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In a random scrutiny, the Parliamentary Standing Committee on Health has found that as many as 33 drugs were approved without clinical trial on Indian patients by the Drug Controller General of India (DCGI), during the period of January 2008 to October 2010. (Source: Pharmabiz.com)

“According to information provided by the Ministry, a total of 31 new drugs were approved in the period January 2008 to October 2010 without conducting clinical trials on Indian patients. The figure is understated because two drugs 29 (ademetionine and FDC of pregabalin with other ingredients) were somehow not included in the list. Thus there is no scientific evidence to show that these 33 drugs are really effective and safe in Indian patients,” said the report which is likely to create ruckus in the coming days.

In order to scrutinize new drug approvals, the Committee sought details [sponsors; pre-approval phase III clinical trials; overseas regulatory status in US, Canada, Britain, Australia and European Union; indications; names of experts if consulted and Post-Marketing Safety Update Reports (PSURs)] in respect of randomly selected 42 medicines from the list of new drugs uploaded by CDSCO on its website. Of these, 38 drugs were approved in the years 2004 to August 31, 2010; one drug had been approved earlier in 2001. Three drugs had been approved earlier in mid 90s. In all DCGI had approved 2,167 drugs in the period January 2001 to 30-11-2010. Thus the sample size for random scrutiny was less than 2 percent, said the panel headed by Brajesh Pathak report said.

“Out of 42 drugs picked up randomly for scrutiny, the Ministry could not provide any documents on three drugs (pefloxacin, lomefloxacin and sparfloxacin) on the grounds that files were non-traceable. All these drugs had been approved on different dates and different years creating doubt if disappearance was accidental. Strangely, all these cases also happened to be controversial drugs; one was never marketed in US, Canada, Britain, Australia and other countries with well developed regulatory systems while the other two were discontinued later on. In India, all the three drugs are currently being sold. It is not possible to monitor if manufacturers are abiding by the conditions of approval viz. indications, dosage, contraindications, precautions etc. Updation of product monographs and safety information in the light of recent developments is also not possible putting patients at risk. Before being withdrawn, major changes in safety profile, including Black Box Warnings (meant to draw attention to serious side effects), were incorporated to the prescribing guidelines of the two drugs sold in the United States but later withdrawn from the market,’’ the report said.

Excerpts from the Report:

7.14 On scrutiny of 39 drugs on which information was available, the Committee found the following shortcomings:

• In the case of 11 drugs (28 per cent) phase III clinical trials mandated by Rules were not conducted. These drugs are i, Everolimus (Novartis), ii. Colistimethate (Cipla), iii. Exemestane (Pharmacia), iv. Buclizine (UCB), v. Pemetrexid (Eli Lilly), vi. Aliskiren (Novartis), vii. Pentosan (West Coast), viii. Ambrisentan (GlaxoSmithKline), ix. Ademetionine (Akums), x. Pirfenidone (Cipla), and xi. FDC of Pregabalin, ethylcobolamine, Alpha Lipoic Acid, Pyridoxine & Folic Acid (Theon);

• In the case of 2 drugs (Dronedarone of Sanofi and Aliskiran of Novartis), clinical trials were conducted on just 21 and 46 patients respectively as against the statutory requirement of at least 100 patients;

• In one case (Irsogladine of Macleods), trials were conducted at just two hospitals as against legal requirement of 3-4 sites;

• In the case of 4 drugs (10 per cent) (Everolimus of Novartis; Buclizine of UCB; Pemetexid of Eli Lilly and FDC of Pregabalin with other agents), not only mandatory phase III clinical trials were not conducted but even the opinion of experts was not sought. The decision to approve these drugs was taken solely by the non-medical staff of CDSCO on their own.

• Of the cases scrutinized, there were 13 drugs (33 per cent) which did not have permission for sale in any of the major developed countries (United States, Canada, Britain, European Union nations and Australia). None of these drugs have any special or specific relevance to the medical needs of India. These drugs are: i. Buclizine for appetite stimulation (UCB); ii. Nimesulide injection (Panacea); iii. Doxofylline (Mars) iv. FDC of Nimesulide with Levocetirizine (Panacea); v. FDC of Pregabalin with other agents (Theon); vi. FDC of Tolperisone with Paracetamol (Themis); vii. FDC of Etodolac with 28 Paracetamol (FDC); viii. FDC of Aceclofenac with Thiocolchicoside (Ravenbhel); ix. FDC of Ofloxacin with Ornidazole (Venus), x. FDC of Aceclofenac with Drotaverine (Themis); xi. FDC of Glucosamine with Ibuprofen (Centaur); xii. FDC of Diclofenac with Serratiopeptidase (Emcure) and xiii. FDC of Gemifloxacin with Ambroxol (Hetero).

• In the case of 25 drugs (64 per cent), opinion of medically qualified experts was not obtained before approval.

• In those cases (14 out of 39 drugs), where expert opinion was sought, the number of experts consulted was generally 3 to 4, though in isolated cases the number was more. In a country where some 700,000 doctors of modern medicine are in practice such a miniscule number of opinions are hardly adequate to get diverse views and come to a well considered rational decision apart from the possibility of manipulation by interested parties. As against this, to review just the dose of popular pain-killer paracetamol, the United States Food and Drug Administration (US FDA) constituted a panel of 37 experts drawn from all over the country. After extensive debate 20 members sought ban on the combination of paracetamol with narcotics (17 opposed), 24 members sought reduction of dose from 500mg to 325mg (13 opposed) and 26 members advised to make high dose (1000mg) formulation a prescription only medicine (11 opposed). The voting pattern shows independent application of mind by each member. The opinions and decisions are in public domain (website of US FDA) so that anyone is free to scrutinize, offer comments and give suggestions. In India, every discussion and document is confidential away from public scrutiny. This matter needs to be reviewed to ensure safety of patients, fair play, transparency and accountability.

7.15 Unless there is some legal hitch, the Committee is of the view that there is no justification in withholding opinions of experts on matters that affect the safety of patients from public. Consideration should be given to upload all opinions on CDSCO website.

7.16 According to information provided by the Ministry, a total of 31 new drugs were approved in the period January 2008 to October 2010 without conducting clinical trials on Indian patients. The figure is understated because two drugs 29 (ademetionine and FDC of pregabalin with other ingredients) were somehow not included in the list. Thus there is no scientific evidence to show that these 33 drugs are really effective and safe in Indian patients.

7.17 The Ministry explained that under the rules, DCGI has the power to approve drugs without clinical trials in “Public Interest.” No explanation is available as to what constitutes Public Interest. How can approvals given to foreign drugs without testing on Indians be in Public Interest? Some of the reasons given for irregular approvals are: “Serious disease” (all the more reason to conduct clinical trials to ensure that patients in India really benefit from such imported, exorbitantly expensive drugs), “Rare disease status according to United States Food and Drugs Administration” (How can US FDA decide which is rare disease in India?), “Orphan drug status in Europe and USA” (There is no provision in Indian laws to give special treatment to such foreign drugs).

7.18 When asked about the reasons for approving New Drugs without clinical trials, the Health Secretary, during the course of oral evidence, stated that approval of new drugs without phase-III clinical trials in “public interest” was being done with the support of technical advice. Explaining about the basis for deciding to waive off the condition of local clinical trials for manufacture/import of new drugs, the Ministry stated that the Drugs and Cosmetics Rules do not prescribe specific situation under which clinical trial exemption can be granted due to “public interest”. However, the DCGI can abbreviate, defer or omit the toxicological and clinical data requirements for drugs meant for life-threatening/serious diseases and diseases of special relevance to Indian health scenario. It was further claimed that in such cases status of regulatory approval of the said drug in other countries and opinion from the medical specialists of the relevant field is obtained for taking decision. Further, the marketing approval is conditional to applicants submitting post-marketing surveillance data.

7.19 In cases where foreign drugs were approved without clinical trials in the country, the Ministry offered the following explanation: “Most of the drugs are approved in other countries based on multinational clinical trials…. on various ethnic/racial populations” implying that Indians would be included and hence conducting trials in India was not necessary. However, this presumptive remark is not accompanied by 30 any evidence. The interest is in those ethnicities that live in India, not Slavs, Caucasians, Hispanics and Negroes. The information in the Status Note on the very first drug of a total of 31 in the list of new drugs permitted in “public interest” without clinical trials, daptomycin, shows that pre-approval studies conducted by the American innovator recruited just 558 patients in United States, South Africa, Europe, Australia and Israel. There is absolutely no evidence of major ethnic groups of India being enrolled in these small trials.

7.20 It would appear that the intention of those who framed the Act and Rules was to leave a small door ajar for entry of new drugs without undergoing trials in serious emergency situations such as epidemic of a new hitherto unknown disease (e. g. SAARS, Bird Flu or Swine flu) where there may not be time enough to test new drugs and there is no alternative but to take calculated risk. None of the 33 drugs fall in this category of emergency treatments. Besides many drugs were launched in overseas markets years ago with ample time to conduct trials in India. The following are some examples:

• Daptomycin (Cubicin) of Novartis was launched overseas on 13-9-2003 and approved in India on 28-1-2008 after a gap of over four years. There was no tearing hurry to approve the drug without trials.

• Pemetrexed (Alimta) of Eli Lilly was approved on 5-2-2004 in the United States. After a gap of more than two years, it was approved by DCGI on 28-6-2006 without trials. There was more than adequate time to conduct phase III trials in India and yet undue favour was shown to the manufacturer.

• Raltegravir (Isentress) of Merk Sharp and Dhome was launched abroad on 12-10-2007 and approved in India on 27-01-2010 without conducting clinical trials even though there was adequate time to conduct mandatory clinical trials.

7.21 Such irregular approvals spare drug producers the cost and efforts but put Indian patients at risk. On an average DCGI is approving one drug every month without trials. This cannot be in public interest by any stretch of imagination. Moreover it was stated that in such cases (i) expert opinion is sought and (ii) Post Marketing Surveillance Data is mandatory.

• However a look at the information on approvals given by DCGI shows that expert opinion was sought in only 5 of 33 such out-of- the-way approvals.

• With regard to Post-Marketing Surveillance data, the Ministry failed to provide even one out of randomly selected 4 drugs approved without trials.

7.22 As stated earlier, the very purpose of phase III trials is to determine any ethnic/racial differences in the safety, efficacy and metabolism of drugs. Hence to serve any useful purpose, patients of different ethnicities living in India should be enrolled. For example, the results of a trial conducted only on Indo-Aryans may not be applicable to Mongoloids or Dravidians due to genetic differences.

The use of industrial gelatin in medicine capsules was exposed by state broadcaster China Central Television in mid-April. This form of gelatin contains excessive levels of chromium and is severely hazardous to human health.

The Ministry of Public Security said Sunday that it has confiscated 77 million capsules made from toxic industrial gelatin, arrested nine criminal suspects, detained 54 others and shut down 8 capsule manufacturing lines in Hebei, Zhejiang and Jiangxi provinces.

毒胶囊事件后的医药行业

来源：新金融观察报

核心提示：十天前，修正药业、通化金马等9家医药企业使用铬金属严重超标的皮革制造药用胶囊事件被央视曝光。这在行业里，乃至社会上掀起了或大或小的波澜。

4月的倒数第二周，合肥酒店爆满，多数酒店坐地涨价。25日和26日，一向冷清的滨湖国际会展中心热闹起来。第67届全国药品交易会和第68届中国国际医药原料药、中间体、包装、设备交易会在这里举办。

而少数原本应到会的医药企业无缘参展。

这次的药交会与以往相比，言语间，多了一个谈论的话题——胶囊。

十天前，修正药业、通化金马等9家医药企业使用铬金属严重超标的皮革制造药用胶囊事件被央视曝光。这在行业里，乃至社会上掀起了或大或小的波澜。

23日的新闻发布会上，国药励展副总经理匡勇向在座的媒体记者表示，胶囊事件发生后的第一时间，国药励展的经营班子和医药事业部的员工立即启动危机应对，与相关企业的中高层管理者取得联系，“所幸的是，这些企业也正在接受当地相关部门和媒体的质询，也在召回一些产品。”

双方在沟通过程中，意见达成一致——在问题未弄清楚之前，涉事企业不予参展。同时，匡勇还强调，在那之后，他们每天都有专人关注媒体报道，一旦发现还有这9家以外的医药企业，他们也会立即做出反应，对其劝退。

毒胶囊事件并没有使会展中心的热情减退，相反的是，这甚至成为许久不见的两位老总相互问好的开场白。新金融记者在会场就听到这样一番对话。

甲说，“这次的胶囊事件对你们没什么影响吧？”乙答，“我们没有用那些，我们主要做出口。”甲说，“我们也没有用。”之后，两人的对话变成，甲调侃，“上有政策，下有对策。”乙无奈，“越搞越乱，不知道怎么搞。”

这段对话映射出的内容——出口到其他国家，所以不敢使用问题胶囊——实在让国人不敢恭维，但这或许就是行业里面的潜规则。

中国医药企业管理协会副会长王波在24日首届中国医药经济战略峰会(下称战略峰会)上表示，“胶囊问题绝不止今天，也绝不是实施基本药物制度后才出现，这种现象是潜规则，可能已经存在很多年。”

业内人士向新金融记者透露，跨国制药企业从不使用中国药用辅料企业生产的胶囊，原因就在于此。

另外，该人士还告诉新金融记者，“浙江省新昌县既然被称为胶囊之乡，其胶囊所供应的医药企业就不可能只有那几家。不仅胶囊，其他的药用辅料，哪个没问题？”

基于此，安徽省药监局药品安全监管处处长刘晓琳在26日API China药用辅料论坛上表示，“药监部门正在全国范围内对药品生产流通领域进行地毯式的清查，对所有用到胶囊的生产企业进行抽检，基本上做到全覆盖。”

而在3月份刘晓琳刚接到论坛主办方——国际药用辅料协会中国分会和国药励展——通知的时候，考虑到药用辅料的监管办法和注册管理办法都在整修意见中，尚未出台，刘晓琳感觉到“确实没有太多话题可以说”，但紧接着胶囊事件的发生，让她又“确实有话要说”。

地毯式的清查不是一项小工程，药监部门最近都在加班加点，可谓忙得不可开交。刘晓琳在结束她的演讲后便匆匆离开，前往下一目的地。

类似的情况也有发生。原本确定参加战略峰会的国家药监局政策法规司副司长巡视员许嘉齐，因胶囊事件，于前一天(23日)下午临时奔赴他地，未能参会。

-蝴蝶效应

毒胶囊事件的曝光在医药行业从业人员的眼中似乎有另外一番解读——他们对于“记者”这个名称更加敏感。

演讲过程中，一位嘉宾在提到毒胶囊事件时，说了这样一句话：“在座的没有记者吧，我也怕。”但其实他所演讲的内容，正是对这类问题的揭露和探讨。

而在台下与记者交换名片时，表现出类似情绪的嘉宾有很多。

更甚者是在会展中心展出的医药企业。往往参展人员一听来者是记者，就表现出较强的抵触情绪，很少有人愿意多聊。当然，这种现象并非绝对。

一位零售药店负责人告诉新金融记者，涉事企业在对胶囊产品进行召回时，“厂家的业务员说，过五六天，检验合格的批次产品，再继续卖。”

对此，中投顾问医药行业研究员郭凡礼向新金融记者表示，相关企业召回部分或者全部胶囊产品，短时间内重回药店销售的可能性是存在的。

他指出两点因素。首先取决于胶囊事件对三方的影响程度，包括各地方政府对胶囊事件的关注度、消费者对胶囊的态度和相关企业对胶囊产品的召回态度。其次，药监部门对于不合格的胶囊产品，会责令企业整改，而合格的，会返还给企业，以便进行市场销售。

27日，国家药监局公布药用明胶和胶囊抽检结果。结果显示，对18家药用明胶生产企业抽验了166批明胶，检出1批产品铬超标；对117家药用胶囊 生产企业抽验了941批药用胶囊，检出15家企业74批胶囊铬超标，不合格率为7.9%。其中涉及浙江的9家铬超标药用胶囊企业全部位于胶囊之乡——新昌 县。

同时，国家药监局责令企业立即召回铬超标药用明胶和胶囊，在监控下销毁，坚决防止再次流入市场；并且，按照法定程序吊销药品生产许可证。

据刘晓琳在会场提供的PPT显示，我国药用辅料生产企业有近400家，生产品种500余种，总产值150亿元，相当于药品制剂的2%。其中具有一定规模的专业辅料企业较少，仅十几家，而超亿元销售规模的只有少数几家。

考虑到胶囊事件可能存在多年，以及此次查处的严厉性，王波有一个很大的担心，“今年下半年，正规胶囊可能会全国断货，供不应求。”此外，他还推测，在这样的情况下，“价格会上涨，原来三分、五分钱的正规胶囊，可能竞争价会涨到八分、一毛钱。”

对此，郭凡礼表示，在胶囊事件影响下，胶囊行业整合步伐加快，产业集中度得到提升，这会引发两方面的反应。一是品牌建设及产品质量较好的胶囊企业， 其经济效益和社会效益将提升；二是就市场层面而言，胶囊企业可能结成联盟，采取囤货、限量、提价等形式维护自己的既有利益，也不失为既保本又让市场不致失 衡的良好举措。

历史上，我国首例使用假药用辅料造成重大药害的事件，是2006年的“齐二药”事件。企业对于辅料供应审计不严，辅料检验流于形式，误将工业二甘醇 当作丙二醇。这与1937年美国发生的磺胺醑剂事件所涉及的辅料成分相似。而结果是，我国这家企业已经不复存在，美国那位涉案的主任药师因内疚和绝望自 杀。

曾经的教训，医药企业没有吸取；如今的恶果，却不止他们在承担，因为这还造成消费者对药品信任度的下降，以及用药的恐慌。

敏感，于是逃避，终究不能解决问题。医药企业还需更加严格地要求自己，做真正的良心药。