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Pharma Uptoday Monthly Magazine - Volume 20; Issue: Nov 2015


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To recap the previous month's pharma highlights to members, Monthly magazine Volume 20 has been released with the following content.

News Uptoday
New Guidance
Audit Findings
- Pernix Receives Form 483 for cGMP Violations
- FDA Hits Pfizer Subsidiary With Second Form 483 in Five Years
- Galena Hit With 10-Item Form 483 Over Unresolved Issues
Warning Letters
- Warning letter: Unimark Remedies Ltd., Mumbai, India
- Warning letter: SSM Health Care St. Louis DBA SSM St. Clare Health Center
Health Canada Non Compliance Report
- Non Compliance Report: Unilever Canada Inc.
EMA Non-Compliance Report
- GlaxoSmithKline (Tianjin) Company Limited (Teda), China
Regulations of the Month
- Sec. 211.42 Design and construction features (c)(5) to (c)(10)
- Sec. 211.44 Lighting

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Pharma Uptoday Monthly Magazine - Volume 20; Issue: Nov 2015

  2. 2. PHARMA UPTODAY 2 Inside this issue 3 News Uptoday 38 New Guidance 51 Audit Findings 483 Observations - Pernix Receives Form 483 for cGMP Violations - FDA Hits Pfizer Subsidiary With Second Form 483 in Five Years - Galena Hit With 10-Item Form 483 Over Unresolved Issues 55 Warning Letters - Warning letter: Unimark Remedies Ltd., Mumbai, India - Warning letter: SSM Health Care St. Louis DBA SSM St. Clare Health Center 58 Health Canada Non Compliance Report - Non Compliance Report: Unilever Canada Inc. 60 EMA Non-Compliance Report - GlaxoSmithKline (Tianjin) Company Limited (Teda), China - CARGILL FRANCE 63 Regulations of the Month - Sec. 211.42 Design and construction features (c)(5) to (c)(10) - Sec. 211.44 Lighting
  3. 3. PHARMA UPTODAY 3 News Uptoday India says EU ban on generic drugs 'unwarranted' The European Union's ban on Indian generic drugs is "unwarranted" and an obstacle to moving trade talks forward, India's foreign secretary said on Monday. Subrahmanyam Jaishankar said EU restrictions on more than 700 generic drugs were unfair. "It's our hope that this matter would be looked at fairly and sensibly and would hopefully not be an impediment to the free trade deal," he told journalists after German Chancellor Angela Merkel met with Prime Minister Narendra Modi during a visit to New Delhi. India and Germany pledged on Monday to revive efforts to reach an Indo-European free trade pact after talks fell apart this year. The Union health ministry henceforth will not insist on repeat pre-clinical or toxicity studies on animals for permission for a new drug or clinical trial if authentic data on animal toxicology has been submitted with the technical data. The health ministry's action in this regard comes in the backdrop of the fact that the Union minister for women and child development Maneka Gandhi had written to the Union minister of health and family welfare regarding pre-clinical/toxicity studies on animals under Schedule Y of the Drugs and Cosmetics Rules, 1945. In her letter, the minister stated that India being signatory of OECD (Organization for Economic Cooperation and Development) Council Act related to mutual acceptance of data is under obligation to respect the data generated by other country regarding pre-clinical/toxicity studies and therefore there is no need for CDSCO to undertake further studies. The molecules of interest have been those that are approved by multiple regulatory agencies and have been through many animal studies which have been made available on sites and published in scientific journals. Under the current regulations of item 4, Appendix-I of Schedule Y of Drugs and Cosmetics Act, 1940, additional tests on animals are then ordered. As the issue was related to pre-clinical or toxicity studies on animals under Appendix I and Appendix III of Schedule Y, the matter was placed before the Investigational New drug (IND) Committee of the Union health ministry. The committee in its meeting held on August 6, 2015 deliberated and agreed with the statement mentioning that, for drugs approved in other countries where complete toxicological data generated in GLP certified laboratory and in alignment with the requirements prescribed under Drugs and Cosmetics Act, 1940 and Rules, 1945 (Schedule Y), further toxicity study may not be required if
  4. 4. PHARMA UPTODAY 4 complete data as per prescribed requirements is submitted during application for new drug approval. It may also be explored, in line with international practices, to encourage the use of other alternative methods than animal studies, wherever such robust validated methods are available for small or large animals, the IND committee further recommended. The IND committee recommendations were then sent to the Drugs Technical Advisory Board (DTAB), the highest authority under the Union health ministry on technical matters. The issue came up for discussion in the DTAB meeting held on August 18, 2015. After deliberations, the DTAB agreed to the recommendations of the IND committee and further recommended that under item 4, Appendix I of Schedule Y, it may be mentioned that if authentic data on animal toxicology as per requirements of annexure III has been submitted with the technical data, then repeat animal testing for permission for a new drug or clinical trial is not necessary. Brazil Suspends Pharma Serialization And Tracing Requirements Last week, Brazil’s pharma industry regulatory agency, the National Agency of Sanitary Surveillance (ANVISA), announced that they were ―suspending‖ at least part of RDC-54/2013, the declaration that mandated drug serialization and tracing, until further notice. Thank you to all who forwarded the link to the official announcement. I was able to translate and read it on Thursday, and I submitted a comment on my own last essay, ―Pharma Serialization Deadlines In Flux―, to include the link. Apparently shortly after that essay was published, ANVISA publicly announced the suspension. However, the ANVISA website was in accessible in the United States Sunday afternoon when I normally write RxTrace essays so I was unable to finish this essay until Monday morning. Now that I can access the site, here are the details. According to a translation of a news article published on the ANVISA website, what they have done is to suspend item II of Article 23 of RDC 54/2013. That’s the section the mandates the 3-lot pilot by each registration holder that was to be completed by December 10 of this year. Apparently ANVISA will publish a new RDC that will officially revoke that requirement ―in the coming days‖. In addition, it appears that the entire regulation will be reviewed and the design of the mandated solution potentially reconsidered. In my view, RDC 54/2013 mandated data exchanges that were excessive and duplicative, but the worst part about that regulation is that it makes registration holders responsible for collecting tracing data from all downstream trading partners. The article indicates that the board members nodded in agreement with the centralized tracing model, but it is unclear if that indicates support for a simplified centralized model, a semi-centralized model (see ―The Viability of Global Track & Trace Models―), or
  5. 5. PHARMA UPTODAY 5 the one they current have as defined in RDC 54/2013 (which is more of a convoluted hybrid model, in my opinion). Also unclear is whether this action changes the deadline for full serialization and tracing, previously specified by RDC 54/2013 as December 10, 2016. The article only mentions the suspension of the pilots but others have indicated that they expect, or they believe, that the 2016 deadline is, or will be, suspended as part of the review and reconsideration. Treat this as more rumor until it is confirmed by an official announcement. Hopefully that will come soon, so stay tuned. Teva Acquires Rimsa to Accelerate its Emerging Markets Growth Strategy Teva Pharmaceutical Industries has entered into definitive agreements under which the company will acquire Representaciones e Investigaciones Médicas, S.A. de C.V. (Rimsa), pharmaceutical manufacturing and distribution company in Mexico, along with a portfolio of products and companies, intellectual property, assets and pharmaceutical patents in Latin America and Europe in a debt-free, cash free set of transactions, for an aggregate of $2.3 billion. Through this acquisition, Teva will become a leading pharmaceutical company in Mexico, the second largest market in Latin America and one of the top five emerging markets globally. Teva expects the deal will yield substantial and achievable synergies and offer a platform for growth in the region. ―This acquisition delivers on our strategy of increasing our presence in key emerging markets in order to position Teva for long-term growth in these markets. Rimsa will provide Teva with a significant platform for growth by combining the strong Rimsa brand, licensed portfolio of differentiated, patent-protected products, promising pipeline, significant relationships with physicians, patients and healthcare providers and its strong commercial presence,‖ said Erez Vigodman, President and CEO of Teva. "The combination of our companies lays the foundation for a leadership position and high long-term, profitable and sustainable growth in the region and further reinforces our commitment to innovation, quality and improving the health of people worldwide." Rimsa had revenue in 2014 of $227 million with an annual growth, year over year of 10.6% since 2011. The company has an extensive portfolio of specialty products, including fixed-dose combination products which have fueled its growth. Rimsa’s well-established sales footprint is expected to provide a platform for additional Teva products. ―For 45 years, Rimsa has operated as a leading pharmaceutical company in Mexico, the second largest healthcare market in Latin America, with a high growth, unique and diversified business model. We share Teva’s focus on providing quality healthcare and we are excited to become a part of Teva in meeting the needs of a population of 120 million,‖ said Luis Jorge Pérez Juárez, CEO of Rimsa.‖
  6. 6. PHARMA UPTODAY 6 ―In addition to this unique portfolio of patent-protected products, Rimsa differentiates itself as a leading provider of branded specialty drugs, including fixed-dose combinations, which increase adherence and reduce overall costs to patients,‖ stated Siggi Olafsson, President and CEO of Teva Global Generic Medicines. ―We will build on their brand reputation, successful sales force model, well-established commercial footprint and loyal customer base to introduce additional specialty and generic Teva medicines to patients in Mexico and across the region.‖ The acquisition was unanimously approved by Teva's Board of Directors, led by the Chairman, Prof. Yitzhak Peterburg. Teva expects to close these transactions by early first quarter, 2016. The acquisition is not expected to impact 2016 non-GAAP earnings and is expected to be accretive starting Q1 2017. The transactions will be funded through a combination of cash on hand and lines of credit. UK and India regulators agree deal for closer collaboration to improve public safety The Medicines and Healthcare products Regulatory Agency (MHRA) has today (5 October 2015) signed a Memorandum of Understanding (MOU) with its counterpart body in India. This agreement will increase collaboration between the 2 countries in the area of medicines and medical devices with the aim of further improving public safety in the 2 countries. This is the first MOU agreed with the Central Drugs Standard Control Organisation (CDSCO), part of the Ministry of Health and Family Welfare of Republic of India and was signed by Dr Gyanendra Nath Singh, India’s Drugs Controller General, and MHRA Chairman, Professor Sir Michael Rawlins. It provides a formal agreement between the 2 organisations, and strengthens relations between the UK and Indian governments. The central understandings of the agreement include promotion of each other’s regulatory frameworks, requirements and processes. Significant outcomes will include the facilitation and exchange of information and opportunities for technical cooperation of mutual benefit, helping to ensure the regulators are better equipped to protect the health of their respective publics. MHRA Chairman, Professor Sir Michael Rawlins said: We are committed to protecting the health of UK citizens and that’s why we are continuing to formalise our collaborative efforts with key partners like India. We operate in a global environment and agreements such as these serve to further strengthen our ability to promote good practices and we look forward to working even closer with our Indian counterparts. Dr Gyanendra Nath Singh commented: The MoU signed between MHRA and CDSCO is going to create a new platform where patients will be given utmost importance. Quality medicine, affordability and transparency will be the tools for making medicines available to the people of the two nations.
  7. 7. PHARMA UPTODAY 7 In 2014, MHRA carried out more than 550 inspections in the UK and 125 in non-EU countries, 49 of which were in India. The India Brand Equity Foundation states that the Indian pharma sector accounts for about 2.4% of the global pharma industry and is the 3rd largest in terms of volume. Approximately 25% of UK medicines are made in India and each batch is tested on importation to ensure it is safe, of good quality and effective and it is important that MHRA assessors continue to inspect Indian sites to ensure Good Manufacturing Practice – a globally recognised regulatory framework. Sir Michael Rawlins added: ―It’s essential that the commitment to good quality manufacturing comes right down from the top levels of management to those on the factory floor, and throughout the entire industry. ―Indian firms already accept and understand this, and the MOU is part of a concerted effort to ensure the UK and wider global public continue to have access to quality and safe medicines.‖ The signing of the MOU took place at CDSCO’s headquarters in New Delhi and was followed by a series of meetings to discuss next steps. The agreement is similar to those already in place between MHRA and other counterpart bodies in China and America, although it is a standalone bilateral document in its own right. FTC Approves Endo’s Acquisition of Par The FTC has cleared the way for Endo Pharmaceuticals to acquire Par Pharmaceuticals, pending the divestiture of two of its generic drugs. To resolve anticompetitive concerns, Endo will sell the rights and assets to glycopyrrolate and methimazole tablets to Rising Pharmaceuticals in New Jersey. Used to treat ulcers and overproduction of thyroid hormone, the medications are not commonly produced and, if the drugmakers were allowed to keep them in their post-deal portfolio, costs would likely have been raised, the FTC said last week. Under the FTC settlement, Endo will supply Rising Pharmaceuticals with the drugs for two years while it arranges for a third-party manufacturer. The $8 billion deal, announced in May, will place Endo among the top five firms in the U.S. generics market, adding more than 100 new drugs and more than 200 ANDAs to its offerings. The Par acquisition follows several large Endo purchases in recent years, the most recent being Auxilium for $2.6 billion last October.
  8. 8. PHARMA UPTODAY 8 Sun Pharma Recalls Over 216,000 Bottles of Blood Pressure, Antidepressant Drugs Sun Pharma is recalling more than 216,000 bottles of felodipine blood pressure tablets and the antidepressant imipramine because the varnish on labels is leaching a chemical into the containers. The news comes on the heels of a July recall of bupropion hydrochloride tablets made at Sun’s Halol, Gujarat, India, plant. The products, produced by Sun’s Mutual Pharmaceutical subsidiary, include 187,106 bottles of felodipine extended-release tablets and 29,660 bottles of imipramine. The problem was detected in stability results, which found trace amounts of benzophenone in the drugs. Sun says the impurity occurs naturally and is unlikely to cause any significant adverse events, and that the recall was initiated as a precaution. The products were distributed between February 2014 and April of this year. The FDA has designated the recalls Class III, the least worrisome rating. The July recall of bupropion hydrochloride followed one in March involving eye solutions, continuing a string of recalls of product made at that site. Those recalls followed 2014 recalls by the Halol facility and Detroit-based Caraco Pharmaceutical Laboratories, which distributes drugs for Sun in the U.S. US FDA Activities Report of the Generic Drug Program (FY 2015) GDUFA YEAR/Actions This Month 14-Oct 14- Nov 14- Dec 15- Jan 15- Feb 15- Mar 15- Apr 15- May 15-Jun 15- Jul 15- Aug 15- Sep FY- 2015 Refuse to Receive (RTR) + 12 11 15 30 27 13 11 15 20 13 19 186 Withdrawals 6 12 2 11 7 13 23 11 21 16 18 140 Approvals 45 28 29 25 27 19 49 47 57 47 58 431 Tentative Approvals 10 7 5 5 13 6 19 13 10 12 6 106
  9. 9. PHARMA UPTODAY 9 Complete Responses (CR) + 43 76 96 104 108 94 115 97 116 134 96 1079 Drug Master File Completeness Assessment (DMF CA) 124 55 71 92 86 55 76 62 65 54 35 775 GDUFA YEAR (Receipts)Submissions This Month 14- Oct 14- Nov 14- Dec 15- Jan 15- Feb 15- Mar 15- Apr 15- May 15- Jun 15- Jul 15- Aug 15- Sep FY- 2015 Abbreviated New Drug Applications (ANDA) ++ 50 27 43 27 29 57 58 49 39 52 431 CBE Supplements + 473 385 434 411 420 439 413 474 472 425 4346 PAS Supplements + 45 22 51 33 37 55 38 48 37 41 407 GDUFA YEAR/ (Receipts)Amendments 14- Oct 14- Nov 14- Dec 15- Jan 15- Feb 15- Mar 15- Apr 15- May 15- Jun 15- Jul 15- Aug 15- Sep FY- 2015 Originals (Pre FY15) Administrative 119 228 388 339 429 372 Originals (Pre FY15) Solicited (CR, ECD/IR) 86 80 178 320 582 503 Originals (Pre FY15) Unsolicited 398 229 108 118 84 130 Originals (FY15) Administrative 1 21 20 30 21 23 Originals (FY15) Tier 1 0 0 0 0 0 1
  10. 10. PHARMA UPTODAY 10 Originals (FY15) Tier 2 0 0 0 0 0 1 Originals (FY15) Tier 3 0 0 0 0 0 0 Originals (FY15) ECD/IR 0 7 4 43 37 54 PAS Supplements (Pre FY15) Administrative 5 21 15 18 14 9 PAS Supplements (Pre FY15) Solicited (CR, ECD/IR) 47 35 88 45 42 53 PAS Supplements (Pre FY15) Unsolicited 43 21 11 11 10 9 PAS Supplements (FY15) Administrative 1 6 3 7 2 7 PAS Supplements (FY15) Tier 1 0 0 0 0 0 1 PAS Supplements (FY15) Tier 2 0 0 0 0 1 0 PAS Supplements (FY15) Tier 3 0 0 0 0 0 0 PAS Supplements (FY15) ECD/IR 0 0 3 4 11 28 CBE Amendments (all years together) 61 34 29 72 71 101 GDUFA YEAR (Receipts) 14- Oct 14- Nov 14- Dec 15- Jan 15- Feb 15- Mar 15- Apr 15-May 15- Jun 15- Jul 15- Aug 15- Sep FY- 2015 Controls +++ 112 86 111 115 104 140 136 124 141 170 1239
  11. 11. PHARMA UPTODAY 11 GDUFA Post CR Meeting Requests ++++ 84 89 96 105 113 123 129 132 134 137 1142 Post CR Meeting Requests This month 0 5 7 9 8 10 6 3 2 3 53 + = Revised to reflect more accurate counting by the GDRP. For example RTRs revised to include both RTR due to failure to pay user fees and RTR due to technical reasons. ++ = Starting FY15 ANDA Original Receipts are reported as raw receipts (versus filed receipts). +++ = FY 15 Controls have been revised to count only those requests appropriate for a control. ++++ = Cumulative and NOT specific to the month. DMF raw receipts have been eliminated since DMF Completeness Assessments present a more accurate indication of workload. Numbers are rounded and do not reflect actual numbers for Congressional reporting purposes. Note: Amendment metrics for April, May and June will be forthcoming Source: ved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm375079.htm FDA Reassures Industry on Use of Quality Metrics The FDA is trying to reassure drug companies by making it clear that the agency won’t use its quality metrics collection to spur 483s, warning letters and other enforcement actions. The quality metrics effort is not an enforcement program; it is a surveillance program, explained Russell Wesdyk, acting director of the Office of Pharmaceutical Quality’s Office of Surveillance. Submission of metrics will be used to determine a firm’s risk score in the selection model used to prioritize scheduling of routine surveillance inspections, he said. To encourage data submission, sites with more metrics could see a greater reduction of score, Wesdyk, said, adding ―more information is better than less information.‖ For example, a drugmaker may worry that high recall or batch failure rates will mean they’ll get inspected more. In fact, it could be just the opposite, as the numbers could be in line with other like manufacturers, Wesdyk said. In fact, a manufacturer that submits fewer data or data showing a very low recall or failure rate could draw more agency scrutiny, he added. He spoke at a session last week at the FDA/PQRI Conference on Advancing Product Quality in Bethesda, Md. Wesdyk said he is also surprised by the amount of feedback from industry groups questioning the agency’s authority to collect quality metrics. He said the FDA is trying to help industry and is not the ―boogeyman hiding behind trees.‖
  12. 12. PHARMA UPTODAY 12 Meanwhile, ISPE said it is nearly halfway through the data submission and collection phase of its quality metrics pilot program, which is continuing despite differences in its metrics and those the FDA has targeted. Three of the four quality metrics the FDA plans to collect — lot acceptance rate, product quality complaint rate and invalidated out-of-specification rate — are accounted for in the eight quality metrics ISPE is collecting. ISPE has collected data from 21 companies covering 88 sites so far. Data collected by Oct. 30 will be analyzed for inclusion in ISPE’s comments on the FDA’s draft guidance on quality metrics, which are due Nov. 27, said Máiréad Goetz, co-chair of ISPE’s quality metrics team. The final deadline for collecting data under ISPE’s pilot program is Nov. 30. The totality of data will be analyzed for ISPE’s final report, expected next February or March, Goetz said. FDA’s Team-Based Inspection Program Taking Shape The FDA’s new team-based inspection program is starting to take shape with a steering committee led by high-ranking FDA officials and three subgroups. The three subgroups are the Pre-Approval Inspection group, the Surveillance Inspection group and the tentatively named For-Cause Inspection group. Tentative scoring systems, investigator training, IT systems and investigator questions have been drafted for the first two groups, while the for-cause group’s functions are being developed, said Russell Wesdyk, acting director of OPQ’s Office of Surveillance. Wesdyk spoke during a session last week at the FDA/Product Quality Research Institute Conference on Advancing Product Quality in Bethesda, Md. The PAI and Surveillance groups have conducted pilot inspections, and more are planned, Wesdyk said. At this time, there are no plans for the for-cause group to conduct pilot inspections, as the pilots for the other two groups may be enough, he said. The pilot program is also testing a new IT system to support investigators while on site. Once fully implemented, PAI will be tasked with performing inspections whose observations inform premarket review decisions. The surveillance group will observe the state of quality in a facility to determine quality risk and perform routine inspections, Lawrence Yu, deputy director of the Office of Pharmaceutical Quality, said. The for-cause inspections will be handled by ORA and look for evidence of cGMP violations to support enforcement actions. Observations made in the PAI or surveillance inspections could trigger escalation or transition into for-cause inspections, Yu said. The New Inspection Protocol Project Steering Committee is co-chaired by Theresa Mullin, director of CDER’s Office of Strategic Operations, and Ellen Morrison, assistant commissioner for operations in the FDA’s Office of Regulatory Affairs.
  13. 13. PHARMA UPTODAY 13 EMA Report Shows 350 GMP Inspections in First Half of 2015 The European Medicines Agency conducted 350 good manufacturing practices inspections in the first half of this year — roughly 50 percent more than in the same period a year ago, a new report shows. The number of GMP inspections nearly reached the annual forecast for the entire year, causing the agency to revise its 2015 forecast from 390 to 425. By comparison, inspections totaled 235 for the first half of 2014. The EMA also met its half-year target of conducting 10 percent of routine GMP reinspections of manufacturing sites using an exchange of information with international partners. The EMA’s mid-year report, released last week, also shows pharmacovigilance monitoring running even with 2014, with 10 inspections, while the number of good laboratory practice inspections increased from zero to one and good clinical practice audits edged up to 35, from 33 a year ago. Indian pharma majors get 113 ANDAs approval from US FDA in Jan-Sept 2015 Major Indian pharmaceutical companies and their subsidiaries have set to get higher Abbreviated New Drug Application (ANDAs) approvals during 2015 with rising investment in research and development. Indian companies already secured final approvals for 113 ANDAs from US FDA during the first nine months ended September 2015 and 32 tentative approvals. This worked out to over 30 per cent of the total approvals by US FDA. The US FDA has approved total 372 final ANDAs during January-September 2015 and 102 tentative ANDAs. The overall approval rate of US FDA during 2015 will be higher as compared to full year 2014. In 2014, it approved 416 ANDAs of which Indian companies secured 122 final ANDA approvals. Aurobindo Pharma and Lupin received highest number of 21 ANDA approvals each during the first nine months ended September 2015, followed by 8 ANDA approvals each by Alembic Pharmaceuticals, Glenmark Pharmaceuticals and Hetero Laboratories. Jubilant Life Sciences, Macleods Pharma and Sun Pharmaceuticals grabbed 6 ANDA approvals each during first nine months of 2015. Torrent Pharmaceuticals and Orchid Chemicals and Pharmaceuticals got 4 and 5 ANDA approvals each. The higher approvals shows that Indian companies are well set to stepped up their presence in the highly regulated market like US, Europe and also in emerging markets by offering new generic products. Patent expiration in coming years may generate higher demand for these products. Aurobindo Pharma, which secured approval for 21 ANDAs between January-September 2015, has
  14. 14. PHARMA UPTODAY 14 incurred an R&D expenditure of Rs.359.88 crore during the year ended March 2015 as against Rs.270.80 crore in the previous year. The company has filed 192 DMFs and 376 ANDAs with the US FDA upto March 2015 and it received 193 ANDA approvals and 183 ANDA approvals are awaiting. Lupin's R&D expenditure moved up by 16.7 per cent to Rs.1,118.54 crore during the year ended March 2015 from Rs.958.28 crore in the previous year. It filed 18 ANDAs for the US market during 2014-15 and its cumulative total reached at 210 ANDAs. Currently it has 99 ANDAs pending for approval. It has 15 exclusive first-to-file ANDAs addressing a market size of US$ 2.5 billion. It also filed 435 patent applications including 97 new inventions taking the cumulative total of 2,197 patents filed. Sun Pharmaceutical, after acquisition of Ranbaxy Laboratories, pushed its consolidated R&D expenditure at Rs.1,955 crore during the fiscal year ended March 2015 as compared to Rs.1,042 crore in the previous year. Its five major R&D centres are located in India, Israel, Canada and USA and strengthening the speciailty pipeline including patented products and complex generics. Sun's cumulative filings of ANDAs reached at 597 and it received cumulative approvals for 438 ANDAs till March 2015. The company and Taro Pharma received final approval for 8 ANDAs during January- September 2015 and 2 tentative approvals. Besides above pharma majors, Ajanta Pharma, Dr Reddy's Laboratories, Emcure Pharma, Granules India, Natco Pharma, Strides Arcolab, Wockhardt, Zydus Pharma received approvals for ANDAs. FDA Inspections at API Manufacturers - current Warning Letter Trends Taking a look at the Warning Letters the FDA issued after inspections of activesubstance manufacturers in the 2015 fiscal year, which ended on 30 September 2015, it is first of all striking that only non-American companies are among the addressees. Almost half of them are Indian companies. Overall the numbers look like this: India (3 WLs); China (2 WLs); Canada (1 WL); Thailand (1 WL); Czech Republic (1 WL). The top issue in the Warning Letters is the non-GMP compliant handling of electronic data or missing data integrity. Each of the 8 warning letters contains the following comment in the same wording: "Failure to prevent unauthorized access or changes to data and to provide adequate controls to prevent omission of data." The lack of access control on electronic (raw) data is an issue the FDA investigators have been observing for a long time, especially during inspections in pharmaceutical companies. In this as well as in the last fiscal year there were significant deficiencies in several companies - medicinal product as well as API manufacturers - as the comments in the appropriate Warning Letters show. For more
  15. 15. PHARMA UPTODAY 15 information also see the GMP news Another FDA Warning Letter with Focus on "Data Integrity" and FDA Warning Letter on Data Integrity. Ultimately these deficiencies can be traced back to a failure of the quality assurance unit which also affects other areas. In the Warning Letters, the following examples can be found for this:  "Failure of your quality unit to ensure that materials are appropriately tested and the results are reported."  "Failure of your quality unit to exercise its responsibility to ensure the APIs manufactured at your facility are in compliance with CGMP, and meet established specifications for quality and purity." Data were manipulated by laboratory staff (change of the file name), to fake results from identity tests in batches which in reality were not performed. Quality assurance was not able to uncover this manipulation.  Despite an unknown peak in the examination for residual solvents the relevant batches were released. Upon receipt of a complaint regarding this peak an examination was conducted with the result that the contamination originated in the production process itself. Preventive control measures to avoid this contamination were not established.  "Failure to adequately investigate complaints and extend the investigations to other batches that may have been affected." As a result of a complaint (bad smell), a cause study was initiated which was completed prior to implementation of the preventive measures again. The CAPA measures subsequently carried out were obviously not associated with the reason for the complaint.  "Failure to have appropriate controls for issuance of batch records". The use of document templates for batch records is out of control. These can be printed out from the production staff's personal computers. Although there is an SOP for the control of batch records there are no appropriate training records.  "Failure to have appropriate documentation and record controls." Data for tracing raw materials are not available. Log entries are without date/visa and partly corrected with Tippex. There is an SOP prohibiting the use of correction fluid, however this was not trained.  "Failure to record activities at the time they are performed and destruction of original records." Original records of critical process data on uncontrolled memos were transferred subsequently in new report templates (after batch approvals) and then destroyed. This selection of examples shows the lack of fundamental GMP principles which leads to a blatant misconduct of staff and ultimately to quality defects in the final product. The main responsibility usually has the quality unit, which task it actually would be to ensure a thorough training in
  16. 16. PHARMA UPTODAY 16 production and quality control and to monitor compliance with the appropriate regulations. These examples of non-GMP-compliant behavior are not limited to active ingredient manufacturers; there are very similar findings in Warning Letters issued to medicinal product manufacturers. USP wants to considerably expand the Monograph for Ophthalmic Preparations <771> The considerably expanded draft monograph <771> in the American pharmacopeia includes topical ophthalmic products like eye drops as well as ophthalmic preparations for injection purposes. These products are manufactured using terminal sterilisation, sterile filtration and aseptic filtration. An overview lists and describes the different pharmaceutical forms in more detail: solutions, suspensions, ointments, gels, emulsions, strips, injections, inserts and implants. However, the part on product quality is particularly interesting, especially the general tests. According to this, all ophthalmic preparations are to undergo a test to determine the integrity of the packaging and to test for visible particles. A 100% test is only mentioned for ophthalmic preparations for injections in transparent containers. If this is not possible due to the characteristics of the containers, reference is made to random sample tests in monograph <790>. The requirements with regard to subvisible particles are depending on the route of adminstration: According to the draft, products for intraocular use are to correspond with the the monograph Particulate Matter in Ophthalmic Solutions <789>, products for extraocular use should comply with the monograph Particulate Matter in Injections <788>. The inclusion of a limit value for invisible particles in ophthalmic preparations is currently being discussed in Europe, too. You can find information on the discussion of expanding monograph 1163 on the EDQM homepage. Further sections in the USP monograph discuss sterility, preservatives and endotoxins (in injectable products). The requirements described for leachables/extractables that may come from the packaging are also new. It is pointed out that a risk assessment of leachables/extractables is not easy to perform, as there is little data about substances that can be absorbed via the eye. Therefore, data that has been determined for other routes of administration can be used for the risk analysis. Furthermore, the special tests that may be relevant for ophthalmic preparations are listed, such as viscosity, particle size distribution (in suspensions/emulsions) and drop size.
  17. 17. PHARMA UPTODAY 17 GDP certification by accredited bodies and GDP audit by QPs - dangerous misunderstandings With the publication of the new GDP Guideline in the year 2013 the legal requirements concerning the Good Distribution Practice have increased significantly. This has manifold consequences because now compliance with the quality requirements is controlled throughout the complete distribution chain until the final release to the patient. This is the objective at least. The competent supervisory authorities carry out GDP inspections of companies that undertake tasks requiring GDP in the course of distribution. And this is where the problem already starts. Since the date of availability of the new GDP Guideline each company which comes into contact with the supply chain of medicinal products tries to receive a GDP certificate. After all, it is the declared objective of the EU to guarantee GDP compliance throughout the complete supply chain. The GDP certificates are listed throughout Europe in a central database called EudraGMDP. Here, the GDP non-compliance reports are also recorded. So what could be more natural than to attempt to be listed there in order to demonstrate GMP compliance to the customers? But the EU GDP Guide defines the group of companies which are subject to supervision very strict. This means that many of the actors in the supply chain are not under supervision but must implement GDP nevertheless. The competent authority for GDP will normally not carry out GDP inspections at transport companies (shipping companies) or at airport hubs. This gap is now filled by a number of service providers that grant GDP certificates. Some accredited or non accredited bodies have started to offer GDP certificates for shipping companies or even airports. An auditor of the (accredited) body carries out an audit and at the end a GDP certificate beckons which will then be advertised in the internet and in company brochures. And here a big misunderstanding arises. Because these commercial certificates cannot be compared to the GDP certificates issued by the supervisory authority. But many actors in the supply chain are not aware of this fact. The GDP certificate might be a marketing instrument such as the ISO 9001 certificate or a certificate certifying compliance with environmental standards. But it does not confirm GDP compliance within the meaning of an official GDP certificate. This can only be done by the competent supervisory authority. One also hears more and more about so-called QP audits carried out by independent consultants who allegedly confirm GDP compliance by means of a GDP Certificate. As QPs play a central role in the pharmaceutical law it is assumed by some companies that these "QP certificates" have a particularly high significance and that they could virtually serve as substitute for the GDP certificate of the supervisory authority. But this is not the case - as has already been explained for the GDP certificates issued by accredited companies. A QP who actually works as part of the supplier qualification for a pharmaceutical company will never issue a GDP certificate or written confirmation.
  18. 18. PHARMA UPTODAY 18 What should companies do that would like to have a GDP certificate but will not be inspected by the authority? It is important that each of these companies implements GDP. The requirements can be checked in the GDP Guideline. A further certificate is not required. The key is an internal quality management system for establishing GDP requirements with sufficiently qualified personnel. In the case of a new customer/supplier relationship, for instance, the external auditor will want to see the concrete implementation of GDP - regardless of a GDP certificate of any organisation. FDA Clears Impax of Issues from 2011 Warning Letter Impax Laboratories says the FDA has inspected its Hayward, Calif., manufacturing plant and cleared it of all issues raised in a 2011 warning letter, paving the way for the launch of new drug products. The pipeline consists of 33 pending ANDAs, with 25 developed internally and eight developed through external partnerships, CEO and President Fred Wilkinson said. Of the 17 ANDAs developed at the Hayward plant, two could launch later this year and eight in 2016. The applications include generics of Sanofi's kidney disease drug Renvela (sevelamer carbonate), Daiichi Sankyo's and Genzyme's diabetes and cholesterol drug Welchol (colesevelam HCI), Teva's ADHD drug Adderall XR and Purdue Pharma's OxyContin TR. The FDA issued the warning letter in May 2011 for manufacturing violations related to finished pharmaceuticals identified during a Dec. 13, 2010, to Jan. 21, 2011, inspection. The inspection found deviations in sampling and testing of in-process materials and drug products and lapses in production record reviews. For example, Impax couldn't demonstrate that the manufacturing process for fenofibrate capsules was capable of controlling weight variations and didn't have data to support the temperature range used during the granulation process of colestipol hydrochloride tablets, according to the warning letter. The letter followed a Form 483 that triggered a voluntary recall of fenofibrate capsules in March 2011. Wilkinson did not say how the company resolved the items in the warning letter. FDA Bans Imports From Major Indian API Manufacturer The US Food and Drug Administration (FDA) on Wednesday added Indian active pharmaceutical ingredient (API) manufacturer Megafine Pharma's Nashik site in Maharashtra, India, to a list of foreign manufacturing sites banned from sending products to the US. Megafine, which was hit with an FDA Form 483 back in May at the site, produces 24 APIs for the US market, including for drugs intended to treat Alzheimer's disease, depression, schizophrenia, multiple sclerosis and overactive bladders. The company also produces the same number of APIs for the EU market, as well as a number of other products for Canada, Australia, Brazil, Mexico and South
  19. 19. PHARMA UPTODAY 19 Korea. The Nashik site, according to the company, has been inspected and approved by regulators including the European Medicines Agency, Japan's Pharmaceutical and Medical Devices Agency, the WHO and others. The notice on Megafine does not indicate the specific issues that caused the import alert and does not indicate if the company's other manufacturing site in Vapi, India will be impacted. Form 483 According to a heavily redacted 13-page Form 483, the company was cited for manipulating lab tests, as well as unjustified and unrecorded deviations from written lab mechanisms. The 483 notes that one of the company's quality control (QC) analysts "manipulated" a test chromatogram "by removing the unwanted peak out of the chromatogram and passed off the passing chromatogram as the valid result." In addition, the FDA inspector found that the QC management could not explain the "wide variation between" an initial test result and a retest result, though, ―It is believed that the initial OOS [out of specification] assay was switched with old passing sample vials and retested to obtain the passing test results." Another QC analyst was cited for manipulating high-performance liquid chromatography software "to obtain passing test results." In addition, FDA found that no "investigation reports were initiated after identification of non-cGMP [current good manufacturing practice] practices within the production and quality control department." Companies on the import alert list that would like to request removal, according to FDA, "should provide information to FDA to adequately demonstrate that the manufacturer has resolved the conditions that gave rise to the appearance of the violation, so that the agency will have confidence that future entries will be in compliance. This may include a letter detailing its corrective actions, accompanied by documentation." Forty-five other Indian pharmaceutical and API manufacturers are currently included on the import alert list, including Ranbaxy, Wockhardt and Ipca Laboratories. Megafine did not respond to a request for comment. For more details browse: um=email&utm_source=govdelivery
  20. 20. PHARMA UPTODAY 20 Register of brokers authorised to deal in human medicines MHRA (Medicines and Healthcare products Regulatory Agency) publishes current listing of UK brokers authorised to broker human medicines, including company name, registration and address. Source: human-medicines EU Court Clarifies When Drug Patents Expire A ruling by the Court of Justice of the European Union has clarified when drug patents expire, in a decision that could prove lucrative for drugmakers even though it adds only a few days of patent protection. The case, Seattle Genetics Inc. v. Austrian Patent Office, deals with a specific aspect of European patent law known as a supplementary protection certificate, which extends the duration of certain rights associated with a patent. SPCs take effect after the general patent expires and typically last for five years. The combined exclusivity from the patent and SPC is normally capped at 15 years from the time the product first receives marketing authorization. The Austrian Patent Office granted an SPC to Seattle Genetics on Oct. 25, 2012, and set the expiration date as Oct. 25, 2027. Seattle Genetics challenged that date, arguing the 15 years of protection should start when the company was notified of the authorization, thereby pushing back the expiration until Oct. 30, 2027. In its Oct. 6 ruling, the CJEU agreed with the drugmaker, saying the term of an SPC begins on the date when the innovator is notified of marketing authorization, not the date when authorities decided to grant that authorization. The case involved Seattle Genetics’ lymphoma therapy Adcetris (brentuximab vedotin). Karnataka’s 27,000 chemists shut stores, KCDA submits memorandum to state health minister to ban all online pharmacy websites Karnataka Chemists & Druggists Association (KCDA) have stated that all the 27,000 chemists shops across the state have brought the shutters down and the strike is a total success. The Association also submitted to Karnataka health and family welfare minister UT Khader a memorandum to ban all online pharmacy websites because it violates the Drugs & Cosmetics Act & Rules. ―Our memorandum was also accepted by Karnataka drugs controller Raghurama Bhandary, said V Harikrishnan, president Karnataka Chemists & Druggists Association and the Bangalore District Chemists and Druggists Association.
  21. 21. PHARMA UPTODAY 21 ―We are confident that the state government has comprehended the issue and will make efforts to arrive at solution at the earliest,‖ he added. The chemists and druggists across the state took out protest marches at various places. In Bengaluru 2,500 chemists carried out peaceful protests at the Freedom Park to fight the cause of online pharmacy players operating in the absence of a set of norms. A dedicated committee for the creation of online pharmacy guidelines led by Maharashtra FDA commissioner Harshadeep Kamble has Karnataka drugs controller Raghurama Bhandary, Odisha drugs controller H Mahapatra, CDCSO assistant drugs controller Atul Kumar Nasa, FDA Goa director Salim A Velijee, Madhya Pradesh State Licensing Authority Pankaj Agarwal and CDSCO joint drugs controller Dr Eshwara Reddy as its members. The committee is now awaiting the comments of the stakeholders covering druggists, chemists and the related associations before the month end. The online pharmacy retailers in the country have formed an association, the Indian Internet Pharmacy Association (IIPA), to promote and protect the public health by ensuring that its members operate in accordance with the existing Drugs & Cosmetics Rules read with Sections 4 & 5 of Information Technology Act, 2008, and Pharmacy Practice Regulations, 2015 issued by government of India through PCI. ―We strongly object to online pharmacy which is currently an unethical mode of doing business. It is heartening to note that the state government is looking into the issue and keen to help us,‖ Harikrishnan told. Both Karnataka Chemists & Druggists Association and the Bangalore District Chemists and Druggists Association have exempted the hospital pharmacies in this 24-hour bandh. This ensured the public and patients have had access to drugs from these outlets. According to a section of people who gathered at pharmacy outlets in the government hospitals of Victoria and Sri Jayadeva Institute of Cardiology, with an increased awareness about the nationwide strike call on October 14, the drugs have been purchased well in advance to offset any immediate emergencies. However, it is the outpatients and in-patients medicines which constituted the usual and major chunk of sales today at the hospital pharmacies in most hospitals. India risks missing boat as biosimilars shake up drug industry India, which has dominated the generic drugs industry for decades, is falling behind in the race to make copies of complex biotech drugs, which are expected to generate tens of billions of dollars in sales in the coming years.
  22. 22. PHARMA UPTODAY 22 While Indian firms have launched a few such products on the domestic market, where regulatory barriers are relatively low, they are being overtaken by European, American and South Korean firms in the race to supply lucrative Western markets. Just three Indian groups - Biocon Ltd, Dr Reddy's Laboratories Ltd and Intas Pharamceuticals Ltd - are working with partners on so-called biosimilars aimed at the United States and Europe. Biotech drugs, which require genetic engineering, account for a growing share of new drugs and the future sales of copycat products will also switch to this category of pharmaceuticals from simple small-molecule pills like aspirin. The global biosimilars market is predicted to have sales of $25 billion by 2020, according to a 2014 Thomson Reuters report. "Biosimilars is a big opportunity," said Sujay Shetty, leader of the life sciences practice at PwC India. "But unlike generics, it is not yet an opportunity (for Indian companies) in the U.S." Copying chemical-based drugs has long been the bedrock of India's $15 billion pharmaceuticals industry. Biotech drugs, however, are more difficult to make and cannot be replicated exactly, which is why regulators have come up with the notion of versions that are similar enough to do the job. That also means regulators will be eagle-eyed on quality, posing a challenge to Indian companies, which have been distracted in recent years by manufacturing problems that have led to some drugs being barred from key overseas markets. Many, including the country's biggest drugmaker Sun Pharmaceutical Industries Ltd, are still struggling to fix issues at their generic drug factories. "FAR BEHIND" Biosimilars have been available in India since the early 2000s, well before their 2006 arrival in Europe and the recent introduction of a regulatory pathway in the United States, where the first biosimilar was launched only last month. But India's experience has not been problem-free. Intas, for example, recently received reports of some patients on its biosimilar version of Roche's eye drug Lucentis developing inflammation barely two months after the drug's launch. An Intas spokesman said the problem was found to be in the drug's "cold chain logistics" distribution channel and has restricted supply of the drug. Arun Chandavarkar, the chief executive of Biocon, seen by analysts as the front-runner among Indian firms developing biosimilars, believes the cost and complexity of developing biosimilars will be a deterrent for many Indian players. "At this time, there can't be too many companies willing to put in that much effort and investment," he said. The three Indian companies that have stated plans to make biosimilars for the United States and Europe are all partnered with larger Western firms. Biocon has a tie-up with Mylan Inc and is testing four molecules in global Phase III trials, for which it plans to seek approvals in the United States and Europe starting in fiscal 2017, Chandavarkar said.
  23. 23. PHARMA UPTODAY 23 Dr Reddy's is developing biosimilars such as rituximab and pegfilgrastim for use in cancer treatment under a pact with Germany's Merck KGaA and said it plans to launch its first biosimilar in the United States by 2018. A spokesman at Intas, which developed pegfilgrastim in partnership with Canada's Apotex Inc, told Reuters the company was considering partnering with a Swiss drugmaker to launch the product in the United States. It declined to name the firm. Chandru Chawla, head of Cipla Ltd's new ventures unit, said India's "fundamental disadvantage" over United States, Europe and South Korea was that biotechnology never evolved in India to the extent that chemistry did. "In terms of having the right knowledge ecosystem and the pools of talent, India is far behind," he said. Globally, Western pharmaceutical firms such as Novartis AG; Pfizer Inc, in partnership with South Korea's Celltrion Inc; and Merck & Co with partner Samsung Bioepis, are leading in the race to dominate the Western biosimilars market. "South Korea has made very significant strides in a very short period of time," said Cartikeya Reddy, Dr Reddy's executive vice president for biologics. "In this regard they have indeed pulled ahead of Indian companies." Indian drug retailers protest against e-pharmacies Indian drug retailers shut up shop for the day on Wednesday to protest against the country's growing online pharmacy industry, and threatened to close indefinitely if the federal government did not shut down e-pharmacies. The nationwide protest was widely supported, with as many as 850,000 chemists closing their doors, leaving patients waiting in long queues at any pharmacies that were open. "I have been to 7-8 shops that were closed. My son has fever, and he needs medicine urgently," said Sukanti Bhoi, 55, as she waited for her turn at a government hospital pharmacy in the eastern state of Odisha. Shops inside and around hospitals as well as 24-hour pharmacies did not join in the one-day strike. Online pharmacies are a relatively new phenomenon in India, where mom-and-pop stores have long dispensed drugs. But online retailers pose a threat to their bricks-and-mortar peers in a market IMS Health estimates is worth about $13 billion. Companies including Zigy and Sequoia Capital-backed 1mg have set up e-pharmacies over the past couple of years. Healthcare company Apollo Hospitals Enterprise plans to start online sales if the government regulates the business. Drug retailers are worried. "It is a matter of our livelihoods, we must be prepared for a fight," said pharmacist Satish Vij, who traveled from northern Haryana state to take part in a protest in New Delhi, where about 1,000 people, mostly pharmacists, wore black arm bands, held placards and shouted slogans against e- pharmacies. "We will struggle if multinationals enter this business," he said.
  24. 24. PHARMA UPTODAY 24 J.S. Shinde, president of the All India Organization of Chemists and Druggists which called the protest, said the retailers' trade group will consider an indefinite strike if the government does not stop online drug sales within two months. The dispute pits drug retailers, many of whom belong to the middle-class voter-base of Prime Minister Narendra Modi's Bharatiya Janata Party, against the leader's push to encourage tech and digital entrepreneurship in India. Late on Tuesday, in a last-minute attempt to get pharmacies to stay open, Modi's Health Ministry said it was studying several representations on how the online pharmacy business should be regulated. It said the views of all stakeholders will be considered. A Health Ministry spokeswoman could not immediately be reached for comment on Wednesday. But retailers do not even want the government to consider online pharmacies as a legitimate business. They say online sales will lead to more cases of drug abuse as medicines will be sold without proper verification. E-pharmacies say they have safeguards in place. Prashant Tandon, president of the newly formed group of e-pharmacies -- Indian Internet Pharmacy Association -- said the internet will also help small drug stores grow faster. Japan's drug regulator PMDA plans India office Japan's drug regulator, the Pharmaceuticals and Medical Devices Agency ( PMDA), is set to open an India office soon, amid concerns over an aging population and burgeoning healthcare costs in a country dominated by branded drugs. The move is expected to help Indian generic drug manufacturers, which have been seeking to increase their presence in Japan either through exports or by forging joint ventures with partners in that country. Japan's market is worth $110 billion. Japan wants to lower healthcare costs by encouraging generic drugs. It's looking to double the share of generics in its healthcare system to 60% by 2017-18 to ease the burden on public expenditure, translating into an attractive op portunity for Indian firms. "Indian drug makers, which are known for their skills in producing efficacious and affordable copycat medicines, couldn't make much headway in the highly attractive but regulated Japanese market for decades," said a senior commerce ministry official, who did not want to be named. "The Japanese drug regulator is of late showing interest to collaborate with its Indian counterpart over the last few weeks."
  25. 25. PHARMA UPTODAY 25 The FDA Could Earn Over $60 Million A Day From Enforcing The Law Many clinical trials on medicines and devices are subject to a 2007 federal law that requires the results to be publicly disclosed on a federally sponsored website within a year after the clinical trial is over. The reason for this requirement is simple: to give doctors and patients full information so that they can make educated decisions about a given treatment. If disappointing clinical trial results remain hidden, while only the most positive results are published and presented in the media, doctors and patients can be wildly misled. Unfortunately, investigators have found that over half the time, clinical trial sponsors fail to abide by the law, sometimes failing to disclose results even after five years have elapsed. Even more unfortunately, the Food and Drug Administration (FDA) has never once imposed the legally authorized $10,000-per-day fine for failure to disclose a clinical trial’s results. Compliance With Reporting Requirements The most recent investigation was published in the New England Journal of Medicine (NEJM) in March 2015. The authors identified 13,327 clinical trials that were registered on, that were completed between 2008 and 2012, and that were subject to the 2007 federal law requiring full disclosure. A mere 13.4 percent of the clinical trials actually disclosed their results within the 12 months required by law, and even after up to four years had elapsed, only 50.5 percent had disclosed the results or asked for a delay (see Figure 2 in the NEJM article). In a twist that ought to embarrass academics, industry-funded trials were more likely to disclose results than the National Institutes of Health (NIH)-funded trials, which were in turn more likely to disclose results than academic medical centers. The authors found 6,599 clinical trials that were overdue on reporting results. Increasing FDA Enforcement If the FDA imposed a $10,000 per day fine on each of these 6,599 outstanding trials, clinical trial sponsors would be responsible for $66 million in payments in the first day alone, adding up to over $24 billion per year. Although the $24 billion figure shows the size and scope of the problem, the collective fines would never reach that amount because as soon as the FDA actually begins enforcing the law, the researchers who conducted these 6,599 trials would finally be incentivized to report the trials’ results. Why doesn’t the FDA enforce the law? Some have argued that is an antiquated and difficult-to-use website. True enough, but given that 38 percent of trials do disclose their results at some point, it is clearly not impossible to do so. This is not a reason to leave the federal law completely unenforced. The NEJM article states that one reason for lack of enforcement is that a new rule on clinical trial report is still pending. But the 2007 law itself requires basic reporting of results; the only point of a
  26. 26. PHARMA UPTODAY 26 new rule is toexpand the requirements to include other items, such as protocols. The mere fact that a rule may be expanded in the future is no reason to leave the current requirements unenforced. Yet another possibility is that the FDA does not want to get bogged down in lawsuits from companies or universities that have a valid reason for delay. But this argument would suggest, at most, that the FDA ought to levy a fine only when truly merited, not that the FDA should never enforce the fine at all. My proposal: as an experiment, the FDA should give the 30-day notice required by statute, and then set aside a single week in which it will levy the $10,000-per-day fine on all overdue trials. Assuming that there are around 6,600 overdue trials that don’t come into compliance within the 30-day grace period, the FDA would end up imposing over $460 million in fines within a week’s time. In so doing, it would make a strong statement that disobeying the law and hiding clinical trial results is no longer acceptable. And within a week, compliance with the law would likely shoot up astronomically, and we would have more complete knowledge about how well or how poorly drugs actually work. In turn, we could all make better decisions about how to improve our nation’s health. Source: enforcing-the-law/ Do fast drug approvals by FDA help or harm patients? Two recent studies published by the British Journal of Medicine (BJM) raise concerns about the speed with which the Food and Drug Administration approves drugs for market in the United States. According to the FDA the stages of drug development and review necessary to gain marketing approval include:  Pre-clinical Testing;  Investigational New Drug Application;  Phase 1 studies – Focused on safety. Seeks to identify frequent side effects, etc.;  Phase 2 studies – Focused on efficacy. Does the drug work on the condition or disease?;  Phase 3 studies – A larger pool of subjects is tested for safety and effectiveness of drug;  Review Meeting between the Drug maker and FDA;  New Drug Application (NDA) – The formal step the drug maker takes in submitting all testing data to FDA for marketing approval. When the NDA is submitted, the FDA has 60 days to decide whether to file the drug for review. The testing phases are potentially the longest timeframes involved with the drug approval process as it takes time to administer the drugs to the test subjects and gather safety and efficacy data. It can take several years for a drug maker to gather sufficient information from testing phase. Fast-track Approval Process Geared to Help Patients There are four programs available that allow the agency to expedite the development and approval process for new drugs: orphan drug- drugs used for diseases that affect very few people, fast track, accelerated approval, and priority review.
  27. 27. PHARMA UPTODAY 27 Regardless of the program used, expedited approvals are supposed to be reserved for drugs that are considered first in class and innovative enough to treat serious life-threatening illnesses that lack satisfactory treatments. However, when researchers from Brigham and Women’s Hospital and Harvard Medical School examined the FDA’s expedited drug development and approval programs between the years 1987 and 2014 they found quicker approvals were not necessarily granted to drugs defined by that criteria. In fact, researchers found a 2.6% increase per year in the number of expedited review and approval programs during the timeframe studied. They noted these newly approved drugs did not always fit the requirement of being considered first in class or innovative. Lack of In-Depth Testing Information Can Increase Patient Risk One reason for the increase in expedited review and approval of drugs might be the passage of the Prescription Drug User Fee Act (PDUFA). This act was enacted in 1992 and authorizes the FDA to collect fees from companies that produce certain drugs and biological products for humans. At the same time that the FDA increased the amount of drugs it approved through the expedited review process researchers with the Cambridge Health Alliance and Harvard Medical School conducted a study to examine black-box warnings and market withdrawals. These researchers found that drugs approved after the passage of the Prescription Drug User Fee Act were more likely to have a black box warning or be withdrawn from the market. These two findings would suggest that shorter approval times lack sufficient information to properly assess drug safety and efficacy and increase a patient’s health risk. Drug Injury Lawsuits When pharmaceutical makers push for expedited development and approval of products, patient safety could be compromised. Lawsuits have been filed against numerous drug makers who put profits ahead of patients by failing to disclose safety and efficacy information gathered during trial phases or failing to alert healthcare providers and the FDA of adverse events that occur once a drug has market approval. Source: Daiichi Sankyo to Cut Thousands of U.S. Jobs Daiichi Sankyo announced on Friday it plans to conduct another round of job cuts this year. The Japanese drug-maker plans to eliminate an estimated 1,000 to 1,200 jobs primarily from its commercial headquarters in Parsippany, New Jersey as well as reduce the headcount for its field salesforce. Ken Keller, the president of Daiichi Sankyo’s U.S. commercial business, said in a statement that this restructuring would help the firm be better positioned to meet the needs of patients with more complex healthcare needs.
  28. 28. PHARMA UPTODAY 28 The Parsippany location lost 16 percent of its work force earlier this year as part of Daiichi’s continued plan to shift resources away from primary care drugs to focus more on a portfolio of specialty drugs. Daiichi is about to lose patent protection for the lucrative blood pressure drug Benicar within the next few months, according to FiercePharma. Benicar brought in $2.6 billion in sales last year, which accounted for over one-quarter of the drug- maker’s revenue for 2014, writes FiercePharma, which is why the firm is looking for a profitable replacement. Reports pegged the Food and Drug Administration (FDA) approved blood thinner Savaysa as a potential alternative to Benicar. However, Pharmalot’s Ed Silverman wrote that the sales potential for this drug remains unclear because it comes with a boxed-warning that alerts prospective customers of serious side-effects in some patients. The FDA's website explains doctors should cautiously assess starting therapy with Savaysa for atrial fibrillation patients with creatinine clearances greater than 95 millimeters per minute. The drug is less effective in this group and can lead to an increased risk of stroke. This new phase of downsizing will conclude by the end of March 2016. Cipla gets FDA's nine observations and issues noticed memo for Indore unit The US Food and Drug Administration has identified nine areas of concern that need correction at Indian drug maker Cipla's manufacturing unit at Indore. Cipla is among the few large domestic companies that has so far not faced any tough regulatory action from the FDA. As part of its observations made during an inspection of the plant in July and August,FDA investigators Ademola Daramola and Nebil Oumer noted that the quality control unit lacked the authority to review production records to ensure that no errors have occurred and to investigate any mistakes made. They said that although one batch of levalbuterol inhalation solution was recalled from the US in May 2015, "the investigation did not extend into other strengths of the product to determine the product's quality, safety and stability." In another observation, they said a failure related to a leakage was documented 35 times but no study was initiated to identify problems that could potentially affect product safety and quality. The FDA officials faulted Cipla's Indore unit for facility and equipment systems and noted that the aseptic processing areas were deficient in monitoring environmental conditions. In an observation related to quality parameters, the FDA staff noted that the sterile filling lines were
  29. 29. PHARMA UPTODAY 29 frequently opened in order to complete manual interventions. "In the packaging hall, sterile product vials exiting the filling line were handled with ungloved and unsanitised hands by packaging line employees," the inspectors said. India maintains GVK Bio’s drug ban issue must be resolved for trade talks with EU India is not ready to play ball yet as Brussels has not made any attempt to sort out the issue of the ban placed on generic drugs tested by Hyderabad-based GVK Biosciences. This is despite leaders such as German Chancellor Angela Merkel pushing for resumption of the proposed India-EU free trade agreement (FTA) talks. ―We have been asking the EU to resolve the matter. We have said that we are even ready for re- testing of the banned medicines. But there is no official response from the bloc on the matter. We will not re-start FTA negotiations till there is some concrete movement on resolution of our problem,‖ a Commerce Ministry official told. EU ban on 700 generics In July this year, the EU had announced a ban on marketing of 700 generics (copied versions of off- patent drugs) tested at GVK Biosciences. Charges of manipulation of clinical trials for bio- equivalence testing (test to prove that generic or copied drugs are as effective as the ones whose patents have expired) of these drugs were made against the lab by a French standards agency ANSM. The ban was implemented on August 21. In protest against the ban, India had called off the talks scheduled in July-end with EU to re-start the FTA negotiations that had not seen movement for more than two years. Merkel, during her recent visit to India, raised the issue of resumption of FTA talks in her meeting with Prime Minister Narendra Modi, but it failed to make an impression on New Delhi. ―The ban on the 700 drugs was implemented despite all our efforts to convince the European Medicines Agency (EMA) that there was nothing wrong with the data. Now that we are prepared for re-tests to be run, the EU is not showing any interest. If the EU can be so stubborn, why should we relent?‖ the official asked. With slowdown gripping the EU, the 27-member bloc is keen to have better access to the Indian markets for its goods, which an FTA can provide. ―If the EU is interested enough in the FTA, we believe it will be more sensitive towards our concerns,‖ the official said. Six-member panel Last month, the Commerce Ministry set up a six-member panel consisting of experts from various departments, including drug regulators and cardiologists, to look into allegations made by ANSM against GVK for manipulation of data related to electrocardiograms (ECGs). The panel confirmed GVK’s assertion that there were no irregularities in the data.
  30. 30. PHARMA UPTODAY 30 ―We feel that the EU may be slow in reacting because of pressure from big pharma companies who benefit if generics are out of the market. Since generics are several times cheaper than the patented variants, the profits of MNCs get dented,‖ the official said. Pharma companies team up to clean industry’s image For the first time ever, some of India's biggest pharmaceutical companies, cutting across their respective associations and representing nearly half the Rs 93,000 crore market, have come together to push for ethical marketing practices to clean up the industry's image. The forum, comprising of 40 to 50 domestic and MNC firms, had its first closed-door meeting on October 14. It has made a "voluntary and moral commitment" to follow ethical marketing practices in "letter and spirit", and will work with the regulatory mechanism to facilitate the exercise. Earlier attempts at bringing about a code acceptable to the entire industry had failed, as the associations the Indian Pharmaceutical Alliance (representing domestic firms), MNCs-led Organisation of Pharmaceutical Producers of India (OPPI) and the Indian Drug Manufacturers' Association (IDMA) were at loggerheads. This comes even as the government has already expressed its intention to make the 'Uniform Code of Pharmaceutical Marketing Practices' mandatory from next year. The code banning cruise tickets, freebies and paid vacations for doctors sponsored by drug companies is voluntary at present. But in light of rampant violations, the government plans to make it binding on companies. The group which includes top MNCs like Novartis, MSD and Abbott, and domestic firms Sun Pharma, Zydus Cadila and Dr Reddy's among others wants to start a movement and build pressure on those who are not following ethical practices. A "voluntary" coming together out of sheer "moral commitment carries greater weightage" than guidelines being thrust on them, said an expert, who is part of the forum. "We have come together voluntarily to push for ethical marketing practices," IPA director general D G Shah said. "Over the years, our industry has been maligned." The 'Forum of Pharmaceutical Ethical Marketing Practices' will draw a core working group from the firms to decide the modalities of taking the "movement" forward, and is in favour of a body similar to the Advertising Council of India which is not a statutory body, to regulate the code. A final proposal will be drawn up soon. Even after the code kicked in this year, complaints continued, with many saying it existed only on paper, as firms try to influence prescriptions. "We plan to seek clarifications from the government so that it (the code) is tweaked into a more practical and implementable code," said Ranjana Smetacek, director general, OPPI.
  31. 31. PHARMA UPTODAY 31 CDSCO begins Induction Programme for assistant drug inspectors to upgrade technical, professional & other functional skills To train the regulatory officers to enable them to devise strategies for optimum utilisation of available resources and to upgrade their technical, professional and other functional skills, the Central Drugs Standard Control Organisation (CDSCO) has begun the Induction Programme for assistant drug inspectors, which is a three-month long training programme from October 5 to December 31, 2015. Major focus of the training, which is being held at National Institute of Biologicals, Noida, will be on technical and regulatory framework in India such as Drugs and Cosmetics Act and Rules, Drugs and Magic Remedies Act, and Narcotic Drugs and Psychotropic Substances Act; legal and administrative issues; managerial and ethical issues; and IT and communication skills. Besides, there will be basic introduction to GMP, GLP, GCP, etc. The CDSCO has roped in a team of high level resource personnel for this programme. To begin with, CDSCO will engage faculty drawn from regulatory agencies, administrative and police services, pharmaceutical industry, management institutes and colleges and also training modules adopted by other regulators. The faculty would comprise retired /current drug regulatory personnel; experts from outside for personality development; officials from CBI, IB, legal departments, subject experts from academic institutions like NIPER, IIT, IISc, etc; subject experts and professionals from industry on GMP, GCP, GLP etc; experts from international organisations including WHO etc; and retired/current senior government officials. The technical areas which will be covered in the programme include good manufacturing practices; good laboratory practices; good clinical practices; good distribution and storage practices; principles of product development and pre-formulation studies; new drug approval process; clinical trials including BA/BE studies; pharmacovigillance; quality audits and inspections – planning, procedures, report writing; and quality assurance and safety aspects in blood and blood products. Besides, the programme will cover special feature of manufacture and quality assurance in vaccines and sera, r-DNA products, active pharmaceutical ingredients, medical devices, stem cells, monoclonal antibodies, antimicrobial resistance etc; advances in biotechnology and immunology; drug discovery and development; and international regulatory framework including WHO. The legal areas of the programme include in-depth knowledge of drug laws – Drugs and Cosmetics Act and Rules; Narcotic Drugs and Psychotropic Substances Act; Drugs Price Control Order; Drugs and Magic Remedies Act; Intellectual Property Rights; and Patent Act.
  32. 32. PHARMA UPTODAY 32 It will also cover principles of jurisprudence, and principles of natural justice; principles of interpretation; applicability of code of Criminal Procedure Code in investigations and trials under drug laws; fundamentals of Evidence Act; investigation techniques including gathering of intelligence and making proper use of such intelligence; and launching of prosecutions. According to senior officials in the CDSCO, there is a constant need for such training programmes as the drug regulatory system needs to keep itself abreast of the fast-changing scientific innovations, evolving international regulatory framework and other developments. The central role of the Indian pharma industry and globalisation necessitate that the regulatory framework has to constantly evolve by integrating new developments. It is, therefore imperative for the present and future drug control officials to continuously upgrade their skills and knowledge, and gain expertise in a variety of subjects to meet with such functional requirements. As the government has started recruiting a number of regulatory personnel, the need of the hour is to train the regulatory officers to enable them to devise strategies for optimum utilisation of available resources. Training that could constantly upgrade their technical, professional and other functional skills would play an important role in their professional growth and diligent execution of their responsibilities, officials said. It is proposed to develop an extensive training programmes for various regulatory officials covering all areas of functions of CDSCO including deputing the inspectors in various zonal offices, port, sub- zonal offices for receiving practical experiences, hands-on training in the various regulatory functions of CDSCO. It has also been decided that all regulatory personnel working in CDSCO will undergo basic and advanced training programmes. FDA Removes Warning Letter Issued to Pacira The FDA has quietly removed a September 2014 warning letter issued to Pacira Pharmaceuticals for touting unapproved uses of its analgesic Exparel. The removal comes after the drugmaker sued the agency late last month claiming a First Amendment right to promote the drug for unproven uses. The Sept. 22, 2014, warning letter cited problems with promotional materials for Exparel (bupivacaine liposome injectable suspension), which is approved as a postsurgical analgesic for bunion and hemorrhoid removal surgeries. According to the FDA, the promotional materials suggested Exparel could be used in aparoscopic cholescystectomy, a procedure to remove gallstones, and in open colectomy to remove part of a patient’s colon. In Pacira Pharmaceuticals Inc., et. al v. Food and Drug Administration et. al, the company maintains that the promotional material is truthful and should be allowed under the same ruling as Amarin Pharma Inc., et. al v. Food and Drug Administration et. al.
  33. 33. PHARMA UPTODAY 33 That ruling rejected the agency’s arguments to prevent off-label promotion, and Pacira said the agency’s arguments are even less persuasive because its promotions met the standards of the drug’s indications and usage section. FDA spokesman Christopher Kelly said the agency cannot comment on the reasoning behind the letter’s removal because it is a matter related to pending litigation. India’s CDSCO Sets Up Three-Month Training Program India’s drug regulatory authority has set up a three-month training program for assistant drug inspectors that will run through the end of this year, as the agency works to ramp up their skill sets. The Central Drugs Standard Control Organization developed an extensive training program for regulatory officials covering all functions of the agency, focusing on technical and regulatory, legal and administrative, managerial and ethical, and IT and communications skills. The program will help bridge a ―huge gap‖ in regulatory science, practices and knowledge, says G.N. Singh, India’s drugs controller general. India’s prime minister approved a $270 million plan in August to strengthen the country’s drug regulatory system, including a training academy for regulatory and drug testing officials. R&D spending of 25 India pharma cos soar by 28.8% in 2014-15 Indian pharmaceutical companies have substantially stepped up investments in R&D during 2014-15 to overcome stiff competition and to create product pipeline and strengthen their presence in world market. A Pharmabiz study of leading 25 companies shows that there is a 28.8 per cent growth in R&D expenditure at Rs. 9,250 crore during the year ended March 2015 from Rs. 7,179 crore in the previous year. These companies have spent almost seven per cent of their consolidated net sales in 2014-15, which is slightly higher from 6.6 per cent in the previous year. These companies have created strong product pipeline by filing ANDAs, DMFs and patents in the world market. With rising healthcare cost, several countries are undertaking cost cutting measures and moving towards cost effective generics and biosimilars products. Indian companies are focusing on novel drug discovery & development (NDDD), generics, biotechnology and biosimilars. These companies are taking steps to strengthen intellectual property area to tap expiration of patent opportunities. Though the R&D investment by Indian companies moved up to Rs. 9,250 crore, it is negligible as compared to major international pharma which are spending over 15 per cent of their net sales on
  34. 34. PHARMA UPTODAY 34 R&D. Indian companies have successfully received higher approvals for ANDAs from the highly regulated authorities. For the nine months ended September 2015, Indian companies received final approval for 113 ANDAs from US FDA as against 122 final ANDAs approval during full year ended December 2014 with Aurobindo Pharma, Lupin, Glenmark Pharmaceuticals, Alembic Pharmaceuticals, Jubilant Life Sciences, Natco Pharma, Sun Pharmaceuticals, Hetero Labs, etc., received good number of approvals. These companies are working towards creating niche and complex products through investments in R&D. Despite high risk of success, gestation periods and uncertainty regarding returns on investment, Indian companies are continuously investing higher funds in R&D efforts. These companies are entering new tie-ups with major international players, universities, academicians and absorbing new technologies. Indian pharma companies are engaged in contract manufacturing in a big way and R&D investments are offering necessary support for these activities. Even these companies are taking up clinical trials for MNCs. Sun Pharmaceutical Industries, after merging Ranbaxy Laboratories during 2014-15, remained on top in R&D spending. Its consolidated R&D expenditure increased almost 87 per cent to Rs. 1,856 crore from Rs. 993 crore in the previous year and enhanced its ability to invest further in R&D. Its consolidated net sales also moved up by 71 per cent to Rs. 27,433 crore from Rs. 16,080 crore. R&D spending as percentage of its consolidated net sales worked out to 6.8 per cent as compared to 6.2 per cent in the previous year. Sun has entered into an exclusive worldwide in-licensing agreement for Merck's investigational therapeutic antibody candidate tidrakiziumab, (MK-3222) to treat chronic plaque psoriasis, a skin aliment. It has setup a joint venture with Intrexon Corporation for developing gene-based therapies for ocular diseases. Sun has strengthen Taro's R&D pipeline and Taro had a pipeline of 35 ANDAs awaiting US FDA approval as at the end of 2014-15. Dr Reddy's Laboratories has pushed its R&D spending by 33.4 per cent to Rs. 1,685 crore during 2014-15 from Rs.1,263 crore, and remained as second highest R&D spender. This was followed by Lupin with R&D spending up by 16.8 per cent to Rs. 1,118 crore from Rs. 958 crore. The fourth largest R&D spender, Cipla invested an amount of Rs. 844 crore in R&D as compared to Rs.518 crore in the previous year, a significant growth of over 63 per cent. Glenmark's R&D investment remained almost same at Rs. 600 crore. Further, Aurobindo Pharma, Biocon, Sun Pharmaceutical Advance Research Co (SPARC), belonging to Sun Pharmaceutical and Ajanta Pharma registered noticeable growth of over 30 per cent in R&D expenditure during 2014-15. Similarly, Ipca Laboratories and Natco Pharmaceuticals also shown strong growth of over 25 per cent in R&D spending during 2014-15. However, the R&D expenditure of Piramal Healthcare, Unichem Laboratories, Orchid Chemicals and Pharmaceuticals, Jubilant Lifesciences, Panacea Biotec and Strides Arcolab declined during 2014-15.
  35. 35. PHARMA UPTODAY 35 Lupin has intensify is research efforts to address opportunities in difficult-to-do generics, dermatology, inhalation, complex injectables and the biosimilars space. It has undertaken biotechnology development program with the help of 190 highly-qualified bio-technologists. Its biosimilars pipeline includes 12 blockbuster molecules. Its two biosimilars are ready to launch in India under the brand names Lupifil and Lupifil-P. Its cumulative ANDA filings with the US FDA reached at 210 with 111 approvals received. Its cumulative DMF filings reached at 157 as at the end of 2014-15. Biocon is developing novel biologics and biosimilars for addressing chronic diseases like cancer diabetes and autoimmune conditions for patients across the globe. Biocon, Asia's largest insulins producer, has stepped up its R&D spending by over 50 per cent to Rs. 200 crore during 2014-15. Its oral insulin under development has the potential to transform diabetes management the world over. The company is setting up integrated insulins manufacturing facility at Malaysia. It is offering niche services to multinational companies like Bristol Myers Squibb, Abbott and Baxter. Its subsidiary Syngene has built a strong reputation of being the 'innovation partner' for many of its clients and well positioned to tap global contract research organization opportunity. It filed over 1,150 patent applications and holds over 530 patents. Syngene International, a leading contract research organisation of Biocon, entered the capital market and now setting up a new manufacturing facility at Mangalore SEZ and is in the process of acquiring 40 acres of land and obtaining necessary approvals. The estimated expenditure for setting up the facility is US$ 100 million. DRL's R&D expenditure increased sharply by 33.4 per cent to Rs. 1,685 crore during 2014-15, which worked out to 11.5 per cent of its consolidated net sales. It filed 77 DMFs, taking the cumulative number of DMF filings to 735 as at the end of March 2015. Similarly it filed 13 ANDAs with US FDA and cumulatively 68 ANDAs pending approval. It has more than 2000 scientists across its development centers in India, UK, US and Netherlands. The company launched 61 new products in FY2015. Aurobindo Pharma, which has set up a revenue target of US$ 3 billion by 2017-18, is moving ahead strongly by investing in R&D activities. Its R&D expenditure increased by 33 per cent to Rs. 360 crore during 2014-15. The company has started investing in peptide technology and is building a commercial facility with two modules commensurate with cGMP standards. It has developed technologies for more than ten products. The company cumulatively filed 192 DMFs and 376 ANDAs. It received total 193 ANDA approvals and 183 ANDAs were under review. Aurobind has developed and made penem filings for four products in injectable portfolio and it is planning to launch products in Brazil and Mexico in current year. The company is now entering the vaccines business with a joint venture for developing pneumococcal conjugate vaccine. The company is also working on 15 oncology products.
  36. 36. PHARMA UPTODAY 36 Glenmark's consolidated R&D spending remained almost stagnant at Rs. 600 crore during 2014-15. It announced first clinical development candidate in oncology, GBR 1302, a bispecific antibody for cancer treatments. The company is initiating a phase I clinical trial for GBR 1302 in Germany. It another product GBR-900 is entering clinical development in current year and first t anti-OX40 monocional antibody has completed phase I and phase II studies in US and EU. The company is moving fast in NCE front also and its mPGES-1 discovery program, GRC 27864 has moved forward in human trials and is nearing completion of phase I. Currently it has 70 applications pending with the US FDA, of which 33 are Paragraph IV applications. Panacea Biotech's R&D expenditure declined sharply by over 47 per cent to Rs. 46.82 crore during 2014-15 from Rs. 88.88 crore due to heavy losses. It has set up four disciplinary R&D centers. at Navi Mumbai, Lalru, Mohali and New Delhi for development of vaccine, biopharmaceuticals, proteins, peptides, monoclonal antibodies, NDDS, etc., It invested 6.8 per cent of net turnover on R&D during 2014-15. Its R&D center is focusing in the fields of oncology and organ transplantation. The company has filed more than 1,500 patent applications worldwide including 230 patent applications in India. Thus, the rising investment in R&D will give necessary push to overall working and presence in regulated and emerging market. Indian companies are pushing the boundaries of innovation to meet niche unmet medical needs. These companies are focusing on R&D to develop new chemical or molecular entities. Anti-cancer treatments and diabetes attract the large R&D investments. It is expected that the new government may initiate steps to offer tax incentives or favorable tax environment for investment in R&D in near future. Source: ICH announces organisational changes On its inaugural meeting on 23 October 2015 the International Council for Harmonisation (ICH), formerly the International Conference on Harmonisation (ICH), announced organisational changes: ICH emphasizes that it is a truly global initiative and more involvement of regulators around the world is welcomed and expected, as they will be invited to join counterparts from Europe, Japan, USA, Canada and Switzerland. This is aligned with the possibility of wider inclusion of global industry sectors affected by ICH Harmonisation. In addition, a more stable operating structure is achieved through the establishment of an ICH association, a legal entity under Swiss law, which will facilitate future growth through the participation of new members. For further information please visit the ICH official website.
  37. 37. PHARMA UPTODAY 37 Terminology data. Data means all original records and certified true copies of original records, including source data and metadata and all subsequent transformations and reports of this data, which are recorded at the time of the GxP activity and allow full and complete reconstruction and evaluation of the GxP activity. Data should be accurately recorded by permanent means at the time of the activity. Data may be contained in paper records (such as worksheets and logbooks), electronic records and audit trails, photographs, microfilm or microfiche, audio- or video-files or any other media whereby information related to GxP activities is recorded. data governance. The sum total of arrangements to ensure that data, irrespective of the format in which it is generated, are recorded, processed, retained and used to ensure a complete, consistent and accurate record throughout the data lifecycle. data integrity. Data integrity is the degree to which a collection of data is complete, consistent and accurate throughout the data lifecycle. The collected data should be attributable, legible, contemporaneously recorded, original or a true copy, and accurate. Assuring data integrity requires appropriate quality and risk management systems, including adherence to sound scientific principles and good documentation practices. data lifecycle. A planned approach to assessing and managing risks to data in a manner commensurate with potential impact on patient safety, product quality and/or the reliability of the decisions made throughout all phases of the process by which data is created, processed, reviewed, analyzed and reported, transferred, stored and retrieved, and continuously monitored until retired. metadata. Metadata are data about data that provide the contextual information required to understand those data. Typically, these are data that describe the structure, data elements, interrelationships and other characteristics of data. They also permit data to be attributable to an individual. For example, in weighing the number 8 is meaningless without metadata, i.e. the unit, mg. Other examples of metadata may include the time/date stamp of the activity, the operator ID of the person who performed the activity, the instrument ID used, processing parameters, sequence files, audit trails and other data required to understand data and reconstruct activities. Ref: GUIDANCE ON GOOD DATA AND RECORD MANAGEMENT PRACTICES - WHO
  38. 38. PHARMA UPTODAY 38 New Guidance Acceptability of Draft Labeling to Support Abbreviated New Drug Application Approval; Guidance for Industry This guidance provides recommendations and information related to the submission of proposed labeling with abbreviated new drug applications (ANDAs) under section 505(j)(2)(A)(v) of the Federal Food, Drug, and Cosmetic Act (the Act) and FDA’s implementing regulations (21 CFR 314.94(a)(8)). This guidance is intended to assist applicants submitting ANDAs under section 505(j) of the Act to the Office of Generic Drugs (OGD) in the Center for Drug Evaluation and Research (CDER). It explains FDA’s interpretation of the regulatory provision related to the submission of copies of applicants’ proposed labeling in ANDAs and clarifies that OGD will accept draft labeling and does not require the submission of final printed labeling (FPL) in order to approve an ANDA. Source: s/UCM465628.pdf FDA Provides New Guidelines for Cleaning Duodenoscopes Following the outbreak of infections related to a deadly superbug, the FDA has provided new guidelines to help healthcare facilities ensure their duodenoscopes are cleaned adequately. Duodenoscopes gained intense media scrutiny after reports of antibiotic-resistant infections in Chicago, Pittsburgh, Seattle and Los Angeles. Earlier this year, the FDA revealed that between January 2013 and December 2014, it had received 75 reports involving about 135 patients suffering from carbapenem-resistant Enterobacteriaceae transmissions linked to these devices. The FDA acknowledges that the duodenoscope's unique design is useful for performing endoscopic retrograde cholangiopancreatography procedures. This utility has its drawbacks, however, as the device has small working parts, including a moveable elevator mechanism with tiny crevices. This elevator is particularly difficult to clean and disinfect properly, even if a healthcare professional adheres to a manufacturer's instructions for use. "Meticulous adherence to the manufacturer's reprocessing instructions is labor-intensive and prone to human error," according to the agency. To combat the threat of infection transmission, the FDA is recommending facilities adopt the following supplemental measures: microbiological culturing; ethylene oxide sterilization; use of a liquid chemical sterilant processing system; and repeat high-level disinfection. "We recognize that not all healthcare facilities can implement one or more of these measures, which require specific resources, training, and expertise," the FDA said. While this may be the case, it is
  39. 39. PHARMA UPTODAY 39 still critical that those professionals in charge of reprocessing the devices have instructions for use at hand and remain proficient in performing all reprocessing steps. In addition to the supplemental measures, the agency is urging healthcare facilities to adopt the following best practices:  Meticulously clean the elevator mechanism and recesses surrounding it by hand;  Implement a comprehensive quality control program for reprocessing duodenoscopes;  Review reprocessing recommendations from a consensus document from the American Society for Gastrointestinal Endoscopy and the Society for Healthcare Epidemiology of America. The FDA notes that it is monitoring the situation and evaluating information from the healthcare community, adverse events reports and other sources. It also is partnering with The Joint Commission, the nation's largest hospital accreditation body, and the Centers for Medicare & Medicaid Services to bolster hospitals' adherence to duodenoscope cleaning instructions. In addition, the agency says it is working with industry as it modifies and validates instructions for cleaning duodenoscopes. EMA Guidance Explains How Drugmakers Can Hasten Antibiotics Development The European Medicines Agency has released draft guidance explaining how drugmakers can use pharmacodynamic and pharmacokinetic analyses to hasten the development and review of new antibiobics. According to the EMA, PD and PK data can replace or supplement human dosing studies, speeding access of badly needed drugs to market. It can also aid in identifying differences and dealing with dose variations for specific demographics, such as children and seniors, the obese and patients with liver and kidney failure, the agency says. Cellular analyses can also bolster drug candidates whose development has been held back by a lack of appropriate trial participants or other feasibility issues, the EMA says. The guideline, which would update 15-year-old recommendations, covers both antibacterial and antifungal treatments. To be most effective, drugmakers should gather specific microbiologic data on:  The time it takes to kill a particular pathogen;  Pathogen distribution markers;  How those markers react to resistance mechanisms when the drug is administered;  Intracellular biologic responses to the bacteria;  Post-drug effects; and  Which bacterial microorganisms are more- or less-resistant.