Clinical trials: collaboration is the secret to successful outsourcing

Bringing new products to market in the era of outsourced clinical trials is reliant on the ability of sponsors and CROs to work together.

The increasing globalisation of R&D has led to a rise in clinical outsourcing, as pharmaceutical companies find it difficult to operate solely with in-house teams.

A recent report by Research and Markets predicts that, by 2020, 72% of clinical trials will be outsourced to contract research organisations (CROs)1, up from just 23% in 2012.2

This is a great way to reduce operational and infrastructure costs, increase clinical timelines and organisational agility, and achieve scalable growth. If done well, CROs have the potential to deliver savings in both time and money, increase patient safety, improve regulatory compliance, and enhance trial data quality.3

Perfect business partnership as a connecting puzzle shaped as two trees in the form of human heads connecting together to complete each other as a corporate success metaphor for cooperation and agreement as equal partners.
Perfect business partnership as a connecting puzzle shaped as two trees in the form of human heads connecting together to complete each other as a corporate success metaphor for cooperation and agreement as equal partners.

But all this is reliant on a collaborative, effective relationship between sponsors and CROs. It must be based on trust and involve transparent communication. This is not necessarily easy to create.

A sponsor’s involvement in highly specialised clinical trials, and the need for multiple CRO partners to manage large pipelines, inevitably results in a complex operating environment.

Sponsors are generally seeking to reduce costs, access specialist knowledge, decrease clinical timelines and adapt quickly. CROs, on the other hand, need partnerships with multiple sponsors to remain economically viable, focusing on business goals related to economic success for their owners, investors and shareholders. These differing goals, processes and culture, can make it a challenge to create an effective collaborative environment.

Although some sponsors have taken positive steps, many still perpetuate a client/vendor mentality at both the operational and management levels. This tends to perpetuate a lack of trust in, and reduces the empowerment of, CROs, ultimately leading to frustration for both parties. This results in inefficiencies and needless duplication of tasks.4

Collaboration means shared decision making, delivery of broad cross-study solutions, performance assessments, and shared risk and reward structures. The goal is for the partners to operate as a team where both parties benefit.

Tips for successful collaboration

  1. Learn each other’s language and culture. Increasing globalisation necessitates both sponsor and CRO to perform due diligence in learning each other’s ‘language’ and culture in order to foster collaboration and trust.
  2. Establish joint, multi-level governance of study activities.2,3 Collaboratively establish a common vision and understanding of the partnership. Develop goals and metrics that measure alignment with, and performance against, the shared vision of both partners.
  3. Establish a mutually agreed practical communication plan.3 To avoid communication breakdown, have a centralised and practical communication plan that includes escalation procedures on both sides at all levels. Define what kind of communication is expected during the study, and what event(s) trigger an escalation.
  4. Develop and maintain a study/site risk assessment plan.5 Sponsors and CROs should work together to identify potential risks and design risk mitigation actions in advance wherever possible. Ongoing risk assessments should be performed on the site and the study itself to assure data quality and prevent problems.
  5. Define business processes, including roles and responsibilities.3 Both study sponsor and CRO have defined business process and systems in place for elements of the study lifecycle, and both will need to adapt to form an effective partnership. Make sure everyone on both teams understands the overall study processes and the role of each person.
  6. Establish key performance indicators (KPIs) for partners and study deliverables.3,6 In order to be meaningful and effective, KPIs need to be created collaboratively and align with incentives for both partners. Team members from both sponsor and CRO must understand how study progress is being measured and why.
  7. Determine how KPIs will be monitored and addressed when deficient.3 What is the level of transparency and accessibility needed to effectively monitor KPIs, and what is the team going to do if there is a problem?
  8. Align team goals with business goals across the partnership.3 The business objectives of both the sponsor and CRO need to be taken into account when defining team goals.
  9. Invest in software tools that enable communication, management, and automation of activities.2 Cloud-based platforms that enable immediate data sharing across partners are ideal for this.
  10. Treat study team members as one cohesive unit, regardless of the organisation.3,4 Give CRO partners a say in things like protocol design, the monitoring plan, and data management practices. Develop incentives to motivate team members to support both the short-term study and the long-term partnership expectations.
  11. Create an atmosphere of positive collaboration and continuous improvement.3 Effective collaboration requires transparency. Put in place mechanisms to enable two-way communication and feedback between CROs and sponsors to ensure the success of the study.

Successfully bringing new products to market in the era of outsourcing clinical trials rests, to a large extent, on the ability of sponsors and CROs to work together. This partnership must operate with open and transparent communications that foster a foundation of trust and mutual commitment.

The process is only one aspect to consider, however. Of equal importance is implementing the right technological tools to support process transparency, data sharing, and communications across company lines. This will, ultimately, speed the delivery of life-saving therapies to patients and disrupt the client/vendor ‘status-quo’ mindset.

Four digital trends in global clinical trials

Could ‘digital health’ be the next worldwide phenomenon? As advanced technology continues to evolve for health information purposes, it’s important to understand what digital health is and how its adoption is likely to impact end users.

Digital health encompasses a few technologies: mobile health (mHealth), health information technology (HIT), wearable devices, telehealth, telemedicine and personalised medicine, for example. But only recently have we seen healthcare providers move from experimenting with these solutions to fully deploying them. This is paving the way for early adoption across developed and developing nations, ensuring that a patient’s data and services are kept consistent.

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While the paperless trial era is not yet in full swing, it won’t be long before paper processes for data capture, labelling, global clinical trial recruiting, regulatory compliance, translation and internal centralisation are phased out. In the meantime, what tools can the industry expect to take advantage of?

1) Social media

Clinical trials are by no means excluded from social media, a modern staple for daily life. In fact, social media is used by trial sponsors and CROs across a variety of applications, from setting up recruitment websites to educating trial participants.

The importance of social media as a platform for educational content, especially to the millennial generation, can’t be overlooked. According to PwC, 40 percent of consumers say social media content affects the way they manage their health, and 90 percent of 18 to 24-year-olds would trust medical information shared by their peers.

2) Apps

Most popular for gaming, mobile apps are in fact becoming integral to the clinical trial process. As compatible mobile devices (including tablets and smartphones) face wider adoption worldwide, so do health information apps. Technology companies have even begun to develop apps for electronic labelling of investigational medicines, using QR codes that can be scanned to convey instructions for use.

Widespread adoption of mobile devices is also helping to collect patient-reported outcomes (PROs), an increasingly important endpoint in clinical trial design, and opening new channels of communication between doctors and patients. Instead of making an appointment to see their GP, patients in remote locations can use their smartphones to initiate e-consultations — a service which the NHS recently launched in the UK. Pharma and biotech companies, too, can use specialised apps to administer patient questionnaires and remind patients about scheduled trial site visits.

3) Wearable devices

Worldwide adoption of wearable devices is expected to jump from 325 million in 2016 to about 830 million in 2020 thanks to an increasingly ‘always-on’ environment. The popularity of Fitbits and other wearables has exploded, helping patients monitor their blood pressure, glucose levels and other risk factors whilst also facilitating medical access to information about symptoms, disease patterns and adverse events.

Wearables not only benefit the user but may have enormous cost-saving potential. If they motivate users to take control of their health, they can help curb unhealthy lifestyles that lead to chronic conditions. An even more exciting development is wearable tech’s ability to detect serious medical conditions.

4) Companion diagnostic devices

Much like the paperless era, the personalised medicine revolution has yet to fully take hold. However, the pharmaceutical industry and research committees are clearly moving in that direction — and advanced analytics may play a key role.

Technology companies are developing in-vitro companion diagnostic devices that pharma companies can use to target specific diseases based on patients’ personalised genomic profiles. Diagnostic tests can help healthcare providers weigh a product’s benefits and risks, and may also be helpful for data-gathering purposes. As a result they may encourage drug companies and regulatory bodies to share data.

The Compliance Factor

We can’t know for sure which new technologies will be accepted as the norm for global clinical trial recruiting and management, especially those in early development or yet to be invented. But these advances are expected to make clinical trials more efficient and possibly shorten drug development timelines, reducing the wait time for lifesaving drugs to reach the hands of those in most need.

Of course, the collection, use and exchange of personal data raise significant concerns about data storage, security and privacy. If they have not already done so, life sciences companies handling sensitive personal information will need to safeguard patient data and ensure global clinical trial compliance with privacy laws of relevant markets.

The debate, now and in the near future, is how compliance will affect the adoption of new technologies — and whether pharma companies are prepared to overcome regulatory pitfalls quickly to adopt innovations before their competitors do.

Contract Delays and Legal Negotiations Become a Growing Concern in Global Site Selection

The largest pain points in global clinical site selection no longer focus just around randomization times and patient recruitment, but have broadened to include slow contract turnaround and legal negotiations.

Total spending on study startups totals over $2.7 billion, and can account for around 19 percent of a sponsor’s expenditures, said Brooke Millman, WCG’s vice president of consulting solutions, during her webinar Strategies that Inform Investigator Selection and Enhance Enrollment.

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Site contracting alone accounts for more than $350 million annually, making budget considerations a much larger sticking point in negotiations.

To help speed contract turnaround and site startup, Millman recommended that sponsors employ a team of global contract negotiators and develop site-specific contracts prepopulated with a range of applicable legal terms. In addition, country-based budget templates can be used to cover non-procedural items, such as overhead costs, site start-up fees and pharmacy setup and maintenance.

Millman identified the main methods that sponsors can employ to improve contract negotiation timelines: work with teams that have international regulatory expertise to deliver a legally sound site agreement; spending time prior to negotiations to build and capitalizie on pre-existing relationships with sites; use harmonized tech solutions to track progress throughout the organization; and data-driven country selection.

“When we think about the consideration of which countries would be most impactful to our enrollment, there are a couple of different factors that we take into consideration,” added Suzanne Caruso, WCG’s vice president for clinical solutions. “One, of course, is how many investigators in the population of that particular country are able to enroll the particular study.”

Increasingly, however, sponsors are paying attention to the amount of time needed to settle on clinical trial agreement and any ancillary negotiations. “You cannot begin a study without a contract,” Caruso said.

For example, if it takes 130 days on average to open a site in Poland and 75 in Spain, with both offering the same patient population, “why wouldn’t you choose to go to Spain?” she asked. Other country-specific factors can affect the budget, such as requirements in Brazil that any woman of child-bearing age has to be on birth control for the duration of the study.

“Every single step we take together impacts the enrollment timeline, and impacts your time to database lock if you’re the sponsor,” Caruso said. “And for the site, it impacts how many patients potentially could get on a study, especially in situations that are life-threatening, where this may be a last resort for some of these particular patients.”

FDA Clarifies Stance on Clinical Trial Reimbursements for Patient Travel, Lodging

The FDA has updated its guidance to institutional review boards and clinical investigators clearly allowing reimbursements to patients in clinical trials for lodging and travel.

While paying subjects for participation in clinical research may raise difficult questions that should be addressed by an IRB, reimbursements for travel expenses to and from trial sites are not considered to raise issues regarding undue influence, according to the agency’s Office of Good Clinical Practice.

FDA Commissioner Scott Gottlieb highlighted the new passage in the guidance on travel reimbursement, saying the agency hopes “this clarity encourages recruitment in clinical trials.”

FDA-building-image

The change in the FDA’s guidance reflects how the industry has begun to shift how it conducts clinical trials, said Lindsay McNair, chief medical officer of WIRB-Copernicus Group.

“It used to be that people who were participating in clinical trials were very near a clinical site,” McNair said. “They would have some parking expenses, or they might have taxi fare.”

“But especially as we move into rare disease areas — where people may be coming from other parts of the country to special treatment centers to participate in research — the amount of reimbursement for travel expenses becomes plane tickets for someone and their spouse and two nights in a hotel.”

For instance, a study on hypertension may have many potential participants available locally; studies in Duchenne muscular dystrophy patients carrying a particular genetic mutation, however, would require a larger recruiting footprint, she said, meaning a higher likelihood of paying travel expenses.

In contrast to reimbursement, the guidance states that ethics reviews should continue to examine how much compensation participants receive, including for reasons such as time, inconvenience or discomfort.

“IRBs should be sensitive to whether other aspects of proposed payment for participation could present an undue influence, thus interfering with the potential subjects’ ability to give voluntary informed consent,” the guidance said, adding that payments should be just and fair.

IRBs should receive the amounts and schedule of all payments, including end-of-study bonuses, during the initial review to ensure that they are not coercive according to federal regulations, including 21 CFR 50.20, the agency said. All information concerning payment should be spelled out in the informed consent document.

Credits for payment should accrue as the study continues, and not be contingent on study completion; however, a small proportionate payment to incentivize completion is acceptable, as long as it is not coercive, according to the guidance.

The question of what type of reimbursement crosses the line into undue influence or coercion has typically caused more stress for sponsors and researchers than IRBs, McNair said.

By comparison, IRBs — as well as Phase I research units with experience recruiting healthy volunteers to studies — all have a pretty good idea of what kind of compensation amounts will be considered appropriate.

“It’s something they’ve been very used to considering,” McNair said. “We very rarely see anything come through where we need to push back on a payment plan,” especially in a study that an IRB has already decided has a reasonable risk.

Many research organizations and sponsors keep payment schedules — detailing how much they compensate for blood draws, nights spent in the clinic and other study procedures, for example — creating a guide to what they know IRBs have considered appropriate in the past.

But sponsors in all phases of clinical trials can be very concerned with the optics of offering patients money to participate in research, and often seek IRB input.

The FDA guidance is a welcome update, McNair said. “It’s nice to have them explicitly clarify the difference between compensation and reimbursement.”

“The previous guidance didn’t really separate those two things out, and I think it did cause some confusion to people in trying to plan what they wanted to do in a study,” she said, adding that it probably won’t change how IRBs weigh the issue.

When examining a submission, the boards typically break those two considerations apart to judge them individually, even if the two are not explicitly described by the sponsor in the protocol or consent form.

“We do think it’s generally appropriate for people not to have to pay out-of-pocket expenses to participate in research,” said McNair. “We don’t want the subject to incur those expenses, and we also look at it from the concept of justice and equitable subject selection.”

If only the people who can participate in research are those who can afford the travel expenses upfront, that could greatly limit who can be recruited into a study, she said. The larger issue of research subject compensation has had a tremendous amount of discussion in the IRB space, and how study protocols should balance the issue of undue influence and respect for patients.

The full FDA guidance is available here: https://www.fda.gov/RegulatoryInformation/Guidances/ucm126429.htm.

Indian pharma firms renew focus; Dr Reddy’s, Cipla eye $100-bn China market

Dr Reddy’s Laboratories (DRL) is expanding its presence in China, the world’s second-largest pharmaceutical market, where other drug manufacturers such as and are exploring opportunities.The more than $100-billion market is dominated by local drug manufacturers and multinationals and India’s of around $160 million are a fraction of the companies’ sales.

 

But recent changes in regulation allowing quicker product approval and growth opportunities in have been drivers for Indian According to The Pharma Letter website, China’s recently decided to acknowledge foreign trial data and hire more people to speed up drug approvals — moves that could benefit India’s drug manufacturers. “While Indian have traditionally focused on the US and Europe, new regulations in China, which could fast-track approvals for products cleared by the US Food and Drug Administration, could help Indian secure a foothold in the market,” said Sriram Shrinivasan, global emerging markets leader, lifesciences, EY.DRL said it was planning to introduce anti-cancer drugs, while and are planning to launch core therapies such as and respiratory drugs in

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“A strong pipeline is in place and this will continue to be strengthened along with the expansion of our field force. Oncology is an area of focus. We are also looking at partnerships to expand our commercial footprint in the market,” said DRL Executive Vice-President M V Ramana.DRL manufactures and sells drugs in in a joint venture with Canada’s Rotam group. The joint venture (JV) has a sales and marketing team covering 5,000 hospitals spread over DRL sells products worth around $20 million in China, according to global health care services firm IQVIA. However, the figure does not include sales of active pharmaceutical ingredients.While DRL has been present in the Chinese market for nearly 20 years, other Indian have had limited success there.

Ranbaxy, which was acquired by in 2014, exited from a JV in and sold its stake to its partners in 2009. Torrent dropped its plans to launch drugs in because of stringent regulatory requirements. In 2013, the firm had initiated talks with a Chinese company but the plan was dropped two years later, a company spokesperson said. Three years ago exited from two investments it had made in But drug manufacturers are preparing to take fresh bets in the market with a focus on core therapies. The operating environment will remain challenging but strong demand and quick approval for innovative products in are an attraction, according to IQVIA.is planning to launch its in and is in talks with local for clinical trials. The company is developing five is keen to make a foray into the respiratory segment through an acquisition or partnership. A spokesperson for the company was not available for comment. “We will explore because it is a very large market for antibiotics,” Chairman Habil Khorakiwala stated. The market in is double that of the US by value and is 25 times bigger in volumes, indicating a huge potential for Wockhardt’s novel drug pipeline. “In we intend to outlicense the We studied the market and found it is too complex for us to market drugs,” Khorakiwala added.Fabrice Egros, Lupin’s president for the Asia-Pacific region, said the company was exploring opportunities for partnerships in However, cultural challenges, along with the fragmented nature of the market, have been seen as hindrances.“Indian have not focused on because of complexities and higher opportunities in markets like and Japan, which are the focus areas after the US,” said D G Shah, secretary-general,

FDA approves smartwatch for epilepsy monitoring

A new smart watch which uses machine learning to monitor for the most dangerous kinds of epileptic seizures has been approved by the FDA.

Cambridge, Massachusetts based Empatica is the company behind the new technology, which it says is the first smartphone approved for use in neurology.

The approval comes against a background of the FDA seeking to accelerate the approval of new digital health products.

Nevertheless, companies in the field need to prove safety and efficacy. In a multi-site clinical study, 135 patients diagnosed with epilepsy were admitted to top level IV epilepsy monitoring units for continuous monitoring with video-EEG, while simultaneously wearing an Empatica device.

 

FDA-building-image

 

From these patients, 6,530 hours of data were recorded over 272 days, including 40 generalised tonic-clonic seizures, also known as ‘grand mal’ the most serious seizures. Embrace’s algorithm was shown to detect 100% of the seizures.

Empatica says the trial used the gold standard of comparing to seizures clinically labelled by at least 2 out of 3 independent epileptologists, who examined the video-EEG data without seeing any data used by Embrace.

The firm says its device is unlike any seizure detection system in that it measures multiple indicators of a seizure. Its unique property is its use of Electrodermal Activity (EDA), a signal used by stress researchers to quantify physiological changes related to sympathetic nervous system activity, also known as the “fight or flight” response.

Embrace gained approval in Europe as a medical device for seizure monitoring and alert in April 2017.

 

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Generalised tonic-clonic seizures result in a loss of consciousness and can leave the person in a state of confusion for some time afterwards. Traditionally, clinical trials have had to rely upon patients to self-report in a diary when a seizure happens, a process known to be inaccurate.

Over 40% of the most dangerous generalized tonic-clonic seizures are not reported, but Embrace’s high sensitivity makes seizure reporting easier and more accurate. The bracelet also sends an alert immediately to a caregiver, to bring help at the time of need.

Orrin Devinsky, director of the Comprehensive Epilepsy Center at NYU commented: “The FDA approval of the Embrace device to detect major convulsive seizures represents a major milestone in the care of epilepsy patients.”

More than 3,000 Americans die each year from Sudden Unexpected Death in Epilepsy (SUDEP).

Devinsky says the smartwatch will help raise the alarm with family or carers that a tonic-clonic seizure is occurring, with rapid attention known to be life-saving in many cases.

Seizure monitoring research started at the MIT Media Lab with Rosalind Picard, where she is Director of the Affective Computing Group and Chief Scientist at Empatica, and later at Boston’s Children Hospital.

“It’s been quite the journey – we have worked for years building wearable stress and emotion sensors, and then accidentally discovered we could pick up changes in the skin elicited by brain activity related to the most dangerous kinds of seizures.

“It has been very meaningful to see this technology move from the lab into the most accurate, beautiful and easy to use sensor on the market.”

Empatica was launched through a crowdfunding campaign in 2015, spinning out from the MIT Media Lab in Cambridge, Mass.

KEY CHANGES IN NEW DRAFT RULES FOR CLINICAL TRIALS IN INDIA

CDSCO has published the new draft Clinical Trial Rules 2018 in Feb 2018 after consultation with the Drugs Technical Advisory Board. This draft Rules shall be taken into consideration on or after the expiry of a period of forty five days. Objections and suggestions which may be received from any person within the period specified above will be considered by the Central Government.

 

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Ethics Committee:

  • The registration granted in Form CT-02 shall remain valid for a period of three years from the date of its issue, unless suspended or cancelled by the Central Licencing Authority
  • On expiry of the validity period of registration an Ethics Committee may make an application for renewal of registration in Form CT-01 along with documents as specified in Table 1 of the Third Schedule three months prior to the date of the expiry of the registration
  • Provided that if the application for renewal of registration is received by the Central Licencing Authority three months prior to the date of expiry, the registration shall continue to be in force until an order is passed by the said authority on the application
  • where a clinical trial site does not have its own Ethics Committee, clinical trial at that site may be initiated after obtaining approval of the protocol from the
  • Institutional Ethics Committee of another trial site; or an independent Ethics Committee constituted in rule 7
  • Provided that the approving Ethics Committee shall in such case be responsible for the study at the trial site or the centre, as the case may be
  • Provided further that, the approving Ethics Committee and the clinical trial site or the bioavailability and bioequivalence centre, as the case may be, shall be located within the same city or within a radius of 50 km of the clinical trial site.

CLINICAL TRIAL OF NEW DRUGS AND INVESTIGATIONAL NEW DRUGS

  • In case of rejection, the applicant may request the Central Licencing Authority, to reconsider the application within a period of sixty days from the date of rejection of the application on payment of fee as specified in the Sixth Schedule and submission of required information and documents.
  • An applicant who is aggrieved by the decision of the Central Licencing Authority under the Ministry of Health and Family Welfare, may file an appeal before the Central Government within forty-five days from the date of receipt of such decision and the Government, may, after such enquiry, and after giving an opportunity of being heard to the appellant, dispose of the appeal within a period of sixty days.
  • Permission to conduct clinical trial of a new drug or investigational new drug as part of discovery, research and manufacture in India;
  • Such application shall be disposed by way of grant of permission or rejection or processed by way of communication to rectify any deficiency of the application, as the case may be, as specified in rule 22, by the Central Licensing Authority within a period of forty-five days from the date of the receipt of the application
  • Provided that, where no communication has been received from the Central Licensing Authority to the applicant within the said period, the permission to conduct clinical trial shall be deemed to have been granted by the Central Licensing Authority and such permission shall be deemed legally valid for all purposes and the applicant shall be authorised to initiate clinical trial under these rules.
  • The applicant who has taken deemed approval under sub-rule (1) shall before initiating the clinical trial inform the Central Licensing Authority in Form CT-4A. On the basis of the said information the Central Licensing Authority shall take on record the Form CT-4A which shall become part of the official record and shall be called automatic approval of the Central Licensing Authority.
  • Permission to conduct clinical trial of a new drug already approved outside India: The application shall be disposed of by way of grant of permission or rejection or processed by way of communication to rectify any deficiency, as the case may be, as specified in rule 22, by the Central Licensing Authority within a period of ninety days from the date of the receipt of the application by the said Authority.

Conditions of permission for conduct of clinical trial:

  • The Central Licencing Authority shall be informed about the approval granted by the Ethics Committee within a period of 15 days of the grant of such approval. This could be informed by site i.e. P.I or CRO or sponsor.
  • Six monthly status report of each clinical trial, as to whether it is ongoing, completed or terminated, shall be submitted to the Central Licencing Authority;
  • the clinical trial shall be initiated by enrolling the first subject within a period of one year from the date of grant of permission, failing which prior permission from the Central Licencing Authority shall be required;

Validity period of permission to conduct clinical trial:

  • The permission to conduct clinical trial granted under rule 22 in Form CT-06 shall remain valid for a period of two years from the date of its issue, unless suspended or cancelled by the Central Licencing Authority.
  • In exceptional circumstances, where the Central Licencing Authority is satisfied about the necessity for an extension beyond two years, the said authority may, on the request of the applicant made in writing, extend the period of permission granted for a further period of one year.

BIOAVAILABILITY AND BIOEQUIVALENCE STUDY

Bioavailability or bioequivalence study of new drug or investigational new drug

  • The Central Licencing Authority may, after scrutiny of the information and documents furnished with the application in Form CT-05 and such further enquiry, if any, as may be considered necessary, grant the permission to conduct bioavailability or bioequivalence study for a new drug or investigational new drug in Form CT-07 within a period of ninety days from the date of receipt of its application.
  • In case of rejection, the applicant may request the Central Licencing Authority, to reconsider the application within a period of sixty days from the date of rejection of the application on payment of fee as specified in the Sixth Schedule and submission of required information and documents.
  • An applicant who is aggrieved by the decision of the Central Licencing Authority under the Ministry of Health and Family Welfare, may file an appeal before the Central Government within forty-five days from the date of receipt of such decision and the Government, may, after such enquiry, and after giving an opportunity of being heard to the appellant, dispose of the appeal within a period of sixty days.

Conditions of permission for conduct of bioavailability or bioequivalence study:

  • The Central Licencing Authority shall be informed about the approval granted by the ethics committee within a period of 15 days of the grant of such approval. This could be informed by site i.e. P.I or CRO or sponsor.

Validity period of permission to conduct bioavailability or bioequivalence study:

  • The permission to conduct bioavailability or bioequivalence study granted under rule 34 in Form CT-07 shall remain valid for a period of one year from the date of its issue, unless suspended or cancelled by the Central Licencing Authority.
  • In exceptional circumstances, where the Central Licencing Authority is satisfied about the necessity for an extension beyond one year, the said authority may, on the request of the applicant made in writing, extend the period of permission granted for a further period of one year.

Compensation in case of death or permanent disability in clinical trial or bioavailability and bioequivalence study

  • In case of death or permanent disability of a trial subject occurs during a clinical trial or bioavailability and bioequivalence study and the Ethics Committee after due analysis of the case, in accordance with the procedure, is of the opinion that the death or the permanent disability, as the case may be, is related to the clinical trial, the sponsor or the person who has obtained permission under rule 22, shall pay an interim compensation of sixty percent of the compensation payable as per the formula, to the legal heir of the trial subject in case of death and to the trial subject in case of permanent disability, within a period of fifteen days from the date of receipt of the opinion of the Ethics Committee by that Sponsor or that person.
  • In case of death or permanent disability of a trial subject occurs during a clinical trial or bioavailability and bioequivalence study and the Central Licensing Authority has decided, as per rule 42, that such death or permanent disability, as the case may be, is related to the clinical trial or bioavailability and bioequivalence study, the sponsor or the person who has obtained permission under rule 22, shall pay a compensation, as determined in accordance with the formula specified in the Seventh Schedule, to the legal heir of the trial subject in case of death and to the trial subject in case of permanent disability as per order of the Central Licensing Authority, within a period of thirty days from the date of receipt of such order by that Sponsor or that person
  • Provided that in case of death or permanent disability, if an interim compensation has been paid under sub-rule, in such case, the quantum of compensation to be paid shall be an amount which is less the amount paid as the interim compensation.
  • The financial compensation shall be over and above any expenses incurred on medical management of the trial subject before his death or in connection with the maintenance of the body after death.

BIOAVAILABILITY AND BIOEQUIVALENCE STUDY CENTRE

  • The Central Licencing Authority may, after scrutiny of the information and documents furnished with the application in Form CT-08 and such further enquiry, if any, as may be considered necessary if satisfied, that the requirements of these rules have been complied with, grant registration to the applicant in Form CT-09 within a period of ninety days from the date of receipt of its application.
  • The registration granted under rule 47 in Form CT-09 shall remain valid for a period of five years from the date of its issue, unless suspended or cancelled by the Central Licencing Authority.

Sl.No

Subject

In Rupees except where specifies in Dollars

1

Application for permission to conduct Clinical Trial
Phase I

300,000

Phase II

200,000

Phase III

200,000

Phase IV

200,00

2

Reconsideration of application for permission to conduct clinical trial

50,000

3

Application for Permission to conduct bioavailability or bioequivalence study

200,000

4

Reconsideration of application of permission to conduct bioavailability or bioequivalence study

50,000

5

Application for Registration of bioavailability and bioequivalence study centre

500,000

6

Reconsideration of application for registration of bioavailability and bio- equivalence study centre

100,000

7

Application for import of new drugs or investigational new drugs for clinical trial or bioavailability or bioequivalence study

5000/Product

8

Reconsideration of application for Import of new drugs or investigational new drugs for clinical trial or bioavailability or bioequivalence study

1000

9

Pre-submission meeting

500,000

10

Post-submission meeting

50,000

IMPORT OF NEW DRUGS AND INVESTIGATIONAL NEW DRUGS FOR CLINICAL TRIAL OR BIOAVAILABILITY OR BIOEQUIVALANCE STUDY

  • The Central Licencing Authority may, after scrutiny of the information and documents furnished with the application in Form CT-16 grant the licence to import of new drug or investigational new drug for clinical trial or bioavailability or bioequivalence study in Form CT-17 within a period of ninety days from the date of receipt of its application
  • The licence granted under rule 68 in Form CT-17 shall remain valid for a period of three years from the date of its issue, unless suspended or cancelled by the Central Licencing Authority.
  • In exceptional circumstances, where the Central Licencing Authority is satisfied about the necessity and exigency, it may, on the request of the applicant made in writing, extend the period of the licence granted under rule 69 for a further period of one year.

World Preview 2017, Outlook to 2022

Highlights

  • Biologics to contribute 52%of the Top 100 product sales by 2022; Roche leads market
  • Roche gains the top spot of the pipeline value creation ranking proving  its leadership ambitions beyond oncology. AstraZeneca and AbbVie complete the podium
  • NovoNordisk’s portfolio expected to yield the highest return on investment in the future
  • Biogen’s aducanumab and J&J’s apalutamide projected to be the most valuable R&D projects
  • Worldwide pharmaceutical R&D spend expected togrow by 2.4%(CAGR)to $181bn in 2022
  • Average R&D spend per NME at $4 bn over the last 10 years
  • Roche forecast to be the biggest spender on pharmaceutical R&D in 2022.
  • New drug approvals in2016 drop to 27 NMEs down 50% vs. the record high of 56 in 2015. Positive trend in the rst 5 months of 2017 with 21 NMEs already approved
  • Oncology is still the largest therapy are a in sales (+12.7%CAGR) 2016-22
  • Roche remains atop the oncology eldbutits leadership is challenged by Celgene. Novartis to drop out of the top 3
  • NovoNordisk is expected to remain the major player in the anti-diabetics market in 2022, but Lilly is gaining ground behind driven by Trulicity
  • AbbVie still dominates anti-rheumatics market in 2022;ABT-494(upadacitinib) set to be the most promising R&D asset in development
  • GSK leads in the vaccine market a head of Merck and Pfizer
  • Pfizer’s pneumococcal vaccine Prevnar 13 remains the top selling vaccine product
  • Gilead lead continues in anti-viral market in 2022 largely due to its HIV portfolio
  • Opdivo and Revlimid to compete for the top selling products in the world in 2022
  • Humira still expected to be the top selling drug in 2022 at $15.9bn a headof Revlimid and Opdivo
  • Keytruda ($9.5bnin2022) nearly closed the gap with Opdivo ($9.9bn) interms of consensus forecast
  • Eliquis took over Xareltoas the leading anti-coagulant in 2022 at $8.5bn
  • AbbVie’s Humira will continue to be the leading product in the USA in 2022, with sales of $12.0bn. Keytruda knocks o Opdivo as the top-selling PD-1/PD-L1 product in 2022

WP17, Outlook 2022

Clinical trials: stringent draft rules put onus of injuries, death on drugmakers

Pharmaceutical firms conducting clinical trials of drugs in India will no longer be able to escape responsibility in case of injury or death of participants.

According to new draft rules for clinical trials and new drugs, if the sponsor fails to provide “medical management” to their trials, not only will the trial be cancelled, but the company will also be restricted from holding any more trials.

However, in a boost to firms wanting to conduct trials on drugs proposed to be manufactured and marketed in India, the permission for trials will be granted within 45 days.

ClinicalTrial-kuyH--621x414@LiveMint

According to the new rules in the works, the sponsor of the trial or bioavailability or bioequivalence (BA/BE) study of a new drug will have to provide free medical management for as long as required. BA/BE studies measure the rate and extent of absorption of drugs in the human body.

Additionally, if the trial subject suffers from any other illness during the clinical trial or BA/BE study, the sponsor should provide necessary medical management and ancillary care. “Where the sponsor or the person who has obtained permission from the central licensing authority fails to provide medical management, the licensing authority shall, after affording an opportunity of being heard, suspend or cancel the clinical trial or BA/BE study or restrict the sponsor to conduct any further clinical trial,” says the proposed regulatory framework for clinical trials and new drugs. Mint has reviewed a copy of the final draft.

Welcoming the move, Daara B. Patel, secretary general, Indian Drugs Manufacturers’ Association, said: “It’s high time that government takes a balanced view. It should be favourable to the companies so that they take advantage in conducting trials; at the same time, the rules on companies which put the lives of candidates at risk need to be tightened and proper compensation has to be given to those who fall prey to these clinical trials”.

As per the draft new drugs and clinical trials rules, 2017, companies will have to pay compensation if the drug fails to provide the intended therapeutic effect or where the required standard care or rescue medication, although available, was not provided to the subject.

If the clinical trial is being conducted for an indication for which no alternative therapy is available and the investigational new drug has been found to be beneficial to the trial subject, the post-trial access will be provided by the company free of cost.

According to the new draft rules, which will soon be put up for comments by stakeholders, if the patient dies or suffers a permanent disability during a trial, the companies conducting the trial will have to pay an interim compensation of 60% of the final amount within a period of 15 days, Mint reported on 22 September. Compensation to victims of clinical trials is given on the basis of a formula that takes into account the age and health risk of the patient.

The proposed regulatory framework also suggests doing away with clinical trials for drugs that have proved their efficacy in developed markets, in a move to speed up the availability of drugs in India.

“The local trial may not be required if no major unexpected serious adverse events have been reported and there is probability or evidence on the basis of existing knowledge, of difference in India population of the enzymes/gene involved in the metabolism of the new drug,” says the draft.

As per the new draft rules, if the company proposes to conduct the clinical trial of a new drug or an investigational new drug and also the new drug is proposed to be manufactured and marketed in India, not only the permission will be granted in a time bound manner of 45 days, if the central licensing authority fails to communicate, the “permission to conduct the clinical trial shall be deemed to have been granted”.

Time line for processing application:

— Clinical trial (in general): 90 days

— CT (innovated in India) within 45 days

— CT (if drug is already approved by other country): within 60 days

— New drug: within 90 days

Indian pharma cos get record 300 USFDA generic drug nods in 2017

Domestic pharmacompanies received more than 300 approvals in 2017 to launch generic drugs in the US, which is an all-time high. The clearances came despite regulatory pressure from the US Food and Drug Administration (FDA), and unprecedented warning letters issued to the pharma companies’ facilities.
The final approvals for Indian players are up by nearly 43 per cent from 211 in 2016, and corner about 40 per cent of all global filings in the highly lucrative around $70-billion US market. This, even as all drug biggies — including Zydus, Sun Pharma, Dr Reddy’s and Cipla — faced regulatory ire, while some were pulled up for manufacturing lapses by the US regulator during last year.

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In terms of each company, Zydus leads with 66 approvals in 2017, followed by Aurobindo (52), Glenmark (18), Lupin (17), Gland Pharma (16) and Cipla (10). Zydus cornered a majority of US filings as its Moraiya facility, which contributes about 60 per cent of US sales, came out from under USFDA scanner in June last year. Sun Pharma remained static at 10 approvals, due to its Halol plant continuing under the regulatory glare.

Master

The US generics market, a key driver of Indian pharma’s growth, has always been a dynamic market. But the pace of change has accelerated in the last few years. The increase in competition and consolidation of distribution channels have led to the US generics business getting commoditised. Price erosion has been at an all-time high and this has impacted operating margins significantly. Major domestic companies earn at least 40 per cent of their overall sales from the US.

To maximise margins, companies are now launching complex generics and speciality products.Glenmark Pharma chairman & MD Glenn Saldanha says, “While the number of ANDA (abbreviated new drug application) approvals continue to remain strong for us, we, however, have begun the process of transitioning the US business to a specialty/innovation business. While the generics business in the US will still grow, the future for us will be in the specialty and innovation business. We plan to file our first specialty NDA in the next few months in the US.”
The US generics market stays very attractive and continues to see the entry of new entrants — Mankind Pharma launched its first product in the US in September last year. An analyst from Credit Suisse says, “Fragmentation is increasing fast in the US generics market and it is validated through ever-increasing ANDA filings. For calender year 2017, overall ANDA filings were one of the highest at 1,128 (up 11 per cent year-on-year). We expect approvals to increase by another 50 per cent over the next two years and therefore expect price erosion to accelerate further. We expect the market to decline at mid-single digit CAGR (compounded annual growth rate) over next three years, and the profit pool for generic industry to decline at high single-digit CAGR.”
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