Jill Wechsler

In a highly unusual decision for a therapy approved by FDA, the Centers for Medicare and Medicaid Services (CMS) took action to limit prescribing and use of Biogen’s new and controversial Alzheimer’s treatment Aduhelm (aducanumab).

 The CMS National Coverage Determination (NCD) did this by applying its Coverage with Evidence Development (CED) requirement to the drug, utilizing a process that has been directed primarily in recent years to a limited number of approved medical products, mainly medical devices and diagnostics.

 If the proposal is finalized, only patients able to enroll in postapproval trials would have access to the drug.

The aim of the NCD process is to gather further evidence to demonstrate the drug’s potential for improving the health of patients suffering mild cognitive impairment due to Alzheimer’s disease. The CMS policy will authorize access to the drug only to those individuals able to enroll in a clinical trial, most taking place at academic research institutes that CMS will identify and list on its website. Under the accelerated approval granted Aduhelm by FDA’s Center for Drug Evaluation and Research (CDER) in June 2021, Biogen is required to conduct at least one Phase IV trial to demonstrate that the drug’s ability to reduce amyloid in the brain has a broader benefit for patients’ cognitive ability, and that drug’s serious side effects are limited. Biogen objected loudly to the CMS proposal, noting that it may take years to design and launch postapproval studies, and that such trials will enroll only a limited number of patients. CMS also indicates that its CED requirement will apply to additional monoclonal antibodies targeting amyloid beta in Alzheimer’s disease.

Aduhelm came to market last year amidst heightened controversy over its approval despite limited evidence of efficacy. The debate turned to outrage when Biogen set the price for the new treatment at $56,000 a year. At that level, Medicare spending on the drug was projected to far exceed any other drug if even just a small portion of some 6 million US Alzheimer’s patients sought treatment. In December 2021, after a year of dismal uptake of the drug, Biogen cut its launch price in half to $28,200 a year in an effort to boost prescribing—and avoid a negative NCD from CMS. However, even that reduced cost continued to promise hefty outlays for Medicare. Many leading health centers and physicians said they still would not prescribe the drug due to its limited evidence of efficacy, known side effects and continued too-high cost. The Institute for Clinical and Economic Review (ICER) calculated that Aduhelm would be cost-effective if priced at $3000 to $8000 a year.

In making national coverage decisions, CMS is supposed to evaluate whether a medical product or process is “reasonable and necessary” and not bring cost into the equation. But the fact that a very high number of Medicare patients are potential users of the new drug made that difficult.Before Biogen cut its price, CMS had announced a whopping 15% boost in premiums for the Medicare Part B program, which administers injectables such as Aduhelm. CMS had explained that about half of the premium increase was designed to protect the program against high spending on the new Alzheimer’s therapy. Following Biogen’s cost reduction, Health & Human Services (HHS) secretary Xavier Becerra said CMS would reassess the scope of the premium hike,

 although the uncertain financial health of the Medicare Trust Fund may deter any significant readjustment in rates.

CMS emphasizes that its CED decision arises from extensive review over the last six months of all relevant published evidence and feedback from stakeholders. The agency opted for the CED process to gain further evidence on whether this new therapy provides any improvement or relief from the effects of Alzheimer’s disease. CMS will accept further public comments on this proposal for 30 days and announce a final coverage decision by April 11, 2022. Alzheimer’s disease groups have called loudly for Medicare coverage of Aduhelm as the only available treatment for the widespread debilitating condition.

It will be interesting to see how the CMS proposal affects other biopharma companies that are testing their own Alzheimer’s therapies. Eli Lilly is conducting clinical trials that directly compare its donanemab to Aduhelm, while Eisai and Roche are moving forward with additional treatments. These and other sponsors now will have to calculate the impact of bringing new drugs to market that would be subject to CED requirements.

Meanwhile, the scientific and medical community continues to criticize the Aduhelm approval. The European Medicines Agency (EMA) recently recommended against approving the drug, and objections have been raised in Canada to a pending review. CMS has navigated its process to greatly limit Aduhelm prescribing and its outlays for the drug, but the debate is far from over.

https://www.cms.gov/newsroom/press-releases/cms-proposes-medicare-coverage-policy-monoclonal-antibodies-directed-against-amyloid-treatment

https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=Y&NCAId=305

https://www.hhs.gov/about/news/2022/01/10/hhs-secretary-xavier-becerra-instructs-cms-reassess-recommendation-2022-medicare-part-b-premium.html

Articles

In a highly unusual decision for a therapy approved by FDA, CMS has taken action to limit prescribing and use of Biogen’s new and controversial Alzheimer’s treatment Aduhelm.

Medicare Limits Aduhelm Coverage to Patients in Clinical Trials

Despite major challenges and demands created by the coronavirus pandemic, FDA maintained a steady pace in 2021 in approving important new therapies for market, including new vaccines and treatments for COVID-19. Last year saw the Center for Drug Evaluation and Research (CDER) approve 50 new molecular entities (NMEs), many benefitting from priority and accelerated review timelines. In addition, the Center for Biologics Evaluation and Research (CBER) approved several vaccines and cellular products to further expand the new medicines list.

The CDER total is slightly less than the 53 novel drugs brought to market in 2020 and the 2018 record total of 59 innovative therapies. As in recent years, a majority of the new products 

, and 15 had indications to treat cancer. More than half moved forward through expedited procedures, 14 benefitting from accelerated approvals and 32 granted priority reviews. Continued requests for faster vetting requires additional involvement of CDER experts to provide R&D advice and to meet tighter deadlines, which agency officials say cannot be sustained without additional review staff and resources. 

Despite similar pressures, CBER approved 10 biologics license applications (BLAs), notably one granting full approval for Pfizer/BioNTech’s Comirnaty vaccine. Some analysts include only about half of these in combined lists of FDA’s new NMEs, notably 

 for Hepatitis B and for tick-borne encephalitis and therapies for myeloma and lymphoma.

Probably the most discussed new drug is Biogen’s Aduhelm for Alzheimer’s disease, which CDER okayed for market despite limited evidence of its efficacy and a thumbs-down on approval from its advisory committee. FDA reviewers, however, decided its benefits outweighed risks, as no other treatment is approved for this very serious condition.

Other notable new therapies from CDER include treatments for myasthenia gravis, lupus, Pompe disease, severe asthma, sickle cell disease, to prevent dwarfism in children and to manage very high cholesterol. Lung cancer, endometrial cancer, and leukemia gained added treatment options, as did transplant patients.

The lists, moreover, do not include those innovative COVID therapies and vaccines granted emergency use authorizations (EUAs). In December 2021, FDA authorized two notable oral medications to treat early COVID infections—Pfizer’s Paxlovid and Molnupiravir from Merck and Ridgeback Biotherapeutics—providing a more accessible alternative to antivirals that require infusion in a clinic or doctors’ office. 

Analysts note that several additional new products failed to gain approval in 2021 due to FDA’s inability to conduct necessary inspections of certain manufacturing sites. That situation is unlikely to change any time soon as the agency has once again pulled back on inspectional activities due to the spread of the omicron variant to COVID-19.

Last July 2021, FDA revived efforts to ramp up inspections of domestic production facilities, an effort that made a notable dent in the agency’s sizeable inspection backlog for medical products. The hope was to visit most of the 3000 sites in need of oversight in 2022 and also to test a new program to enhance foreign inspection operations.

These goals were put on hold with the agency’s 

 that it would continue only mission-critical inspections through January 19, 2022, and postpone most other inspectional activities, including foreign site visits. Also delayed is the planning effort set to begin in February for revising foreign inspection assignments in an effort to address challenges in staffing overseas offices and rebuilding the cadre of U.S.-based inspectors willing to travel to foreign drug production sites.

A new report from CDER provides more complete information on new drug approvals for 2021, including certain existing therapies that gained important new uses and advances in biosimilars. Click here for the 

Meanwhile, FDA will continue to utilize remote tools to maintain oversight of foods, drugs, medical products and tobacco at home and abroad.

New therapies were approved at a steady pace in 2021.

FDA Keeps New Drugs Coming

FDA authorized emergency use of Pfizer’s oral antiviral drug Paxlovid on December 22, 2021, skipping the advisory committee review to make the drug available as quickly as possible. This decision was followed on December 23 with FDA providing similar authorization for Merck’s Molnupiravir, with certain restrictions due to questions raised as to its safety and efficacy during its 

 last month. These actions by FDA offer patients a take-at-home pill that can keep them out of the hospital at a time when the U.S. is being devastated by the spreading Omicron variant.

Pfizer’s Paxlovid (nirmatrelvir/ritonavir) gained 

 (EUA) from FDA for patients over age 12 experiencing mild-to-moderate COVID-19 infection as a way to prevent progression to more severe illness or hospitalization. The treatment is specified for use at early stage of infection and involves taking a packet of three pills taken twice daily for five days, adding up to 30 pills overall.

Being able to treat COVID-19 with a drug taken orally at home is “a major step forward in the fight against this global pandemic,” said Patrizia Cavazzoni, director of the Center for Drug Evaluation and Research (CDER). And the approval, she added, comes “at a crucial time in the pandemic as new variants emerge.” At the same time, FDA continued to emphasize the importance of vaccination in protecting individuals from COVID infection.

Despite concerns that the antiviral drug molnupiravir developed by Merck and Ridgeback Biotherapeutics may be less effective and riskier than the Pfizer treatment, FDA granted an EUA for the product to provide an additional option for treating patients (over 18 only) with early symptoms and in need of treatment quickly to prevent hospitalization or more serious disease. Cavazzoni stated that molnupiravir use should be limited to situations where other authorized treatments “are inaccessible or are not clinically appropriate.”

Merck’s drug ran into trouble at the Nov. 30, 2021, meeting of FDA’s Antimicrobial Drugs Advisory Committee, where concerns were raised about possible birth defects if used by pregnant women and potential damage to patients’ DNA. The drug suffered from data released just before the meeting that showed only a 30% decrease in hospitalizations, compared to 50% in preliminary results, a drop that the sponsors had difficulty explaining. Consequently, the panel recommended approving the drug by only a very slim margin.

However, scientists involved with the drug’s development and testing made the case for molnupiravir being a useful weapon in combatting COVID-19. An 

 in the New England Journal of Medicine Dec. 16, 2021 emphasizes that molnupiravir is an effective treatment that can reduce the risk of hospitalization or death in patients infected with COVID-19. The authors provide details on the clinical trials and analysis, including safety issues. A 

 summarizes these issues, noting that the drug has been licensed in the United Kingdom and may be particularly valuable in other markets.

Merck’s drug may be particularly helpful in the lesser developed countries where access to new therapies is limited. Merck has said it plans to make its patents available to the World Health Organization patent pool and to generic drug manufacturers so that it can be produced for developing countries at low cost. Similarly, Pfizer stated that it will provide the new drug through a tiered pricing program, where high-income countries will pay more than lower income countries. And the company has signed a voluntary license agreement with the Medicines Patent Pool to expand access to its oral antiviral treatment to 95 low- and middle-income countries.

The main factor clouding the immediate impact of these new drugs is limited supplies. Pfizer said that it planned to provide 10 million treatment courses “between 2021 and 2022,” as per a $5.3 billion advance purchase agreement with the U.S. government. The company also aims to produce 120 million courses of treatment in 2022 through expansion of its own manufacturing and 

 with contract manufacturers. But analysts count less than 200,000 courses of the pills now available, raising questions about how quickly the firm will be able to meet what is expected to be widespread demand.

Similarly, Merck has said it is ramping up production to expand its supply. The United Kingdom, where the drug was already authorized, is purchasing more than 2 million courses of treatment, and the company has an agreement to supply some 3 million courses of treatment to the U.S. Merck says it expects to produce 10 million courses of treatment by the end of 2021 and at least 20 million in 2022.

Pfizer’s Paxlovid has gained emergency use authorization at a time when the U.S. is being devastated by the spreading Omicron variant.

Here Come the COVID Treatment Options

As the nation awaits further decisions from the Supreme court on the legality of restricted abortion policies adopted by certain states, FDA has become embroiled in the debate over access to “chemical” or “medication” abortions through the prescribing and distribution of the abortifacient, mifepristone. The two-dose treatment to bring on a miscarriage of an early pregnancy was approved by FDA in 2000 with the requirement that patients receive the pill directly from a physician, with administration of the initial dose in the doctors’ office. That physician dispensing requirement has been contested by reproductive rights groups and state officials since 2017. In 2020, the in-person prescribing and dispensing requirement was lifted as part of efforts to reduce the need for patients to go to health care facilities during the pandemic.

Under pressure to determine whether to continue the use of telemedicine and remote office visits for prescribing mifepristone, FDA disclosed on December 16, 2021 that it would retain its more flexible prescribing policy, reflecting the broader adoption of telemedicine by public health programs. In this controversial decision, officials at the Center for Drug Evaluation and Research (CDER) said they would modify the Risk Evaluation and Mitigation Strategy (REMS) for mifepristone to remove the requirement for physicians to physically hand the drug to a patient.

 However, the agency retained the requirement that patients sign a special form to be prescribed the drug, and that clinicians pre-register and receive training under the REMS program. The rationale is that prescribing physicians should be able to date pregnancies accurately and provide any necessary surgical intervention or other treatment if needed.

At his Senate confirmation hearing this week, Robert Califf sidestepped a query on how he would prevent policies that permit abortifacient pills to be casually dispensed to patients, responding that he would rely on FDA staffers to “make good decisions.” Anti-abortion activists already are predicting that Califf will collaborate with Democrats and abortion advocates to speed the drugs to patients through the mail. Conversely, abortion rights groups plan campaigns to better inform patients of the availability of the drugs, their safety and proper use. In fact, medical abortions have risen in popularity, accounting in 2019 for 44 percent of pregnancy terminations by women who sought abortions in clinics before 10 weeks of pregnancy, according to data from the Centers for Disease Control and Prevention.

Meanwhile, states are acting on this issue. Last October, Texas added to its controversial six-week limit on surgical abortions another law that limits medication abortions to the first seven weeks of pregnancy, even thought mifepristone is considered effective for up to 10 weeks after conception. The Texas law also blocks sending the pills through the mail or prescribing the treatment through telemedicine.

At the same time, FDA faces high-profile decisions on whether to authorize over-the-counter access to birth-control pills, another policy change backed by reproductive rights groups. Several pharmaceutical companies have been conducting clinical trials to test the ability of patients to use contraceptives appropriately and safely without physician oversight, but the switch process has been slow. More recently, anti-abortion groups have entered the debate, claiming that decisions on such drug use should be made only in consultation with a physician.

https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/mifeprex-mifepristone-information

https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/questions-and-answers-mifeprex

FDA has become embroiled in the debate over access to “chemical” or “medication” abortions through the prescribing and distribution of the abortifacient, mifepristone.

FDA Caught In Abortion Battles

The Biden administration’s choice to lead FDA successfully navigated a Senate confirmation hearing on Dec. 14, setting the stage for full Senate approval early next year. The leading Republican on the Senate Health, Education, Labor and Pensions (HELP) committee, Sen. Richard Burr, praised the stellar academic and medical research credentials of his fellow North Carolinian, eliciting support from other Republicans on the panel. HELP Committee chair Patty Murray (D-Wash.) set the stage for a speedy conclusion to the vetting process and votes on Califf’s confirmation in early January.

The main opposition to Califf came from liberal Democrat Sen. Bernie Sanders (I-Vt), who questioned the nominee’s long ties to the drug industry and involvement in industry research that has generated high-priced medicines. At the same time, Califf received letters of support from six former FDA commissioners and a long list of academic, public health and patient organizations. The nominee, who headed FDA in 2016, said he would hit the ground running and noted the importance of working closely with Congress and other federal health agencies.

The main point of controversy during the two-hour hearing centered on FDA approval of opioids leading to the addiction and hundreds of thousands of deaths from drug overdoses. Califf promised irate Senators from New Mexico and New Hampshire that he would take a “very aggressive approach” towards opioids and conduct a “comprehensive review” of their status and labeling as a first order of business.

The Biden administration’s choice to lead FDA successfully navigated a Senate confirmation hearing on Dec. 14, setting the stage for full Senate approval early next year.

Califf Gains Bipartisan Support for FDA Confirmation

As Congress struggles to reach agreement on major legislation to fund leading administration social and spending initiatives and to raise the debt limit to avoid default on government borrowing, the White House is emphasizing that reduced spending on prescription drugs can help offset some of the steep costs. President Joe Biden highlighted how current proposals for curbing outlays on pharmaceuticals will help protect patients’ health and save the government billions in a 

 on strategies for controlling drug costs.

Even though Biden applauded the efforts by pharmaceutical companies in developing life-saving vaccines and treatments for fight COVID-19, he criticized industry for jacking up prices on medicines that have been on the market for years. This leaves Americans paying “the highest prescription drug prices of any developed nation in the world,” he stated, lamenting that many patients struggle to afford needed therapies as a result.

Biden pointed to provisions in the Build Back Better (BBB) bill, which is pending before the Senate, that would change the equation. To help all consumers afford medicines, the legislation would set a $35-a-month cap on cost-sharing for insulin for all patients, impose a stiff tax on manufacturers that raise prices faster than inflation, and expand access to health insurance and Medicaid.

And to reduce Medicare drug expenditures, the legislation would open the door to government negotiation of prices on certain older drugs, while also capping annual outlays for seniors at $2000 a year. These provisions were approved by the House following lengthy negotiations with moderates anxious to protect incentives for biopharmaceutical R&D. One result is that the current measure limits Medicare price negotiations to only 20 drugs that have been on the market enough years to have lost exclusivity.

Even so, there’s strong opposition to the drug pricing proposals from Republicans, and the provisions may need to be revised and narrowed to avoid violating Senate budget rules that limit the type of legislative changes eligible for consideration in spending bills. At the same time, a calculation by the Congressional Budget Office (CBO) that the drug pricing provisions would save the government about $160 billion over 10 years has built support for the package from Senate moderates who object to excessive federal spending. Senate majority leader Charles Schumer (D-NY) has set a goal of enacting the $1.7–$2 trillion BBB social-spending and climate change legislation by Christmas, but there’s a lot of skepticism on Capitol Hill about meeting that time frame. A more immediate deadline is for Congress to authorize an increase in the federal debt ceiling before it expires next week, a situation that continues to muddy the broader negotiations on spending and revenues.

President Biden highlighted how current proposals for curbing outlays on pharmaceuticals will help protect patients’ health and save the government billions.