如何看待 FDA 禁止 23andMe 公司為其基因檢測設備進行市場營銷活動？

01-02

如何看待此事，這個行為是否表明在DNA等醫藥高科技創新企業存在著巨大的政策風險？
美禁止無許可證23andMe公司提供DNA檢測服務
----------------------------------------

11月22日，美國食品藥物管理局(簡稱FDA)要求生物基因公司23andMe，停止為其基因檢測設備進行市場營銷活動。
23andMe公司於2007年開始提供解譯基因組服務。該公司由谷歌聯合創始人謝爾蓋·布林前妻安妮?沃西基創立。谷歌公司對此項服務進行了投資。用戶
只需花費99美元，將2.5毫升唾液放入試管寄到23andMe公司，即可進行DNA測試。數周后，客戶便可在線查看檢測結果。通過該項測試，客戶可以了
解自己的家族起源、遺傳性疾病和過敏藥物等。
美國食品藥品管理局(FDA)指出，23andMe公司尚未獲得提供此項服務的許可證。不準確的檢測結果可能危害公民健康，引發不必要的手術。FDA指出在取得許可證前，23angMe要停止此項服務。

更正一個概念，

FDA叫停的是該公司與健康有關的數據解讀服務（ health-related genetic tests），而涉及到的祖先檢測（ancestry-related genetic tests）等娛樂型數據解讀還是提供解讀服務的。

最重要的是，他們也會提供檢測原始數據（raw genetic data），這意味著你可以拿著自己的數據找懂行的人or信賴的醫生or遺傳諮詢師為你解讀。

即，FDA把數據解讀和分析建議這一塊最重要的部分收回了自己手上，看必要的時候才放開。

這意味著，

1、目前DNA檢測數據解讀結果的可信程度存疑且需要大量臨床前瞻性試驗來驗證預測模型的準確性。（冰島的全民基因組測序數據以及英國10w病人的基因組測序是一個良好的開端，可以為相關人種提供重要的基因組與健康風險關係預測的數據基礎，反觀我國，呵呵呵呵）

2、結果告知存在倫理風險，不準確的結果可能會增加普通人心理壓力從而導致過度醫療。

3、政策風險加強，這對國內外提供相關服務的公司提出了預警信號。SFDA在藥物批准和監管方面向來是跟著FDA走，甚至比FDA還保守，這個信號不太妙，不過也要看相關機構跟政府關係搞的怎麼樣了，這方面自有專家來談，我就不多說了。

ps，就我個人來說，23andme的報告已經做的比其他公司好很多了，做了這5、6年，案例也積累了不少，就像安妮自己說的，他們擁有了超過50w人的個人基因組數據，這是一大筆金礦，政策阻擋不會太久。

又ps，安妮上周的官方blog真是打了一手好委屈牌，文案贊，以及，那些還沒拿到CLIA認證的臉疼嗎？不知道fxxxxxxxxxxxe是怎麼玩政策躲避球的？

又又ps，國內那些做個人基因組的小公司你們的報告真是基於中國人的基因組資料庫來預測和解讀的嗎？額呵呵呵

拜託，FDA 不是 Federal Trade Commission，他們不管你壟斷不壟斷行業，也不管制定醫藥政策或控制醫藥市場價格，不要拿中國的思路去推測美帝的機構好不好。查一下美帝媒體對這件事的報道就可以知道，FDA 禁止的是 23andme 直接向消費者推銷「你有多少幾率得啥啥病」這種近似診斷結果的信息。賣診斷測試 (diagnostic test) 要達到一定的精確標準，賣診斷測試直接給無醫學知識的消費者更是要傻瓜都能懂能用 (fool proof)，門檻是很高的，所以被 FDA 批準直銷的診斷測試很少，只有電子血壓測量器，血糖手指測量器，早孕測紙等那麼幾個而已。複雜一點的，哪怕精確度高，都需要經手醫生的解釋。

23andme 之前就是在打擦邊球，對消費者的賣點是，我拿你的基因 markers 對照目前發表的致病基因資料庫，然後告訴你，你得啥啥病的幾率比普通大眾高多少多少，其實已經涉及了診斷疾病的範疇，又是直接賣給消費者的。但是他們從來沒有向 FDA 證明過，這個測試東西準不準，普通程度的消費者看完了是否正確理解結果的意思，以及消費者是否了解做這個測試的風險 --- 也就是說，實質是賣 direct-to-consumer diagnostic test ，卻未經過 FDA 的審查程序（因為他們知道肯定不能通過）。怎麼辦？他們的擦邊球做法就是寫了一大堆警告，說這個測試結果並不是疾病診斷，僅供研究和教育 (research and education) 作用，具體請詢問醫生等等。FDA 說你這個警告有名無實，毫無用處，不能算數，實質上還是在賣 diagnostic test.

至於基因測試能不能正確地幫普通人明白自己得啥啥病的幾率，幾天幾夜也說不完，簡而言之，搞基因的專家都說完全不行，實際上連大多數的醫生都不明白，更別提沒有醫學知識的大眾了。

*****

最近剛上知乎，恰好遇到這條我確知一二的問題。說實話我很驚奇有那麼多人對美國政府機構拿中國政府機構的思路推測，這種思路還特別走紅；這不禁讓我反思，是不是平時常見的對中國政府機構的思路的各種肯定說法實際上也相當不可靠。

僅就 @Akira Meno 所說的「他們擁有了超過50w人的個人基因組數據，這是一大筆金礦，政策阻擋不會太久」說一點自己的看法。

從技術上講，50 萬人的基因組，應該不都是全基因組（基於唾液的話，甚至都不是？一般應該只能測有限的變異點）。再加上有多少個人信息，這倒底是多大一個金礦，還很難說。

比如，我曾去過一家公司，跟 23andme 差不多年頭，收集各種專門樣本數年。技術方面，他們當然在整合這些數據。但，生產主管跟我直說，這些年，收集數據的方法，也隨著技術的發展，在不停變化。數據的覆蓋廣度，深度，和準確度，隨著技術進步，都在提高，說整合，談何容易。簡單點說，只一個 NextGen Seq 出來，就讓它幾年的努力，一下子拉回到了和許多新公司一樣的起點。

再就比如說產前檢查吧，sequenom 是做血液唐篩的。跟那裡的朋友聊過，每次換技術，所有舊樣本全廢，重新測，重新採集。因為設計診斷方法，衡量預測準確度所用的數據，當然要與你當下提供的產品本身的技術統一，舊技術收集的數據，當然就廢了（除非你能證明它們和新數據的功用是一樣的），否則 FDA 過不了。

還是 sequenom，10 月 31 日輸了一個官司。加州高院認定它所持有的，從母體血液中找出嬰兒 DNA 的專利，是無效的。這等於是把 sequenom 的技術壟斷給打破了。sequenom 股票那天跌了 25% 左右吧。

第二天，加州宣布，政府會補貼孕婦做這項基於血液的唐篩，等於是把這個市場給打開了。

我不知道這兩個有什麼關係，但，時間上太湊巧。

政策這方面，我只是想說，FDA 收回 23andme 的解讀，肯定是有它一貫保守的作法。這個從最近在其他一些關於診斷的 app 上放出風聲可以看出。據我所知，有不只一家公司想效仿 23andme，繞過 FDA，提供早期檢查方法。

但是這之後，政府準備如何放開，這事情後面，又有什麼樣的考量，有什麼樣的較量，可能並不簡單，這從這幾十年關於止痛藥的爭論，可以看出（http://www.nytimes.com/2013/10/28/business/fda-shift-on-painkillers-was-years-in-the-making.html?_r=0）。23andme 敢這麼說，要麼對自己的遊說本領有信心，要麼就是個保護性的說辭。

@Jun Yan 的答案中說 FDA 不是 FTC，是出於其管理醫理的目的，這個我同意。但是，從另一個角度，FDA 的決定，會對行業產生巨大的影響。當年 FDA 成立，就是針對各州自己的肉食品衛生監管而出台的，用聯邦管理取代州管理，其目的不僅是食品安全，也同時打破了各州的地方保護主義（比如很多州規定，牛必須在本州檢查後才能宰殺，就是針對跨州的肉製品企業）。結果是地方肉製品企業迅速消失，地方農業轉向牛奶這樣的方向。

回來說 23andme，FDA 一但拉住了韁繩，什麼時候，怎麼放開，就是另一回事了。不管它是出於什麼目的，客觀上，它是給了其他公司以追趕的可能，實質上把大家拉回到了相似的起跑線上。因為 23andme 既有的樣本和數據，很可能是不能滿足 FDA 的要求的。

health-related genetic tests 害怕的是桑德爾擔心的問題哈佛教授邁克爾·桑德爾:避免「完美」經濟下的危機太了解自身基因會帶來人類還無法處理的倫理風險

涉及個人隱私，未來買保險和就業均受到影響

23andme 已經批准了。

天要下雨你能阻止嗎

我和家人完成了23andMe的基因檢測，閱讀了檢測報告，昨晚看了關於祖先的成分和遷徙分析，十分激動，做的夢都開始不一樣了。

人家不是做社交的嗎嘻嘻

FDA沒有禁止23andme提供測序服務，禁止的是23andme提供的疾病風險預測

ASR
and LDT update

Analyte
specific reagents (ASRs) fall under product classification code MVU, Regulation
Number 864.4020, require good manufacturing practices (GMP as defined in
21CFR820), and are subject to registration, listing, medical device reporting
and restricted distribution requirements.
Analyte specific reagents (ASR"s) are antibodies, both polyclonal and
monoclonal, specific receptor proteins, ligands, nucleic acid sequences, and
similar reagents which, through specific binding or chemical reaction with
substances in a specimen, are intended for use in a diagnostic application for
identification and quantification of an individual chemical substance or ligand
in biological specimens.

These
reagents can be used for either research or by other IVD manufacturers or by
labs to develop their own tests. The
Federal Register Notice of Friday November 21, 1997, Volume 62, No. 225, page
62253 clearly announced that reagents that were ASRs did not have to be
relabeled for Research Use Only, in order to be used for research
purposes. In response to a question of
whether or not ASRs could be sold to universities conducting pure research, and
if so, would such ASRs require a separate research use only (RUO) label the
response was that:

「ASRs
can be sold to universities doing research and FDA has amended 809.30 to
clarify this point. ASRs and products
labeled 「for in vitro diagnostic use」 can be used for research purposes so an
additional label would not be necessary in those circumstances. However, products that have not been
manufactured in accordance with CGMP』s and are labeled 「for research use only」
cannot be marketed under the ASR classification or used by laboratories to
develop clinical diagnostics.

Labeling
of ASRs is defined in 21CFR809.10 and restrictions are defined in 21CFR 809.30. It is very limited what a manufacturer can
state about an ASR, and basically includes the following elements:

(i)
The proprietary name and established name (common or usual name), if any, of
the reagent;

(ii)
A declaration of the established name (common or usual name), if any;

(iii)
The quantity, proportion, or concentration of the reagent ingredient; and for a
reagent derived from biological material, the source and where applicable, a
measure of its activity. The quantity, proportion, concentration, or activity
shall be stated in the system generally used and recognized by the intended
user, e.g., metric, international units, etc.;

(iv)
A statement of the purity and quality of the reagent, including a quantitative
declaration of any impurities present and method of analysis or
characterization. The requirement for this information may be met by a
statement of conformity with a generally recognized and generally available
standard that contains the same information, e.g., those established by the
American Chemical Society, U.S. Pharmacopeia, National Formulary, and National
Research Council. The labeling may also include information concerning chemical/molecular
composition, nucleic acid sequence, binding affinity, cross-reactivities, and
interaction with substances of known clinical significance;

(v)
A statement of warnings or precautions for users as established in the
regulations contained in 16 CFR part 1500 and any other warnings appropriate to
the hazard presented by the product;

(vi)
The date of manufacture and appropriate storage instructions adequate to
protect the stability of the product. When applicable, these instructions shall
include such information as conditions of temperature, light, humidity, date of
expiration, and other pertinent factors. The basis for such instructions shall
be determined by reliable, meaningful, and specific test methods, such as those
described in 211.166 of this chapter;

(vii)
A declaration of the net quantity of contents, expressed in terms of weight or
volume, numerical count, or any combination of these or other terms that
accurately reflect the contents of the package. The use of metric designations
is encouraged, wherever appropriate;

(viii)
The name and place of business of manufacturer, packer, or distributor;

(ix)
A lot or control number, identified as such, from which it is possible to
determine the complete manufacturing history of the product;

(x)
For class I exempt ASR"s, the statement: "Analyte Specific Reagent.
Analytical and performance characteristics are not established";

Classification

Sec. 864.4020
Analyte specific reagents

(b)(1) Class I
(general controls). Except as described in paragraphs (b)(2) and (b)(3) of this
section, these devices are exempt from the premarket notification requirements
in part 807, subpart E of this chapter.

(b)(2) Class II
(special controls/guidance documents), when the analyte is used in blood
banking tests that have been classified as class II devices (e.g., certain
cytomegalovirus serological and treponema pallidum nontreponemal test
reagents).

(b)(3) Class III
(premarket approval), when (i) The analyte is intended as a component in a test
intended for use in the diagnosis of a contagious condition that is highly
likely to result in a fatal outcome and prompt, accurate diagnosis offers the
opportunity to mitigate the public health impact of the condition (e.g., human
immunodeficiency virus (HIV/AIDS)or tuberculosis (TB)); or

(ii) The analyte
is intended as a component in a test intended for use in donor screening for
conditions for which FDA has recommended or required testing in order to
safeguard the blood supply or establish the safe use of blood and blood
products (e.g., tests for hepatitis or tests for identifying blood groups).

(c)Date of
510(k), or date of PMA or notice of completion of a product development
protocol is required. (1) Preamendments ASR"s; No effective date has been
established for the requirement for premarket approval for the device described
in paragraph (b)(3) of this section. See 864.3.

(2) For
postamendments ASR"s; November 23, 1998.

Restrictions:

Restrictions on
the sale, distribution and use of ASR"s are set forth in 809.30 of this
chapter.

the issued FDA
Guidance Document (Frequently Asked Questions) issued on Sept. 14, 2007
includes the following as examples of ASRs:

· a single forward/reverse
oligonucleotide primer pair (e.g., a primer pair for amplification of a single
amplicon, such as for amplification of the ΔF508 locus of the gene encoding the
cystic fibrosis transmembrane regulator (CFTR)), or single forward or reverse
primer individually. For the purposes of this
guidance, a primer is defined as a nucleic acid sequence that is intended to
initiate amplification by binding selectively to a complementary sequence in a
large nucleic acid polymer.

· a nucleic acid probe (whether untagged
or tagged, e.g., conjugated to biotin or Cy?3) intended to bind a single
complementary amplified or unamplified nucleic acid sequence. For the purposes of this guidance, a probe is
defined as a molecule that is intended to isolate, bind, or identify a specific
target or ligand.

Although
ASRs do not have an intended use, they should not to be used in blood banking
tests, nor should they be used for blood product donor screening, nor should
they be used the diagnosis of a contagious condition that is highly likely to
result in a fatal outcome (for example for diagnosing cancer, HIV/AIDS or tuberculosis
identification). Additionally, class I ASRs
should not be used in the identification of hepatitis or for the identification
of blood groups. Class I ASRs cannot have instructions for use and have no
intended purpose, and no clinical performance claims.

It
is important to note that ASRs are 『higher quality』 than the general reagents
that can be available as general purpose reagents (whether these are antigens,
antibodies, primers or probes, enzymes or other reagents), and as such, serve
an important purpose for labs to be utilized in either research or in their lab
developed tests.

Lab developed tests (LDTs) that are made by labs are an important aspect of any healthcare
system, and allow a lab to make tests that are appropriate for their local patient
population. They also allow the lab to
tailor existing tests to suit their patient』s needs. Finally, for some rare patient populations
for whom there are no IVD manufactured tests available, the availability of a
lab developed test, versus physician guesswork is often considered to be very
valuable information, particularly when patient history is difficult to obtain,
or the patient may be from the pediatric or elderly population, and is unable
to clearly describe symptoms and history for example. Furthermore, lab developed tests are
regulated in the US by the State (each individual state monitors labs). There are a variety of categories of lab
developed test from simple,
low complexity tests, to moderate complexity, to highly complex tests. Individual labs are certified by the State to
what level of test they are allowed to perform, and are audited frequently,
based on the patient populations they serve, and the tests that they
offer. Clinical laboratories regulated
under the Clinical Laboratory Improvement Amendments of 1988 (CLIA), are
qualified to perform high complexity testing under 42 CFR part 493 or these
tests can be performed by labs or clinical laboratories regulated under VHA
Directive 1106 (available from Department of Veterans Affairs, Veterans Health
Administration, Washington, DC 20420).

CLIA
certification of a lab indicates that the lab has passed rigorous scrutiny and
that validation data for the tests being utilized (for New York State
specifically) have been independently reviewed and approved by CLIA. Categorization of an FDA cleared or approved
IVD test for CLIA categorization level is performed by the FDA (IVD test are low,
moderate or high complexity, based on the requirements of the user to perform
the testing).

There is much
controversy regarding lab developed tests in the US, and many uncertainties
remain. FDA had announced in 2010 at a
public meeting (July 19 and 20) that was well attended by industry, patient
advocates, physicians, and labs and regulators that they were going to regulate
lab developed tests.[1] FDA has announced that they plan to release 3
guidance documents, however, these have not yet been issued. Current developments are as follows (based on
the following blog from Steve Gutman, former head of FDA at the reference
below)[2]:

OIR has promised
delivery of no fewer than three draft guidance documents addressing how FDA
would regulate lab developed tests ( LDTs) and has variously signaled use of a
risk based approach, the likely need for classification panels, and the slow
but steady phase in expected time (to be counted in years not months) for such
a new program. A category of high risk devices for immediate action is
likely to be listed.

There has also
been intense lobbying. An interesting addition to the Food and Drug
Administration Safety and Innovation Act requires FDA to notify Congress at
least 60 days prior to issuing a draft or final guidance on the regulation of
LDTs. Rarely has an office at FDA been afforded such a unique opportunity for
personal attention by Congress.

On June 2, 2013
eyebrows were raised by comments made by FDA Commissioner Hamburg at a speech
before the American Society of Clinical Oncology (ASCO). There was no mistake
in the choice of venue: ASCO has been a sponsor of clinical practice guidelines
since the early 90』s and is an advocate for evidence based medicine. Hamburg
delivered a clear message: FDA is developing a risk-based framework that is
intended to 「make sure that the accuracy and clinical validity of high risk
tests are established before they come to the market.」

However, on June
4 the American Clinical Laboratory Association (ACLA) fielded the latest
in a growing list of citizen』s petitions to FDA on this subject. ACLA argues
that LDTs are not devices and are not in commercial distribution. While the ACLA petition clearly adds to the variety
of opinions on the subject, it is probably worth noting that FDA still has IOUs
out on the last two petitions on this subject fielded by the Washington Legal
Foundation in 2006 and Genentech in 2008.

Providing a hint
as to where the hang up in policy might be, on June 26 Representative Louise
Slaughter (D-NY) issued a letter to the Office of Management and Budget (OMB)
urging the release of the FDAs draft guidance for LDTs. As Slaughter notes 「the time has come for
the Administration to address this regulatory gap and resolve the uncertainty hanging over
this critical area of medicine by affirming FDA』s oversight of diagnostics」.

The
same request was made in a more public venue in an editorial in the New York
Times entitled 「The Gap in Medical Testing.」 IVD issues seldom appear as lead
pieces in the Times but this commentary puts this issue clearly in the news
again.

It
is clear that the war over regulatory ownership of lab developed tests as IVDs
goes on. What happens next is anybody』s guess. It is also clear that having ASRs available is
important (to have quality reagents) versus the alternative, or people using
whatever general reagents (not made under quality requirements) are available.

[1]FDA/CDRH Public Meeting: Oversight of Laboratory Developed Tests (LDTs), Date July 19-20, 2010

[2] July 11, 2013, MYRAQA, Laboratory Developed Tests by Steve Gutman, Laboratory Developed Tests