India Issues Guidance on Audiovisual Recording of Informed Consents

Videotapes of patients giving informed consent to partici-pate in clinical trials must show the investigator explaining the study protocol in language the subject can understand, accord-ing to a draft guideline by India’s Central Drugs Standard Con-trol Organization.

The draft — published Jan. 15 — is intended to help compa-nies and researchers comply with a Nov. 21 order from the Min-istry of Health and Family Welfare requiring the videotaping of informed consents (IPRM, December 2013). The guideline was accompanied by a formula to calculate the amount of compen-sation patients or families receive if a serious adverse event or death occurs.

According to CDSCO, the consent process must include an explanation of the study’s purpose and general design, as well as a description of potential risks and expected benefits. If no clear benefit is anticipated, this must also be explained to participants.

During the recording session, the camera should capture facial details of the subject and investigator, while avoiding unre-lated people, the guideline says. A photo ID should be used to document the subject’s identity if the video is not adequate. In cases where a participant is unable to give consent, due to a dis-ability or impairment, a legal representative should be recorded during the consent process, the guideline says.

The videotaped consent should be preserved for at least five years after the trial is completed or terminated.

Injury Compensation Formula

CDSCO stresses that trial subjects are to receive free medi-cal care for the duration of the study. If a trial-related injury or death occurs, the sponsor, or whoever obtained permission from the licensing authority to conduct the trial, is required to provide financial compensation.

The agency released an interim formula for clinical trial investigators to use when calculating compensation requirements. The formula includes a base payout of about US $19,000, multi-plied by age and risk factors and divided by 99.37. Patients with

India Issues Guidance on Audiovisual Recording of Informed Consents ........................... 1

China Asks Sponsors to Submit Timely SAE Reports in Vaccine Trials .................. 2

Japan Cracks Down on Misuse of Trial Data; Pfizer Confirms It Faces Probe .................... 2

EMA Updates Advice on Use of Novel Drug Development Tools in Submissions .............. 3

Placebos in Trials of Monotherapy Lipid Disorder Drugs No Longer OK: EMA................... 3

Pharma Denies Plot to Derail South Africa Patent Reform ................................... 5

U.S. High Court Says Patent Holder Bears Proof Burden .................................... 5

EMA Outlines Timeline, Process For Postmarket Safety Reviews ............................. 6

Genomic Data Integral to Drug Safety Assessments, EMA Says .............................. 7

MHRA Offers Tips on Handling Suspected Quality Defects ...................................... 7

Health Canada Highlights QbD In Updated Quality Guidance ................................ 7

Process Validation Should Take Lifecycle Approach, European Commission Says ................ 8

Japanese Regulators Update Blueprint For GMP Inspection Preparations ........................ 8

81 Medicines Clear EU Marketing Hurdles In 2013, Including Two ATMPs ............................. 9

U.S. FDA Says Poor Information Is Main Cause of Approval Delays ............................. 9

Health Canada: Comparisons Have No Place in Drug Labeling .......................... 10

EMA Reviewing Effect of Weight On Emergency Contraception .............................. 11

U.S. Aims to Rid Pharma of Pay For Performance Sales Practices ......................... 11

In Brief ................................................................... 12

Editor’s Note: The International Pharmaceutical Regulatory Monitor is available in an electronic edition, which includes web access to seven years of archived issues. For information on convert- ing to an electronic subscription, contact us at (888) 838-5578.

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a 90 percent expectancy of dying within 30 days would get about $4,800, CDSCO says.

The compensation formula is based on recommen-dations in a 2013 parliamentary report on needed clini-cal trial oversight reforms (IPRM, December 2013).

In comments to CDSCO, the Association of Clinical Research Organizations suggests the agency expand the language in the guideline to encompass “any device that can adequately capture the images and sounds required. ACRO notes that some research sites may use smart-phones or iPads to record consents, rather than a video camera, the device prescribed in the draft.

The group also recommends allowing sites that lack the infrastructure to store the recordings to employ a third party to do so — with the strict proviso that the content won’t be viewed.

ACRO spokesman John Lewis said the draft guideline suggests “progress is being made” to raise the quality of clinical trial conduct in India, but noted the government has never clarified whether an ear-lier draft guideline on trial compensation has been

finalized (IPRM, August 2013). “This is another exam-ple of the regulatory uncertainty that is crippling clin-ical research in India,” he said.

View the draft guideline at www.fdanews.com/ext/resources/files/02/02-14-IndiaConsent.pdf. The compen-sation formula is at www.fdanews.com/ext/resources/files/01/01-17-14-India.pdf. — Nick Otto

China Asks Sponsors to Submit Timely SAE Reports in Vaccine Trials

Chinese authorities are urging vaccine manufacturers to implement better adverse event reporting procedures during clinical research and to adhere to reporting timelines.

Sponsors of vaccine trials intended to support a marketing submission in China have seven days to report study-related fatalities and another eight days to file follow-up reports, according to a new China Food and Drug Administration guideline.

Nonfatal serious adverse events should be reported within 15 days, the agency says. All reports may be sub-mitted electronically or on paper.

The guideline — intended to boost reporting of SAEs in vaccine trials — calls for companies to appoint a full-time SAE manager, establish a clinical trial safety information reporting system and train relevant person-nel in proper SAE reporting.

Reports should include the initial diagnosis, basic information on the vaccine and test, whether the event was unexpected, the severity and how it was handled. Follow-up reports should note any changes since the ini-tial reaction and provide a more in-depth analysis of the SAE, along with the patient’s safety-risk evaluation.

Sponsors’ annual reports to the CFDA should include periodic safety reports and a summary of all SAEs, includ-ing suspected nonserious adverse events, the guideline says.

CFDA provincial offices may suspend or terminate trials, with justification, at any time, based on a safety risk assessment, the agency adds. — Nick Otto

Japan Cracks Down on Misuse of Trial Data; Pfizer Confirms It Faces Probe

Japanese officials launched an investigation Jan. 10 into claims that falsified clinical trial data were used in an Alzheimer’s study involving several major drugmak-ers, marking an expansion of the country’s scrutiny of trial data misuse.

Document Index

The following documents covered in this issue of the Interna-tional Pharmaceutical Regulatory Monitor are available for download at www.fdanews.com/IPRMdocs.

CDSCO Draft Guideline on Audiovisual Recording of Informed Consent

CDSCO Trial Compensation Formula

EMA Guideline on Novel Drug Development Tools

EMA Guideline on Lipid Disorder Drugs

Draft National Policy on Intellectual Property (IP) of South Africa

EMA Q&A Guideline on Postmarket Safety Reporting

EMA Guideline on Pharmacogenomics

MHRA Guidance on Handling Quality Defects

Health Canada Guidance on Quality in Drug Development

European Commission Guideline on Annex 15 to EU GMPs

PMDA Memo on Postapproval GMP Requirements

Health Canada Guideline on Drug Labeling

ICH Photosafety Guideline

Scottish Report on Patient-Centered Research

INTERNATIONAL PhARmAcEuTIcAL REGuLATORY mONITORFebruary 2014 Page 3

Pfizer spokeswoman Sally Beatty told IPRM that the pharma giant is aware of the health ministry’s probe and is taking immediate action to investigate the matter as well.

The clinical trial in question, the Japanese Alzheim-er’s Disease Neuroimaging Initiative, or J-ADNI, involved 11 drugmakers, including Pfizer, across 38 clinical sites in Japan. The study commenced in 2007 and, as of 2010, had recruited 460 individuals with vary-ing levels of cognitive impairment. Analysis of J-ADNI data is ongoing, according to the study’s website.

Other drugmakers in the study include Astellas, Bristol-Myers Squibb, Daiichi-Sankyo, Dainippon-Sum-itomo, Eisai, Eli Lilly, Merck-Banyu, Shionogi, Takeda and Tanabe-Mitsubishi. Merck’s U.S. office was, as of press time, unaware of the investigation. BMS declined to comment on the probe, but acknowledged it was under scrutiny. The other companies did not respond to reporters’ requests for comment as of press time.

Only days earlier, Japanese officials slapped Novartis with a criminal complaint alleging its Japanese unit exag-gerated trial data in advertising for blood pressure drug Diovan (valsartan). — Melissa Winn, Nick Otto

EMA Updates Advice on Use of Novel Drug Development Tools in Submissions

The European Medicines Agency is encouraging drugmakers looking to apply novel drug development tools to first seek the agency’s blessing and get qualifica-tion or prospective advice.

According to a recent guideline, the process may include discussions with a qualification team from the Committee for Medicinal Products for Human Use, which could open up the company’s proposed methodol-ogy to CHMP’s public consultation process.

The goal of the guideline is to help drugmakers ensure that tools used to create drug submissions are adequate before the submission progresses too far.

To qualify a new tool, companies should submit a letter of intent describing the tool’s scientific rationale and its intended use in the context of research and devel-opment. An EMA science official will be assigned to support each qualification request.

The guideline includes a proposed format for sub-mitting requests and methodology data. To support the qualification request, sponsors should include a

description of the utility and limitations of currently available clinical and laboratory tools.

Fifteen days prior to the start of the qualification review, the sponsor will meet with EMA officials to dis-cuss whether the data set that was submitted is likely to be sufficient for a CHMP qualification opinion.

The agency’s Scientific Advice Working Party will then review the data. Sponsors may request a clock-stop, if needed, at any time during the process.

View the guideline at www.fdanews.com/ext/resources/files/01/01-09-14-EMA.pdf. — Nick Otto

Placebos in Trials of Monotherapy Lipid Disorder Drugs No Longer OK: EMA

The European Medicines Agency says it’s no longer acceptable for sponsors to conduct placebo-controlled clinical trials when developing monotherapy drugs for lipid disorders.

The directive comes in an updated guideline and aims to address an ethical dilemma: how to develop effective lipid disorder drugs while ensuring trial par-ticipants aren’t deprived of safe and effective treatments that are already available, such as statins.

According to the EMA, clinical studies that require morbidity and mortality outcomes will be dependent on the class of drugs, their mechanisms of action and the tar-get population. The agency foresees no such studies being needed to register a new statin, the Jan. 16 guideline says. For nonstatins, sponsors should note in the summary of product characteristics that beneficial effects on mortality and morbidity have not been evaluated.

This is particularly good news for drugmakers, such as Amgen, with nonstatins in their pipelines. The Thousand Oaks, Calif., drugmaker recently completed a Phase II trial of its PCSK9-binding monoclonal antibody evolocumab.

According to ISI Group analyst Mark Schoenebaum, a Phase III Amgen trial of evolocumab is not expected to show results for another two to three years, and wait-ing for those results could put the drugmaker behind the competition. The EMA guideline gives Amgen’s next-generation heart drug a potentially shorter pathway to approval, Schoenebaum says.

However, the success of the emerging class of drugs hinges on the outcome of cholesteryl ester transfer pro-tein inhibitors being developed by Eli Lilly and Merck.

February 2014Page 4 INTERNATIONAL PhARmAcEuTIcAL REGuLATORY mONITOR

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If those trials succeed, then physicians are likely to wait for the pill form of CETP inhibitors rather than shift patients to the injectable PCSK9 antibodies, Schoene-baum says.

Echoing U.S. recommendations on PCSK9 antibod-ies, the EMA says lipid-disorder drugs for patients with hypercholesterolemia should use lowering of bad cho-lesterol as a primary efficacy endpoint. In November, the U.S. regulator said efficacy requirements for PCSK9 antibodies should focus on the drugs’ ability to lower bad cholesterol, blood pressure and inflammation.

Read the guideline at www.fdanews.com/ext/resources/files/01/01-17-14-Guidelines.pdf. — Ferdous Al-Faruque

Pharma Denies Plot to Derail South Africa Patent Reform

Brand drugmakers last month denied accusations they’d joined forces with a lobbying group in a covert campaign to block proposed patent law changes that would improve access to generics in South Africa.

The Pharmaceutical Research and Manufacturers of America and the Innovative Pharmaceutical Associa-tion of South Africa were forced to defend themselves as details leaked to the public about a cryptic plot to delay the passage of the country’s draft intellectual property policy, which would, among other things, curb patent evergreening and expand the government’s ability to issue compulsory licenses for generics.

Outlined in a proposal to the trade groups by U.S.-based lobbying group Public Affairs Engagement, the multistage campaign was to employ a massive public affairs effort that would ultimately pressure officials to modify the policy to protect the country’s existing IP laws.

South Africa’s current patent laws, which allow drugmakers to obtain patents without proving innova-tion or newness, benefit brand drugmakers by “grant-ing an excessive number of patents” compared with both developed and developing countries, Doctors Without Borders says. The medical nonprofit supports the coun-try’s patent reform efforts.

PAE warned pharma that if the proposed patent changes are adopted, not only will South Africa become less hospitable to industry, but developing nations such as India and Brazil could follow the country’s lead.

PAE’s proposal called for pharma trade organizations to ally with business, advocacy groups, associations and

academia under the moniker “Forward South Africa,” to warn legislators and officials that there would be a “high price to pay for a weakened IP regime.”

The “energetic campaign,” which PAE likened to a political campaign, was to include academic papers and op-eds to sway public opinion in favor of retaining cur-rent IP laws. The effort would also drum up pressure from leaders and investors outside South Africa — a move designed to make “South African political leaders pay attention.”

The plan also called for a “counter-movement” mobilization of free market-oriented African officials and policy experts to warn of a global backlash to the IP reform, threatening South Africa’s “leadership role.”

“This African element of the plan is delicate” the plan noted.

Both PhRMA and IPASA denied contracting with PAE to lobby on their behalf against the draft IP policy, which was issued in September. They said they support “the objectives” of the proposed policy, but feel exist-ing laws already accommodate the country’s aim to foster innovation and provide access to low-cost pharmaceuticals.

Drug giant Novo Nordisk withdrew its membership in IPASA in protest of the alleged scheme.

View the Draft National Policy on Intellectual Property (IP) of South Africa at www.fdanews.com/ext/resources/files/01/01-21-14-SoAfrica-IP-policy.pdf. — Melissa Winn

U.S. High Court Says Patent Holder Bears Proof Burden

In a 9-0 decision, the U.S. Supreme Court ruled Jan. 22 that the patent holder bears the burden of proof for infringement, regardless of whether it is the plaintiff or defendant in a patent lawsuit.

Shifting the burden of proof could create unneces-sary complexity for parties to patent licenses by compel-ling them to prove the negative, that they didn’t infringe a patent, the court held in Medtronic Inc. v. Mirowski Family Ventures.

The decision could make it more difficult for drug-makers to win patent infringement suits filed against their generic competitors.

In the case, Mirowski claimed that some of the pat-ents it licensed to medical devicemaker Medtronic were

February 2014Page 6 INTERNATIONAL PhARmAcEuTIcAL REGuLATORY mONITOR

infringed by subsequent Medtronic patents. Medtronic responded with a request for declaratory judgment.

Lower U.S. courts have differed on the question of which party bears the burden of proof in infringement challenges, and the case wound up before the Supreme Court. The court was asked to decide whether that bur-den shifts when the patentee is a defendant in a declara-tory judgment action, and the plaintiff — the potential infringer — seeks a judgment that it does not infringe the patent. — Melissa Winn

EMA Outlines Timeline, Process For Postmarket Safety Reviews

Drugmakers have 60 days to resolve safety concerns about products once they have been flagged by an EU member state. Failure to do so in the allotted time could mean revocation or modifications to the marketing autho-rization, a European Medicines Agency guideline says.

The EMA announced the new timeline Jan. 22, along with details of how it intends to administer reviews under the 2010 pharmacovigilance law that took effect in July 2012.

The review process begins with what’s called an Article 31 referral to the EMA’s Pharmacovigilance Risk

Assessment Committee by an EU member state, the European Commission or the drug’s sponsor.

Once that occurs, PRAC will provide the sponsor with a summary of its procedures, a notification of what triggered the investigation, a list of concerned products and a list of questions and timetables for responding. Data and responses should be submitted electronically, the EMA says.

The guideline, published in question-and-answer format, covers safety referrals involving a specific drug product, all medical products containing the same active ingredient and all products belonging to a particular class of drugs.

Drugmakers should submit responses in triplicate — to the EMA, the PRAC rapporteur assigned to the case and the committee itself. They should also identify a desig-nated company liaison to work with PRAC, as participation in the review process is mandatory, the guideline says.

PRAC will issue a recommendation within 60 days of the start date of the review, but can extend the dead-line to 120 days if a public hearing is needed.

Companies have 15 days from the committee’s ver-dict to request a reexamination.

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The new guideline is part of ongoing EMA efforts to implement the 2010 law, which created PRAC to assess postauthorization safety and efficacy studies. The law also for the first time requires drugmakers to notify the agency and national regulators and provide rationale when they withdraw a drug from the market anywhere in the EU (IPRM, June 2013).

View the Q&A guidance at www.fdanews.com/ext/resources/files/01/01-23-14-EMA.pdf. — Nick Otto

Genomic Data Integral to Drug Safety Assessments, EMA Says

The European Medicines Agency is asking drug com-panies to keep pharmacogenomics in mind when doing pre- and postauthorization safety assessments, noting that the selection of biomarkers is key to maintaining a robust safety profile as part of pharmacovigilance activities.

Manufacturers possess some data on how spe-cific biomarkers may correlate with a drug’s efficacy or safety at the time of approval. The EMA wants com-panies to build on that when they monitor drugs post-approval. The agency notes that analyzing pharma-cogenomic biomarkers postapproval may increase a company’s understanding of how certain patients react to a given drug, leading to updates to drug labels.

The data could also prompt companies to conduct further clinical studies of a drug’s safety and perfor-mance in special populations, the EMA says in a draft guideline. Special attention should be paid to variations in genetic responses to drugs in older patients who often suffer from multiple health conditions, take multiple medications and are generally frailer, the guideline says.

The guideline is part of ongoing EMA efforts to implement the EU’s 2010 pharmacovigilance law (see story, page 6).

Comments on the draft are due July 30. View it at www.fdanews.com/ext/resources/files/01/01-31-EMA methodologies.pdf. — Johnathan Rickman

MHRA Offers Tips on Handling Suspected Quality Defects

The UK’s Medicines and Healthcare products Regula-tory Agency has released a guide for drugmakers on how to differentiate between defects, errors and adverse drug reac-tions and what to do when quality defects are suspected.

Companies must report all defects that could lead to a recall immediately upon discovery and provide regular

updates on internal investigations into the problem, the agency says, adding the reporting obligation is sometimes overlooked and frequently confused with adverse event reporting requirements. In fact, defects require a separate report and are handled by a separate regulatory unit, the Defective Medicines Report Centre, the guide notes.

The reports trigger talks between the manufacturer and DMRC on whether to implement a recall and the urgency of the recall. While the MHRA has authority to impose recalls of defective medicines, it prefers to use the collaborative reporting process.

Initial reports to DMRC should include the follow-ing information:

● Dates of drug manufacture and release to the market;

● An impact assessment quantifying the number of batches affected;

● Where admixture has occurred, dates of manu-facture and release of the admixed product clos-est to the complaint batch;

● Batch and pack sizes; ● Date of first and last distribution to the market; ● Review of complaint records for reports of simi-

lar defects; ● Estimation of stock; and ● Information on distribution of the same batch to

other countries.

Following the initial report, drugmakers must pro-vide regular updates on the progress of their investiga-tions, and a final report should be provided no more than 12 weeks after the initial report.

View the MHRA guide at www.fdanews.com/ext/resources/files/01/01-31-14-MHRA.pdf. — Nick Otto

Health Canada Highlights QbD In Updated Quality Guidance

An updated Health Canada guidance on quality infor-mation drugmakers must submit with marketing applica-tions includes harmonized references on how to document a quality-by-design approach during drug development.

According to the draft guidance, released Jan. 24, manufacturers should summarize the risk assessment and results from the design of experiments in the com-mon technical document. Care should be taken to use terminology consistent with International Conference on Harmonisation definitions, and companies should be clear about any claims made using QbD, the guidance

February 2014Page 8 INTERNATIONAL PhARmAcEuTIcAL REGuLATORY mONITOR

says. They should also discuss the role of QbD in the overall control strategy.

Companies seeking marketing authorization should also provide:

● A quality overall summary. According to Health Canada, this can help expedite the review pro-cess by enabling reviewers to spend time more efficiently on the application;

● A certificate of suitability if the drug substanc-es or reagents were obtained from a region affected by bovine spongiform encephalopathy or transmissible spongiform encephalopathy agents;

● Certification of a product’s comparability with monographs of the European Pharmacopoeia; and

● A drug master file with detailed information on the ingredients and processes used in manufac-turing the proposed product.

If such materials are proprietary, the supplier can submit a confidential drug master file directly to Health Canada. The drug master file should comply with ICH’s registration for human-use quality standards.

The draft guidance supersedes three existing docu-ments, including a 2001 draft that was never finalized. The other documents are a 2003 guidance on stability testing and a 2005 draft guidance on impurities.

Comments, due April 13, can be submitted elec-tronically to bps_enquiries@hc-sc.gc.ca. To read Draft Guidance Document: Quality (Chemistry and Manu-facturing): New Drug Submissions (NDSs) and Abbre-viated New Drug Submissions (ANDSs), visit www.fdanews.com/ext/resources/files/01/01-27-14-Canada DraftGuidance.pdf. — Robert King

Process Validation Should Take Lifecycle Approach, European Commission Says

Drugmakers should clearly define their validation activities in a validation master plan that accounts for the lifecycle of a product and related plant equipment, the European Commission says.

For large and complex drug development projects that require additional planning, it may be helpful to create a separate VMP for each product, the Commis-sion recommends in a draft guideline on Annex 15 — qualifications and validation — of the EU good manu-facturing practice guidelines.

The VMP should be a concisely worded summary document and include data on the company’s validation policy; the organizational structure for validation activi-ties; a summary of the facilities, equipment and pro-cesses on site; template formats to be used for protocols and reports; processes for handling acceptance criteria; and change control and deviation management processes for validation.

The plan should also confirm that the materials used for validation meet the required quality and that suppli-ers are appropriately qualified, the guideline says.

The VMP should be supported by an ongoing pro-cess verification program conducted under an approved protocol, with separate reports prepared to document any program findings.

Validation protocols should include a brief descrip-tion of the process, a summary of both the critical pro-cess parameters and critical quality attributes, a list of all equipment and facilities, a list of analytical meth-ods and method validation, and a sampling plan and the rationale behind it.

The U.S. Food and Drug Administration also pro-motes a lifecycle approach to process validation. Vali-dation should begin with the process design stage and continue through commercial production to ensure the process remains in a state of control. The FDA leaves it to industry to cover validation activities as part of an overall project blueprint or to document them individu-ally as a VMP.

Stakeholders can comment on the final draft guide-line through May 31. View it at www.fdanews.com/ext/resources/files/02/02-07-14-GMP.pdf. — Nick Otto

Japanese Regulators Update Blueprint For GMP Inspection Preparations

The Pharmaceuticals and Medical Devices Agency is asking drugmakers to submit information on stability mon-itoring and water purity when they apply for mandatory postapproval good manufacturing practice inspections.

The agency released the new postapproval require-ments in a Jan. 24 memorandum, replacing a 2008 list. No changes were made to requirements for preapproval inspection applications.

For postapproval GMP inspections, which are con-ducted every five years, manufacturers must now sub-mit a review of results from their stability monitoring

INTERNATIONAL PhARmAcEuTIcAL REGuLATORY mONITORFebruary 2014 Page 9

programs, as well as a list of all types and specifications of water used in manufacturing the drug and the fre-quency of water sample testing.

Companies should continue to provide:

● Drawings of the manufacturing site layout, in-cluding maps of the main sites and adjacent areas;

● Key details of the quality assurance system — i.e., a GMP organization chart that indicates roles and duties;

● Manufacturing process flow charts showing process parameters, specifications and testing methods;

● The latest product quality review conducted within the last two years or documents summa-rizing the review; and

● A review of the raw materials, and packaging and labeling materials used in the approved product.

The memo specifies additional requirements for non-Japanese drugmakers seeking inspection. For instance, if the manufacturer resides in a country that has an agreement with Japan, it must submit a GMP compliance certificate issued by that country’s regula-tory authority.

To read the memo, visit www.fdanews.com/ext/resources/files/01/01-24-13-JapanGMP.pdf. — Robert King

81 Medicines Clear EU Marketing Hurdles In 2013, Including Two ATMPs

EU drug approvals jumped 42 percent in 2013 over the previous year as the European Medicines Agency authorized 81 new drugs for marketing.

Of those, 44 were new medicines; 11, orphan treat-ments; four, biosimilars; two, advanced therapies; and 20, generic, hybrid and informed-consent applications, the EMA reports. The tally brings to four the number of advanced therapy medicinal products recommended for approval by the Committee for Medicinal Products for Human Use since the ATMP regulation took effect in December 2008.

In line with previous years, the number of drugs con-taining a new active substance was “quite high” — 38 in 2013 versus 35 a year earlier, 25 in 2011 and 15 in 2010.

Seeking and following CHMP’s scientific advice significantly increased the likelihood a submission would get a positive nod, the EMA notes. Half of drug-makers sought CHMP input on applications in 2013, and 90 percent of those won approval. Only 30 percent of

drugmakers that didn’t seek advice got a green light to market their therapies.

Nine drugs received conditional marketing authori-zation, a pathway aimed at speeding access to medicines for unmet medical needs. The candidates included three anticancer agents — Pfizer’s Bosulif (bosutinib), Genen-tech’s Erivedge (vismodegib) and Exelixis’ Cometriq (cabozantinib); Bavarian Nordic’s Imvanex (MVA-BN) smallpox vaccine; and five treatments for rare conditions — Aegerion Pharmaceuticals’ Lojuxta (lomitapide), Gentium’s Defitelio (defibrotide), FGK Representative Service’s Cholic acid FGK, Otsuka Novel Products’ Del-tyba (delamanid) and Janssen’s Sirturo (bedaquiline).

“Listening to the specific needs and views of patients and healthcare professionals has become increasingly important for the Agency as it enriches the scientific evaluation of medicines,” the report says.

The EMA’s 2014 work program is due out this month, Labbé said. The agency’s management board approved the program in December. — Nick Otto

U.S. FDA Says Poor Information Is Main Cause of Approval Delays

A U.S. Food and Drug Administration review of drug approvals and denials over a 12-year period shows many delays could be avoided if drugmakers submitted more accurate and useful information.

According to a recent report in the Journal of the American Medical Association, many drugs fail to win approval not because they are unsafe or ineffective but because the sponsors’ applications lack sufficient infor-mation to make that determination.

Of 302 applications for new molecular entities submitted between 2000 and 2012, only 151 were approved upon first submission. Seventy-one required one or more submissions before being approved, according to the report by Rachel Sherman and Leon-ard Sacks, of the FDA’s Office of Medical Policy, and four other agency officials.

The top five reasons for delay were:

● Failure to select the optimal dose to maximize efficacy and minimize safety risks;

● Clinical trials populations differed from the tar-get population;

● Study endpoints showed no clinically meaning-ful effect;

February 2014Page 10 INTERNATIONAL PhARmAcEuTIcAL REGuLATORY mONITOR

● Efficacy results were inconsistent when different endpoints were compared; and

● Efficacy was poor compared with the standard of care.

More than 60 percent of drugs whose delays were tied to safety concerns eventually gained FDA approval, compared with 31 percent of drugs delayed for efficacy reasons, the study shows.

Another factor associated with approval on first submission: strong communication with the FDA early in the drug development process to address critical aspects of study design such as population and end-point selections and optimal doses, the authors say. — Melissa Winn

Health Canada: Comparisons Have No Place in Drug Labeling

Drugmakers should be careful not to use language in product labeling that could be considered promo-tional, such as comparisons with an alternate treatment, a Health Canada final guidance says.

The guidance — posted on the agency’s website Jan. 10 — covers all aspects of drug labeling, from how to characterize a product’s directions for use to where lot and drug identification numbers should be affixed

on different types of drug packages. But it pays special attention to comparison claims in labeling, which Health Canada says tend to exaggerate the importance of a product’s advantages.

Even an implied comparison using language such as “better” and “stronger” can throw a label out of com-pliance with Canada’s Food and Drug Act, the agency notes. “Where a drug product has been reformulated to be significantly more effective or to provide an addi-tional therapeutic advantage over a previous formula-tion, the use of ‘better’ may be acceptable, if carefully explained,” the guidance says. However, it’s best to describe those drugs as “new” or “improved” formula-tions, the agency adds.

Manufacturers that insist on adding therapeutic comparisons in labeling should seek preapproval, Health Canada warns.

The guidance stresses that certain types of infor-mation, such as promotional material and general dis-ease information, are generally not considered to be drug product labeling and should not be included on the packaging material.

Information about a disease that includes a discus-sion of the treatment without emphasizing a particular

Beyond GMP TrainingImproving Human Performance and Reducing Errors

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INTERNATIONAL PhARmAcEuTIcAL REGuLATORY mONITORFebruary 2014 Page 11

product — even if it’s balanced and comprehensive —is not considered labeling, and should not appear in the labeling, the guidance says. Neither should scientific papers and review articles, as they may present a bias.

The guidance recommends drugmakers provide the product’s directions for use on both the inner and outer labeling, a provision that was in the 2010 draft guidance (IPRM, August 2010).

View the guidance at www.fdanews.com/ext/resources/files/01/01-14-14-CanadianLabeling.pdf. — Johnathan Rickman

EMA Reviewing Effect of Weight On Emergency Contraception

The European Medicines Agency is following in step with U.S. regulators and, at the request of Sweden’s medicines authority, is reviewing the efficacy of emer-gency contraceptives in heavier women.

Specifically, the agency is investigating reports that emergency contraceptives such as Teva’s Plan B One-Step may lose effectiveness in women who weigh more than 165 pounds. The U.S. Food and Drug Administra-tion launched a similar inquiry in November.

The review is being conducted by the EMA’s Com-mittee for Medicinal Products for Human Use and includes a number of levonorgestrel medicines marketed at the national level, including HRA Pharma’s NorLevo, Bayer’s Levonelle and Novartis’ Levodonna. The com-mittee also plans to investigate HRA’s ellaOne, which contains ulipristal acetate.

Both the EU and U.S. inquiries were prompted by a request from Swedish officials to update the label for NorLevo with language warning of lower efficacy in patients whose weight exceeds 165 pounds and a com-plete lack of effectiveness in women who weigh 176 pounds or more. A note on the NorLevo website says it is under maintenance.

NorLevo relies on levonorgestrel to prevent unwanted pregnancy when taken within 72 hours of unprotected sex. Levonorgestrel-containing emergency contraceptives are available over the counter in some European countries; ellaOne can only be obtained with a prescription. In June, the FDA approved Teva’s Plan B One-Step for sale without a prescription for all women of child-bearing potential. — Nick Otto

U.S. Aims to Rid Pharma of Pay For Performance Sales Practices

The U.S. Department of Justice wants to rid the pharmaceutical industry of pay-for-performance sales compensation packages, believing they fuel fraud, off-label marketing and other deceptive behaviors, a former top prosecutor says.

The initiative ties in with the department’s recent focus on senior executives in fraud investigations, which stems from a 2012 court ruling that discussions of off-label drug uses by sales reps are protected speech.

Currently, government efforts to change the way drug companies compensate sales reps are largely lim-ited to suggestions and friendly advice, but DOJ does have enforcement tools such as False Claims Act suits and corporate integrity agreements to promote alternate sales models, according to Jonathan Diesenhaus, a part-ner with Hogan Lovells and a former senior trial counsel in DOJ’s civil division.

Speaking at a briefing hosted by the Washing-ton Legal Foundation, Diesenhaus said that the recent free-speech decision in U.S. v. Caronia has not deterred DOJ prosecution of off-label promotions. Rather, the Second Circuit’s decision defending a sales rep’s off-label promotion as protected speech has redi-rected the DOJ’s efforts.

Since sales agents are essentially viewed as “off-limits” under Caronia, an opinion with which DOJ feels other circuit courts will eventually agree, drug company officials are the next likely target, the attorney said.

“A guy like Mr. Caronia will not likely be pros-ecuted for a long time,” Diesenhaus said. “A sales rep who engages in speech only, where the conduct is lim-ited to speech that is not directly false, will not be prose-cuted because the Second Circuit said speech alone can-not be the crime.”

At least one company is ahead of the curve in antic-ipating DOJ’s thinking. GlaxoSmithKline, which is under scrutiny for a bribery scandal in China, said last month it will stop compensating sales personnel world-wide based on sales targets.

Yet despite government scrutiny, many drugmakers continue to stand behind the pay-for-performance sales model. Amgen, Novartis and Eli Lilly all offer pay-for-performance packages for employees. — Melissa Winn

February 2014Page 12 INTERNATIONAL PhARmAcEuTIcAL REGuLATORY mONITOR

ICH Rolls Out Photosafety Testing StrategiesDrugmakers should evaluate a product’s UV-visible

absorption spectrum before starting clinical development, according to an International Conference on Harmonisa-tion guideline aimed at standardizing photosafety test-ing standards across the EU, U.S. and Japan. The initial test determines whether risk-minimization measures are needed to prevent adverse, light-induced tissue reactions to a photoreactive chemical and can establish that no further photosafety evaluation is needed, the ICH S10 final guide-line says. Released Jan. 8, it provides specific guidance on testing strategies for new active pharmaceutical ingredi-ents, new formulations of excipients for dermal applica-tions and photodynamic therapy products, including when testing is warranted. Read the guideline at www.fdanews.com/ext/resources/files/01/01-08-14-ICH.pdf.

BfArM, SwissMedic Sign MOUThe heads of the German and Swiss drug authorities

inked a collaborative agreement last month, formaliz-ing the agencies’ existing cooperative relationship. The memorandum of understanding includes the exchange of information and increasing understanding of each authority’s regulatory framework and processes. Swiss-Medic and BfArM plan to “launch concrete initiatives for collaboration,” the Swiss agency said.

Sklamberg Heads U.S. FDA Global RegulatoryHoward Sklamberg is the U.S. Food and Drug

Administration’s new deputy commissioner for global regulatory operations, assuming the role from John Taylor who had stepped in after Deborah Autor left in June to work for Mylan (IPRM, May 2013). For the last year, Sklamberg has directed the Center for Drug Evaluation and Research’s compliance office, where he helped implement the generic drug user fee program and develop new policies on drug quality. He also had a hand in shaping new rules for compounding pharmacies.

Scotland Pushes Patient-Centered Development The Scottish Medicines Consortium plans to launch

a new initiative on patient-centered research, giving patient groups and clinicians a stronger voice in how drugs for life-threatening and rare diseases are devel-oped and approved. The effort, dubbed Patient and Cli-nician Engagement, calls for soliciting patient input in cases where SMC reviewers determine that an orphan drug candidate does not meet the conventional thresh-olds for cost-effectiveness, according to a working group report. The plan follows SMC’s introduction in December of a new decisionmaking framework for orphan drugs that downplayed cost-based criteria. View the Feb. 3 report at www.fdanews.com/ext/resources/files/02/02-04-14-Scotland.pdf.

Malaysia Updates Drug Registration GuideMalaysia’s National Pharmaceutical Control

Bureau has issued a revised guidance document on drug registration. The guidance — dated December 2013 and released late last month — covers the regis-tration process, quality control, inspection and licens-ing, post-registration requirements, fees and more. The last revision was in November 2012. View the guid-ance at www.fdanews.com/ext/resources/files/02/02-14-bpfk.drugregis.pdf.

NICE Xtandi Guidance Draws FlakProstate Cancer UK CEO Owen Sharp calls the

National Institute for Health and Care Excellence’s rec-ommended use restrictions for Xtandi (enzalutamide) a “blatant u-turn” and “disheartening.” NICE draft guid-ance released last month withholds support for the drug in patients who have already been treated with Janssen’s Zytiga (abiraterone), saying there is no evidence Xtandi would be effective in that group of patients. The cost-benefit watchdog’s recommendations inform national coverage decisions in the UK. Comments on the draft are due Feb. 18. View it at http://guidance.nice.org.uk/TAG/354/ACD2/DraftGuidance.

Reporters: Johnathan Rickman, Elizabeth Orr, Ferdous Al-Faruque, Lena Freund, Robert King, Melissa Winn

President: Cynthia Carter; Content Director: Dan Landrigan; Executive Editor: Meg Bryant

Copyright © 2014 by Washington Business Information Inc. All rights reserved. International Pharmaceutical Regulatory Monitor (ISSN 1934-600X) is published monthly, 12 issues, for $795. Photocopying or reproducing in any form, including electronic or facsimile transmission, scanning or electronic storage is a violation of federal copyright law and is strictly prohibited without the publisher’s express written permis-sion. Subscribers registered with the Copyright Clearance Center (CCC) may reproduce articles for internal use only. For more information, contact CCC at www.copyright.com or call (978) 750-8400.

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