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# New Proposed Rulemaking to the Common Rule, Recent FDA Approvals, NCCN's New Value Initiative, and more

December 30, 2021
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HHS Announces New Proposed Rulemaking to the Common Rule Protecting Human Subjects in Research

The U.S. Department of Health and Human Services (HHS) Office for Human Research Protections (OHRP) recently announced new proposed rulemaking (NPRM) amending the Federal Policy for the Protection of Human Subjects (also known as the Common Rule), the regulations that govern research on individuals who participate in clinical research.

The NPRM was issued in response to the changing social, cultural, and technological environment and is intended "to better protect human subjects involved in research by modernizing, strengthening, and making more effective" the Common Rule, which have been in place since 1991, according to a press release from the agency.

Proposed changes include:

• Strengthened informed consent provisions to ensure that individuals have a clearer understanding of the study's scope, including its risks and benefits, as well as alternatives to participating in the study
• Requirements for administrative or IRB review that would align better with the risks of the proposed research, thus increasing efficiency
• New data security and information protection standards that would reduce the potential for violations of privacy and confidentiality
• Requirements for written consent for use of an individual's biological samples, for example, blood or urine, for research with the option to consent to their future use for unspecified studies
• Requirement, in most cases, to use a single institutional review board for multisite research studies

The proposed rule would apply to all clinical trials, regardless of funding source, if they are conducted in a U.S. institution that receives funding for research involving human participants from a Common Rule agency.

For more details, and to read a full summary of the proposed changes, visit www.hhs.gov/ohrp/humansubjects/regulations/nprm2015summary.html.

"[The Common Rule] was developed at a time when research was predominantly conducted at universities, colleges, and medical institutions, and each study generally took place at a single site," the press release continued. "The expansion of research into new scientific disciplines, such as genomics, along with an increase in multisite studies and significant advances in technology, has highlighted the need to update the regulatory framework."

On October 20, 2015, OHRP held a public Town Hall meeting in order to respond to questions related to the NPRM. The NPRM is open to comments from the public until December 7, 2015. Go to www.hhs.gov/ohrp/humansubjects/regulations/nprmhome.html to voice your opinion.

Jerry Menikoff, MD, JD, director of OHRP, provided some examples of how the NPRM would better protect human subjects, including making consent forms clearer for individuals participating in research, allowing individuals more autonomy to decide how their DNA is used by de-identifying biospecimens, and making the IRB system more flexible and less burdened by bureaucratic processes.

One of the main topics of interest at the Town Hall meeting was the issue surrounding consent under the proposed reforms, particularly the language of the consent document.

Document examples will eventually be released to the public for analysis and feedback. OHRP hopes this will prompt institutions to pay more attention to protecting participants and better informing them if they are aware that OHRP will be developing examples of consent forms.

There were also many concerns about the proposed consent rules for the use of biospecimens. Panel members explained that two criteria would need to be met for IRB to waive consent: the IRB would have to be presented with a situation in which there would be a compelling need for the biospecimen to be used in the research, and the IRB would also have to determine that there would be no other biospecimen types that might be used in substitute for samples that could receive consent. Currently, NPRM does not have any specific regulations or guidance to help IRBs determine or identify what biospecimens or what research would be of absolute necessity in such a situation, and, as a result, invited comments from the public on this matter.

In addition, the panel noted that biospecimens used in research that is not geared to collecting information of individual participants would be exempt from expansion.

Another point of discussion was the protection of minorities and vulnerable populations; currently, there was no language included in the proposed reforms concerning this, but the panel members noted that a conscious decision was made to not address these issues yet. Instead, it was decided that the new structure of the Common Rule would be addressed first before subsequently creating protective language for such populations.

Sources: HHS press release, September 2, 2015; HHS, "NPRM 2015 – Summary.

To get the editor's take on these suggested changes, read this month's Editor's Corner, "Take My Leftover Tissue, Please!" by Mikkael A. Sekeres, MD, MS.

FDA Approves Idarucizumab as First Reversal Agent for Dabigatran

The U.S. Food and Drug Administration (FDA) granted accelerated approval for idarucizumab for patients who were taking the anticoagulant dabigatran and required a reversal of the drug's blood-thinning effects during an emergency situation.

Dabigatran was approved by the U.S. FDA in 2010 for the prevention of stroke and systemic blood clots in patients with atrial fibrillation and for the treatment and prevention of deep-vein thrombosis and pulmonary embolism. Idarucizumab is the first approved reversal agent that specifically works with dabigatran by binding to the drug compound to neutralize its effect.

The approval of idarucizumab was based on the results of three trials involving a total of 283 healthy participants who were taking dabigatran. In the patients who were also given idarucizumab (administered via intravenous injection), there was an immediate reduction in the amount of dabigatran measured in the participants' blood – lasting for a period of at least 24 hours. The most common treatment-related adverse event was headache.

In another ongoing study of 123 patients taking dabigatran who also received idarucizumab due to uncontrolled bleeding or an emergency surgery, the anticoagulant effect was fully reversed in 89 percent of patients within four hours of receiving idarucizumab. The most common treatment-related adverse events in this trial were hypokalemia, confusion, constipation, fever, and pneumonia.

The label for idarucizumab recommends that patients resume their anticoagulant therapy as soon as medically appropriate, according to their health-care provider's decision.

Source: U.S. FDA Press Release. "FDA approves Praxbind, the first reversal agent for the anticoagulant Pradaxa," October 16, 2015.

FDA Approves New Drug to Treat Hyperkalemia

The U.S. FDA has approved patiromer for the treatment of hyperkalemia. Patiromer, a powdered substance that patients mix with water and take orally, works by binding potassium in the gastrointestinal tract and decreasing its absorption.

"Too much potassium in the blood can lead to dangerous, even fatal, changes in heart rhythm," said Norman Stockbridge, MD, PhD, director of the division of cardiovascular and renal products at the Center for Drug Evaluation and Research at the U.S. FDA, in a press release from the agency. "It is important to have treatment options for hyperkalemia available to patients."

The approval of patiromer was based on clinical trials that evaluated its efficacy in lowering potassium levels in hyperkalemic patients with chronic kidney disease who were on at least one drug that inhibited the renin-angiotensin-aldosterone system. The most common treatment-related adverse events included constipation, hypomagnesemia, diarrhea, nausea, abdominal discomfort, and flatulence.

Patiromer carries a boxed warning because it binds many other orally administered drugs, which could decrease their absorption and reduce the effects. The warning recommends taking patiromer and any other orally administered medication at least six hours apart.

Source: U.S. FDA press release, "FDA approves new drug to treat hyperkalemia," October 21, 2015.

NCCN Unveils New Value Initiative, Releases Clinical Practice Guidelines

The National Comprehensive Cancer Network (NCCN) recently unveiled the NCCN Evidence Blocksâ„¢, a new tool for evaluating treatment decisions that enables physicians and patients to better understand cancer treatments and values. This new initiative will provide patients with guidance about the cost of drugs, in addition to treatment effectiveness, side effects, and evidence-based regimens.

Published in a new version of the NCCN Guidelines, the Evidence Blocks are a visual representation of five key value measures that provide important information about specific Guidelines recommendations:

• Efficacy of regimens
• Safety of regimens
• Quality and quantity of evidence for regimens
• Consistency of evidence for regimens
• Affordability of regimens

Previous guidelines from the NCCN did not consider cost in treatment recommendations, but the new guidance accompanying the NCCN's Evidence Blocks will include an additional set of information doctors can share with patients while discussing treatment options.

The guidance will not include actual treatment dollar figures or account for how much is covered by insurance, but instead will rank the drugs on a scale of 1 to 5 for affordability. The affordability measurement represents an estimate on the overall total cost of therapy, which includes acquisition, administration, inpatient versus outpatient care, supportive care, infusions, toxicity monitoring, antiemetics and growth factors, and hospitalization. The infographics also include supportive care indications, such as antinausea medicine, monitoring expenses, treatment of toxicity or side effects, and hospital or caregiver fees associated with a particular drug.

Sources: National Comprehensive Cancer Network, "NCCN to unveil oncology value tool at Oct. 16 press conference in San Francisco," October 16, 2015; National Comprehensive Cancer Network, "NCCN Unveils evidence blocks for CML and multiple myeloma," October 16, 2015; FiercePharma, "Cancer group fuels drug price debate with data comparing cost and effectiveness," October 14, 2015.

Bill Introduced in Senate Would Add Nurses, Physician Assistants to Open Payments Database

Though the 2010 Physician Payment Sunshine Act requires drug manufacturers and medical device manufacturers to disclose payments to doctors, dentists, chiropractors, optometrists, and podiatrists for any promotional talks, consulting, meals, and other interactions, loopholes in the law do not extend the requirements to nurse with advanced degrees and physician assistants – other health-care professionals with prescribing abilities. A recent bill was proposed by two U.S. senators to require companies to publicly disclose interactions with these health-care professionals as well.

The Provider Payment Sunshine Act was introduced by Senator Charles Grassley (R-Iowa) and Senator Richard Blumenthal (D-Conn.) and is drafted to go into effect beginning in 2017 and include physician assistants, nurse practitioners, clinical nurse specialists, certified registered nurse anesthetists, and certified nurse midwives.

Currently, no data are publicly reported on these health-care professionals, though in recent years, providers who are not doctors have been criminally charged with taking kickbacks. For example, in June, a nurse practitioner in Connecticut pled guilty to taking $83,000 from Insys Therapeutics in exchange for prescribing fentanyl for cancer pain. According to an analysis from ProPublica, nurse practitioners and physician assistants wrote approximately 10 percent of the 1.4 billion prescriptions in the Medicare Part D program in 2013. In addition, they wrote approximately 15 percent of all prescriptions nationwide – not just in the Medicare program – in the first five months of 2015. Sources: ProPublica, "Bill would add nurses, physician assistants to pharma payments database," October 8, 2015; Congress.gov, "S.2153 – Provider Payment Sunshine Act." Scientists Alter Genes to Produce More Red Blood Cells Researchers have developed a new method for manufacturing red blood cells from stem cells that involves turning off a single gene, according to an article published in Cell Stem Cell by Vijay Sankaran, MD, PhD, assistant professor of pediatrics at Boston Children's Hospital, and colleagues. This method leads to a roughly three- to five-fold increase in red blood cell yield compared with other laboratory methods. "There is a variation in SH2B3 found in about 40 percent of people that leads to modestly high red blood cell counts," Dr. Sankaran said in a press release discussing the study's findings. "But if you look at people with really high red blood cell levels, they often have rare SH2B3 mutations. That said to us that here is a target where you can partially or completely eliminate its function as a way of increasing red blood cells robustly." The researchers combined stem cells, powerful gene editing tools, and data from genome-wide association studies to develop the new, more cost-effective approach to red blood cell production. The researchers used RNA interference to turn down SH2B3 in donated adult human hematopoietic stem and progenitor cells (HSPCs) and from human umbilical cord blood. Upon turning off the SH2B3 with RNA interference, the HSPC's profile of cell production was skewed to favor red blood cells. Further analysis found that the laboratory produced red blood cells were almost indistinguishable from the control cells. The findings from this study has implications for other cell types, such as muscle and nerve cells destroyed by disease, they added. Current methods to force different kinds of stem cells to produce transfusion-grade red blood cells in a laboratory cost from$8,000 to $15,000 per unit of blood. Dr. Sankaran hopes his method will cost as low as$2,000 per unit.

Sources: Dana-Farber Cancer Institute press release, October 22, 2015; Giani FC, Fiorini C, Wakabayashi A, et al. Targeted application of human genetic variation can improve red blood cell production from stem cells. Cell Stem Cell. 2015 October 22. [Epub ahead of print]

FDA Approves First Factor X Concentrate to Treat Patients with Hereditary Factor X Deficiency

The U.S. FDA approved coagulation Factor X (human) for hereditary Factor X deficiency. Prior to this approval, no specific coagulation factor replacement therapy was available for this patient population.

Patients with the disorder are usually treated with fresh-frozen plasma or plasma-derived prothrombin complex concentrates to stop or prevent bleeding. The approval of coagulation Factor X (human), which works by activating enzymes to help with normal blood clotting in the body, increases treatment options for patients with this rare bleeding disorder.

Coagulation Factor X (human) is indicated for patients 12 years or older with hereditary Factor X deficiency for on-demand treatment control of bleeding episodes and for perioperative management of bleeding in patients with mild hereditary Factor X deficiency.

The drug's approval was based on the results of a multicenter, non-randomized study that included 16 patients with mild to moderate hereditary Factor X deficiency, who experienced a total of 208 bleeding episodes during the study, for the treatment of spontaneous, traumatic, or heavy menorrhagic bleeding episodes.

Coagulation Factor X (human) was also evaluated in five patients with mild to severe Factor X deficiency who underwent seven surgical procedures. The drug effectively controlled blood loss during and after surgery.

No safety concerns were identified in these studies.

Source: U.S. FDA Press Release, "FDA approves first factor X concentrate to treat patients with rare hereditary bleeding disorder," October 20, 2015.