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Leadership 4 ways for leaders to make a decision

Business leaders are faced with dozens of decisions that need to be made every day. As our organizations grow, the decisions generally become more frequent, more complicated, and have more serious ramifications. Sometimes it’s not about making the right decision, but just making a decision at all. The most successful entrepreneurs and business leaders in the world will tell you they have made many wrong decisions throughout the lifetime of their careers, but those failures always lead to valuable learning experiences, so above all, it’s important to find ways to make the tough decisions.

Business owners, executives and managers must master the ability to make good decisions quickly in order to keep the business moving forward. The best leaders, however, know when they need input from the team. Good leaders surround themselves with trusted advisors and subject matter experts, so that they can access a constant flow of data to make better decisions.

There are four basic decision-making styles that leaders can use:

Command: Command decision-making is where leaders make decisions without consulting their teams. This is an effective style, especially when things are moving quickly and the team is looking for immediate guidance. In a business setting, leaders use this style the most effectively on large financial decisions and in crisis situations. 

Collaborative:  Collaborative decision-making is just what it sounds like. Leaders gather their teams and request feedback and insight. The leader still makes the final call, but is armed with the proper data to make a more informed decision. This can also be referred to as evidence-based decision-making. With this style, and really in all business decisions, avoid surrounding yourself with people that always agree with you. You need people who are able to strongly argue the other side. Whether you use their advice or not, it will help clarify your decision.

Consensus: Consensus-based decision-making is done more like a democratic vote. Leaders gather their teams and everyone votes. Majority rules. This process can work well when the outcome of the decision affects the entire team, and generally won’t immediately affect the bottom line. In a quick-moving business environment, this is not the most efficient way to make a decision, but there are still some decisions that can be made this way. In a business, however, this type of decision-making can help mold the culture when the team is allowed to vote and have a voice. Just remember you generally can’t please everyone.

Convenience:  When surrounded by trusted peers, sometimes the best decision a leader can make is to not be the one to make a certain decision. Complete delegation (convenience decision-making) has many benefits including measuring the decision-making abilities of your managers, empowering your team, and maintaining your own sanity! By handing over some decision-making responsibilities, leaders are also building a better management team and giving them the confidence they need as their responsibilities increase. And, convenience-based decision-making is a great way to avoid the decision trap of “we’ve always done it this way.” New decision makers take fresh approaches to solving problems.

How Good is Your Decision-Making?

Each decision presents its own challenges, and we all have different ways of approaching problems. So, how do you avoid making bad decisions – or leaving decisions to chance? You need a systematic approach to decision-making so that, no matter what type of decision you have to make, you can take decisions with confidence.

Sandoz proposed biosimilar rituximab accepted for review by the FDA

• Rituximab is indicated to treat blood cancers and immunological diseases such as rheumatoid arthritis
• Sandoz believes the comprehensive data package submitted to the FDA for review confirms that our biosimilar rituximab matches the reference medicine in terms of safety, efficacy and quality
• The global leader in biosimilars, Sandoz has five biosimilars approved worldwide including biosimilar rituximab, which was approved in Europe* in June 2017

Holzkirchen, September 12, 2017 - Sandoz, a Novartis Division, and the pioneer and global leader in biosimilars, announced today that the US Food and Drug Administration (FDA) has accepted its Biologics License Application (BLA) under the 351 (k) pathway for a proposed biosimilar to the reference medicine, Rituxan®** (rituximab).

Rituxan®** is used to treat blood cancers including non-Hodgkin's lymphoma (follicular lymphoma and diffuse large B-cell lymphoma) and chronic lymphocytic leukemia, as well as immunological diseases such as rheumatoid arthritis.

"The cost of treating cancer in the US is a major concern for many patients and their families as well as for the healthcare system[3]" said Mark Levick, MD PhD, Global Head of Development, Biopharmaceuticals. "With the FDA acceptance of our regulatory submission for proposed biosimilar rituximab, we plan to deliver patients a high-quality Sandoz biosimilar that, following approval, could help drive healthcare savings and increase competition, while freeing up resources for and supporting patient access in other areas of cancer care including innovative therapies."

The BLA consists of a comprehensive data package that includes analytical, preclinical and clinical data. Clinical studies included apharmacokinetic/pharmacodynamic (PK/PD) trial in rheumatoid arthritis (ASSIST-RA)[4], and a Phase III confirmatory safety and efficacy study in follicular lymphoma (ASSIST-FL). Sandoz believes these data provide confirmation that the proposed biosimilar matches the reference medicine in terms of safety, efficacy and quality.

Sandoz is committed to increasing patient access to high-quality biosimilars. As the pioneer and global leader in biosimilars, Sandoz has five biosimilars marketed worldwide, as well as a leading global pipeline. We plan to launch a total of five major oncology and immunology biosimilars between 2017 and 2020. This includes biosimilar rituximab, which was approved by the European Commission for use in Europe in June 2017 (marketed as Rixathon®).

Sandoz is well positioned to continue leading the biosimilars industry based on its experience and capabilities in development, manufacturing and commercialization. As a division of Novartis, the first global healthcare company to establish a leading position in both innovative and off-patent medicines, Sandoz benefits strongly from this unique blend of experience and expertise in many different market environments.

Sandoz also continues to champion policy and legislation that enables patients and the healthcare system to benefit from biosimilars. This was demonstrated by the recent US Supreme Court unanimous positive decision related to the Notice of Commercial Marketing (NCM). The Supreme Court ruled that NCM can be provided before FDA approval, accelerating patient access to future US biosimilars by 180 days. The Court also provided additional clarity on how the "patent dance," the process by which biosimilar manufacturers may provide confidential and proprietary information to the manufacturer of the reference medicine in the patent exchange process, will function.

About Sandoz

Sandoz is a global leader in generic pharmaceuticals and biosimilars. As a division of the Novartis Group, our purpose is to discover new ways to improve and extend people's lives. We contribute to society's ability to support growing healthcare needs by pioneering novel approaches to help people around the world access high-quality medicine. Our portfolio of approximately 1000 molecules, covering all major therapeutic areas, accounted for 2016 sales of USD 10.1 billion. In 2016, our products reached well over 500 million patients and we aspire to reach one billion. Sandoz is headquartered in Holzkirchen, in Germany's Greater Munich area.

FDA approval brings first gene therapy to the United States

CAR T-cell therapy approved to treat certain children and young adults with B-cell acute lymphoblastic leukemia


This release was updated on Aug. 30, 2017 to correctly identify the FDA designations granted to Kymriah.

The U.S. Food and Drug Administration issued a historic action today making the first gene therapy available in the United States, ushering in a new approach to the treatment of cancer and other serious and life-threatening diseases.

The FDA approved Kymriah (tisagenlecleucel) for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL).

“We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer,” said FDA Commissioner Scott Gottlieb, M.D. “New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses. At the FDA, we’re committed to helping expedite the development and review of groundbreaking treatments that have the potential to be life-saving.”

Kymriah, a cell-based gene therapy, is approved in the United States for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.

Kymriah is a genetically-modified autologous T-cell immunotherapy. Each dose of Kymriah is a customized treatment created using an individual patient’s own T-cells, a type of white blood cell known as a lymphocyte. The patient’s T-cells are collected and sent to a manufacturing center where they are genetically modified to include a new gene that contains a specific protein (a chimeric antigen receptor or CAR) that directs the T-cells to target and kill leukemia cells that have a specific antigen (CD19) on the surface. Once the cells are modified, they are infused back into the patient to kill the cancer cells.

ALL is a cancer of the bone marrow and blood, in which the body makes abnormal lymphocytes. The disease progresses quickly and is the most common childhood cancer in the U.S. The National Cancer Institute estimates that approximately 3,100 patients aged 20 and younger are diagnosed with ALL each year. ALL can be of either T- or B-cell origin, with B-cell the most common. Kymriah is approved for use in pediatric and young adult patients with B-cell ALL and is intended for patients whose cancer has not responded to or has returned after initial treatment, which occurs in an estimated 15-20 percent of patients.

“Kymriah is a first-of-its-kind treatment approach that fills an important unmet need for children and young adults with this serious disease,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research (CBER). “Not only does Kymriah provide these patients with a new treatment option where very limited options existed, but a treatment option that has shown promising remission and survival rates in clinical trials.”

The safety and efficacy of Kymriah were demonstrated in one multicenter clinical trial of 63 pediatric and young adult patients with relapsed or refractory B-cell precursor ALL. The overall remission rate within three months of treatment was 83 percent.

Treatment with Kymriah has the potential to cause severe side effects. It carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T-cells causing high fever and flu-like symptoms, and for neurological events. Both CRS and neurological events can be life-threatening. Other severe side effects of Kymriah include serious infections, low blood pressure (hypotension), acute kidney injury, fever, and decreased oxygen (hypoxia). Most symptoms appear within one to 22 days following infusion of Kymriah. Since the CD19 antigen is also present on normal B-cells, and Kymriah will also destroy those normal B cells that produce antibodies, there may be an increased risk of infections for a prolonged period of time.

The FDA today also expanded the approval of Actemra (tocilizumab) to treat CAR T-cell-induced severe or life-threatening CRS in patients 2 years of age or older. In clinical trials in patients treated with CAR-T cells, 69 percent of patients had complete resolution of CRS within two weeks following one or two doses of Actemra.

Because of the risk of CRS and neurological events, Kymriah is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). The FDA is requiring that hospitals and their associated clinics that dispense Kymriah be specially certified. As part of that certification, staff involved in the prescribing, dispensing, or administering of Kymriah are required to be trained to recognize and manage CRS and neurological events. Additionally, the certified health care settings are required to have protocols in place to ensure that Kymriah is only given to patients after verifying that tocilizumab is available for immediate administration. The REMS program specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Kymriah.

To further evaluate the long-term safety, Novartis is also required to conduct a post-marketing observational study involving patients treated with Kymriah.

The FDA granted Kymriah Priority Review and Breakthrough Therapy designations. The Kymriah application was reviewed using a coordinated, cross-agency approach. The clinical review was coordinated by the FDA's Oncology Center of Excellence, while CBER conducted all other aspects of review and made the final product approval determination.

The FDA granted approval of Kymriah to Novartis Pharmaceuticals Corp. The FDA granted the expanded approval of Actemra to Genentech Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines, and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

What Impact Will the Shinal Case Have on Informed Consent in Clinical Research? By Darshan Kulkarni and Erin Grant

Introduction:

Informed consent recently made the headlines with Congress and the U.S. Food and Drug Administration (FDA) expounding on circumstances where they will accept the alteration, minimization or even outright elimination of informed consent in certain clinical research trials. Some might argue that this continues the slide towards weakened protections afforded to patients and clinical study participants. However, some courts have taken to interpreting the requirements for informed consent rather strictly, especially as they apply to the performer of the informed consent process. 

Background:

 According to the Code of Federal Regulations as applied by the Department of Health and Human Services, an investigator may only involve a human being as a subject in research if the investigator has obtained legally effective informed consent from the subject or the subject's legally authorized representative. The Code of Federal Regulations, as applicable to the FDA,echoes these expectations. However, FDA guidances further explaining these practices4 allow not only the investigator, but also “other study staff” to “[conduct] the informed consent interview [with] the subject.” The FDA repeatedly states that the informed consent requirements in 21 C.F.R. § 50 do not preempt any applicable federal, state or local laws that require additional information to be disclosed for informed consent to be legally effective. Instead,“[w]here the regulations differ, the regulations that offer the greater protection to human subjects should be followed.”This approach ensures that clinical research subjects receive the maximum protection offered under the law.

Who is an Investigator? 

Informed consent laws and regulations apply to investigators and subinvestigators. The regulations define an investigator as “an individual who actually conducts a clinical investigation (i.e., under whose immediate direction the drug is administered or dispensed to a subject). In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. Subinvestigators include other members of the team that perform certain significant functions. Clinical research is almost always conducted by a team of individuals, typically led by the principal investigator listed on FDA Form 1572 as the “responsible leader of the team.” The FDA clarifies, however, that the principal investigator need not be a medical doctor and that a “physician can be a subinvestigator to perform those study functions requiring the appropriate level of medical expertise.” This suggests a great deal of flexibility in federal regulations and their interpretation as to who may be considered a principal investigator or a subinvestigator, and it also means that an individual who is not a physician may be delegated the primary responsibility to obtain a subject’s informed consent. In recognition of the time constraints investigators might face, FDA guidance allows “other study staff” to conduct the informed consent interview.Practically speaking, this typically involves the study nurse or coordinator. Still, the regulations seem relatively clear that they expect the principal investigator to obtain legally effective informed consent.

The Shinal Case :Although federal guidance is relatively flexible as to how the clinical research informed consent process is to be performed, a recent court case may signal a change to a stricter model. On June 20, 2017, a divided 4-3 Pennsylvania court, speaking on a seemingly unrelated issue, interpreted the law to support the plain meaning of the regulations themselves and not the interpretation of these regulations as seen in the FDA guidance. (It is not clear whether the court was even aware of FDA’s guidance or if it deemed clinical research relevant.) The case, Shinal v. Toms, involved a woman undergoing surgery to treat brain cancer.The treating physician’s assistant obtained a signed informed consent form from Mrs. Shinal prior to surgery. Unfortunately, during surgery, Mrs. Shinal suffered permanent injury from complications and sued the physician, alleging his failure to explain the risks of and alternatives to her surgery. Until the Shinal case, physicians interpreted the duty to obtain informed consent as one that could be delegated to a qualified staff member. This delegation could include the entire of informed consent process, including talking with the patient, discussing the procedure in question, and then obtaining the patient’s informed consent. However, the Shinal Court found that effective informed consent stems from the contractual nature of the physician

patient relationship and consequently requires a “meeting of the minds” between the parties, which could only occur by a physical interaction between the doctor and patient. In support of its holding, the Court quoted Kelly v. Methodist Hospital, noting that the physician’s unique relationship with the patient, as well as the physician’s education and training, mean that “the physician is in the best position to know the patient’s medical history and to evaluate and explain the risks of a particular operation in light of the particular medical history.”Further, the physician has a duty to disclose these risks to the patient.Consequently, the Court held that, in the state of Pennsylvania, the duty to provide informed consent belonged to the physician alone and was non-delegable, because “obtaining informed consent results directly from the duty of disclosure, which lies solely with the physician.

Implications for Informed Consent in Clinical Research 

Although the Shinal case applied to medical practice, its reverberations can already be felt in clinical trials, where some might argue that informed consent requirements are, if anything, more stringent than for medical care. A prima facie interpretation of the Court’s opinion suggests that informed consent by the physician is non-delegable. While this reading is not any more burdensome than a strict reading of the regulations, which prima facie require that only the principal investigator can perform the informed consent interview, it does place an unexpected burden on clinical research facilities. Although it is unclear whether the Court intended to apply this opinion to clinical research, there is little to suggest that courts would not uniformly apply the same informed consent standards used in the medical practice to clinical research. If this interpretation of the law applies, the Court’s holding in Shinal will likely have a significant implication on the speed of clinical research in the face of an already timeconsuming informed consent process. The Court’s interpretation of this law suggests that investigators will likely need to personally engage with each potential study participant to discuss the procedure, possible alternatives, and to make all necessary disclosures.  

Investigators are notoriously busy and typically delegate much of the process of obtaining informed consent to qualified study personnel. However, they should, at minimum, ask the person if he or she has any questions about the study and determine whether the person is giving proper informed consent. This flexibility allows greater efficiency and smoother process flow even as the investigators workflow grows more demanding. In fact, in some cases, the study nurse might be more knowledgeable about certain study details than the principal investigator. In addition, consent by the study nurse minimizes the chance of undue influence that is inherent in the patient/physician relationship. Since informed consent is a time-consuming process, reserving the responsibility to just the principal investigators — who probably have the least amount of time — raises other issues about the adequacy of consent. It adds one more burden to physicians who already feel overburdened by clinical research duties and are not always available when it is convenient for the patient.

Issues with the Shinal Ruling The court found for the plaintiff because the physician relied on a subordinate to obtain informed consent from the patient, which the court held was a duty non-delegable by the physician. This raises several issues: First, it is not clear whether the explanation was inadequate because the physician possessed a duty inherent in his or her role to obtain informed consent, or whether the informed consent process must simply be performed by the professional in the best position to do so. In medical practice, it is reasonable to expect that the physician is the individual best-placed to discuss the clinical implications of a potential procedure. The physician will know the patient’s health condition better than the other individuals participating in the procedure, will have the most experience and training in performing the patient’s procedure, and will best understand the risks and alternatives. However, informed consent in clinical studies requires a broader discussion that might need the involvement of additional team members. For example, clinical trial subjects must be informed of the possibility of compensation in the event of injury caused by the trial.Although the physician might be the best individual to obtain a subject’s informed consent with respect to medical procedures, other team members might need to participate in the informed consent process to ensure the patient is adequately informed in all aspects of the clinical study. If the study involves a technical procedure, an expert in that procedure might be better qualified to explain it to the subject. Similarly, the investigator might not be the best person to explain the logistics or financial ramifications of the study. In some cases, a subinvestigator might be more expert in the specifics of the medicine than the principal investigator, who might be more knowledgeable in the mechanics of clinical research. Ultimately, the Shinal court found that the reason the physician is in the best position to obtain informed consent is the “education, training and expertise” upon which the patient relies.Requiring the physician to serve as the sole touchpoint for informed consent in clinical studies might not accomplish that objective. Exacerbating this issue is the time span for informed consent. In medical practice, the informed consent process begins when the patient meets with his or her physician for the first time to discuss treatment. However, the time span is much longer in clinical trials and does not always involve human interaction. Many human subjects protection experts assert that the informed consent process starts with the first advertisement the potential subject sees and continues through the end of a clinical study. Considering the extended time span of informed consent in the clinical trial setting and the additional procedures and issues that might arise not involving the original investigator, it is impractical to expect the investigator to manage all aspects of the informed consent process from beginning to end. Accordingly, additional team members will become involved as different aspects of the trial process call for their unique expertise.

Causing further confusion is the difference in professional designations between medical practice and clinical trials. While the Shinal Court refers to the “physician,” the term “physician” is not synonymous with the term “principal investigator.” This might cause confusion as to who obtains the subject’s informed consent. As mentioned above, the principal investigator in a study might not even be a physician, so under a strict reading of Shinal suggesting that only a physician performing the procedure can obtain informed consent, the Shinal case might not apply. However, in the scenario where the subinvestigator is a physician, then that physician might have the duty to the patient. Under a looser reading of Shinal, where the person obtaining informed consent must be the individual in the best position to do so, this duty might fall ultimately on the principal investigator or on other team members, depending on their areas of expertise.

Causing further confusion is the difference in professional designations between medical practice and clinical trials. While the Shinal Court refers to the “physician,” the term “physician” is not synonymous with the term “principal investigator.” This might cause confusion as to who obtains the subject’s informed consent. As mentioned above, the principal investigator in a study might not even be a physician, so under a strict reading of Shinal suggesting that only a physician performing the procedure can obtain informed consent, the Shinal case might not apply. However, in the scenario where the subinvestigator is a physician, then that physician might have the duty to the patient. Under a looser reading of Shinal, where the person obtaining informed consent must be the individual in the best position to do so, this duty might fall ultimately on the principal investigator or on other team members, depending on their areas of expertise.

Additionally, as stated above, the Shinal Court found that effective informed consent stems from the personal, interactive nature of the physician-patient relationship, noting that “[w]ithout direct dialogue and a two-way exchange between the physician and patient, the physician cannot be confident that the patient comprehends the risks, benefits, likelihood of success, and alternatives [to treatment].”If this ruling were to be fully applied, it could invalidate all consent obtained without a physical physician-patient interaction. While the relationship is justifiably special, there is nothing in the contractual aspect of that relationship that requires physical interaction. The success of telemedicine even argues against the need for physical interaction in the medical part of the relationship. Additionally, if the principal investigator is in the process of explaining the study to a potential participant, it is unlikely that the court would prohibit the study nurse from interjecting a clarification or providing supplemental information. Or, if the principal investigator and the study participant cannot converse fluently in the same language, it is doubtful that the court would disallow the use of an interpreter.

Conclusion 

The Shinal case, like many, raises more questions than it answers, especially when applied to clinical research, which does not constitute traditional medical care due to its investigative nature.Physicians conducting clinical research in Pennsylvania should obtain advice from their legal counsel, should probably be involved in the consent process if they are the principal investigator, and, in consideration of the potential demands placed on researchers regarding adequate informed consent, should certainly strive to obtain informed consent using either their physician researchers or their experts best positioned to obtain effective informed consent. With the issues discussed above, the mere existence of the ruling invites plaintiff attorneys to argue it in other cases, even outside Pennsylvania 

Author 

Darshan Kulkarni, Pharm.D, MS, Esq., is Principal Attorney at The Kulkarni Law Firm. He is also a Visiting Professor at the University of the Sciences and is Vice Chair of the Life Sciences Interest Group of the American Bar Association. Contact him at 1.215.948.8183