Laura Rose Bobolts

Regulatory and clinical considerations for biosimilar oncology drugs

Biological oncology products are integral to cancer treatment, but their high costs pose challenges to patients, families, providers, and insurers. The introduction of biosimilar agents-molecules that are similar in structure, function, activity, immunogenicity, and safety to the original biological drugs-provide opportunities both to improve health-care access and outcomes, and to reduce costs. Several international regulatory pathways have been developed to expedite entry of biosimilars into global marketplaces. The first wave of oncology biosimilar use was in Europe and India in 2007. Oncology biosimilars are now widely marketed in several countries in Europe, and in Australia, Japan, China, Russia, India, and South Korea. Their use is emerging worldwide, with the notable exception of the USA, where several regulatory and cost barriers to biosimilar approval exist. In this Review, we discuss oncology biosimilars and summarise their regulatory frameworks, clinical experiences, and safety concerns.

Generic oncology drugs: are they all safe?

Although the availability of generic oncology drugs allows access to contemporary care and reduces costs, there is international variability in the safety of this class of drugs. In this Series paper, we review clinical, policy, safety, and regulatory considerations for generic oncology drugs focusing on the USA, Canada, the European Union (EU), Japan, China, and India. Safety information about generic formulations is reviewed from one agent in each class, for heavy metal drugs (cisplatin), targeted agents (imatinib), and cytotoxic agents (docetaxel). We also review regulatory reports from Japan and the USA, countries with the largest pharmaceutical expenditures. Empirical studies did not identify safety concerns in the USA, Canada, the EU, and Japan, where regulations and enforcement are strong. Although manufacturing problems for generic pharmaceuticals exist in India, where 40% of all generic pharmaceuticals used in the USA are manufactured, increased inspections and communication by the US Food and Drug Administration are occurring, facilitating oversight and enforcement. No safety outbreaks among generic oncology drugs were reported in developed countries. For developing countries, oversight is less intensive, and concerns around drug safety still exist. Regulatory agencies should collaboratively develop procedures to monitor the production, shipment, storage, and post-marketing safety of generic oncology drugs. Regulatory agencies for each country should also aim towards identical definitions of bioequivalence, the cornerstone of regulatory approval.

Melanoma complicating treatment with natalizumab for multiple sclerosis: A report from the Southern Network on Adverse Reactions (SONAR)

A 43‐year‐old female with multiple sclerosis developed urethral melanoma. The only potential risk factor was treatment with natalizumab, a humanized monoclonal antibody against α4 integrins. To investigate the risk‐exposure relationship, we reviewed this case, all other published cases, and cases of natalizumab‐associated melanoma reported to regulatory agencies. Data sources included the Food and Drug Administrations (FDA) Adverse Event Reporting System (FAERS) (2004–2014), a FDA Advisory Committee Meeting Report, and peer‐reviewed publications. In the United States, the manufacturer maintains an FDA‐mandated Tysabri Safety Surveillance Program (part of the Tysabri Outcomes Unified Commitment to Health (TOUCH)) of natalizumab‐treated patients. We statistically compared reporting completeness for natalizumab‐associated melanoma cases in FAERs for which information was obtained entirely from the TOUCH program versus cases where FAERS information was supplemented by TOUCH program information. FAERS included 137 natalizumab‐associated melanoma reports in patients with multiple sclerosis. Median age at melanoma diagnosis was 45 years (range: 21–74 years). Changes in preexisting nevi occurred in 16%, history of cutaneous nevi occurred in 22%, diagnosis within 2 years of beginning natalizumab occurred in 34%, and 74% had primary surgical treatment. Among seven natalizumab‐treated MS patients who developed biopsy‐confirmed melanoma on treatment and reported in the literature, median age at diagnosis was 41 years (range: 38–48 years); and the melanoma diagnosis occurred following a median of 12 natalizumab doses (range: 1–77 doses). A history of mole or nevi was noted in four patients and a history of prior melanoma was noted in one patient. Completeness scores for reports were significantly lower for FAERS cases reported from the TOUCH program versus FAERS cases supplemented by TOUCH information (median score of 2 vs. 4 items out of 8‐possible items, P < 0.0007). Clinicians should monitor existing nevi and maintain suspicion for melanoma developing in natalizumab‐treated patients. The TOUCH Safety Surveillance Program, currently focused on progressive multifocal leukoencephalopathy, should be expanded to include information on other serious complications including malignancies, particularly if they are immunologic in nature.

Adjuvant colon cancer care quality, risk, value, and level one data and guideline compliance among the elderly privately insured in southeastern USA.

249 Background: Oxaliplatin-containing regimens are among the most efficacious adjuvant treatments for locally-advanced colon cancer, although significant toxicity can occur. Because of relevant level I data, the NCCN revised its guidelines in 2012, recommending omission of oxaliplatin from combination adjuvant chemotherapy regimens for older patients (>70yo) with colon cancer. We examined prescribing behavior of oncologists between 2009 and 2014 to evaluate how rapidly NCCN guidelines were adopted into practice. METHODS This is a retrospective observational study of chemotherapy request data from more than 2,000 community oncologists in the southeastern United States. We examined 57 consecutive months of chemotherapy requests for stage II and III colon cancer patients 70 years and older, based on three epochs. During the middle epoch, one phase III trial evaluating oxaliplatin-containing regimens as adjuvant chemotherapy (NSABP C-07), and a revised 2012 NCCN guidelines, each supported omission of oxaliplatin from adjuvant chemotherapy regimens for older persons with colon cancer. Multivariate analyses evaluated associations among patient characteristics (age, gender, and performance status), disease stage, and time-period, with the odds of receiving oxaliplatin-containing regimens as adjuvant chemotherapy. RESULTS Among 266 persons with stage II or III colon cancer 70 years of age and older, over the six-year span, most adjuvant chemotherapy requests (184/266, 69.2%) contained oxaliplatin. Older age, male gender, and poor performance status were associated with significantly lower odds of receiving oxaliplatin-containing adjuvant chemotherapy regimens (p<0.05), while time period (epoch) was not significantly associated with temporal changes in patterns of use. CONCLUSIONS Use of oxaliplatin containing adjuvant chemotherapy regimens among older persons with colon cancer did not decrease following publication of phase III clinical trial data and revised NCCN guidelines recommending against oxaliplatin use in this setting. Focused quality improvement initiatives for this population of cancer patients may be helpful.

National Comprehensive Cancer Network petitions: Submissions and outcomes.

248 Background: The National Comprehensive Cancer Network (NCCN) invites petitions to its scientific panels. Most ( > 95%) are from the pharmaceutical industry lobbying to include their products in the NCCN Guidelines. Rarely, physicians request scientific scrutiny of the guidelines. We report the experience of Oncology Analytics (OA) with petition submissions and the possible impact on guidelines. METHODS From 2011-2015, OA made 7 petitions to NCCN. The content of each was tracked into subsequent NCCN Guidelines to ascertain whether any changes resulted. RESULTS 1) The Survivorship Panel was petitioned to add liposomal doxorubicin to the list of cardiotoxic anthracyclines: No changes were made. 2-3) The NSCLC Panel was asked in 2014 to remove the category 2A listing for trastuzumab and afatinib as HER-2 targeted drugs, and cabozantinib as a RET rearrangement target based on absence of phase I-III full text scientific literature. This was done, however, cabozantinib was reverted to 2A status late 2015 based on abstract-only data. 4) Per FDA approval, the NSCLC Panel was asked to recommend bevacizumab only in combination with carboplatin/paclitaxel for 1st line non-squamous NSCLC based on a survival advantage in ECOG 4599: No changes were made. 5) Given the FDA-approval, the Ovarian Cancer Panel was requested to add doxorubicin: This was done. 6) A 2012 Supportive Care Panel petition pointed out the absence of data supporting palonosetron as the preferred 5-HT3 antagonist with aprepitant for moderate or high emetic risk chemotherapy: No change was made upon request; however, preferred status was removed in 2015 from high emetic risk. 7) Based on a preponderance of evidence, a Supportive Care Panel petition requested re-categorization of the febrile neutropenia risk for carboplatin/paclitaxel from intermediate to low except in patients of Japanese ancestry and/or carboplatin AUC > 6: This was done. CONCLUSIONS Majority of NCCN physician petitions came from OA, yet constituted less than 5% of all petitions submitted. NCCN does not provide direct petitioner feedback, so we cannot say for certain that our petitions led to changes in subsequent guidelines. Not all requests resulted in NCCN changes, despite level one supportive data or accentuating an absence of data.

Quality and value implications of NCCN-compliant use of maintenance rituximab for patients with low-grade NHL.

36 Background: Rituximab maintenance for indolent, incurable non-Hodgkin lymphoma (NHL) remains controversial. NCCN supports maintenance rituximab for a span of up to two years as an alternative to watchful waiting following induction therapy. At least a dozen scientific papers have been published describing rituximab maintenance results; none has demonstrated overall survival benefit. The strongest data support comes from the PRIMA phase III trial which showed an increased PFS but no survival advantage. Increased toxicity, however, is clear and can be serious. Reports of progressive multifocal leukoencephalopathy, a rapidly fatal neurodegenerative disease, should be of especial concern to patients whose disease course can span many years. Oncology Analytics (OA) enhances cancer care quality and value by providing oncology decision-support to providers in SE USA. We hypothesized that the use of maintenance rituximab in this area of the country produces profound cost and real risk for a highly uncertain benefit to this population. METHODS We reviewed all requests for rituximab maintenance for low-grade NHL submitted by oncology practices to a major health insurer in one US region from Jul 2009-May 2014. We calculated the cumulative cost for blanket approval of such requests and the savings associated with our decision-support discussions of this questionable but NCCN-compliant practice. RESULTS 470 requests for maintenance rituximab for low-grade NHL were initiated within this 59-month span. The proportion of maintenance rituximab requests relative to the total chemotherapy requests decreased consistently over time, from 4.5% in the first six months of OA involvement in 2009, down to 1.5% in May 2014. The annual cost of rituximab maintenance, which depends on the dose schedule, ranges from about

Ensuring evidence-based cancer medicine by influencing prescribing behavior.

30,000 to

Use, misuse, and overuse of white cell growth factors (GF) in community oncology practices in southeastern United States.

40,000 per year. Additionally, we discovered many rituximab maintenance requests for durations exceeding two years without evidence-based support, most of which were rescinded after OA intervention. CONCLUSIONS Ongoing OA intervention reduces risk of toxicity and enhances the quality and value of cancer care for these patients.

Annual rhythm in filgrastim use in southeast Florida.

212 Background: Oncology Analytics, Inc. (OA) promotes evidence-based, guidelines-compliant cancer therapeutic decision-making on behalf of healthcare payers. The OA web-based 1,300 protocol treatment request system screens several hundred applications each month. Evidence-based requests are automatically approvable within seconds (Auto); those needing medical director (MD) review, within hours (Non-Auto). Some 10% of all requests require real-time consultation between OA board-certified medical oncologists/hematologists and the prescribing cancer specialist. Three-quarters of these non-compliant residual requests are rescinded by the treating oncologist. The remainder are either approved because of additional information while about 1% are recommended for an adverse determination. METHODS We hypothesize that OAs presence in a cancer market gradually improves the likelihood of evidence-based oncologist prescribing behavior. We tested this over 44 consecutive months of rapid growth, from May 2009 through December 2012, within a single southeastern US market. Since Auto requests are evidence- and guidelines-based, and Non-Auto requests are either not supported by evidence or have evidence support but with less toxic or less costly alternatives available, we reasoned that any sustained directional change in the ratio of Auto to Non-Auto represents a characteristic change in cancer specialist behavior over that span. The monthly ratios of Auto to Non-Auto were analyzed for trends by least squares and the slopes of each were contrasted by ANCOVA. RESULTS During the first six months, Auto-processed requests approximately equaled Non-Auto-processed request numbers, for a baseline ratio of one. Over the next 38 months, this ratio rose to approximately 1.4, meaning that 40% more requests were eventually approved automatically each month than those requiring MD review. The slopes of this relationship between Auto and Non-Auto approvals are statistically distinct (F = 43.34; p<0.001). CONCLUSIONS This progressive quality improvement reflects malleability of cancer doctor prescribing behavior, results in substantial savings, occurs quickly, persists and grows over time.