医薬品の迅速承認制度に関する問題点に関して

Will the FDA change how it vets drugs following the Alzheimer's debacle?

The accelerated approval of aducanumab has triggered US lawmakers to push for more oversight from the agency.

アデュカヌマブ（英: Aducanumab、商品名：アデュヘルム、Aduhelm）は、アルツハイマー病（AD）の治療に用いられる医薬品である。本剤は、アルツハイマー病患者の脳内に見られるアミロイドベータ（Aβ）の凝集体を標的として、その蓄積を抑えるアミロイドベータ指向性モノクローナル抗体である。アメリカ合衆国（米国）のバイオジェン社と日本のエーザイにより開発された。アデュカヌマブは、米国食品医薬品局（FDA）により2021年6月に医療用として承認された。その際、本剤が有効であるという証拠がないことから、3人のFDAアドバイザーが辞任するという非常に議論を呼ぶ決定がなされた。FDAは、本剤はアルツハイマー病の治療薬として承認された最初の治療法であり、2003年以降、この疾患に対して承認された初めての治法薬であると述べている。アデュカヌマブの承認は、その有効性を巡る曖昧な臨床試験結果のために議論を呼んでいる。2020年11月、FDAの外部専門家委員会は、アデュカヌマブの重要な試験について、有効性に疑問があることやデータ解析に複数の「危険信号」が見つかったことを理由に、薬の効果を示す「強力な証拠」を示すことができなかったと結論付けた。とはいえ、この薬はFDAの迅速承認制度（英語版）の下で承認されており、FDAはバイオジェン社に対して、この薬がアルツハイマー病の治療に役立つかどうかを確認するための追跡調査を行うことを要求している。米国監察官は、本剤の承認前の製薬会社とFDAの間のやりとりを調査するよう要請された。

今回の問題は、迅速承認制度（医薬品が仮免許を受け販売する）と、仮免許から本免許への移行のプロセスに関わるもの（仮免許から本免許に移行する医薬品もあるが、仮免許取り上げというケースもある。ただ、結論が出るまでは、販売し続ける事が可能なのが問題。医薬品メーカーも仮免許さえ取得してしまえば、本当の有効性・安全性のデータを取得することに消極的になる。）。今回、塩野義の経口コロナ医薬品が、まさにこれに該当。まだ、審査中で、仮免許は降りていないが、仮免許が下りたら、塩野義は積極的に販売してくるだろう。そもそも、迅速承認制度というものは、治療薬のない、致死的疾患に対して適応されるべきものであるが、今回の塩野義の経口コロナ医薬品は、迅速承認制度にはそぐわない医薬品だと私は思う。

わたしのnoteにおいては、最新の科学・経済・社会等の問題に関して、英語の記事を引用し、その英文が読み易いように加工し、「英語の勉強ツール」と「最新情報収集ツール」としてご利用頂くことをmain missionとさせて頂きます。勿論、私論を書かせて頂くこともしばしです。

Max Kozlov / 13 May 2022 / nature news

Nearly a year after the US Food and Drug Administration (FDA) gave the green light to a controversial drug to treat Alzheimer’s disease, lawmakers are attempting to amend the process that led to its approval.

The House Committee on Energy and Commerce, which oversees drug safety and biomedical research, announced last week that it hopes to grant the FDA greater authority to rescind (取り消す、撤回する/risínd) accelerated approvals if a company fails to complete follow-up studies on the treatment in a reasonable amount of time.

The provision, which was introduced as part of an FDA funding reauthorization bill, likely to be passed before September, comes on the heels of (～に続いて起こる、～の直後に起こる) the agency’s 2021 approval of aducanumab, an antibody drug shown to reduce the accumulation of plaques in the brain associated with the progression of Alzheimer’s. Despite a nearly unanimous vote against the approval by an independent panel of experts, the agency fast-tracked the drug, which was developed by Biogen, a biotechnology company based in Cambridge, Massachusetts. Three advisory-panel members resigned in protest against the decision, and the approval is the subject of multiple investigations by federal regulators.

Aducanumab is not the only reason that this drug-approval pathway is coming under fire: since its inception (始まり、開始、発端/insépʃən), the programme has led to 279 treatments reaching the market, with nearly two-thirds in the past decade alone (see ‘Growing momentum for accelerated approval’). The programme’s increasing popularity signals a shift away from its original intent, says Diana Zuckerman, president of the National Center for Health Research, a non-profit organization in Washington DC. “Accelerated approval started out as a special programme for a small number of drugs, and now most cancer drugs are going through accelerated or some other expedited pathway,” she says.

Companies, moreover, have been slow to produce the follow-up studies promised as part of the approval process. The FDA has limited power to compel them to provide the data, but the legislative proposal — which could still change significantly as it wends its way (向かう) through the House of Representatives and the Senate — could grant it (FDA) more authority to do so.

Days before his appointment in February, FDA commissioner Robert Califf　pledged to make accelerated-approval reform a priority for the agency. Researchers who spoke to Nature agree that reforms are needed to protect the integrity of the programme, and that the proposed legislation is a good start. But they also recommended more agency oversight and other changes that would further prevent pharmaceutical firms from abusing this route to the market.

“Instead of the drug companies living up to and working to ensure that they are employing the accelerated-approval pathway as intended, we have too many (drug companies) that are willing to take advantage of the loopholes (抜け穴、抜け道/lúːphòul) where they can find them,” says David Mitchell, president of Patients for Affordable Drugs, a non-profit organization in Washington DC, who serves as a consumer representative on the independent panel that reviews cancer drugs for the FDA.

The need for speed

The FDA created the accelerated-approval pathway in 1992, largely in response to the HIV–AIDS crisis, to get urgently needed drugs to the market without delay. Instead of demonstrating efficacy through clinically-meaningful endpoints (primary endpoints : 主要評価指標), such as patient survival or reduction of symptoms, drug candidates reviewed under this pathway often rely on what are known as surrogate endpoints (副次的評価指標), which may be faster or easier to track than conventional clinical-trial endpoints. For example, tumour shrinkage is a common surrogate used in cancer-drug clinical trials, but this metric is not necessarily linked to a direct benefit to patients (要は、tumour shrinkage の効果が認められても、それ自体が患者の生存期間を延ばしたり、生活の質を高めたりすることを保証するものではないということ。).

Gregg Gonsalves, an epidemiologist and global health specialist at Yale University in New Haven, Connecticut, was among the group that persuaded the FDA to adopt this programme. “We pushed for this accelerated approval pathway because people were dying,” he says. “I’m HIV positive, so I get the desperation and need for hope.”

The pathway has turbocharged the number of immunotherapies and cancer treatments on the market. But some of these drugs cost hundreds of thousands of dollars per year, despite, in many cases, limited data showing their clinical utility. Gonsalves argues that the programme has been co-opted by the pharmaceutical industry to speed approvals. Cancer treatments approved through the pathway have made it to market on average about three years earlier than they would through standard routes. And a single study using surrogate endpoints could be enough to get a treatment on the market.

Part of the problem, says Caleb Alexander, an internal-medicine specialist and epidemiologist at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, is that drug companies aren’t upholding their end of the bargain (約束を守る) with timely post-market studies confirming the benefits of the drug (市販後速やかに薬のbenefitsを確認する). Some researchers question whether companies are given too much time to produce such data. A 2021 analysis found that 13% of drugs granted accelerated approval between 1992 and 2016 hadn’t been converted to full approval within five years — and remained on the market for a median of 9.5 years without the data needed for conversion.

The FDA granted Biogen nine years to complete its confirmatory trial on aducanumab — a timeline that Alexander calls “frankly offensive (イライラする)”. Biogen has since said it will complete the trial in four years, and a spokesperson for the company says that data from the trial — not yet published or peer-reviewed — show a slowing in clinical decline for some people who are taking the drug.

Post-market trials can take a long time, especially for slowly-progressing conditions such as neurodegenerative diseases, says a spokesperson for the Rare Disease Company Coalition, an organization in Washington DC that represents 21 pharmaceutical firms.

It is also difficult for companies to recruit participants, because people would much rather be guaranteed an approved medicine than risk getting a placebo. Instead of demanding that a company stop selling a drug that hasn’t been converted to full approval, says Zuckerman, the agency often requests that the company voluntarily withdraw it from the market. “The FDA loses an enormous amount of leverage once a product is approved,” says Alexander.

For example, in 2011, the FDA revoked its accelerated approval of the antibody drug bevacizumab to treat breast cancer, citing a lack of clinical benefit. This resulted in public backlash as people with breast cancer gave emotional testimonies in an attempt to keep the approval in place. For many people, accelerated approval offers a “valuable source of hope”, noted the National Organization for Rare Disorders, a non-profit organization in Danbury, Connecticut, in a 2021 report. But Mitchell, who has multiple myeloma, argues: “It is not the FDA’s job to give me hope. Hope is not what keeps me alive. It’s drugs that are safe and effective.”

Jeremy Kahn, a spokesperson for the FDA affirmed in an email that the agency is committed to ensuring the integrity of the accelerated-approval programme and noted that the agency believes people who lack treatment options for serious diseases are willing to "accept some uncertainty" in clinical benefit for new treatments. Clinical benefit has been verified in the vast majority of accelerated approvals, he added.

Changing rules, same problems

The accelerated-approval programme has served as a model for other countries. But adopters including the European Union and Japan have given drug regulators more authority. Regulators can require companies to submit data from confirmatory trials in a set time period; if they do not, their approvals can be withdrawn.

How effective the proposed rule changes for the US FDA would be is unclear. Although they would make it easier for the agency to withdraw approval, they would also lengthen the bureaucratic process of rescinding (取り消す、撤回する/risínd) approvals. This defangs (無力化する) the provision, Zuckerman says. She would have preferred to stick with an earlier proposal, which would have automatically revoked approvals once confirmatory trials were one year overdue.

Zuckerman also recommends that the FDA commissioner’s office create a separate independent advisory group to review agency approvals that go against advisory panel recommendations — as happened for aducanumab. “The vast majority of advisory-committee votes recommend approval, so when they don’t recommend approval, there’s usually a really good reason,” she says.

Alexander suggests using health-care coverage as leverage. The US Centers for Medicare & Medicaid Services (CMS) in Baltimore, for example, decides which treatments will be funded for tens of millions of US residents. Earlier this year, concerned about the efficacy of aducanumab, the CMS stated that it would cover the annual US$28,800 cost of the drug only for people enrolled in clinical trials.

Although that decision is nearly unprecedented, Alexander thinks that the CMS should consider a lower reimbursement rate for other accelerated-approval treatments that have not yet gained full approval. Such a move could “light a fire underneath manufacturers” to complete their trials, he says. “Why should taxpayers be on the hook (困難な立場に置かれて) for paying the full price of a drug when we don’t know the full scope of its safety and effectiveness?” he asks.

But Mitchell worries that cutting reimbursement would remove companies’ incentive to produce potentially life-saving medication. He credits three accelerated-approval drugs with keeping him alive after his myeloma diagnosis.

Mitchell considers the aducanumab debacle a “blip (ささいなこと)” in the grand scheme of accelerated approvals, but says it has brought more attention to the need for confirmatory trials for some drugs. Reform won’t be simple. Once a medicine enters the market, Mitchell says, “drug companies aren’t anxious to find a reason to take it off”.

Still, many researchers and drug-safety advocates are eager to see change. “We started out trying to fix a pendulum that was too far in one direction,” says Zuckerman, “and look how far we’ve come in this direction now.”