為什麼孩子們必須等待數年才能獲得新藥 – 愛滋防治宣導-財團法人台灣紅絲帶基金會

AIDS Q&A

愛滋Q&A

為什麼孩子們必須等待數年才能獲得新藥

參與者短缺意味著兒科試驗需要更長的時間，對製藥公司的經濟激勵也更少。

資料來源：展望/2022 年 12 月 19 日/自然/財團法人台灣紅絲帶基金會編譯

圖片來源：Oli Winward

丹尼·本傑明 (Danny Benjamin) 的四個兒子，年齡在 14 至 20 歲之間，都參加了 COVID-19 疫苗的臨床試驗。其中兩人是美國第一批接種疫苗的兒童。北卡羅來納州達勒姆市杜克大學的兒科醫生本傑明說：「他們對這樣做非常興奮」。「他們已經將其發佈在他們的 Instagram 帳戶上」。

但同時擔任美國國家兒童健康與人類發展研究所兒科試驗網絡主席的本傑明認為，COVID-19 疫苗在兒童身上進行試驗的時間太長了。他認為，所有針對兒童的臨床試驗都應該在 2021 年 5 月之前完成，屆時一些國家已經為其成年人口接種了數百萬劑疫苗。相反，兒童試驗直到當年 3 月才開始，有些試驗至今仍未結束。他說：「如果我們在開發 COVID 疫苗的過程中保持道德和榮譽，而不是讓孩子再受苦一年，我們應該在 5 月之前完成所有兒童研究」。

《自然》期刊「展望」的部分：兒童健康

兒科臨床數據的短缺不僅限於 COVID-19。儘管這些年來針對兒童的試驗數量有所增加，但數據的缺乏仍在延遲藥物的兒科仿單，並使醫生對這些藥物對兒童是否有效或安全的信息知之甚少。

2008 年對瑞典醫院約 11,000 份兒童處方的分析發現，近一半是仿單標示外用藥，這意味著歐洲藥品管理局 (EMA) 尚未批准這些藥物用於兒科。樣本中年齡最小的兒童以最高的比例開出了仿單標示外藥物。「我們沒有更好的選擇」，瑞典哥德堡大學的兒科臨床藥理學家 Jenny Kindblom 說。

加利福尼亞州洛杉磯 Cedars-Sinai 的兒科胃腸病學家 David Ziring 說，這種方法的問題在於兒童不是小大人。「這些藥物對兒童身體的作用非常不同」，他說。如果沒有試驗來確定一種藥物應該如何用於兒童，「我們要麼使用 30 到 40 年之前效果較差的藥物，要麼嘗試使用最近批准的藥物並試圖向保險公司證明，儘管它沒有用於兒科的 FDA [美國食品和藥物管理局] 仿單，但我們認為它是安全有效的」，他說。

Ziring 說，成人批准的藥物通常至少需要七年時間才能被授權用於兒童。多年來，他一直提倡更快地批准藥物用於兒科，但收效甚微。「我們取得的進展很小」，他說。「我所屬的兒科專科醫生社區變得非常沮喪」。

Ziring 說，長期以來，製藥公司幾乎沒有動力緊迫地尋求兒科仿單。兒科試驗通常比成人試驗更慢且更昂貴，因為招募參與者更難，道德標準更高，而且賺的錢更少。

但在 2002 年，美國國會通過了《兒童最佳藥物法案》，根據該法案，進一步的營銷獨占權將激勵那些自願對美國食品和藥物管理局確定為優先藥物進行兒科試驗的公司。同樣，在 2007 年，歐盟出台了法規，以改善兒童藥物的可及性、提高產品信息的透明度並增加兒科研究的數量。

10 月，丹尼·本傑明 (Danny Benjamin) 的兒子斯科蒂 (Scotty) 參加了北卡羅來納州達勒姆杜克健康中心的輝瑞 COVID-19 疫苗試驗。圖片來源：杜克健康攝影

儘管針對兒童的臨床試驗仍然很少，但數據顯示它們正在增加。一項 2021 年的研究2發現，在 2008 年至 2010 年期間，在美國臨床試驗註冊中心 ClinicalTrials.gov 上註冊的兒科試驗剛剛超過 7,000 項。但在 2017 年至 2019 年間，這個數字增加到了 11,700 人左右。然而，這些試驗中的大多數都是小規模的、單一地點的，並且沒有得到美國國家衛生研究院或工業界的資助。 Ziring 認為，製藥公司和 FDA 將制定新的立法，以爭取早日批准兒科藥物。「兒科醫生能做的只有這麼多」。

但是有一些進展的跡象。 2020 年，濕疹藥物 dupilumab 成為第一個被批准用於 6 歲及以上兒童的生物藥物，距離它獲得成人使用批准僅三年。今年 6 月，法國跨國製藥公司賽諾菲和美國生物技術公司 Regeneron 開發的這種療法擴大到六個月大的兒童。「不知何故，他們能夠最有效地招收大量兒童」，齊林說。「向他們致敬」。他補充說，該批准顯示藥物的早期兒科標籤是可能的。「如果製藥公司做出承諾並且他們與 FDA 密切合作」，他說，「那是非常可行的」。

成功的障礙

製藥商缺乏在兒童身上測試治療的動力並不是兒科試驗很少見的唯一原因。即使對於積極進取的研究人員來說，開展兒科試驗也很困難。

首先，兒童試驗更難獲得倫理認可。澳大利亞雪梨大學的學術兒科醫生帕特里娜·考德威爾 (Patrina Caldwell) 說，要使一項試驗被認為是合乎道德的，兒童參與試驗所面臨的風險必須不超過他們在日常生活中所經歷的風險。這導致一些公司將他們的試驗轉移到低收入國家，這些國家的兒童被認為每天面臨更大的風險，因此設定的門檻較低。「有時，製藥公司會前往發展中國家，以跳過道德困境」，考德威爾說，但她認為，將較貧窮兒童的生命視為不那麼有價值是不道德的。此外，她補充說，低收入國家的試驗通常被認為審查不那麼嚴格，進行起來也不那麼有力，因此高收入國家的監管機構可能不會接受結果。

考德威爾說，兒童試驗的更高道德標準意味著即使是簡單的測試和監測進展的程序也可能更加複雜。「在成人試驗中，你可以很容易地進行血液測試，但在兒科試驗中，你必須證明你為什麼需要這樣做」，她說，因為這些測試被認為對兒童更具侵入性和痛苦。

即使試驗獲得批准，也很難找到志願者。兒童疾病比成人少見，因此可供選擇的人群較少。為了招募足夠的兒童，試驗通常必須在多個地點同時進行。「進行多中心研究很複雜，因為它涉及不同的監管系統、研究中心、不同的規章制度以及不同的政府」，Caldwell 說。「這本身就是一場噩夢」。

考德威爾說，提供金錢獎勵以鼓勵參與是提高成人試驗數量的一種常見方式，但在兒童試驗中卻存在爭議，因為如果父母僅僅為了物質利益而讓孩子報名參加，這一過程可能容易被濫用。在許多國家——例如澳大利亞——倫理委員會不允許支付兒童參與試驗。

考德威爾說，另一個問題是父母經常擔心實驗藥物可能導致的長期副作用。她回憶起父母曾問：「如果有一天這種藥物被證明會致癌，當他們 60 歲時他們得了癌症，他們會因為我讓他們在年輕時參與的事情而責備我呢」？

來自《Nature》期刊 Outlooks中更多的部合

然而，考德威爾說，一旦她解釋說兒童試驗通常沒有安慰劑組，這與成人試驗不同，她通常不會很難說服父母。相反，兒童試驗通常使用所謂的臨床平衡——測試兩種治療方法以確定哪種更有效。考德威爾說：「要使對兒童的試驗符合道德標準，就需要保持平衡」。她說，解釋這一點傳達了不確定性，同時給予父母做出決定所需的自主權。當孩子患有危及生命的疾病時，父母知道他們的孩子將接受至少一種可能有效的治療而不是安慰劑會更加安心。

儘管總體上缺乏兒童參與者參與研究，但一旦可以參與的孩子的父母被說服，那麼孩子的加入率確實往往高於成人試驗。 Caldwell 指出，患有白血病的兒童的存活率已顯著提高。成年人的健康結果遠沒有那麼高。「它基本上顯示了試驗的力量」，她說。

更重要的是，研究顯示，與未參與任何試驗的參與者相比，參與試驗的參與者——無論他們屬於哪個研究組——的健康結果更好。這個被稱為霍桑效應的概念顯示，當人們知道自己被監視時，他們的行為會有所不同，因此與非參與者相比，參與者更有可能過上健康的生活方式。

進行試驗的人需要仔細解釋風險和好處，並且必須自己確定參與對個人來說是正確的事情。「招募試驗的人必須真正相信試驗」，考德威爾說。

最終，她認為政府可能需要直接介入以資助更多的兒科研究。「孩子們自己沒有研究數據是不公平的，因為如果不賺錢，人們就不會去做」。

《自然》612，S54-S55（2022 年）；doi: https://doi.org/10.1038/d41586-022-04346-4

本文是《自然展望：兒童健康》的一部分，關於這個內容，是一份在第三方資助下製作的獨立編輯增刊。

參考文獻：

1.Kimland, E., Nydert, P., Odlind, V., Böttiger, Y. & Lindemalm, S. Acta Paediatr. 101, 772–778 (2012).

2.Zhong, Y., Zhang, X., Zhou, L., Li, L. & Zhang, T. BMC Pediatr. 21, 212 (2021).

3. Caldwell, P. H. Y., Murphy, S. B., Butow, P. N. & Craig, J. C. Lancet 364, 803–811 (2004).

4.McCarney, R. et al. BMC Med. Res. Methodol. 7, 30 (2007).

Why children have to wait years for new drugs

A shortage of participants means that paediatric trials take longer and there is less financial incentive for pharmaceutical companies.

OUTLOOK/19 December 2022/Nature

Credit: Oli Winward

All four of Danny Benjamin’s sons, aged 14 to 20, took part in clinical trials of COVID-19 vaccines. Two of them were among the first children in the United States to be vaccinated. “They’re super pumped about having done that,” says Benjamin, a paediatrician at Duke University in Durham, North Carolina. “They’ve posted it on their Instagram accounts.”

But Benjamin, who also chairs the National Institute of Child Health and Human Development’s Pediatric Trials Network, thinks that it took too long for the COVID-19 vaccines to be tested in children. He thinks that all the clinical trials on children should have been completed by May 2021, by which point some countries had already administered millions of doses to their adult populations. Instead, trials in children didn’t even start until March that year, and some still haven’t concluded. “We should have had all the children’s studies done by May if we’d been ethical and honourable about how we developed COVID vaccines, rather than have children suffer for another year,” he says.

Part of Nature Outlook: Children‘s health

The shortage of paediatric clinical data is not limited to COVID-19. Although the number of trials in kids has increased over the years, lack of data is still delaying paediatric labelling of drugs and leaving physicians with little information about whether the drugs are effective or safe in children.

An analysis of around 11,000 prescriptions for children at Swedish hospitals in 2008 found that nearly half were off-label, meaning the medicines were not yet approved for paediatric use by the European Medicines Agency (EMA). The youngest children in the sample were prescribed off-label medicines at the highest rate. “We don’t have a better alternative,” says Jenny Kindblom, a paediatric clinical pharmacologist at the University of Gothenburg in Sweden.

The problem with that approach, says David Ziring, a paediatric gastroenterologist at Cedars-Sinai in Los Angeles, California, is that children are not small adults. “The drugs act on children’s bodies very differently,” he says. Without trials to determine how a drug should be used in children, “we’re left using either drugs that are 30 to 40 years old and less effective, or trying to use the most recently approved drugs and trying to justify to insurance companies that, despite its lack of an FDA [US Food and Drug Administration] label for paediatrics, we feel that it would be safe and effective,” he says.

It usually takes at least seven years for adult-approved drugs to be authorized for use in children, Ziring says. For years, he has been advocating for drugs to be approved for paediatric use faster, but to little avail. “We’ve made very little progress,” he says. “The community of paediatric sub-specialists that I belong to has become very frustrated.”

For a long time, there was little incentive for pharmaceutical companies to pursue paediatric labelling with any urgency, Ziring says. Paediatric trials are generally slower and more expensive than adult ones because it is harder to recruit participants, the ethical bar is higher and there is less money to be made.

But in 2002, the US Congress passed the Best Pharmaceuticals for Children Act, under which further marketing exclusivity is given as an incentive to firms that voluntarily conduct paediatric trials on drugs identified as a priority by the US Food and Drug Administration. Similarly, in 2007, the European Union brought in regulations in a bid to improve access to medicines for children, increase transparency around product information and boost the amount of paediatric research.

In October, Danny Benjamin’s son, Scotty, participated in a Pfizer COVID-19 vaccine trial at Duke Health in Durham, North Carolina.Credit: Duke Health Photography

Although clinical trials in children remain few, data suggest that they are on the rise. A 2021 study2 found that between 2008 and 2010, just over 7,000 paediatric trials were registered on the US clinical trial registry ClinicalTrials.gov. But between 2017 and 2019, this figure had increased to around 11,700. However, most of these trials were small-scale, single-site, and not funded by the US National Institutes of Health or by industry. Ziring thinks it will take new legislation for pharmaceutical companies and the FDA to work towards earlier approval of paediatric medicines. “There’s only so much that paediatricians can do.”

But there are some signs of progress. In 2020, the eczema drug dupilumab became the first biologic medicine to be approved for children aged six and up, just three years after it won approval for use in adults. And in June this year the therapy, made by French multinational pharmaceutical company Sanofi and the US biotechnology firm Regeneron, was extended to children as young as six months. “Somehow they were able to most efficiently enrol a very large cohort of children,” Ziring says. “Hats off to them.” The approval shows that early paediatric labelling of drugs is possible, he adds. “If there’s a commitment from pharma and they work closely with the FDA,” he says, “that is very doable.”

Obstacles to success

Lack of incentives for drug makers to test treatments in children are not the only reason that paediatric trials are few and far between. Even for motivated researchers, getting a paediatric trial off the ground can be tough.

First, it’s harder to obtain ethical approval for children’s trials. For a trial to be considered ethical, the risk to the child from participating has to be no greater than the risks that they experience in their everyday life, says Patrina Caldwell, an academic paediatrician at the University of Sydney in Australia. That has led some companies to move their trials to low-income countries, where children are considered to be exposed to greater risk on a daily basis and the bar is therefore set lower. “Sometimes drug companies have gone to developing countries to jump through the ethical hoops,” Caldwell says, but she thinks it is unethical to treat the lives of poorer children as less valuable. Besides, she adds, trials in low-income countries are often said to be reviewed less rigorously and conducted less robustly, so results might not be accepted by regulators in high-income nations.

The higher ethical bar for children’s trials means that even simple tests and procedures to monitor progress can be more complicated, says Caldwell. “In an adult trial, you can just do a blood test pretty easily, but in a paediatric trial you’d have to justify why you need to do it,” she says, because the tests are considered more invasive and distressing for children.

Even if the trial is approved, it can be difficult to find volunteers. Childhood diseases are rarer than those in adults, so there are fewer people to choose from. To recruit enough children, trials often have to be run concurrently in several locations. “There are complexities to doing multicentre studies because it involves different regulatory systems, research centres, different rules and regulations, and different governments,” Caldwell says. “That in itself is a nightmare.”

Offering monetary incentives to encourage participation is a common way of boosting trial numbers in adults, but it is controversial in children’s trials because the process could be prone to abuse in cases in which parents enrol their children solely for material gain, Caldwell says. In many countries — including Australia, for example — ethics committees do not condone paying children to participate in trials.

Another problem is that parents are often worried about the possible long-term side effects that could result from experimental drugs, Caldwell says. She recalls parents asking: “What if one day this drug is proven to cause cancer, and when they’re 60 they have cancer and they blame me for something I let them be part of when they were younger?”