drug. Other than the requirement for bioequivalence testing, ANDA applicants are not required to conduct, or submit results
of, non-clinical or clinical tests to prove the safety or effectiveness of their drug product. Drugs approved in this way are commonly
referred to as “generic equivalents” to the listed drug and can often be substituted by pharmacists under prescriptions written
for the original listed drug.
The ANDA applicant is required to certify to
the FDA concerning any patents listed for the approved product in the FDA’s Orange Book. Specifically, the applicant must certify
that (i) the required patent information has not been filed; (ii) the listed patent has expired; (iii) the listed patent
has not expired but will expire on a particular date and approval is sought after patent expiration; or (iv) the listed patent is
invalid or will not be infringed by the new product (a Paragraph IV certification). The ANDA applicant may also elect to submit a section
viii statement certifying that its proposed ANDA label does not contain (or carve out) any language regarding the patented method-of-use
rather than certify to a listed method-of-use patent. If the applicant does not challenge the listed patents or certifies that the listed
patents will not be infringed by the new product, the ANDA application will not be approved until all the listed patents claiming the
referenced product have expired. If the ANDA applicant has provided a Paragraph IV certification, the NDA and patent holders may then
initiate a patent infringement lawsuit in response. The filing of a patent infringement lawsuit within 45 days of the receipt of a such
certification automatically prevents the FDA from approving the ANDA until the earlier of 30 months, expiration of the patent, settlement
of the lawsuit, or a decision in the infringement case that is favorable to the ANDA applicant.
Exclusivity
Upon NDA approval of an NCE, which is a drug
that contains no active moiety that has been approved by FDA in any other NDA, that drug receives five years of marketing exclusivity
during which FDA cannot receive any ANDA seeking approval of a generic version of that drug. An ANDA may be submitted one year before
NCE exclusivity expires if a Paragraph IV certification is filed. If there is no listed patent in the Orange Book, there may not be a
Paragraph IV certification, and, thus, no ANDA may be filed before the expiration of the exclusivity period. Certain changes to a drug,
such as the addition of a new indication to the package insert, can be the subject of a three-year period of exclusivity if the application
contains reports of new clinical investigations (other than bioavailability studies) conducted or sponsored by the sponsor that were
essential to approval of the application. FDA cannot approve an ANDA for a generic drug that includes the change during the period of
exclusivity.
Patent Term Extension
After NDA approval, owners of relevant drug patents
may apply for up to a five-year patent extension. The allowable patent term extension is calculated as half of the drug’s testing
phase (the time between IND application and NDA submission) and all of the review phase (the time between NDA submission and approval
up to a maximum of five years). The time can be shortened if FDA determines that the applicant did not pursue approval with due diligence.
The total patent term after the extension may not exceed 14 years, and only one patent can be extended. For patents that might expire
during the application phase, the patent owner may request an interim patent extension. An interim patent extension increases the patent
term by one year and may be renewed up to four times. For each interim patent extension granted, the post-approval patent extension is
reduced by one year. The director of the United States Patent and Trademark Office must determine that approval of the drug covered by
the patent for which a patent extension is being sought is likely. Interim patent extensions are not available for a drug for which an
NDA has not been submitted.
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Other Healthcare Laws
In the United States, biotechnology company activities
are subject to regulation by various federal, state and local authorities in addition to the FDA, including but not limited to, the Centers
for Medicare & Medicaid Services (CMS), other divisions of the U.S. Department of Health and Human Services (HHS) (e.g., the Office
of Inspector General and the Office for Civil Rights), the U.S. Department of Justice (DOJ) and individual U.S. Attorney offices within
the DOJ, and state and local governments.
The federal Anti-Kickback Statute prohibits, among
other things, persons and entities from knowingly and willfully offering, soliciting or receiving or providing remuneration, directly
or indirectly, in cash or in kind, to induce, or in return for, purchasing, leasing, ordering or arranging for the purchase, lease or
order of any healthcare item or service reimbursable under Medicare, Medicaid, or other federally financed healthcare programs. The Patient
Protection and Affordable Care Act as amended by the Health Care and Education Reconciliation Act (collectively, the ACA) amended the
intent element of the federal statute so that a person or entity no longer needs to have actual knowledge of the statute or specific intent
to violate it in order to commit a violation. This statute has been interpreted to apply to arrangements between pharmaceutical manufacturers
on the one hand and prescribers, purchasers and formulary managers, among others, on the other. Although there are a number of statutory
exceptions and regulatory safe harbors protecting certain common activities from prosecution or other regulatory sanctions, the exceptions
and safe harbors are drawn narrowly, and practices that involve remuneration intended to induce prescribing, purchases or recommendations
may be subject to scrutiny if they do not qualify for an exception or safe harbor. In addition, a person or entity does not need to have
actual knowledge of the Anti-Kickback Statute or specific intent to violate it in order to commit a violation.
Federal civil and criminal false claims laws, including the federal
civil False Claims Act, prohibit any person or entity from knowingly presenting, or causing to be presented, a false claim for payment
to the federal government, or knowingly making, or causing to be made, a false statement to have a false claim paid. This includes claims
made to programs where the federal government reimburses, such as Medicare and Medicaid, as well as programs where the federal government
is a direct purchaser, such as when it purchases off the Federal Supply Schedule. Pharmaceutical and other healthcare companies have been
prosecuted under these laws for allegedly inflating drug prices they report to pricing services, which in turn were used by the government
to set Medicare and Medicaid reimbursement rates, and for allegedly providing free product to customers with the expectation that the
customers would bill federal programs for the product. In addition, certain marketing practices, including off-label promotion, may also
violate false claims laws. Additionally, the government may assert that a claim including items or services resulting from a violation
of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal civil False Claims Act. Most
states also have statutes or regulations similar to the federal Anti-Kickback Statute and civil False Claims Act, which apply to items
and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payor.
Other federal statutes pertaining to healthcare
fraud and abuse include the civil monetary penalties statute, which prohibits, among other things, the offer or payment of remuneration
to a Medicaid or Medicare beneficiary that the offeror or payor knows or should know is likely to influence the beneficiary to order
a receive a reimbursable item or service from a particular supplier.
Further, pursuant to the federal Physician Payment Sunshine Act, CMS,
has issued a final rule that requires manufacturers of prescription drugs to collect and report information on certain payments or transfers
of value to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), physician assistants, certain
types of advance practice nurses and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate
family members. The reports must be submitted on an annual basis. The reported data is made available in searchable form on a public website
on an annual basis. Failure to submit required information may result in civil monetary penalties.
In addition, several states now require prescription
drug companies to report certain expenses relating to the marketing and promotion of drug products and to report gifts and payments to
individual healthcare practitioners in these states. Other states prohibit various marketing-related activities, such as the provision
of certain kinds of gifts or meals. Still other states require the posting of information relating to clinical studies and their outcomes.
Some states require the reporting of certain drug pricing information, including information pertaining to and justifying price increases
and new high-cost drug introductions. In addition, certain states require pharmaceutical companies to implement compliance programs and/or
marketing codes. Certain states and local jurisdictions also require the registration of pharmaceutical sales and medical representatives.