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    商業

    新藥在商業失敗了,就不再有價值了嗎?

    Mike Rea, Eneida Pollozi 2019年08月14日

    在制藥行業,“失敗”這個詞既被濫用了,同時也沒有得到足夠的重視。

    對于制藥行業來說,失敗是一件不可避免的事。沒有一次次的失敗,我們就不可能知道人工干預健康或疾病是一件多么困難的事。因此,我們預期的目標不斷因為各種意外而落空,也就不是什么奇怪的事了。

    在制藥行業,“失敗”這個詞既被濫用了,同時也沒有得到足夠的重視。乍一看,這似乎是顯而易見的。當失敗發生時,大家的借口都是:“我們努力了,但沒有成功。”

    為什么會有這么簡單的失敗觀?這與對我們對藥品研發的成功率,以及對新藥成功上市的難度(以及成本)的一般估計不無關系。新藥開發的成功率會直接影響到行業“保護創新”的需求。假設在當前體制下,我們每年只能夠上市40到50種新藥。徜若我們又降低了這個成功率,會發生什么呢?

    制藥企業一提起“損耗”一詞,就好像損耗總是巨大的、不可避免的且不可預測的。不過我們不妨設想一下,如果有一名服務員,他在給你上菜的過程中,連續打碎了4個盤子,第5盤菜終于沒有打碎,不過他卻可以理直氣壯地把前面4盤菜的價格也算到你的飯錢里,那他還有什么動機去練習上菜的技術呢?

    乍一看,這個類比似乎站不住腳——這些菜已經做出來了,并且交到了服務員的手上,并非沒有做出來。不過如果這位服務員覺得這些菜不值得給客人上,因此決定將它們留在廚房里,又會發生什么呢?(當然,你還是得給所有這些沒有上的菜付錢。)

    就這一點,我們從藥物第三期臨床試驗的失敗數據中,可以看出一些有意思的東西——第三期臨床試驗也是藥物測試成本最高昂的階段。從2008年到2017年的10年間,有420次藥品的第三期臨床試驗以“終止、暫停或停藥”告終。(另有350次試驗以“未指明或其他”為理由叫停了試驗。”

    在以上試驗中,有整整三分之一的“失敗”是由于參與者數量或試驗完成率過低導致的。超過四分之一(27%)的失敗是由于藥品功效不足——藥效未顯著超出安慰劑效應或比較療法(這個比例比因為不良反應或副作用而失敗的比例高出兩倍多)。那么,有多少盤子是在服務員的手上摔碎的?答案是,有51次失敗由于“商業/戰略決策”導致的。(當然,這些數據可能隱藏了大量的模糊定義,所以我只能指出一個大概方向,而不可能給出十分精確的數字。)

    By necessity, pharma embraces, or wraps itself in, failure. It is where we measure the difficulty of intervening in the biological complexity of health or illness, so it is perhaps unsurprising that our intended consequences are continually humbled by the unintended.

    The word ‘failure’ is both overused and under-challenged in pharma. At first glance, it seems such an obvious concept – “We tried, but didn’t succeed.”

    But the simple notion of failure sits behind our common understanding of success rates in drug development, and how difficult (and therefore expensive) it is to even get one medicine to market. That ratio is at the core of industry demands to “protect our innovation.” If we launch only 40-50 new medicines per year in the current system, just imagine what might happen if we start to lower the reward, the thinking goes.

    The word “attrition” is used as if losses are inevitable, massive, and unpredictable. However, if your waiter drops 4 of the 5 plates he is bringing to your table, but is able to load the cost of all 5 onto the bill for the appetizer that does make it, it might be reasonable to ask what incentive there would be to improve his carrying skills.

    At first glance, the analogy falls down – these dishes have already made it into the waiter’s hands, rather than failing in development. But what if our waiter decided just to leave them there under the kitchen hot lamps, because, well, it just isn’t worth it to bring them to you? (Oh and, by the way, you’re still paying the big check regardless.)

    On that note, here’s something interesting in the figures from the most expensive phase of drug R&D – discontinuations in late-stage, phase 3 clinical trials. In the 10 years from 2008 to 2017, 420 pharma phase III trials cited “termination, suspension, or withdrawal” (another 350 gave “unspecified or other” as their toe tag for their would-be drugs).

    Fully one third of the “failures” were for low trial recruitment and completion rates. More than one in 4 (27%) failed for lack of efficacy – the drug worked no better than placebo, or a comparator treatment (that’s more than twice the number that failed for adverse events or side effects). Those ultimately doomed plates that made it to the waiter’s hands? 51 of the terminations were for “Business/Strategic Decision.” (These data can of course hide a great deal of “definition” murk, so I am using them directionally, rather than as numerically accurate.)

    Source: GlobalData

    很多試驗竟然是因為招不到足夠的病人導致的,我們不禁好奇為什么會發生這種事。原因有很多,有的是因為外包機構(也就是那些給制藥公司干雜活的第三方公司)做了過度承諾,有的是因為試驗本身缺乏真正需要滿足的醫療需求,有的是因為難以將病人送到試驗地點,還有的可能是由于某份研究將試驗的對照組置于了不利地位。

    (另外,還有一種人們可能意想不到的后果:我們習慣于尋找一種藥物的潛在療效的純粹“信號”,但同時我們也應該意識到,真正世界的用藥并非這樣簡單——它還必須不能給真實的、活生生的病人造成傷害。)

    以上這些數字,代表的并非是失敗,而是機會。我們沒有理由認為這些藥品都是無效的,或是都是不安全的——它們只是沒有被批準。

    為了檢驗一種試驗性療法的效果,試驗的失敗率往往是驚人的。藥品的早期研發階段往往只是為了尋找某種藥品是否有效的一個極微小的信號,制藥公司仍然需要開展大規模的三期測試,以試驗藥品的效果是否足夠好。我們必須對我們的期望抱小心謹慎的態度。當然,如果我們在三期測試里只搞一些“簡單”的研究,將失敗率降到0%也不是沒有可能。但沒有人想要這種試驗。

    同樣,0%的成功率對我們所有人來說也是災難性的。不過,“飛魚”菲爾普斯游泳是一把好手,讓他玩潛水可能并不在行。同理,一種藥品在三期測試中失敗了,是否等于說它一定不是一種好藥呢?一個問題換另一種問法,會不會得到不同的答案?

    在我們這些希望制藥行業能夠向患者提供更多藥品(同時希望新藥上市的速度更快、成本更低)的人看來,“商業/戰略決策”一項自然就成了一個值得研究的類別。請注意,這個類別跟財務問題無關,跟“因為缺錢而失敗”不是一回事。這些藥品之所以被制藥企業擱置了,是因為企業覺得與它們的營銷成本和開發它們的機會成本(比如沉沒成本、持續成本等)相比,它的潛在回報太低。如果擴大價值的外延,我們必須承認,在這一類別的藥品中,也包含了能夠為病人提供價值的藥品。

    一筆資產不符合公司的戰略方向,原因可能有很多——比如公司決定朝著某個特定方向發展,或者公司決定退出某個特定的治療領域。再或者公司在該領域研制的幾種藥品都有效果,公司只能決定保留其中希望更大的一個。

    無論是以上哪種情形,這些藥品都可能是對患者有用的藥品。如果一種藥品為了給另一種藥品讓路而不得不被束之高閣,我們惋惜之余,不禁會想:有沒有別的辦法可以繼續研究這種藥品?要知道,在制藥行業的歷史中,很多成功的藥品在研發階段都有過“假失敗”的歷史。(可能要比那些靠胡蒙瞎猜的“專家”們愿意承認的還要多。)

    一種完美的藥品“由于商業計劃而失敗”的原因有很多,比如如果它的賺錢前景不夠理想,公司就有可能將它裁掉。比方說,一家公司對一筆資產的預期回報是每年10億美元。如果預計達不到這個回報率,公司就沒有動力推動這個研發項目。不過,在藥品上市之前,即便預期收益再樂觀,也經常會被現實狠狠地抽一記耳光——反之也是如此,預期中的冷門藥熱賣的情況也不是沒有。所以,光靠推測一種藥物一年能不能賣出10億美元就去給它判死刑,并非明智的做法。這種藥品可能是該領域里最好的甚至唯一的藥品,但很多這種藥品,卻因為被錯誤地認為沒有遠期價值,而折戟于一場錯誤的測試。

    也可能有人認為,某種藥品之所以在三期試驗中被拿下了,是因為它的效果不如市面上已經存在的競品。事實上,光靠三期試驗的數據,是很少能夠做出這樣的結論的——因為這些數據很少與有效的治療標準做針鋒相對的比較。光靠目前的研究,也很難回答這些藥品與其他競品相比的有效性問題。

    所以,雖然一種藥品因為“商業計劃”而被扼殺的原因可能有很多,但我們也有充分理由相信,不同的利益主體,很可能會就此做出不同的決定。兩家看似大同小異的公司,很可能會做出完全不同的決策,更不用說預測本身就是個非常主觀的行為。哪怕是同一個人,同一個團隊,在不同的環境下(或者面臨來自高管層的不同壓力時),也可能做出不同的決策。

    如果一家公司不那么貪心,或者在藥品研發組合上采取了不同的配置,那么它可能樂于向市場推出更多的產品。一家公司如果在經濟上沒有迫切需求,也可能將這個“垃圾填埋場”視為寶庫,發掘出更多的“可回收材料”。

    彼得·阿迪曾經在播客里采訪過音樂制作人里克·魯賓,魯賓在談到他的經歷時,曾經說過一句很有意思的話:“哥倫比亞公司有一個政策,他們寧可讓這些作品死掉,也不愿意看到別人靠它們成功……”

    如果一種藥品“由于商業計劃”而失敗了,我們理應去問,還有誰有權拿到這個藥物?畢竟,其他人可能會對它的戰略價值給出不同的結論,甚至有可能在它的基礎上推出一款成型的藥物——它雖然沒能滿足一開始研發它的那家公司的需求,但卻仍然能夠滿足病人的需求。(財富中文網)

    本文作者之一的邁克·雷(Mike Rea)是IDEA Pharma公司的CEO,另一作者埃內達·波洛茲(Eneida Pollozi)是該公司的戰略顧問。

    譯者:樸成奎

    When so many studies “fail” for their ability to recruit patients, we of course might wonder why. The reasons are legion, from over-promising by hard-tendering contract research organizations (the third-party firms hired to do the major leg work for many pharma companies), to lack of a true unmet medical need, to difficulty getting patients to trial sites, or possibly a study that would put a control group at a disadvantage.

    (By the way, there’s another unintended consequence: We’re conditioned to look for pure “signals” of a drug’s potential efficacy, but we need to recognize that can be at odds with how prescribing works in the real world – doing no harm to real, live patients).

    One thing to take away, however, is not the failure, but the opportunity. We’ve no reason to believe that these medicines are ineffective, or unsafe – just unproven.

    The failure rate associated with an experimental treatment’s efficacy is staggering. There is a consequence of using early phases of R&D just to look for the tiniest signal that a drug might work: Companies are still using massive phase III programs just to find out if their drugs work well enough. We have to be careful what we wish for. It is, of course, possible to have a 0% failure rate for efficacy in phase III, by only conducting “easy” studies. None of us need that.

    Equally, a 0% success rate would be disastrous for all of us. However, like judging Michael Phelps by his ability to dive, let’s acknowledge that a drug that “fails” a phase III study could equally ask, “Did the study fail a good drug?” That is, could a different question asked of the same drug have yielded a different answer?

    That then makes the category of “Business/ Strategic Decision” an appealing one , for those of us who wish that the industry would get more medicines to patients (and thereby get them there faster and more cost-effectively). Note that this category is separate from financial reasons, where “failure for lack of money” would sit. No, these are products shelved because the company has decided there’s less value coming back from the drug than the marketing and opportunity cost of developing it (sunk cost and/or ongoing commitments, for example the cost of marketing. While we’re discussing that broader notion of value, this category, let’s be clear, does also include drugs that may provide value to the patient.

    There may be many reasons an asset doesn’t fit strategically – a decision to move a company portfolio in a certain direction, or out of a particular therapeutic area, for example. It could be that more than one candidate worked, and a choice had to be made as to which would be the one taken forward.

    In either case, these kinds of drugs could potentially be useful medicines. If shelved to make way for another medicine in the portfolio, we’re left wondering – was there a different way that this medicine could have been studied, or could still be? This history of pharma’s successes includes many medicines that had “false fails” in their development (more, perhaps than any of our prediction-based scientists would like to acknowledge).

    Among the reasons that a perfectly good medicine might “fail for business plan” is that the company might have a cut-off for a business case that the asset doesn’t clear. Let’s say, for example, that a company won’t progress an asset that can’t be forecast to return $1 billion per year. Unfortunately, even the most optimistic estimates of revenue forecasting in pre-launch suggest it is usually wrong (and wrong equally in both directions). So, that $1 billion figure seems an odd number to rely upon to nix a drug. It may be the best and only one we have, but let’s focus on what matters – many of these medicines have wrongly been estimated to have no forward value: They “failed” a false test.

    Or, perhaps, the drug is expected to perform less well than a competitor that’s already out there. Well, phase III data are rarely useful enough to draw such a conclusion – because they are rarely head-to-head with the effective standard of care, and registrational studies are unfortunately still not set up to answer questions about such drugs’ comparative effectiveness versus others.

    So, for all the reasons a drug might “fail for business plan,” there are a host of reasons to believe that a body with different interests might make a different decision. As we know, two similar-looking but different companies might well have taken different decisions, not least because forecasts are remarkably subjective – the team or the individual producing those forecasts might produce a different forecast in a different environment (or with different senior management pressures).

    A company with lighter appetites, or a different approach to portfolio positioning, may progress more products that happily sit on market together. An organization with less of a financial motive, of course, may regard this landfill site as, instead, being full of recyclable material.

    There was a fascinating line in the Peter Attia podcast with Rick Rubin, discussing the history Rubin had experienced, in hoping a major might let artists move between stables, for their own sake: ‘Columbia has a policy: they’d rather see these works die than see someone else have success with them…’

    If a product fails “for business plan,” it is legitimate to ask the question about who else should have access to that drug, to arrive at a different conclusion about its strategic value, and potentially to launch a medicine that may not have satisfied its original company that worked on it – but which still might meet patients' needs.

    Mike Rea is the CEO of IDEA Pharma, and Eneida Pollozi is a strategy consultant at the company.

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